TW209213B - - Google Patents

Description

itr 〇α ,. l3 Λ 6 η 6 V. Description of the invention (1 Technical field The present invention relates to a novel 4-amidoamino azole derivative or angiotensin [I (hereinafter referred to as A i I) antagonism Background Art AII is known to be a physiologically active peptide with a strong boosting effect, and is regarded as a variety of mammalian hypertensive causative substances. Although there are two or three ways to produce Λ II in the body, the representative way is In order to produce angiotensin I from angiotensinogen due to the action of renal enzymes, this is converted to All by the action of angiotensin converting enzyme (ACE). The compound of the present invention acts on the All receptor and inhibits All The role of human beings, so it can be regarded as "All antagonists". The anti-antagonism of the medicine is called first. Note that this page contains a halogen. The bit 4 is azole derivative AI imidazole. Lizhuzhou Ou Ruzhi has the base of the nitrate 4 No. 4 and other 3'-based 53-ene rsu substitution line Spermidine The difference between the I 4 and the construction cost is not completed.

The Ministry of Economic Affairs, Bureau of Standards, Employee Consumer Cooperatives printed $ L under the formula as a compound chemical compound (I. The model version is issued as a new bio-derivative imidazole amine-derived 4-azole I)术 <Using Amino Acid on the paper standard "《家« 毕 （CNS) T4 regulation (2 丨 0X297 public goods) 81. 7. 20, U00i (c (II) V. Description of the invention (2)

Printed by the β-Consumer Cooperative Society of the Central Bureau of Economics and Development of the Ministry of Economic Affairs ^ (where R 1 is a lower alkyl group R 2: R 6 〇, 〇 | 11 or a V s -N-C-R5 l ^ _AiJ R5 is a carboxyl group, Amino group, low alkylamino group, low alkyl carbonyl group or aryl group optionally substituted lower alkenyl group; lower alkyl group substituted by either lower alkoxy group or aryl group; low alkyl carbonyl group, or —CH> R 6 Is hydrogen or lower alkyl, A1 is C2-6 alkylene which may be substituted by lower alkyl, 0 II 7 R 3 is cyano or a C — 0 — R7 R 7 is hydrogen or ester residue, R 4 is Hydrogen or aralkyl ^ Η Detailed description of the compound of formula (I) above. In the definition of formula (I), unless otherwise specified, "low j means (please read the notes on the back-end notes first f. Binding-Thread · This paper standard is used in the troubled country «quasi (CNS) A 4 specifications (210X297 g) 81. 7. 20.000¾ (II) Department of Economics, Ministry of Economic Affairs, Census Bureau cs: industrial and consumer cooperation Printing-V. Description of the invention (3) Cl-6 straight or branched β so the lower alkyl can be, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl , Tert-butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methyl Butyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1- Dimethylbutyl, 1,2-Dimethylbutyl, 2,2-Dimethylbutyl, 1,3-Dimethylbutyl, 2,3-Dimethylbutyl, 3,3- Dimethylbutyl, ethylbutyl, 2-ethylbutyl, 1,1, 2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methyl Propyl, 1-ethyl-2-methylpropyl, etc. Lower alkenyl is 〇2_ s straight or branched alkenyl, such as vinyl, allyl, propenyl, 2-propenyl, propylene Alkenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methylallyl, 1-methyl-1-propenyl, 1-methylallyl , 1,1-dimethylvinyl, 1-pentenyl, 2-pentyl, 3-pentanyl, 4-pentyl, 3-methyl-1-butyl, 3-methyl -2-butenyl, 3-methyl-3-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl , 1-methyl-butenyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 1,1-dimethylallyl, 1,2-dimethyl Base-propenyl, 1,2-dimethyl -2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1,1-dimethyl-bubutenyl, 1,1-dimethyl-2-butenyl, 1, budimethyl-3-butenyl, 3,3- Dimethyl-1-butenyl, 1-methyl-1-pentenyl, 1-base paper »Standard use of" National Standard (CNS) A 4 regulations (210X297 public Λ) 81. 7. 2U, 000ik (ll) V. Description of the invention (4 Λ 6 Π 6 methyl-2-pentenyl, 1-methyl-3-pentenyl, 4-methyl-1-pentenyl, 4-methyl- 2-Pentenyl, 4-Methyl-3-Pentene, Ministry of Economic Affairs, Pyongyang Bureau of Industry and Commerce Printed by the Consumer Cooperative, these lower olefins can be replaced by carboxyl groups and aminoaryl groups. The lower alkylamino group may be, for example, methylamino group, pentylamino group, hexylamino group, dimethylamine ethylmethylamino group and the like. The low-alkane carbonyl group may be methyloxycarbonyloxycarbonyl, pentyloxycarbonyl and the like. Unless otherwise specified, aryl refers to a group, xylyl, biphenyl, phenyl, phenyl, nitrophenyl, etc. As for the lower alkyl gas or aromatic gas, ethoxy, propylene Oxygen, iso, second butanyl, third butoxypentyl, neopentyloxy, 2-methyl, 1-ethylpropanyl, hexyloxy and other methyl groups, biphenoxy Or naphthalene group A 1 "C ethyl group, propyl group, tetramethylene group, alkyl group, pentamethylene group, 1,2-diethyl group, etc. which may be substituted by lower alkyl group, lower alkylamino group, , Ethylamino, diyl, propylethylamino lower alkyl carbonyl, amino, butylamino, dipropylamino,, ethyl carbonyl, propyl carbonyl, butanesulfonyl aryl, such as phenyl, tolyl, Phenyl, phenanthrenyl, etc., or lower alkyl 0. The lower alkyl optionally substituted may be methylpropoxy, butyl, isobutyl, pentyl, isopentyl, third butyl, 1 , The above-mentioned lower alkyl 2-s alkylene group substituted with a 2-alkylpropoxy lower alkyl gas group or an aromatic gas group such as benzene gas group, tribenzene, etc. may be, for example, 2-methyltrimethylene, Ethylene extends ethyl, ethyl extends dimethyl and so on.

The "ester residue" refers to the lower alkyl group, which is of the formula -A 2-0--X-R. This paper uses the "《楳 楳 准 (CNS) A 4 regulation (210X297 Gong;") 81. 7. 20,000¾ (II) The precautions for WI are filled in%. Page 5 5. Description of the invention (Substituted lower alkyl group of 5 is as follows: CH2 R8 V 0 or Λ 6η 6

The "low alkylene" in A2 above refers to straight or branched main bonds, which may be methylene, ethylidene, propylidene, dimethylmethylene, tetramethylene, pentamethylene, hexamethylene Methylene and so on. The "cycloalkyl" of R8 may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and the like. Therefore, in the formula-A2 -OCO-X-R8, the group where X is a single bond may be, for example, acetyloxymethyl, 1-ethoxyethyl, 2-ethylacetoxyethyl, or pentyloxymethyl, 2 , 2-Dimethylpropionyloxymethyl, 1- (terpentylamino) ethyl, 1- (topentyloxy) propyl, 2- (terpentylamino) ethyl, 2- (Pivaloyl) propyl, pivaloyloxy) propan-2-yl, 2-diethylbutaneoxymethyl, 2, 2-dipropylpentylaminomethyl, cyclopropylcarbonyl Methyl, cyclobutanyl methyl, cyclopentyl carbonyl, cyclohexyloxymethyl, etc.

Th Read the notes for the first time and fill in Λ. An employee of the Ministry of Economic Affairs Bureau of Standards and Public Security Co., Ltd. prints a base ethyl methyl gas and a gas. For example, the oxygen is carbonyl gas. The T gas 2 is 'Base ethoxycarbonyloxyethane gas K carbonyl 1-gas' Methyl / V methyl ethyl ethane} carbonyl .. ¾ Oxygen 2 ethyl, T ethyl 2 ethyl ethyl ethane} carbonyloxycarbonyl oxygen propyl methyl carbonyl Gas carbonyl gas propionyl ethyl carboxy carbonyl gas gas butyl hexyl cyclyl methyl acetyl gas carbonyl carbonyl gas butyl pentyl cyclyl ethyl oxo carbonyl carbonyl oxygen propyl pentyl cyclyl methyl ethoxygen paper »Standard to use "« Home «Quasi (CNS) Xuan 4 specifications (210 father 297 male dragon) 8 !. 7. 20.000¾ (! 1) V. Description of the invention (6 Λ 6 η 6 oxymethyl, cyclohexane gas carbonyl gas ethyl , Cycloheptane carbonyl methyl, etc. The representative groups of the formula CH, R8 WV 0 are as follows -ch2 ^, ch3V 〇CH2 CH3 ~ CH2v / CH2CH2CH3 J \ / * \ 0 V, 〇γ CH, -CH2 CH-CH3 ch2 ch2ch2ch2ch3 V 〇V o Ministry of Economic Affairs, Central Bureau of Standards C3: Gongxin &quot; Cooperative Du-printed aralkyl group is a group in which any hydrogen in the lower alkyl group is replaced by an aryl group. For example Benzyl, benzhydryl, phenethyl or trityl α The compound (I) of the present invention can form salts with acids and bases. Salts with acids can be hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, Mineral acids such as nitric acid, phosphoric acid, or such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, sulfonic acid , Acid addition salts of organic acids such as picric acid, methanesulfonic acid, ethanesulfonic acid, glutamic acid, etc. The salt with the salt can be combined with inorganic ages such as sodium, potassium, magnesium, calcium, aluminum, etc., such as methylamine, ethyl Organic bases such as amines, ethanolamines, etc., or salts of basic amino acids such as lysine, ornithine, or ammonium salts. 8-This paper is not suitable for the use of "Household Standards (CNS) 〒 4 specifications (210X297 Α) 81. 7. 2U.000ik (H) The Ministry of Economic Affairs, Central Bureau of Trade and Industry A, cooperation and cooperation Du Yin 3i _Λ] _ V. Description of the invention (7) The compound of the present invention has the presence of a double bond, depending on the substituent The type contains asymmetric sulfon atoms. Therefore, the compounds of the present invention also include mixtures of geometric isomers, optical isomers and other various isomers or their isolated ones. The compounds can be used to manufacture a variety of synthesis methods. The following illustrates representative of the production method thereof. Process 1

Re R «

(Where R1, R3, R4, RS and Re are the same as above). The compound Ua) of the present invention can be produced by reacting an amine of formula (Ila) with a carboxylic acid of formula (III) or a reactive derivative thereof. The reaction is to make the compound UII) or its reactive derivative and the compound (Ila) with an equivalent molar amount or one side in excess, in an organic solvent inert to the reaction, such as pyridine, tetrahydrofuran, dioxane, ethyl, benzene, Toluene, xylene, methylene chloride, difluoroethylene, nitroform, dimethylformamide, ethyl acetate, acetonitrile and other solvents. When the compound (ΙΗ) is reacted with free carboxylic acid, it should be used in the dicyclohexyl master paper Λ scale for ease of use «Home tt quasi (CNS) Ή regulations (210x297 public; ¢) 81. 7. 20.000ik (li) Λ 6 II 6 V. Description of the invention (8) Carried out in the presence of a condensing agent such as diimine or 〖, 1'-carbonyl dibenzozole. As for the reactive derivative of compound (111), it can be aldehyde halide such as amide nitrogen, amide bromide; amide azide; active ester with N-hydroxybenzotriazole or N-hydroxysuccinimide; etc. Anhydride; mixed anhydride with alkylsulfonic acid or p-toluenesulfonic acid. Depending on the type of reactive derivative, organic bases such as triethylamine, pyridine, picoline, lutidine, Ν, Ν'-dimethylaniline, or potassium sulfonate, Na a Inorganic bases such as Η will react smoothly. Pyridine can also be used as a solvent. The reaction temperature also depends on the type of reactive derivative, and is not particularly limited. The second system method (please read the back-note * market item before filling in this page ^ Outfit-Printed by the Cooperative Society of the Ministry of Economic Affairs, Central Standards Bureau

-10- The ft scale of this paper is used in the middle of the family. The family standard (CHS) T4 regulation (210X297) "81. 7. 20.000¾ (H) V. Description of the invention (9

2nd process Μ (V) Λ 6 Π 6

R &quot; (where Y is a halogen or sulfonic acid residue, R1, R3, R4 and A1 are the same as above). This preparation method is a preparation method in which R2 in formula (I) is the target compound of the following formula amide group

OHC-N AJ _Monohalide \) / VI / (\ The formula and the amine ih first read the notes and instructions for installation and ordering _ the base amide sulfonamide or it (The formula of I should be reversed, or the method of preparing the carboxyl alkane by the method of acid) (Square C (the process of the process of the combination of the objects of the V It can be converted into a base ring (V)). The project of the Ministry of Economic Affairs of the Ministry of Economic Affairs of the Central Bureau of Employee Consumption Cooperation will print the compound of the base amine. The process of making it possible to enter the environment is based on the 2nd place. It is soluble in inertia in Chinese medicine, erythromethan, difuran 0H, hydrogen pyridine, tetrapyridine, potassium, acid, formic acid. 0, the paper size is used in the middle II sleepy family standard (CNS) T4 specification (210X297 mm) benzene Η a Na genus benzalkonol methylamine methyl 81. 7. 2U.U0Uik (l!) Λ 6 Π 6 V. Description of the invention (10) etc. This reaction is easy to proceed at room temperature after cooling the third production method

R8 I M / NC0-R5 R '-/ Ί

IT (please read the back-end notes first # fill in this ^ (where R1, R3, R4, R5, R6, Y are the same as above.) The compound (Ic) of the present invention can make the amide compound of formula (VI) and The alkyl halide (or alkyl sulfonate) compound of formula (VII) is reacted to produce. This reaction can make the compound (VI) react with the corresponding amount of compound (VII) in the aforementioned inert solvent at room temperature ~ heating, In order to promote the reaction, it is advisable to add the aforesaid alkali. The fourth method is installed, the line · Ministry of Economic Affairs, Bureau of Biology and Censorship C3: the work of consumer cooperation permit Du Du

This paper uses the Chinese Weijia Zheng (CHS) T4 specification (210X297). 81. 7. 20,000¾ (II) The Ministry of Economic Affairs, the Central Bureau of War Industry, the Military Industry Consumers Cooperation and Du Du! U 5. The description of the invention ( 11) (where R4 1 is aralkyl, other symbols are the same as above). In the compound U) of the present invention, where R 4 is hydrogen, a compound in which R 4 is an aralkyl group can be obtained by a conventional reduction reaction such as catalyst reduction, liquid ammonia reduction, or acid treatment. The catalyst reduction can be carried out in the presence of precious metal catalysts such as Pd-C, vaporized platinum, etc., in solvents such as methanol, ethanol, ethyl acetate, etc., which are conventionally used for catalyst reduction, under normal pressure ~ pressurized. Liquid ammonia reduction is the reaction of liquid ammonia alone or with ether as a co-solvent, adding sodium, potassium, and lithium at -3 3 ° C. For acid treatment, use acetic acid, trifluoroacetic acid, trigas acetic acid, hydrochloric acid, sulfuric acid, hydrobromic acid acetic acid, etc. This reaction is usually in organic solvents such as methanol, ethanol, propylene, etc. or in water. Perform at room temperature ~ under heating (or under reflux). Fifth production method In the compound of the present invention, the compound in which R3 is a free carboxylic acid can be obtained by treating the compound in which R3 is esterified with acid or age. As for the acid, it can be, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, etc., and the base can be, for example, caustic soda, caustic potash, potassium stearate, sodium disulfonate, sodium methoxide, sodium ethanol, etc. INDUSTRIAL APPLICABILITY Since the compound of the present invention has angiotensin ΙΙ (ΑΙΙ) antagonistic effect, it can be used to treat various diseases caused by All physiological effects (such as hypertension, chronic heart exhaustion, heart hypertrophy, arteriosclerosis, diabetes mellitus) Nephropathy, Diabetic Retinopathy, Chronic Miscellaneous Globules, Inflammatory Glomerulus Jin-1 3-A 6 Π 6 (Please read the precautions first ΛΛ? Tips for this paper »Standards in use "Sleepy Home Sample (CNS) 1M Specification (210 father, 297 male 4) 81. 7. 20,000¾ (II) V. Description of the invention (12) Λ 6 Π 6 The second highest in terms of its nature and the hypertrophic gland Sexual benign hair, the original symptom-consider good focus, not circulatory symptoms, forgetfulness of the end, obstacles due to green urine uhr, 32¾ inflammation with symptoms used as anti-0 Shikou X- ^ If and other obstacles also hinder II tube \ The formation of blood brain and the production of renal inhibitory enzymes through the fermentation of ketones E-C The Mingmai mobilizes the principal. The sub-spectrum rabbit presses down and extracts the antagonists that are more potent against Guangnai as enzymes for fermentation The kidney covering effect is used to suppress the spinal ridge of the rat that should counteract the rise of IIA. The opponent and the Ding 2 test evening} In vivo organism S related eb phase K amount is used to suspend the suspension, the specimen is the standard I Η I ti spins the snail into the body and extracts the veins. 8 &lt; | ^ The main body of the tester will be added with the middle liquid and the middle liquid will be added to the front side to increase the concentration of the high drug. Calculate for the purpose of reducing the amount of force used to shrink the collection II big 5 B take this Q w I so that A 〇According to the contraction order or add a line of curvature: the characteristics of the ΛΛ elffi® BU with t concentrated work M high break 3 cover the tortoise 2 two a &quot; after 1¾ shift the most or the degree is to use force}. As the value of the number of children's system is used to inhibit the negative shrinkage 1 (the degree of harvest is large Α2 thick (please read first Contrary precautions: Dan fills in this book-Stranding · Value 2 Number P Pair or negative degree of concentration 0 Need for breaking off% ο 5 Inhibition force shrinks most greatly / IV value shows the Ministry of Economic Affairs Printed and introduced by quasi-bureau β industry consumer cooperatives to insert CU veins. Static and pulsating rat old m Broken money ridge under the suction test call test Η The human skeleton is in the life test The test body risheng o A line 10 pairs into 1 (. And the AI ascending tube is put on the blood pressure to continue the internal holding of the vein (8 静 Η in the mill rat 7 old)-bad 5 broken is is -SJ πυ ， In order to suppress the amount of use of dependent factors, use «Μη as a), cut off the cover / have 8 tk body / accept the paper ft scale to use the Chinese National Standard (CNS) 1» 4 specifications (210X297 public address) 81 . 7. 20.000ik (II)

C .-9 ···· 66 ΛΒ V. Description of the invention (13) A [[The blood pressure is held up, so the A I I antagonism is examined from the blood pressure drop after the drug is administered. The effectiveness of the blocking effect of the A I I receptor is expressed as the I C 30 value (the amount by which the blood pressure decreases by 3 G b m H g after A I I administration). The results of the above experiments are shown in Table 1. Table 1 Examples of AII receptor blocking effect of the compounds of the present invention In vitro (pA2 value) ipD / value) In vivo (IC3 〇mmHg (mg / kg, iv)) D up 7 5 3 EP 253310 Example 8 9 E β-compound 8. 2 0.1 f Example 3 7 (compound of the present invention) 9.67 0. 0 0 7 Example 4 4 inventive compound) 8.76 0. 0 3 through Example 4 7 inventive compound j 8. 1 7 0.03 (Please read the back-to-back notes first and then the page on this page) Binding · Order _ Line. Printed by the Employee Consumer Cooperative of the Department of Economics, Ministry of Economic Affairs. In addition, the compounds of the present invention are low in toxicity and suitable for use as pharmaceuticals. (I) One or two or more of its salts as active ingredients can be prepared with conventional carriers or excipients and other additives. The carriers or excipients used in the formulation can be solid or liquid, such as lactose , Magnesium stearate, starch, talc, gelatin, lettuce, pectin, gum arabic, olive oil, flax oil, cocoa butter, ethylene glycol, etc. and other commonly used ones. Administration can be tablets, nine doses, capsules, Granules, powders, liquids, etc. are taken orally, or intravenous and intramuscular injections, etc. Agents, transdermal, etc. -1 5-This paper uses the Zhongming National Huahua (CNS) T4 specification (210x297 g) 81. 7. 20, () 00ik (II) V. Description of the invention (1 sentence not included) Any form of oral administration. The dosage can be determined according to the symptoms, the age and sex of the subject, and it can be appropriately determined according to the situation. However, when it is taken orally, the adult takes 10 to 1 0 0 in g daily. Or it can be administered in 2 to 4 times. Best Mode for Carrying Out the Invention The compounds of the present invention and their preparation methods have been described above, and more detailed explanations will be given below by way of example. Among the raw material compounds used in the examples, their preparation methods are shown in Reference Examples. Reference Example 1 Γ P η

Printed by the Employee Consumer Cooperative of the Department of Economics, Biyangmiao, Ministry of Economics, abenben methyl a) 159 g of butyronitrile was added with anhydrous ethanol 5QQinl under argon gas, and after cooling to 0 ° C, it was cooled below 30 ° C and blown in Dry the HC 1 gas for 2 hours and 3 at 5 ° C. After overnight, the solvent was distilled off under reduced pressure, and 1 liter of ether was added. The white crystals were collected and washed with a large amount of ether to obtain 260 g of ethyl butylimidate hydrochloride, hygroscopic white crystals. Physical and chemical properties Ή-NMR (CDC13) δ (ppm): 4. 6 5 (2 H, q), 2. 7 3 (2 H, t), 1. 6 6-1. 91 (2 H, m ) f 1. 4 9 (3 H, t), 1 · 0 2 (3 H, t) b) Dissolve 30 g of ethyl butylimidate hydrochloride in absolute ethanol 60ml -1 6 _ this paper The standard is used in the "National Standards (CNS) A4 Regulations (210X297);» :) 81. 7. 2U.000ik (ll) Λ 6 It 6 Printed by the Ministry of Economic Affairs, the Central Bureau of Industry and Commerce, A Industrial and Consumer Cooperative 3. Description of the invention (15), and 8.3 g of cyanamide is added at room temperature. After stirring at room temperature overnight, the ammonium oxychloride precipitate was filtered off, the solvent was removed under reduced pressure, ethyl acetate 200 m 1 was added, and washed twice with water 50 m 1. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to obtain 25.7 g of ethyl N-cyano-butylimidate, as a colorless oil. Physical and chemical properties' H-NMR (CDC13) δ (ppm): 4. 29 (2 H, q), 2. 67 (2 H, t), 1.54-1.96 (2H, m), 1. 35 (3 H, t), 1. 00 (3 H, t) mass spectrometry (GC-MS): m / z 1 4 0 (M +) c) 18.6 g of this gas-based ethyl butylimidate was dissolved in anhydrous Ethanol 150 in 1, and after adding 20 g of ethyl glycinate hydrochloride at room temperature, 30 g of triethylamine was added dropwise at U ° C. After slowly reaching room temperature, stir overnight. After evaporating the solvent under reduced pressure, add ethyl acetate 1 5 0 οι 1 to the residue, wash with saturated citric acid solution and saturated brine in this order, dry with anhydrous sulfuric acid, and evaporate the solvent under reduced pressure. The residue was chromatographed on a silica gel column (ethyl acetate: n-hexane = 1: 1) to obtain 11.9 g of methyl N′-cyano-N- (carbonylethoxy) butylimidate, as a yellow oil. Physicochemical properties' H-NMR (CDC13) δ (ppm): 6.38 C 1 H, br), 4. 30 (2 H, q)--«&lt;« «« 4 ······ · · · (Please read the notes on the back # fill in this one ^ Binding-the paper size of the book is not to use the Chinese B home «quasi (CNS) T4 regulation (210X297 public *) 81. 7. 20,000 ^ (11) Λ 6 Η6

5. Description of the invention (lb) 4. 0 7 (2 H, d), 2. 6 4 (2 H, t), 1. 66-1. 9 2 (2 Η, m), 1. 31 (3 Η , t), 1. 05 (3 Η. t) mass spectrometry (GC-MS): m / z 1 9 7 (M *) d) the Ν '-amino-N- (carbonylethoxy) butylene 9 g of ethyl amine acid in dimethylformamide 50 m 1, and Na a H (content 60%) 1.9 g under ice cooling. After stirring at room temperature for 20 minutes, 30.5 g of N-trityl-5- (4-bromomethylbiphenyl-2-yl) tetrazole was added under ice-cooling, and the temperature was gradually raised to room temperature for 5 hours. After ice cooling, 1.0 g of NaH (60%) was added, and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, ethyl acetate / n-hexane (2: 1) was added to the residue, washed with water and saturated brine in sequence, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was deposited on the silica gel column layer Analysis (ethyl acetate: n-hexane = 1: 1) to give 4-amino-2-n-propyl-1-(〔2- (N-trityl-tetrazol-5-yl) biphenyl- 4-yl] methyl] -1H-quinazole-5-carboxylic acid ethyl ester 9.8 g, yellow oil. Physical and chemical properties 1 Η-NMR (CDC 1 3) δ (ppm): Employee consumption cooperation of the Central Bureau of Economics and Trade of the Ministry of Economic Affairs Du Yin 51 6. 79 — 7. 89 (23H, m), 5. 32 (2 H , s), 4. 94 (1 H, s, br), 4. 16 (2 Η, q), 2. 4 0 (2 Η ,, q), 1. 59-1. 69 (2Η, m) , 1. 20 (3 Η, br), 0.8 7 (3 Η, t) mass spectrometry (FAB): τη / ζ 6 7 4 (ΜΗ &quot;) -1 8-81. 7. 20,000 ^ (11) paper 5 Burst Standard Use Medium Beta Beta Family (CNS) Τ4 Specification (210x297 g; «: &gt; V. Description of the Invention (17) Reference Example

ΞBenzyl group Following Reference Example 1, the following compounds were obtained. Product: ν'-cyano-Nm-methyl-Dingfa physical properties A 6 It 6 (please read the precautions first • write the wood one k; the Ministry of Economic Affairs Bureau of the Central Government Bureau ΙΙ: Consumer &quot; printed by cooperatives ’H-NMR (CDC 1 3) &lt; 5 (ppm): 4. 18 (2 H, d), 2. 6 3 (2 H, t), 1.5 0-2. 02 ( 2H, m). 1. 0 4 (3 H, t) Mass spectrometry (El): m / z 150 (M *) Product: N 1 -Amino-N -Aminomethyl-N-[〔2… ( N-Trityltetrazol-5-yl> biphenyl-4-yl] methyl] butamidine physical and chemical properties Ή-NMR (CDC13) &lt; 5 (ppm): 6. 84 — 8. 02 (23H, m), 4. 56 (2 H, s), 3. 99 (2 H, s), 2. 70-2. 90 (2 H. m), 1. 6 0-1. 7 8 (2 H, m), 1.08 (3 H, t) ^ Spectrum (FAB): m / z 6 2 7 (Μ H +) -1 9-This paper uses Λ scale to use Zhongyin B's quasi (CNS) &lt; P4 Regulation (210x297 g *) 81. 7. 20.000ik (! L)% Λ 6 η 6 V. Description of the invention (丄 8) Product: 4-amino-5-amino-2-propyl-1- [[2- (Ν-Trityl-tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-imidazole physical and chemical properties Ή-NMR (CDC13) δ (ppm): 6. 8 0-8. 02 (23 H, m). 4. 89 (2 H, s) 4. 16-4. 23 (2 H, m), 2. 41 (2H, t) 1. 5 0-1. 7 8 (2 H, m). 1. 18-1. 33 (2 H, m), 0. 88 (3 H, t (please read back to note first, Ping Shuo Er fills the book i, "Mass Spectrometry Example (FAB): m / z

2 7 (MHO

Me

Benzyl group ·-Ministry of Economic Affairs, Bureau of Biology and Biology, Nonggongxiao # Cooperation Du Yin ^ 4-amino-2-n-propyl-1- [〔2 ′-(N -trityl-tetrazole -5-yl) biphenyl-4-yl] methyl] imidazole-5-carboxylic acid ethyl ester 1.0 g dissolved in pyridine 10 m 1, methyl methacrylic acid gas was added dropwise under ice cooling 1 7 ϋ mg . After stirring overnight at 15 ° C} 1, the solvent was distilled off under reduced pressure. The residue was dissolved in SiQi 20 m 1, washed with water and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. 2 ϋ-This paper is used in standard _ B Jiayu standard (CNS) Ή specification (210X297 mm) 81. 7. 20,000i | c (II)

Vju'0 Λ 6 It 6 V. Description of the invention (19) The residue is chromatographed on a silica gel column (n-hexane: ethyl acetate = 1: 2) to obtain 4 -N-U-methacryloylamino)]- 2 -n-propyl-1-[[2 1-(PJ-] benzyl-tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-squint-5-carboxylic acid ethyl ester 5 1 ϋ mg, blister. Physical and chemical properties ^ -NMR (CDC13): δ (ppm) 9. 43 — 9. 5 6 (1 H, m),

C Read the contradictions first and then fill in% meters. 6. 7 0 — 7. 9 5 (2 3 H, m) 5. 8 9 -5. 9 5 (1 H, m), 5. 4 2- 5. 5 1 (1 H, m), k 5. 3 6 (2 Η ts), 4. 17 (2 H, dd), 2. 6 2 (2 Η tt), 2. 0 8 (3 H, s), order 1. 5 8 -1. 9 0 (2 H, m), 1. 1 4 (3 Η »t), 0. 8 9 (3 H, t) k (FAB): m / z 7 4 2 (Μ Η +) Example of Mass Spectrometry Co-production by the Ministry of Economic Affairs

The benzyl imitation example 1 produced 4- [N- (3-methylbutenyl) amine i]-2--2 1 in paper ft scale and used in China National Beta Standard (CNS) T4 specification (210x297 Mm) 81. 7. 20.000¾ (II) 3, fJοο, ο 6 ΛΠ V. Description of the invention (20) n-propyl-1-[〔2 '-(N -trityl-tetrazole-5- Group) biphenyl-4-ylmethyl] -1 H-quinazol-5 -carboxylic acid ethyl physicochemical properties 1 H-NMR (CDC13): δ (ppm) 8. 86 (1 Η, s), 6. 7 2-7. 93 (23 Η, m), 6. 06 (1 Η, s), 5. 35 (2 Η, s) 4.11 (2 Η, dd), 2. 58 (2 Η , t), 2. 25 (2 Η, d), 1.91 (2 Η, d), 1.59-1. 8 4 (2 Η, m), 1. 1 7 (3 Η, t) , 0.89 (3 Η, t) mass spectrometry (FAB): m / z 7 5 6 (MH +) Example 3 η —

4-(Ν -methoxyethoxy) amino-2 -n-propyl-i-[〔2 '-(Ν -trityl-tetrazol-5-yl) biphenyl was prepared by imitating Example 1 -4 -yl] methyl] -1 Η -Penazole-5 -ethyl carboxylate physicochemical properties benzyl first read the meaning of the matter Sun 塡%工 消 # Cooperation Du Yin Μ 2 2- This paper is used in the scale of β »home" quasi (CNS) regulations (210X297 male dragon) 81. 7. 20,000 ^ (11)

C 00 3ι, · &gt; β, ο Λπ 5. Description of the invention (21) ah-nmr (CDClg): δ (ppm) 6. 7 1-7. 94 (23 H, m), 5. 39 (2H, s). 4. 19 (2 H, dd) 4. 0 8 (2 H, s), 3.51 (3 H, s), 2. 6 0 (2 H, t), 1. 60 — 1. 79 (2 H, m), 1. 23 (3 H, t), 0.88 (3H, t) mass spectrometry (FAB): m / z 7 4 6 (M H +) Example 4

(Please first read the back and attention matters # 建 裒 木 页) Installation-Line-Central Bureau of Economic Affairs CSC 工 消 # Cooperate with Du Yin to make imitation example 1 to prepare 4-(N-ethoxycaoyl) amine Yl-2 -n-propyl-bu [〔2 1-(N -trityl-tetrazol-5-yl) biphenyl-4-yl] methyl] -1 Η-簯 azole-5 -carboxylic acid Physical and chemical properties of ethyl ester ^ i-NMR (CDCI3): δ (ppm) 10. 45 C 1 Η, s), 6.7 5-7. 9 0 (2 3 H, m), 5. 41 (2 Η, s), 4. 4 2 (2 Η, q), 4. 2 3 (2 Η, q), -2 3-The paper standard is used in the National Beta Standard (CNS) T4 specifications (210X297 public; ¢) 81. 7. 20,000 怅 （Η) Γ ， ο Λ 6 Β (; 5. Description of invention ρ2) 2. 5 9 (2 H, t), 6 7-1. 7 3 (2 Η, m), 1. 4 1 (3 Η, t), 1.0. 2 9 (3 Η, t) mass spectrometry (FAB): m / z Example 5 29 (3 H, t: 7 7 4 (Μ Η +)

Example of trityl imitation] 4-(Ν-Benzene acetyl) amino-2-n-propyl-i-[〔2 '-(N-trityl-tetrazole-5- Group) biphenyl-4-yl] methyl] -1H-quinazol-5-carboxylic acid ethyl ester physicochemical properties are read back and forth. It matters matters% wood page one decoration line staff of the Central Bureau of Economic Development of the Ministry of Economic Affairs Printed by Xiao # Cooperative Society-NMR (CDC 1 3): δ (ppm) 9 · 9 9 (1 H, br), 6. 76-7. 89 (28 Η, m), 5. 39 (2 Η, s ). 4.67 (2 Η, s, br), 4. 16 (2 Η, q), 2. 6 0 (2 Η, t), 1. 68-1. 74 (2Η, m), 1. 15 (3 Η, t), 0.8 9 (3 Η, t) Mass Spectrometry (FAB): m / z 8 0 8 (MH +) Example 6 -24 The paper Λ scale is used in China_Country «CN (CNS) T4 specification (210χ297ΑΑ) 81. 7. 20,000 ^ (II) 3 rl. 9nu_

An 5. Description of the invention (23)

The Ministry of Economic Affairs, Central Bureau of Standards, CX Industrial Consumer Cooperatives printed the imitation example 1 to prepare 4- (N-phenylacrylamino) -2-n-propyl-1- [[2 '-(N-tribenzone -Tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-quinazol-5-ethyl carboxylate physical and chemical properties ^-NMR (CDC 1 3): δ (ppm) 9. 0 6-9. 25 (1 H, br), 6. 45-7. 89 (30 H, m). 5. 3 8 (2 H, s), 4. 20 (2 H, q), 2. 5 7 (2 H, t), 1. 74-1. 7 9 (2 H, m), 1. 19 (3 H, t), 0.9 3 (3 H, t) Mass Spectrometry (FAB): m / z 804 (ΜΗ +) Example Ί

The size of this paper is based on the Chinese National Standard (CNS) T4 (210X297) 41.7. 20,000¾ (II) Q ο £ Λιι 5. Description of the invention (24) 4-(H- Cyclohexylethylidene) amino-2 -n-propyl-1-[[2 1-(N -trityl-tetrazol-5-yl) biphenyl-.4-yl] methyl]- 1 Physicochemical properties of Η- 篯 azole-5-ethyl carboxylate ^ -I-NMR (CDC13): δ (ppm) 8. 8 7 (1 H, s), 6. 6 5-7. 9 3 ( 2 3 Η, m) 5. 8 5-6. 00 (1 Η, m). 5. 34 (2 Η, s) 4. 15 (2 Η, dd), 2. 81-3. 09 (2 Η , m) 2. 5 7 (2 Η, t), 2. 10-2. 35 (2 Η, m) 1. 48-1. 8 9 (6 Η, m), 1. 16 (3 Η, t ) ih first read the meaning of the contrary% this 1 0. mass spectrometry example 8 9 (3 Η, t) (FAB): m / z 7 9 6 (ΜΗ Ο

Benzyl N-NU) 4-amino-2-n-propyl-Bu [〔2 ^ (N-trityl-tetrazol-5-yl) biphenyl-4-yl] methyl]- 1 Η-簯 azole-5 -carboxylic acid ethyl cool 1. 4 grams dissolved in two gas methane 15 m 丨, and at room temperature sequentially add triethylamine 4 7 丨] mg and 4-fenbutane gas 3 50 mg after stirring at room temperature for 1 hour, add water 1 5 m 1 to the Ministry of Economic Affairs Central Kezhun Bureau A Gongxiao # Cooperative Society Printing 3i 2 6 HI. 7. 20,000¾ (II) This paper is in use _ standard _ « CNS specifications (210X29V) *) IH) 5. Description of the invention (25) Central Ministry of Economic Affairs ^ A printed and irrigated ^ A industrial and consumer cooperative society. After the organic layer is dried with magnesium sulfate, the solvent is distilled off under reduced pressure. The residue was chromatographed on silica gel (gas imitation) to obtain 4-(4 -butanyl) amino-2 -n-propyl-1 CC 2 '-(N -trityl-tetrazole-5-• Group) biphenyl-4-yl] methyl]--imidazole-5-carboxylic acid ethyl _ 1.17¾, foam. Physical and chemical properties 1 Η -NMR (丨 CDC 1 3): &lt; 5 (ρ pm: 1 8. 9 1 (1 H, s), 6.7 0-1 8. 0 2 (2 3 Η. M ), 5. 3 7 (2 Η, s), 4 • 14 (2 H, dd), 3. 6 8 (2 Η,, t). 2. 1 3-.2 .6 2 (6 Η, m ), 1. 5 8--1. 8 5 (2 Η, m) (1.1 8 (3 Η, t), 0.8 7 (3 Η, t) Mass Spectrometry (FAB): m / z 7 7 ! 9 (MH +) (b) 4- (4-Gasobutylamino) amino-2 -n-propyl-1 -CC 2 '-(N -benzyl-tetrazole- .5-yl) biphenyl -4 -yl] methyl]-1 Η -B methazol-5 -carboxylate ethyl ester 1.17 g, dissolved in tetrahydrofuran 1 0 IH 1, and added potassium butyl ester 18 5 mg at 5 ° C. Increase to After stirring at room temperature for 3 hours> Add methanol 2 m 1 and evaporate the solvent under reduced pressure. The residue is chromatographed on a silica gel column (nitrogen: methanol = 10 0: 1) to obtain 4-(2 -gas-1- Pyrrolidinyl) -2 -n-propyl-1-cr 2 '-(N-—-..._ · »methyl_tetrazole-5 -yl) biphenyl-4 -yl] methyl]-1 Η-W ί azole_ 5-ethyl carboxylate 750mg. Physical and chemical properties • * 2 7 · * This paper ft遑 用 中 《B 家 戳 Bi (CNS) Y4 gauge tft (21〇X297 public address) 81. 7. 20,000¾ (II) _ I? 6_ V. Description of the invention (26) ^ I-NMR (CDClg): δ (ppm) 6. 7 7-7. 9 4 (2 3 H, m), 5. 4 3 (2 H, s) 4. 1 6 (2 H. dd), 3. 89 (· 2 H, t), 2. 4 1-2. 60 (4 H, m), 2. 18-2. 28 (2 H, m), 1. 5 3-1. 8 3 (2 H, m), 1. 21 (3 H, t), 0.87 (3 H, t) mass spectrometry (FAB): m / z 7 4 2 (M H +) Example 9 Please read ifi and then m η wood

Printed by the Industrial and Consumers Cooperative Society of the Central Standards Bureau of the Phenylmethyl Ministry of Economics 2. 3 2-2 2. 0 5-2 1. 4 8-1 Mass Spectrometry (FAB) (a) Processed as in Example 8 (a), 4- (4-Azetyl) amino-5 cyano-2-n-propyl-1-[-trityl-tetrazol-5-yl) biphenyl] methyl] -1H-quinazole . Physical and chemical properties 1 Η-NMR (CDC 1 3): δ (ppm) 6. 7 8-8. 04 (23 H, m), 5. 05 (2 Η, s), 3.65 (2 Η, t), 7 0 (4 Η, m), 3 1 (2 Η, m), 8 2 (2 Η, m), 0.8 7 (3 Η, t: m / ζ 7 3 2 (Μ Η + ) H___ This paper uses Zhongou's "CNS" T4 specification (2〗 0χ297 Gong A) 81. 7. 20,000 ^ (11) .. X-G ο ΛΠ V. Description of invention (27) (b ) Imitate the treatment of Example 8 (b) to obtain 5-amino-4-(2 -air-pyrrole p $ yl) -2-n-propyl S-!-[〔2 ′-(N -tribenzone -Tetrazol-5-yl) biphenyl] methyl] -1H-imidazole. Physical and chemical properties ^ -NMR (CDClg): δ (ppm) 6.87 — 8.02 (23 H, m), 5. 05 (2 Η, s), 3. 97 (2 Η, t), 2. 0 4-2. 72 (6 Η, m), 1.47-1.79 (2 Η, m), 0 . 87 (3 Η, t) mass spectrometry (FAB): m / z 6 9 4 (MH +) Example 10 (please read first-pay attention to the terms and forget the page) n

The Ministry of Economic Affairs, Ministry of Economic Affairs, Central Bureau of Examination and Cooperation permits the cooperation of Du Printing (a) to process Example 8 (a) to obtain 4-[N-(5-nitropentyl) amino] -2-n-propyl Yl-bu [[2 '-(N-trityl-tetrazole-Γ) -yl) biphenyl-4-yl] methyl]-〖Η- 眯 azole-5-carboxylic acid ethyl ester. Physical and chemical properties This paper uses the Chinese beta family standard (CNS) T4 regulation (210x297 male dragon) HI. 7. 20,00 () ife (II) 2〇 如-'

Λ G It G 5. Description of the invention (2ϋ) H-NMR (CDC13): δ (ppm) 6.76-7.90 (2 3 Η, m), 5. 36 (2 Η, s), 4. 18 (2 Η, q), 3. 5 6 — 3.59 (2 Η, m), 2.5 5 4-2. 58 (2 Η, br), 1.6 7-1. 91 (8 Η, m), 8 (3 Η, t), 0 0 (3 Η, t) Mass Spectrometry (FAB): τη / ζ 7 9 2 (Μ Η +) (b) Following the treatment of Example 8 (b), we get 4 -(2-oxo-1-piperidinyl) -2-n-propyl-1- [[2 '-(Ν-trityl-tetrazol-5-yl) biphenyl-4-ylmethyl] -1Η-imidazole-5-carboxylic acid ethyl ester. Physical and Chemical Properties ^ -NMR (CDCI3): δ (ppm) 6. 8 0-7. 90 (2 3 H, m), 5. 45 (2Η, s), 4. 16 (2 Η, q), 3. 6 7-3. 7 0 (2 Η, m), 2 · 4 6-2.5 4 (4 Η, m), 9 2 — 1. 9 6 (4 Η, m, br),] Read first in Contrary to note, fill in this page. This page contains π Printed by the Ministry of Economic Affairs, the Central Bureau of Industry and Economics, the Beigong Consumers ’Cooperative Society 1 ΙΑ Spectral Example B 4 α 2 F 1 V„ 1 • Η) ζ t \ mmb 8 Η Η ο Η t 7 Η Μ This paper standard is in use * »Home Standard (CNS) f 4 specifications (210 father 297 male:" :)

Bl. 7. 20,000i | c (ll) i 3 ο Γα 6 G Λ: 5. Description of the invention (2¾ η

The Ministry of Economic Affairs, Central Bureau of Accreditation and Employee Consumer Cooperatives printed 5i (a) as in Example 8 (a), to obtain 4- [Ν- (3-gas-2,2-dimethyl-propionyl) amino 〕 -2 -n-propyl-1-(〔2 '-(N-trityl-tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-quinazol-5-chanoic acid Ethyl ester. Physical and chemical properties ^ -NMRCCDC ^): δ (ppm) 9. 51 (1 H (s), 6. 7 4-7. 90 (2 3 Η, m), 5. 3 4 (2 Η, s) , 4. 17 (2 Η, q), 3. 74 (2 Η, s), 2. 60 (2 Η, t), 1. 6 5-1. 7 6 (2 Η, m), 1. 43 (6 Η, s), 1.49 (3 Η, t), 0.88 (3 Η, t) Mass spectrometry (FAB): m / z 7 9 2, 7 9 3 (MH +) (b) Example 8 (b) treatment, to obtain 4- (3,3-dimethyl-2-gas-1-acridinyl-2-n-propyl-1- [〔2 '-(Ν-trityl-tetrazole -5-yl) biphenyl-4-yl] methyl] -1Η-benzoxazole-5-carboxylic acid ethyl ester. Physical and chemical properties of $.-: I 1-(please read the notes on the back # 塡This page} Install-Line-This paper uses standard «quasi (CNS) T4 specifications (210X297 public address) 81. 7. 20,000 sheets (II) V. Description of invention (j0) lH-NMR (CDClg): δ (ppm) 6. 7 8-7. 91 (2 3 H, m), 5. 42 (2 Η, s) 4. 19 (2 Η, q), 3. 6 7 (2 Η, s), 1. 6 0-1. 6 6 (2 Η, m) 1. 2 3 (2 Η, t), 2.5 1 (2 Η, t) 1. 4 3 (6 Η, s) 0. 8 7 (3 Η, t) mass spectrometry (FAB): m / z Example 1 2 7 5 6 (Μ H +) η-Pr

Trityl (please read back and pay attention to the item er item ^. &Gt;,) installed · '1T_ line-Central Bureau of Standards of the Ministry of Economic Affairs IS: printed by the industrial and consumer cooperatives will 4- ((2-A Propenyl acetyl) amino] -2 -n-propyl-1- [[2 '-(N-trityl-tetrazol-5-yl) biphenyl-4-yl] methyl] -1H- 260 mg of ethyl amidazole-5-carboxylate was dissolved in 5 ml of dimethylformamide, and Na 5 mg was added under ice cooling. After stirring for 2 minutes, 55 mg of methyl bromide was added. After warming to room temperature and stirring overnight, it was evaporated under reduced pressure. The residue was dissolved in gaseous 10 m 1, and after washing with water and saturated saline, the solvent was distilled off under reduced pressure. The residue was analyzed on a silica gel column (nitroform: methanol = 100: 1) to obtain 4- [N-methyl-N- (2-methylacryl) amino] -2-n-propyl-l- [ Trityl-tetrazole-32- This paper is not suitable for use on the paper, "Mexican Standard (CNS) 1M Standard (210x297 g: it) 81. 7. 20,000¾ ^ (II) Λ β Π 6 V. Invention Description (31) -5 -yl) biphenyl-4-yl] methyl] -1H-squint-5-ethyl hexanoate 140mg, foamy. Physical and chemical properties ^ I-NMR (CDC13): δ (ppm) 6. 6 5-7. 93 (2 3 Η, m), 5. 45 (2 Η, s). 4. 9 6-5. 11 (2 Η, m), 4. 17 (2 Η, dd), 3. 2 7 (3 Η, s), 2. 4 8 (2 Η, t), 1.8 1 (3 Η, s), 1. 50-1. 72 (2 Η, m), 1. 2 6 (3 Η, t), 0.8 5 (3 Η. T) mass spectrometry (F ΑΒ): m / z 7 5 6 (ΜΗ + ) Example 13 (please read back to note the sequence item # 项 艿 一 K)

The Ministry of Economic Affairs, Central Bureau of Industry and Commerce, β-work, t-cooperation, Du Yin 9i, imitation-based benzylamine synergistic example, implementation of fmi treatment, 5 2 propylmethyl-methyl 3 2 morphological study, zomidazole 3 3 yl} amide 5-butyl butyl methyl 3-yl ester I methylethyl-N benzoic acid tricarboxymethyl N 5 azole tetram. 7. 'iOMmk (ii) This paper is used in a Η home «bi (CN5) f 4 specifications ( 210X297 public release} 〇A 6 Π 6 V. Description of the invention (32) ^ -NMR (CDClg): δ (ppm) 6. 70 — 7. 90 (2 3 H, m), 5. 4 8 (3 H, s) 4. 13 (2 H, dd), 3.24 (2 H, s), 2.51 (2 H, t), 2. 06 (3 H, d), 1. 65 (3 H, d ), 1. 4 1-1. 82 (2 H, m) 1. 23 (3 H, t), 0.95 (3 H, t) Mass Spectrometry (FAB): m / z 7 7 0 (MH +) Implementation Example 1 4 (please read the note ^ Xiang Er Xiang Research ^

Me

Trityl. Order _ line, imitation example 12 printed by the β-consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, to obtain 4- (N-methoxyethoxyl-l-methylamino) -2-positive Propyl-1- [[2 '-(N-trityl-tetrazol-5-yl) biphenyl-4-yl] methyl] -1 H-quinazol-5-carboxylic acid ethyl ester. Physical and chemical properties ^ i-NMR (CDClg): δ (ppm) 6. 7 0-7. 9 2 (2 3 H, m), 5. 49 (2Η, s), 4. 19 (2 Η, dd ). 3. 9 0 (2 Η. S), -34- This paper standard uses the Chinese National Standard (CNS) 1Μ specification (210x297 g; ":")

Hi. 7. 20,001) ¾ (II) J- ό A 6 Π 6 5. Description of the invention (33) 3. 34 (3 H, s), 3.23 (3 Η, s), 2. 52 (2 Η , t), 1. 5 8 — 1. 85 (2 Η, m) 1. 23 (3 Η, t), 0.88 (3 Η, t) mass spectrometry (FAB) *: m / z 760 (ΜΗ + ) Example 15

Me

Benzyl group (please read the note beforehand. Fill in the item _ pack. The central government of the Ministry of Economic Affairs β work consumer cooperation Du Yin 3i imitated in Example 12 processing, to obtain 4- (N-acetoacetyl- N-methylamino) -2 -n-propyl-bu [〔2 '-(N-trityl-tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-quinazol- 5-Carboxylic acid ethyl ester Physical and chemical properties ^ -NMR (CDC13): δ (ppm) 6 · 7 4-7. 9 0 (2 3 Η, m), 5. 44 (2 Η, s), 4 . 21 (2 Η, q), 4. 17 (2 Η, q), 3. 32 (3 Η, s), 2. 50 (2 Η. T), 1. 6 6-1. 71 (2 Η , m), 1. 28 (3 Η, t), 1.0 8 (3 Η, t), 0.8 7 (3 Η, t) mass spectrometry (FAB): m / z 7 8 8 (MH +) 3 5- This paper is used in the standard of 戳 楳 擳 (CNS) T4 specifications (210X297 male; 81. 7. 2 (), (the line (N) line ... 3 Λ 6 η 6 V. Description of invention () 4) Example 1 6

Me

Following the treatment of Example 12, 4- [N-methyl-N- (phenoxyethanoyl) amino] -2-n-propyl-1-([2 '-(M-trityl-tetra Azole-5-yl) biphenyl-4-yl] methyl] -1H-imidazole-5-carboxylic acid ethyl ester. (Please read the note to the back first. Xiang Zaicheng. ^ Installation · Central Bureau of Standards of the Ministry of Economic Affairs only cooperates with the consumer to print the properties of physical and chemical cooperation-NMR (CDC 1 3): (5 (ppm) 6. 77-7. 91 (28 H, m), 5. 4 7 (2 H, s), 4.55 3 (2 Η, s), 4. 12 (2 Η, q) 3. 2 6 (3 Η , s), 2. 51 (2 Η, t) 1. 6 7-1. 7 2 (2 Η, m), 1. 2 1 (3Η, t), Ο · 8 9 (3 Η, t) (FAB): m / z 8 2 2 (Μ H +) -36- The size of the paper + home 4 * standard (CNS) f4 specifications (210X297 male tf) HI. 7. 2 (), 000¾ (II) line- Λ 6η 6 V. Description of the invention (35) Example 1 7

Me

-Following the treatment of Example 12, 4- (N-phenylacryloyl-N-methylamino) &gt; -2-n-propyl-1- [[2 '-(N-trityl-tetrazole- 5-yl) biphenyl-4-yl] methyl] -1H-imidazol-5-carboxylic acid ethyl ester. Physical and chemical properties ^ -NMR (CDC13): δ (ppm) Packing-Line · Ministry of Economic Affairs The cooperation between CX, CX, C & I and DuPont ^ 6. 3 7-7. 9 4 (3 OH, m), 5.50 (2 Η, S) 4 · 1 3 (2 H, q), 3.3 4 (3 Η, s), 2. 5 6 (2 H, t), 1. 7 1-1. 7 7 (2 Η, m) 1. 2 0 (3 Η, t). 0. 9 1 ( 3 Η, t) Spectrum (FAB): να / ζ 8 1 7, 8 1 8 (ΜΙ-Ι +) -37- HI. 7. 2 (1,00 (1¾ (Η) This paper scale is used in the " National «Bi (CNS) Ή Regulations (210X297; it) Λ 6 η 6 V. Description of the invention (π) Example 1 8

The benzyl imitation example 12 was treated to obtain 4- (Ν-cyclohexylidene-acetyl-N-methylamino) -2-n-propyl-1- [[2 '-(Ν-trityl- Tetrazol-5-yl) biphenyl-4yl] methyl] -1H-squint-5-carboxylic acid ethyl ester. Physical and chemical properties 1 Η-NMR (CDC 1 3): δ (ppm) 6. 7 0-7. 9 6 (2 3 H, m), 5. 47 (2 Η, s) 5. 4 2-5 . 4 3 (1 Η, m) r 4. 15 (2 Η, dd) 3. 2 4 (3 H, s), 2. 5 3-2. 7 8 (2 H, m) 2. 50 (2 Η, t), 1. 8 9 — 2. 0 8 (2 Η, m) installed-line. The Ministry of Economic Affairs Central Liangzhun Bureau Industrial and Consumer Cooperation Du Yin 5i 1 ο Spectrum quality

i Β 8 7α 3 8 F Λ— / m Η '6 r \ ο 6 4 2 Η 3 Η 3 Η Μ / ι \ 6 9 7 ζ 8 3 81. 7. 20,000 ^ (11) The paper size is in use Ming Dynasty Standard "CNS" T4 (210X297); 5. Description of the invention (37)

The Ministry of Economic Affairs's Bureau of Standards and Standards only works to eliminate 51 cooperatives. The 4-C N- (2-methacryloyl) amino group] -2 -n-propyl-1 _ [21-(N-trityl -Tetrazol-5-yl) biphenyl-4-yl] methyl] benzozole- -carboxylic acid ethyl ester 250 mg in 5% acetic acid-ethanol mixture 1 ϋιη 1 after mixing at an external temperature of 9 0 ° C for 4 hours »Reduced pressure Distill off the solvent. The residue was chromatographed on a silica gel column (aeroform: methanol = 2 0: 1) and recrystallized from acetonitrile to obtain 4- CN-(2 ~ methacryloyl) amino] -2-n-propyl-1 [2 -(Tetrazol-5-yl) biphenyl- -yl] methyl]-1 H-quinazol-5-carboxylic acid ethyl ester 85 mg, white crystals. Physical and chemical properties Hi-NMR (CDC 1 3): δ (p P m) 9.6 2 (1 H, s), 7 9 1 (1 Η, d), 7.5 5 (1 H, t) , 7 4 9 (1 Η, t), 7.3 6 (1 H, d), 7 1 2 (1 Η, d), 6.9 2 (1 H, d), 5 9 1 (1 Η, s), 5. 5 3 (1 H, s), 5 5 0 (2 Η, S), 4 2 8 (2 H, dd) t 2. 7 3 (2 Η, t), -39- · Set the line. The 5 good scales of this paper are used in "Public Samples (CHS) 〒 4 specifications (2 丨 0X297 public it) 81. 7. ^ (Jf00 (h'k (II) A 6 Π 6 5. Description of the invention (38) 2. 0 0 (3 Η, S), 1.60 — 1. 6 9 (2 H, 1.2 3 (3 Η, t), 0.9 1 (3 H, t) mass spectrometry (FA Β) : m / ζ 5 0 0 (MH melting point: 1 3 3 -1 3 6 ° C elemental analysis value (C 27H29 N7 ° c I * 〇 · 2 H2 0) C (° / 〇) H (° / 〇) N (° / 〇) Calculated value 6 4, .45 5. 8 9 19. 4 9 Measured value 6 4. 27 5. 8 6 19. 4 7 Example 2 0

Me 'Me

Η Treated in Example 19 to give 4- [Ν-methyl-Μ- (3-methylbutenyl) amino] -2-n-propyl-Bu [[2 '-(tetrazole-5- Group) biphenyl-4-yl] methyl] -1H-imidazole-5-carboxylic acid ethyl ester. (Be familiar with the first reading and pay attention to the writing of the erroneous item ^ Pack &lt; Order _ line. The Central Standards Bureau of the Ministry of Economic Affairs A industrial consumption t cooperation to print the physical and chemical properties of ^ -NMR (CDClg): 5 (ppm) 8. 0 2 (1 H, d), 7. 5 9 (1 H, t), 7. 5 3 (1 H, t), 7. 4 0 (1 H, d), -4 ϋ-K paper Ift scale is used, the median a S family rate (CNS) Ή specification (210 &gt;: 297 g; Μ :) HI. 7. 20, () () 0ik (II) Λ 6 H 6 5 2 8 (ΜΗ + ) 5. Description of the invention (39) 7.18 (2H, d). 6.9 7 (2H, d), 5.59 (2 Η, s), 5.4 2 (1 Η, s). 4.17 (2 Η, dd), 3. 14 (3 Η, s) 2. 65 (2 Η, t), 2. 〇〇 (3 Η, s) 1. 72-1. 78 (2Η, m ), 1. 62 (3 Η, s), 1. 2 4 (3 Η. T), Ο. 9 6 (3 Η, t) mass spectrometry (FAB): m / ζ Example 2 1 (please read the back And pay attention to the ice term again i K) η — Pr

Me Me I I NCOC = CH2 C02Et

H Central Ministry of Economic Affairs and employee Xiaoxian cooperated to produce the imitation example 19, 4- [N-methyl-N- (2-methacryloyl) amino] -2-n-propyl- l- [[2 '-(tetrazol ° 5-yl) biphenyl-4-yl] methyl] -1H-triazole-5-carboxylic acid ethyl ester. Physical and chemical properties ^ I-NMR (CDClg): δ (ppm) 8 · UH, d), 7. 6 0 (1 H, t), 7. 5 4 (1H, t), 7. 27 (2 H , d) -4 1-The standard of this paper is used in "Ming Jiayu Bi (CNS) T4 specification (210X297 g) HI. 7. 2 (), () () 0¾ (II) V. Description of invention (40 ) 6. 9 4 (2 H, d). 5. 5 5 (2 H, s), 4. 9 6-5. 0 0 (2 Η, m), 4. 21 (2 Η, d), 3 . 21 (3 Η, s), 2. 62 (2 Η, t), 1. 70-1. 75 (5 Η, m), 1.2 8 (3 Η, t), 0.94 (3 Η, t) Mass spectrometry (FAB): m / z 514 (ΜΗ +) Melting point: 1 5 2-1 5 4 ° C Example 2 2 (Be sure to read the precautions and then drive one K) n — Pr

Me NCOCH2OMe C〇2Et

H The Ministry of Economic Affairs, Bureau of Accreditation, Employee, Consumers, Consumers, Du Yin, 3i, imitated in Example 19, and obtained 4- (N-methoxyethoxy-N-methylamino) -2-n-propyl-l- [[ 2 '-(tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-quinazol-5-carboxylic acid ethyl ester. Physical and chemical properties lH-NMR (CDC 1 3): δ (ppm) 8. 0 1 (1 Η, d), 7.5 9 (1 Η, t) 7.5 4 (1 Η. T), 7 . 4 2 (1 Η, d) 7. 19 (2 Η, d), 6. 9 9 (2 Η, d) 4 2 The paper size is not in accordance with Zhongming's "Home" Standard (CNS) T4 specification (210X297 ; ¢) 81. 7. (II)-. · 1 V. Description of the invention (41) 5. 5 8 (2 H, S) t 4. 2 3 (2 H, dd), 3. 8 5 (2 H, S), 3. 2 9 (3 H, s), 3. 1 8 (3 H, S), 2. 6 7 (2 H, t), 1. 7 4--1. 7 7 (2 Η, m) t 1 2 6 (3 H, 0.98 (3 H, t) mass spectrometry (FAB): m / z 5 1 8 (ΜΗ *) Example 2 3

(Please read the notes first and then write the item ^ k) Pack-line. Printed 3i by the Mongong Consumer Products Cooperative of the Bureau of Standards, Ministry of Economic Affairs, imitated in Example 19, and obtained 4- (2-oxo-1-pyrrole) Pyridyl) -2-n-propyl-1-[[2 '-(tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-imidazole-5-carboxylic acid ethyl ester. Physical and chemical properties ^ -NMR (CDClg): &lt; 5 (ppm) 8. 00 (1 H, d), 7. 58 (1 H, t), 7. 5 4 (1 H, t), 7. 4 1 (1 H, dd), 7. 09 (2 H, d), 6. 99 (2 H, d), -4 3-In this paper, the standard "CNS" T4 specification (210X297 Male dragon) H1. 7. 20,000 ^ (11) Ο V. Description of invention (42) 5. 4 8 (2 H, s), 4.19 (2 Η, dd), 3. 8 3 (2 H, t ),, 2. 6 2 (2 Η, t), 2. 7 4 (2 H, t), 2. 14-2. 2 1 (2 H, m) 1. 6 9-1. 7 5 (2 H, m), 1. 25 (3 H, t), Ο.96 (3 Η, t) mass spectrometry (FAB): m / z 5 0 0 (MH +) Example 2 4 0

Following the treatment of Example 19, 5-amino-4- (2-oxo-1-pyrrolidinyl) -2-n-propyl-1- [[2 '-(tetrazol-5-yl) biphenyl -4-yl] methyl] -1H-quinazole. Physical and chemical properties ^ I-NMR (CDClg): δ (ppm) '(please read back and forth and pay attention to Bian, Xiang Sun Dang writes 4--Ministry of Economics, Bureau of Standards IS: Printed by Industrial and Consumer Cooperative 7. 9 6 (1 Η, d) t 7. 5 9 (1 H, t) 7. 5 2 (1 Η, t) t 7. 4 2 (1 H, d) 7. 1 3 (2 Η, d) t 7. 1 0 (2 H, d) 5. 1 8 (2 Η, s) t 3. 9 7 (2 H, t) 2. 6 6 (2 Η, t) t 2. 5 6 (2 H , t) 2. 1 6 -2 .2 3: 2 H, m) 1. 6 9-1. 78, Ο. 98 (3 Η, t) -4 4-This paper is used in size B »Family 楳Bi (CNS) specifications (210X297 public: «:) Si, 7. 20, () 00 ^ (II) ό Λ fi It 6 5. Description of invention (43) Mass spectrometry (FAB): m / z 453 (MH +) Elemental analysis value (C25H24N8.0.0 8H2〇) C (%) Η (%) Ν (%) Calculation value 64.30 5.5 3 2 4.0 0 Continuous measurement value 64.60 5. 4 7 2 3. 7 0 Example 2 5

Me

Following the treatment of Example 19, 4- (N-ethoxypyranoyl-N-methylamino) -2-n-propyl-1- [[2 '-(tetralin-5-yl) biphenyl-4 -Yl] methyl] -1H-imidazole-5-carboxylic acid ethyl ester. (Be sure to read the notes before you ^ Items and then write ^ One outfit · line · The traits of the employee cooperation of the Ministry of Economic Affairs 'Bureau of Standards and Consumers' Du Printing and Physical Chemistry lH-NMR (CDC 1 3): δ (p pm) 7 . 9 9 (1 H, d), 7. 59 (1 H, dd), 7. 53 (1H. Dd), 7. 41 (1 H, d), 7. 18 (2 H, d), 6 . 96 (2 H, d), 5. 54 (2 H, s), 4. 21 (2 H, q), 4. 02 (2 H. q). 3. 25 (3 H, s), original paper In the ft scale, the Chinese Standard «Home Sample Standard (CNS) 4 specifications (210X297 g) η β_ V. Description of the invention (44) 2. 61 (2 H, t), 1. 7 Ο-1. 7 6 ( 2 Η, m), 1. 28 (3 Η, t), 0.95 (3 Η, t) mass spectrometry (FAB): m / z 5 4 6 (ΜΗ +) Example 2 6

Following the treatment of Example 19, 4- (2-gas-: 1-piperidinyl) -2-n-propyl-1-[[2 '-(tetrazol-5-yl) biphenyl-4-yl] Methyl] -1H-imidazole-5-carboxylic acid ethyl ester. Physical and chemical properties-NMR (CDCI 3): 5 (ppm) (please read first-note to the contrary * ^ Item and then Item 鈛 一,-Ministry of Economic Affairs, Bureau of Standards, Industrial and Commercial Cooperative Printed 31 7. 8 1 ( 1 Η d), 7.5 4 (1 Η, dd), 7.4 7 (1 Η »dd), 7.3 7 (1 H .d), 6.9 7 (2 Η I d). 6 . 8 7 (2 H, d), 5. 4 2 (2 Η ts), 4. 1 7 (2 H, q). 3. 5 4 -3 • 5 8 (2 Η, mrbr), 2.5 0 (2 Η »t), 2. 3 8 -2 • 4 2 (2 Η, m, br), 1. 8 5 -1 8 9 (4 Η, m, 1 br), -46- this paper size遑 用 中 《β Family Sample Standard (CNS) TM Specification (210X297 public) 81. 7. 20,0 () 0¾ (t!) Λ 6 Π 6 V. Description of the invention (45) 1. 64-1. 68 (2H. M), 1.23 (3 H, t), 0.91 (3 H, t) Mass spectrometry (FAB): m / z 5 1 4 (Μ H +) Example 2 7 η

Following the treatment of Example 19, 4- (3,3-dimethyl-2-gas-1-acridinyl) -2-n-propyl-1-[[2 '-(tetrazol-5-yl) Biphenyl-4-yl] methyl- (please read the net terms first and then the hard item-]-1H-imidazole-5-carboxylic acid ethyl ester. Physical and chemical properties ^-NMR (CDC 1 3): 5 (ppm) Order _ Line-Printed by the Ministry of Economic Affairs, Central Bureau of Industry and Commerce only cooperatives 7. 8 9 (1 Η, d). 7. 5 6 (1 Η, dd), 7. 5 0 (1 Η, dd), 7 • 4 0 (1 Η .d), 7.0 4 (2 Η, d), 6.9 0 (2 Η, d), 5. 4 5 (2 Η, s), 4.2 0 (2 Η, q), 3. 6 1 (2 Η, s), 2.5 6 (2 Η, t), 1. 6 3 -1 .6 7 (2 Η, m) t 1. 3 8 (6Ή, s), 1.2 4 (3 Η, t), 0.9 2 (2 Η, t) mass spectrometry (F AB): m / Z 5 1 4 (MH +) -4 7-Original paper »Scale In the use of "楳 戳 Bi (CNS) T4 regulation (210X297 male dragon) 81. 7. 20, () 00 ^ (II) 3 9 ο 2 β 6 Λ: V. Description of the invention (4b) Example 28

A copy of the example 19 was processed in cooperation with the Industrial Standards Bureau of the Ministry of Economic Affairs and the Ministry of Economic Affairs to obtain 4- [N-methyl-N- (phenoxyethyl acetyl) amino] -2-n-propyl-bu [ [2 '-(Tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-imidazole-5-carboxylic acid ethyl ester. Physical and chemical properties-NMR (CDC 1 3): δ (ppm) 7.9 7 (1 H, d), 7. 58 (1 Η, dd), 7. 51 (1 H. dd), 7. 39 (1 H, d), 7. 10-7. 16 (4 Η, m), 6. 9 4 (2 Η, d), 6. 87 (1 Η, dd), 5. 55 (2 Η, s ), 4. 46 (2 Η, s), 4. 14 (2 Η, q), 3.21 (3 Η, s), 2.64 (2 Η, t), 1. 7 0-1. 7 9 (2 Η, m), 1.2 1 (3 Η, t), 0.97 (3 Η, t) mass spectrometry (FAB): m / z 5 8 0 (MH +) (please read the opposite first Pay attention to the re-entry% 1, &gt;,) Packing-Line-This paper scale uses Zhongming Yinjia «Bi (CNS) Τ4 specifications (210X297 :: :)

Mi. 7. 2〇 (〇〇〇 ^ (μ) 209 L3 Λ 6 Π 6 V. Description of the invention (47) Example 2 9

Me

Following the treatment of Example 19, 4- (N-phenylacryloyl-N-methylamino) -2-n-propyl-1-[[2 '-(tetrazol-5-yl) biphenyl-4- Group] methyl] -1 H-quinazol-5-carboxylic acid ethyl ester. Physical and chemical properties ^ I-NMRCCDClg): δ (ppm) (please pay attention to the net items first>) installed. •? Τ_ Printed by the Employee Consumer Cooperative of the Bureau of Standards, Ministry of Economic Affairs ^ 7. 9 9 (1 Η, d), 7. 4 9- 7. 5 9 (3 H, m) 7. 3 6 (1 Η, d), 7. 19- 7. 2 5 (5 H, m) 7. 1 0 ( 2 Η, d) .6: 9 6 (2 H, d) r 6. 3 0 (1 Η, d), 5. 5 8 (2 H, s), ► 4. 1 4 (2 Η, q) .3. 2 5 (3 H, s) r 2. 6 9 (2 Η, t),, 1. 7 3- 1. 8 1 (2 H, m) 1. 1 9 (3 Η, t), 〇. 9 9 (3 H, t) mass spectrometry (FA 'B): m. / Z 5 7 6 (M H +;) line · This paper scale uses Chinese β- 漳 楳 Bi (CKS) f 4 regulations (210x297 Mm) 8 !. 7. 20,0 () i) i) c (II) ·· 0, 'Shang 9 ο 2 6 6 ΛΠ V. The invention is called (48) Example 3 0

Following the treatment of Example 19, 4- (N-cyclohexylidene-acetyl-N-methylamino) -2-n-propyl-1- [[2 ^ (tetralin-5-yl) biphenyl- 4-yl] methyl] -1H-quinazol-5-carboxylic acid ethyl ester. Physical and chemical properties element analysis value (C32H37N7 〇3) C (%) H (%) Ν (%) Calculated value 67.70 6. 5 7 17.27 Measured value 67.65 6.4 9 17.2 7 Flame point: 2 1 3-2 1 5 ° C Mass Spectrometry (FAB): m / z 5 6 8 (MH +) Example 31 Me Me (please read first and pay attention to the apple. Item #fill the poor k, pack-book_line-Ministry of Economics and Social Security Bureau IS ： Industry and consumer cooperation Du Yin &quot;

-50- This paper is used in the "Standard Family Standard (CNS) Specification (210X297): it) SI. 7. 2 (), () () 0 ^ (11) CC Γ · '6 t V. Invention Description (49) in 4-[N -methyl-N-(2 -methacryloyl) amino] -2 -n-propyl- [〔2 ·-(N -trityl-tetrazole- 5-yl) biphenyl-4-yl] methyl] -1 H-quinazol-5-ethyl carboxylate 5㈣m g plus formic acid 8 m 1, and after stirring at room temperature for 48 hours, it was evaporated under reduced pressure. The residue was dissolved in ethanol 5πι 1 and 1 N N a 0 H water was added 3.6 οι 1. After stirring at room temperature for 3 days, the solvent was distilled off under reduced pressure. The residue was dissolved in 5 ml of water and 1N hydrochloric acid was added to adjust to PH2. The mixture was extracted with ethyl acetate and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (chloroform: methanol: acetic acid = 100: 10: 1) to give 4- [N-methyl-N- (2-methacryloyl) amino] -2-n-propyl Yl-1- [[2 '-(tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-squinted-5-carboxylic acid, giving 100 mg. Physical and chemical properties ^ I-NMR (DMSO): δ (ppm) 7.5 7 (1 Η. D), 7.5 1 (1 Η, t) 7.4 5 (1 Η, d), 7. 4 1 (1 Η, d) 7. 0 6 (1 Η, d), 6. 8 0 (1 Η, d) 5. 5 8 (2 Η, s), 5. 0 0 (1 Η, s) 4. 8 3 (1 Η, s) (3. 1 1 (3 Η, s) Please nil ύ Back to the note Λ 塡% 47-2. 5 2 (2 H, m), 1. 7 4 (3 H, s), 1. 52-1. 59 (2Η, m), 0.82 (3H, t) mass spectrometry (FAB): m / z 4 6 8 (MH +) This paper scale is used in China «Homewood Standard (CNS) 悀 4 regulations (2 丨 0X297 public: it) 81. 7. 20,000i) t (II) V. Invention description ( 50) Example 3 2 Λ 6 U 6

Me, Me

Η With 4- [N-methyl-N- (3-methylbutenalyl) amino] -2-n-propyl-1-[[2,-(tetrazol-5-yl) biphenyl- 4-yl] methyl] -1H-imidazole-5-carboxylic acid ethyl ester as raw material, treated as in Example 3 1 to give 4- [N-methyl-N- (3-methylbutenyl) amine Yl-2-n-propyl-1- [[2 '-(tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-quinazol-5-carboxylic acid. Physical and chemical properties of 'H-NMR (CDC13): &lt; 5 (ppm) Ml read back to the precautions -fb filling and binding line Ministry of Economic Affairs, Bureau of Standards, the Ministry of Economic Affairs, the negative work and elimination cooperation printing 7. 7 8 (1 Η, d), 7.5 6 (1 Η, t) 7. 4 7 (1 Η, t) (7.4 1 (1 Η, d) 7. 0 7 (2 Η, d), 6.8 0 (2 Η, d) 5. 5 2 (2 Η, s), 5. 4 3 (1 Η, s) 3 · 1 5 (3 Η, S), 2. 6 3 (2 Η, t) 1 · 7 5 (3 Η, S), 1. 6 4-1. 7 5 (1. 6 0 (3 Η, S), 0.9 1 (3 Η, t) mass spectrometry (FAB): m / z 5 0 0 (ΜΗ +) 5 2- 81. 7. 20.000ik (H) ft scale of this paper instead of Zhongming National Standard (CNS) T4 specification (210X297 public address) V. Description of invention (51) Example 3 3 Λ 6 η 6 0

Η With 4-(2 -chloro-1 -pyrrolidinyl) -2 -n-propyl-: [-[[2 '-(tetrazol-5-yl) biphenyl-4-yl] methyl] -1Η -Ethyl imidazole-5-carboxylate is used as the raw material and treated as in Example 31 to obtain 4- (2-gas-pyrrolidinyl) -2-n-propyl-1-[[2 '-(tetrazole- 5-yl) biphenyl-4-yl] methyl] -1Η- 簯 azole-5-carboxylic acid》 Physical and chemical properties of 'Η-NMR (CDC 1 3); δ (ppm) % The Central Bureau of the Ministry of Economic Affairs IS: printed by the industrial and consumer cooperatives 7. 8 9 (1 Η, d) t 7. 5 6 (1 H, t), 7. 4 9 (1 Η, t) »7. 4 0 (1 H, d), 7. 0 5 (2 Η, d) t 6. 9 3 (2 H (d), 5. 4 8 (2 Η, s) t 4. 0 1 (2 H, t), 2. 5 5 -2 • 6 4 (4 H, m) 2. 2 1 -2 .2 6 (2 H, m) 1 _ 6 8 -1 .7 6 (2 H, m) 0. 9 6 (mass spectrometry (FAB): m / z 4 7 2 (ΜΗ -53 paper Λ scale and using the middle-sleepy home standard (CNS) A 4 specifications (210X297 g: in 81. 7. 20,000 ^ (11) Description of the invention (52) Example 34 Λ 6 Η 6

For trityl 4-amino-2-n-butyl-1- [[2'-U-trityl-tetrazol-5-yl) biphenyl-4-yl] methyl] mazole 5-Carboxylic acid ethyl ester and 3, 3-dimethylacrylic acid gas, treated as in Example 1, to obtain 2-n-butyl-4-4-: N- (3-methylbutenyl) amino group] -1- [[2 '-(Ν-trityl-tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-quinazol-5-carboxylic acid ethyl ester. Physical and chemical properties' H-NMRCCDCla): Read first »n Contrary to Note Matters Master Refill

F Printed by the Employee Consumers of the Central Bureau of Economics and Trademark of the Ministry of Economic Affairs (PP m) 8. 8 7 (1 H, s), 6. 7 2- 7. 9 2 (2 3H, m) 6. 0 0- 6. 1 1 (1 H, m), 5. 3 5 (2 H, s) 4. 1 5 (2 H, q), 2 6 1 (2 H, t), 2. 2 5 (3 H, d), 1 9 2 (3 H, d), 1. 3 1 -1. 8 2 (4 H, m), 1. 1 6 (3 H, t) 0. 8 6 (3 H, t) (FAB) m / z: 7 7 0 (MH +) 5 4 This paper is used in «Standard (CNS) T4 specification (210X297 male tf) 81. 7. 20.000i | c (1!)

ο -X ... 1 C;} ο CW 66 ΛΠ V. Description of the invention (53) Example 3 5 / Me

With 2-n-butyl-4- [N-methyl-N- (3-methylbutenyl) amino]]-l- [[2 '-(N-trityl-tetrazole-5 -Yl) biphenyl-4-yl] methyl] -1H-imidazole-5-carboxylic acid ethyl ester and methyl bromide, treated as in Example 12, to give 2-n-butyl-4- [M-methyl -N- (3-methylbutenyl) amino] -1-[[2 '-(N-trityl-tetrazol-5-yl) biphenyl-4-yl] methyl]- 1H-Fenazole-5-carboxylic acid ethyl ester. Physical and chemical properties 丨 Η-NMR (CDC 1 3): δ (ppm) IW] Contrary to the precautions and then fill out this page a package Ding printed by the Ministry of Economic Affairs, Biyang, Bureau of Industry and Commerce, Co., Ltd. Du printed 6. 7 1 _ 8 .0 0 (2 3 H, m) t 5. 4 1 -5 .5 0 (3 H, m), 4. 1 4 (2 Η, q). 3. 2 4 (3 H, s) 2. 4 9 (2 Η, t), 2.0 7 (3 H, d) 1. 6 5 (3 Η, d), 1. 3 1 -1 .7 5 (4 H, m), 1. 23 (3 H, t), 0.86 (3 H, t) Quality (FAB): m / z 7 8 4 (MH +) -5 5-This paper is widely used in the «Home Sample Standard (CNS) A 4 specifications (210x297 mm) 81. 7. 20, U00ik (! L) V. Description of the invention (54) Examples;) 6

Me

Η With 2-n-butyl-4- [Ν -methyl- Ν- (3-methylbutene acryloside) amino-bu [[2 '-(N-trityl-tetrazole-5- Group) Biphenyl-4-yl] methyl] imidazole-5-carboxylic acid ethyl ester was treated as in Example 19 to obtain 2-n-butyl-4- [N-methyl-N- (3. -Methylbutyl Alkenyl) amino]]-; 1-[[2 '-(tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-quinazol-5-carboxylic acid ethyl ester. Physical and chemical properties element analysis value (C3eH35N7〇3) C (° / 〇) Η (%) Calculated value 6 6.5 2 6.5 1 Actual measured value 6 6.5 0 6.5 1 Ν (° / 〇) 8 · 10 8. 0 5 first Read the notes on the contrary 5 fill in the content of this ･ Ministry of Economic Affairs, the Central Bureau of Quorum βWork Consumer &quot; Cooperative Du Printing Melting Point: 1 8 4-1 8 5 ° C Mass Spectrometry (FAB): m / z 5 4 2 ( MH +) -56- The ft scale of this paper is used in the "National Standard (CNS) T4 specification (210X297 public release) 81. 7. 20,00 () ¾ (II):;: V- V. Description of the invention (55) Example 3 7 Λ 6 Π 6

Me

Η With 2-n-butyl-4- [Ν-methyl-Ν- (3-methylbutenyl) amino] -1 [〔2 '-(N-trityltetrazole-5-yl ) Biphenyl-4-yl] methyl] benzoazole-5-carboxylic acid ethyl ester was treated as in Example 31 to give 2-n-butyl-4- [N- (3-methylbutenyl) amino 〕 -L- 〔[2 '-(tetrazol-5-yl> biphenyl-4-yl] methyl] -1H-quinazol-5-carboxylic acid ethyl ester. Physical and chemical properties element analysis value (C28H3, N7〇3 · 0.3H20) C (%) Η (%) N (%) calculated value 64.80 6.1 3 1 8.89 measured value 64.93 6.16 1 8.81

Tk Read the notes on the back and fill in%. The page is filled with the quasi-bureau of the Central Committee of the Ministry of Economic Affairs CS: printed by the Cooperative Society. Melting point: 1 5 6-1 5 8 -C Mass Spectrometry (FAB): m / z 5 1 4 (ΜίΤ) 57 This book "Zhang Deng Duan Zhongzhong" «Home« Quasi (CN5) «P4 Specification (2 丨 0X297 ft)

Bl. 7. 2U.U00ik (ll) 5. Description of the invention (56) Example 38 Λ 6 Η 6, Me

Me η-Bu

Printed by the Ministry of Economic Affairs, the Central Bureau of Taxation, the Tax Consumers Cooperative on 2-n-butyl-4- [N-methyl-N- (3-methylbutenyl) amino] -ΙΕ 〔2 '-(三Benzyl-tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-quinazol-5-carboxylic acid 5.0 g ethanol solution 20Qml, under ice-cooling was added O.lmol dropwise in 20 minutes / JI alcoholic KOH solution 69.5ml. After stirring for 10 minutes under ice cooling, the solvent was distilled off under reduced pressure. The residue was dissolved in C_20Qml, and 10% NaI aqueous solution 2 G m U was added in sequence under ice-cooling to prepare 1.54 g of valeric acid gas methyl ester. After heating to reflux for 7.5 hours, the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate and washed twice with water, dried, and evaporated under reduced pressure. The residue was chromatographed on a silica gel column (hexane: ethyl acetate = 2: 1) to obtain 2-n-butyl-4-[N-methyl-N- (3-methylbutenyl) amino]]- 1-[[2 '-(trityltetrazol-5-yl) biphenyl-4-yl] methyl] -1H-quinazol-5-carboxylic acid to be pentafluoromethyl methyl ester 3.80 g, foam . Physical and chemical properties 1 H-NMR (CDC13): &lt; 5 (ppm) 5 8- ft scale of the paper, using t «β 家« quasi (CHS) f 4 specifications (210x297 public goods) 81. 7. 20.000 ^ ( II) (Please read the precautions before writing this page) Install. V. Description of the invention (57) Λ 6η 6 6. 7 1-7. 9 3 (2 3 H, m), 5. 75 (2 H, s) 5. 4 6 (3 Η, s), 3. 22 (3 Η, s), 2. 5 1-2. 59 (2 Η, m), 2 1. 48-1. 72 (5Η, m), 1. 25-1. 3 2 (2 Η, m), 1 Ο. 8 6 (3 Η, t) 0 6 (3 Η, s) 15 (9 Η, s) mass spectrometry (FAB ): m / z 870 (Μ +) Example 3 9 η-Bu-

Me 1 / Me / NCOCH = C \ Me, co2ch2,, Me

C

Note on the back of the third reading of the base toluene Fill in the example on this page to implement the imitation of iminomethyl butane based on the printing of the base dimethine ffi bis-pentyl methacrylate by the Pengong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 2 A i-, sr base c A-

Acid carboxylic acid f 5 IC azole 1-imid ~ I ο 31H Ester monomethylamine 3}) r-yl-yl-methyl 4-acid Dfcs alkenyl-like 4-S-based benzene-IB's bicarbonate Chemicals and paper-based papers for use in the middle of troubled β- 揳 戳 Bi (CNS) «Τ4 specifications (2Κ1Χ297 mm) azole tetrakisyltoluene 3 '-\-2 gas 1 2 I base methyl 81. 7. 20,000¾ (II ) i 5. Description of the invention (58) H-NMR (CDC δ (ppm) 6.7 3 -7 9 2. (2 3 H 5 · 4 4 (2 Η, s) 4. 3. 2 1 (3 Η , s) 2. 2. 0 5 -2 .1 0 (6 H, 1 · 5 2 -1 .7 2 (5 H, 1. 2 1 -1 .3 2 (2 H, (FAB): m / z 8 Example 4 〇η — Bu

Λ 6 Η 6 2 H, s),

Me Me -NCOCH = = C \] vie C02CH0C02Et

Me Read the back of the notes, and then write a copy π- pretend that the Central Ministry of Economic Affairs of the Ministry of Economic Affairs employees cooperated with the du printing to make an example of C Shi ’-[actual chlorine-1 imitation 1 ethyl 8 3

2 Η C

Substituted by methyl tolyl formate Methanoic acid CN Pent-4 Tetra-Butyl, Butyl Metrazole Tetramethyl Idibenzyl} Methyl} Methyl 1 Carbonyloxycarbonyl 4 Ethyl- (Methyl 3 ylbenzene Joint ο 6 This paper is used in the "《家« 准 (CNS) 言 4 訙 悙 (210X297 public; it) 81. 7. 20.000¾ (II) Λ 6 Η 6 V. Description of invention (59) base]- 1 Η-簯 azole-5 -carboxylic acid I 1 -ethane gas carbonyl gas physicochemical properties ^ -NMR (CDC13): 5 (ppm) 6.7 0-7. 95 (24 H, m). 5 . 3 9-5. 57 (3 H, m), 4, 17 (2 H, q), 3. 23 (3 H, s), 2. 4 2-2. 6 7 (2 H, m), 2. 86 (3 H, d), 1. 4 2-1. 7 6 (1 0 H, m), 1. 17-1. 34 (3 H, m), 0. 85 (3 H, t) Mass spectrometry (FAB): να / z 8 7 2. (ΜΗ +) Example 4 1 η-Bu.

Me .Me NCOCH = C 〇 ^ Me • CO〆 Vo

Tk first read the background and pay attention to the items. Fill in% Date% Central Bureau of Economics of the Ministry of Economic Affairs, Industry and Consumers Cooperation, Duyin 3i base, 8 cases, implementation of imitation base

C

Benzene toluene gas-base 3 phthaloyl esters with amine esters, methanoic acid, pentylpyridinium, I 2, and acetylenes I ~ *怙 (210X297 公 龙) 81. 7. 2U.00Ui (t (11) fi-2 9 ο £ ο G Λli V. Description of invention (ϋ0) (trityl-tetrazol-5-yl) biphenyl- 4-yl] methyl] -1H-quinazol-5carboxylic acid phthalate. Physical and chemical properties ^ I-NMRCCDClg): δ (ppm) 6. 7 7-7. 93 (28 H, m), 5 . 35-5. 4 8 (3 Η, m), 3. 0 3 (3 H, s). 2. 5 2-2. 6 2 (2 H, m), 1. 9 1 (3 H, d ), 1. 6 6 (3 H, d), first read the notes on the back of ill and then 5 2-1. 7 2 H, m), 1. 25-1. 30 (2 H, m), 0 · 88 (3 H, t) Mass spectrometry (FAB): m / z 8 8 8 (MH +) Example 4 2 η-Bu- nN-

Me I / Me, NCOCH = C XMe, C02CH20C0CMe3 installed η Printed by the Employee Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 2 Η c

Η 81. 7. 20,000 ^ (II) The ft scale of this paper is used in the sleepy home «quasi (CNS) f 4 specifications (210X297 public; tt)

Λ (i MG V. Description of the invention (bl) 2- (4-)-N-methyl-N- (3-methylbutanoyl) amino group]-Ι-ί 〔2 ′-(三Benzomethyl-tetrazol-5-yl) biben-4-yl] methyl] methyl] -1 []-myrazole-5-carboxylic acid pivaloyl gas methyl ester 3. 6 Q g dissolved in 5% acetic acid- Ethanol 1 5 0 ΙΗ 1, and after heating to reflux overnight, the solvent was distilled off under reduced pressure, and azeotrope with toluene 3 0 in 2 times. The residue was crystallized from acetic acid to give 2-butyl-4- [N-methyl- N- (3 -methylbutenyl) amino] -1- [[2 ^ (tetrazol-5-yl) biphenyl-4-yl] methyl] -1H -quinazol-5-carboxylic acid To be 2.0 grams of pentamethylene oxide, white crystals. Physical and chemical properties Melting point: 1 4〗 -1 4 2 ° C elemental analysis value (C34H4〇N7〇5. 〇. 2H2〇) C (%) Η (%) Ν (%) calculation value 64.79 6.46 15.55 analysis value 64.59 6.60 1 5. 4 0 Example 4 3 (please read back and forth and pay attention to the matter first Sun Sun fill-[&gt;? This page} Ministry of Economic Affairs 殮 央 棂 准 扃Alpha Engineering Consumer Cooperative Du Print

-63- This paper uses the Chinese national «rate (CNS) f 4 specification (210X297:« :) 91. 7. 20,000¾ (II) 209 ^^ ° Λ () Π (i V. Invention description (b2 ) Example 4 2, but 2-butyl-4- [N-methyl-N- (3-methylbutenyl) amino] -1-[[2 '-(trityl- Tetrazol-5-yl) biphenyl-4-yl] methyl] -1 Η- 篯 azole-5 -carboxylic acid to be replaced by valeraldehyde methyl ester Example 2 9 Compound 2 -Butyl-4- [Ν -methyl-Ν-(3 -methylbutenalyl) amino] -1- [[2, (trityl-tetrazol-5-yl) biphenyl-4-yl] methyl 〕 -1H-Pyrazole-5-carboxylic acid (5-methyl-2-oxo-1,3-diII No. II-carboene-4-yl) methyl ester, to give 2-ΪΓ group-4- [Ν- 甲Group-Ν- (3-methylbutenyl) amino] -l- [tetrazol-5-yl) biphenyl-4-yl] methyl] -1H- quinazol-5-carboxylic acid- ( 5-methyl-2-gas-1,3-di-B-phenocenen-4-yl) methyl ester. Physical and chemical properties

Melting point: 1 3 9-1 4 0 ° C Elemental analysis value (CuH ^ N ^ Oe) C (%) H (%) N (%) Calculation value 63.35 5.64 15.6 7 Analysis value 63.16 5.65 15.67 Example 44 "(Please (Read the back-to-back precautions and fill out this page) Printed by the Ministry of Economic Affairs, Central Bureau of Industry and Commerce, A Industrial Consumer Cooperative

81. 7. 20,000 sheets (11) of this paper are used in China ’s “China Family Standard (CNS) T4 regulation (210X297 male dragon) Μ Central Ministry of Economic Affairs Standard Λ; β Industrial Consumer Cooperative Printed 2-μ Λ Π 6 V. Description of the invention (6 present

Imitating Example 42, except 2-n-butyl-4- [N-methyl-N- (3-methylbutenyl) amino] -1-[[2 '-(trityl-tetra Oxazol-5-yl) biphenyl-4-yl] methyl] -1 Η-imidazole-5-carboxylic acid with methyl ester of pentane gas and the compound of Example 40 2-butyl-4- [Ν- Methyl-Ν- (3-methylbutenyl) amino] -Bu [[2 ^ (trityl-tetrazol-5-yl) biphenyl-4-yl] methyl] -1H- Pyrazole-5-carboxylic acid-; Τ-ethoxycarbonyloxyethyl ester, to give 2-n-butyl-4- (N-methyl-N- (3-methylbutanoyl) amino]] — 1- [[2 '-(tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-imidazole-5-carboxylic acid 1'-ethoxycarbonyloxyethyl. Physical and chemical properties Melting point: 1 1 2-1 1 4 ° C Elemental analysis value (C33H39N7〇6 * 0.6H2〇) C (%) Η (° / 〇) Calculation value 6 1.8 8 6.3 3 Analysis value 6 1.7 0 6.1.7 Examples 4 5

Η -N

JLL t paper standard is used in "Home" (CNS) &gt; F4 regulations (210X297 public; it) First read th and pay attention to the matter before filling in% This page is a decoration N (%) 5. 3 1 5 . 3 2 lines 81. 7. 20,0 () 0¾ (II)

C Λ (i l \ (i

V. Description of the invention (64) Imitating Example 4 2, except that 2-n-butyl-4- [N-methyl-N- (3-methylbutenyl) amino]]-Bu [[2'- (Trityl-tetrazol-5-yl) biphenyl-4-yl] methyl] -1 Η- 眯 azole-5-carboxylic acid is replaced by the compound 2 of Example 41 by pentyloxymethyl N-Butyl-4- [Ν -methyl- Ν- (3-methylbutenyl) amino] -1- [〔2 ^ (trityltetrahydro-5-yl) biphenyl-4 -Yl] methyl] -1H-quinazol-5-carboxylic acid phthalic acid to give 2-n-butyl-4-(Ν-methyl-Ν- (3-methylbutenyl) amino]]- 1- [[2 '-(tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-quinazol-5-carboxylic acid phthalate. Physical and chemical properties Melting point: 2 ϋ 2-2 0 3 ° C Elemental analysis value (C36H35N7〇5) c (° / 〇) Calculation value 66.96 Analysis value 6 6.82 Η (%) 5. 4 6 5. 4 7 Ν (%) 5. 18 4. 9 9 (please first Read the back-to-back precautions and write a code on this page} Example 4 6 Central Slave Bureau of the Ministry of Economic Affairs A Industrial Consumer Cooperative Indo

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Imitate Example 38, except that methyl valerate is replaced by 1-cyclohexyl carbonyl gas B-66- The paper standard is used in "National Standard (CNS) T4 Specification (210X297; it) 81. 7. 20,000¾ (II) 00 01 3 eL 飞 .- 6 ο ΛΠ V. Description of the invention (6ί;) Based on chlorine, 2-N-butyl-4- [N-methyl-N- (3-methylbutene Acetyl) amino] -1- [[2 '-(trityl-tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-quinazol-5-carboxylic acid 1'- Cyclohexyl carbonyl ester. Physical and chemical properties ^ -NMR (CDClg): δ (ppm) 6. 72-8. 0 8 (2 4 H, m), 5.30-5. 6 4 (3 Η, m), 5. 53- 5. 60 (1 Η, m), 3. 23 (3 Η, s), 2. 5 4-2. 6 7 (2 Η, m), 2. 09 (3 Η, s), 1.15- 1. 92 (20H-m), 0.86 (3Η, t)) Mass Spectrometry (FAB): m / z 9 2 6 (M +) Example 4 7 Read the notes on the contrary and re-% of the Ministry of Economics and Trade Center Enclosure E: Co-operation with the Consumer Council

Imitate Example 42, except that 2-n-butyl-4- [N-methyl-N- (3-methylbutan-6 7-81. 7. 20,000 ^ (11) is used on the ft scale of this paper. «国 楳Standard (CNS) T4 specifications (210x297 g)

, ^ The Ministry of Economic Affairs, Central Bureau of Industry and Commerce, Co., Ltd. cooperates in the production of CO. Ο V. Description of the invention 6) Enilyl) amino] -1- [[2 '-(trityl-tetrazole-5- Group) biphenyl-4 -yl] methyl] -1 Η-?-Azole-5-carboxylic acid methyl ester of pentane gas was replaced by the compound of Example 46 2-n-butyl-4- [N-methyl -Ν- (3-methylbutenyl) amino] -1- [[2 -_ (trityl-tetrazol-5-yl) biphenyl-4-yl] methyl] -1Η- 眯Azole-5-carboxylic acid-1'-cyclohexyl carbonyl gas ethyl ester to give-2-n-butyl-4- (Ν-methyl-Ν- (3-methylbutenyl) amino] -l -[[2 '-(tetrazol-5-yl) methyl] -1H-quinazol-5-carboxylic acid 1, -cyclohexyl carboxyethyl ester. 1 Physical and chemical properties ih Please read beforehand Fill in the items again.% Page 1 Melting point: 1 7 7-1 7 8 ° C k Elemental analysis value (37 only 45 ^? 〇6 C (%) Η (° / 〇) Ν (%) Calculated value 6 4.99 6. 6 3 1 4. 3 4 Analysis value 6 4.79 6. 6 8 1 14. 26 Line example 4 8

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Use 2-n-butyl-4- [N-methyl-N- (3-methylbutenyl) amino] 6 8- on the ft scale of this paper in the "National Standards (CNS) ^ Specification (210X297 Male: Jt) 8 !. 7. 20,000¾ (II) Λ (i W (i V. Description of the invention (G7) -1-[[2 '-(tetrazole-5-yl) biphenyl-4-yl] Methyl] -1 Η-簯 azole-5-bag acid 5 ϋ 0 in g was dissolved in ethanol 1 m 1, and was added dropwise under ice cooling 〇. 〖M 〇1 / sense ethanolic K Ο Η solution 9. 7 4 m]. After stirring for 1 Q minutes, the solvent was distilled off under reduced pressure without heating. The residue was powdered to give 2-n-butyl-4- [N-methyl-N- (3-methylbutenyl) ) Amino] -1- [[2 '-(tetrazol-5-yl) biben-4-yl] methyl] -1H-quinazol-5-carboxylic acid potassium salt 430mg. Physical and chemical properties' Η -NMR (DM S Ο) .δ (ppm): 7. 5 4 (1 Η, d), 7. 3 5- • 7. 4 1 (2 Η, m) 7. 3 0 (1 Η, ά) , 7. 0 6 (2 Η, d), 6.8 3 (2 Η, d), 5. 6 1 (2 Η, S), 5. 4 4 (1 Η, s), 3. 0 6 ( 3 Η, s) 2.5 7 (2 Η, t), 1. 9 4 (3 Η, s), 1. 6 1 (3 Η, S), 1.5 0- 1. 5 6 (2 Η , m) 1. 2 3 -1 .2 7 (2 Η, m), 0. 8 0 (3 Η, t) (please read the note on the back first To fill out this page, the Central Standards Bureau of the Ministry of Economic Affairs prints a mass spectrometer (FAB) printed by only the Zhongzhong Cooperative Society: m / z 5 5 0 (M—H)-, 5 13 (Μ-K)- In use, "« Family Standard (CNS) f 4 regulations (210X297 public tf) 81. 7. 20,000ilt (II) &quot; X 9 ο ri it. Γ \ Λπ V. Description of invention (68) Example 4 9

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Put 2-n-butyl-4- [N-methyl-N- (3-methylbutenyl) amino]] (please read the back-end notes first #fill Κ 采 页 j -1- [〔 2 '-(tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-quinazol-5 -carboxylic acid 1'-ethane carbonyl gas ethyl ester 990mg dissolved in ethanol 20ml, and under ice cooling Add 0.18ml / Jl ethanolic KOH solution 15.8ml dropwise. After stirring for 10 minutes below 5.0, evaporate the solvent under reduced pressure to obtain 2-n-butyl-4- [N-methyl-N- (3- Methylbutenylamino) amino] -1- [[2 '-(tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-quinazol-5-carboxylic acid I1-ethane Carbonate ethyl ester potassium salt 1.0 g, foamy. Physical and chemical properties Ή-NMR (DMSO) δ (ppm): 7. 54 (1H, d), 7. 36-7. 41 (2 H, m ), 7. 2 9 (1 H, d), 7. 0 7 (2 Η, d), 6. 83 (2 Η, d), 6.6 6 (1 Η, t) 5. 54 (2 Η , dd). 5. 38 (1 Η, s), -70- This paper is fully equipped with Zhongou's "Home« Standard (CNS) Ή Specification (210x297 g: tfr) installed · line · Ministry of Economic Affairs Bureau εχIndustry and Consumer Cooperation Du Printing 81. 7. 20r000ifc (II)

·, .R .L Λ (i H () V. Description of the invention 4. 10 (2 Η, q), 3.0 4 (3 Η, s), 2. 63-2. 6 6 (2 Η, m ), 1.96 (3 Η, s) 1. 61 (3Η, s), 1. 53-1. 59 (2Η, m) 1.2 4-1. 2 8 (2 Η, m), 1- 1 7 (3 Η, d), 0.82 (3 Η, t) mass spectrometry (FA Β): m / ζ 6 2 8 (Μ — Κ) Example 5 0 η-Bu

(Please read the precautions for filling in Er's page first) Benzene Η NCOCH = CHC02Et CO, Et base and amine 4-,

Kylpyridine mixed with water P and 5 refers to 1 S in acetic acid chloroacetate dissolved in slag, adjusted residual IB1 chlorine will be 10 amide, chlorpyrifos Ministry of Economics, quasi-accurate, know employees to cooperate with Du Yin Production of B: -Alkane cis-hexyl 3-ester acetate ethyl. Characters: -5 blezozole, chemistry 8 4 m, base 0 4 ene-propylbenzene carbonyl gas> base group leaching I-7 delamination CN base ester steam column, methyl ethyl pressure gel-4 benzoic acid minus silicon base After tricarboxylic acid, r ± l—115, after nl-hour, 2- &quot; small order is &quot; Zomibene paper standard is used in the middle-sleepy national standard (CNS) T4 specification (210X297 public phantom 81. 7. 20 (000ifc (H)

Ο Du-printed by the Ministry of Economic Affairs, Central Bureau of Industry and Commerce ο-CM Λ (i Π () V. Description of invention (7〇) 'H-NMR (CDC13). &Lt; 5 (ppm): 6. 7 0 -7. 9 4 (2 5 H, m), 5. 5 7 (2 H, s) 4 · 08-4. 41 (4 H, m), 2. 56 (2 H, t) 1. 12- 1. 90 (10H, m), 0.86 (3H, t MS Example 5 1

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Trityl will 2-n-butyl-4- [N- (3-cis-ethoxycarbonylpropenyl acetyl) amino] -1 [〔2 '-(trityl-tetrazol-5-yl ) Biphenyl-4-yl] methyl] -1H-quinazole-5-carboxylic acid ethyl ester 1.61 g was dissolved in DMF 2Gml, and methyl iodide 3 20 mg, Na Η 90 mg were added under ice cooling . After stirring at 5 ° C for 5 hours, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and washed twice with water, dried, and the solvent was distilled off under reduced pressure, and the silica gel column chromatography (hexane: ethyl acetate = 5: 1), to give 2-n-butyl-4-[N -Methyl-N-(3 -cis-ethoxycarbonylpropenyl amidyl) amino]-[〔2 1-(trityl-tetramin-5-yl) biphenyl-4-yl] methyl 〕 -1H-Fuzole-5-carboxylic acid ethyl ester 1.40 g, foam. The physical and chemical properties of this paper are based on the Chinese National Standard "CNS" T4 (210X297 male dragon) HI. 7. 20,000¾ (I!) (Please read the precautions before filling in this page " £ 03 Λ (i Κ6 V. Description of the invention (1 II-NMR (CDC 1 3) δ (ppm): 6. 7 4-7. 9 2 (2 5 H, m), 5. 48 (2 H, s), 4 · 12 (4 H, q), 3. 3 1 (3 H, s), 2. 54 (2 H, t), 1. 4 5 — 1. 82 (2 H, m), 1 . 0 5-1. 40 (8 H, m), 0.86 (3 H, t) Mass Spec Example 5 2 NCOCH = CHC02Et n-Bu

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(Please read the back first of the section #Fill in the surgery page; Binding · Bookmark _ Line. 2 JJ will be based on the aminobutyrazole _ ethyl acetate methyl ethyl toluic acid N-tricarboxyl cisazole four Ministry of Economic Affairs Central calendar = 5 printed by the industrial and commercial cooperatives. 20 benzene solution was dissolved with J. estriol. 3 g g acetyl-_en-4 propylene phenyl ethyl carbonyl% oxygen. 5 ethyl group in the dissolution layer- Behind the column _ when Si Xiaozai is mixed in the v, 3itI residue-4 stirring. The base ° c times butadiene 9 2 is boiling 2- and a total of methyl methylamino group-5 I ο g gazole m four 60 (9 2 C Acetic acid-carboxyl 1-* 5-azole-like imidic H-based-1-carboxylic acid 1 alkenyl propyl carbonyl reagent gas capacity \ 1 i imitation 7 4 except for Ma-chloroli steam ¢-) benzene pressure Analysis of the use of 3-fold S-sub-methyl methyl paper in the "B home standard (CNS) Ή regulation (210x297 public: jfc) 81.7.20,0 (ΧΜΜΠ) 9 ο, 0,0 ΛΠ 2 (7 Mingfa five H-NMR (CDC 1 3) δ (ppm): 8.0 3 (1 H, d), 7.5: 3-7.6 1 (2 7. 4 3 (1 H, d), 7. 1 9 (2 H, d), 7. 0 3 (2 H. d) .6. 8 6 (1 H, d), 6. 7 4 (1 H, d), 5. 5 7 (2 H, s) r 4. 1 9 (2 H, q), 4. 0 1 (2 H, q), 3. 3 2 (3 H, s ),, 2. 8 0 (2 H, t), 1. 7 4-1 · 8 0 (2 H, m), 1. 4 0-1. 4 7 (2 H, m), 1. 23 ( 3 H, t), 1. 18 (3 H, t), 0.9 5 (3 H, t) Mass Spectrometry (FAB): m / z 5 8 6 (MH +) Example 5 3 (Please read first Contrary to note, Sun Jie writes the art page 』Ministry of Economic Affairs 汮 央 擂 准 局 Employee # Cooperative seal 51

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Put 2-n-butyl-4- [N-methyl-N- (3-cis-ethoxycarbonylpropenylamide) amino] -1-[[2 '-(tetrazole-5-yl) biphenyl -4 -yl] methyl] -1} 1-imidazole-5-carboxylic acid ethyl ester 8 5 0 mg dissolved in ethanol 2 0 m 1, and add 7 4 dropwise under ice-cooling «Standard (CNS) regulations (210x297:« :) 81. 7. 20,000 sheets (II) 09 ^: 13 Λ (i II Γ, printed by the Central Bureau of Standards, Ministry of Economic Affairs, A Industrial Consumer Cooperative Society ¾ V. Description of Invention (73 ) 1 NN a ϋ Η 7 · 3 m was raised to room temperature and stirred for 18 hours, then the solvent was distilled off under reduced pressure. The residue was dissolved in water 5 in 1, and · 1 N hydrochloric acid 7.3 ra 1 made p Η 2 ~ 3. Extract twice with ethyl acetate 2 0 m 1 and wash with water, dry and evaporate under reduced pressure. The residue is crystallized from acetone-B_ to give 2-n-butyl-4- [N-methyl-N- ( 3 -cis-ethoxycarbonylpropenylamino) amino] -1-[[2 1-(tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-quinazol-5-carboxylic acid 3 60 mg, white crystals. Physical and chemical properties Element analysis value (C27H2TN7Os · 1 H2〇> C {%) Η (%) Ν (%) Calculation value 59.22 5. 3 4 1 7.9 1 Theoretical value 59.09 5.23 17.80 'Η-NM R (DMS Ο) δ (ppm): 7. 5 2-7. 70 (2 Η, m), 7. 08 (2 Η, d), 6. 92 (2 Η, d), 6. 7 4 ( 1 Η, d), 6. 46 (1 Η, d), 5. 63 (2 Η, s), 3. 17 (3 Η, s), 2. 59 (2 Η, t), 1. 49- 1. 5 4 (2 Η, m), 1. 23-1. 27 (2 Η, m), 0.80 (3 Η, t) mass spectrometry (FAB): m / z 5 3 0 (ΜΗ +) 7 5 The ft scale of this paper is used in the "National Standards (CNS) Ή Regulations (2) 0X297 public;" :) 81. 7. 20, _ίΜΗ) Read the meaning of the matter in advance and fill in the page 1 V. Description of the invention (74) Example 5 4 Η

Λ 6η 6 Read it first and pay attention to it. Fill out this page. The Ministry of Economic Affairs, the Central Bureau of Industry and Fisheries Co., Ltd. cooperates with Dugong to produce 4-amino-2-n-butyl-1- [〔2 '-(. Diphenyl Methyl-tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-quinazol-5-carboxylic acid ethyl ester 1. (! G dissolved in pyridine 10 m 1, and added under ice cooling IQml of Dioxin Nail Salon Solution prepared by (Ε)-(3-Dimethylaminemethyl) acrylic acid 285 mg and chlortetracycline 420 mg. After stirring at 15 ° C for 4 hours, it was distilled off under reduced pressure Solvent. Aerated imitation and water were added to the residue. The organic layer was separated and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel column (hexane: ethyl acetate = 1: 1 ~ 1: 2), To give 2-n-butyl-4- [N- (E)-(3-dimethylaminomethyl) acrylamido: -1- [〔2 '-(trityl-tetrazol-5-yl ) Biphenyl-4-yl] methyl] -1H-quinazol-5-carboxylic acid 1'-ethoxycarbonyloxyethyl 450mg, foamy. Physicochemical properties 1H-NMR (CDC13): 6 (ppm) 9. 12 (1 H, brs), 6. 71-7. 9 6 (2 8 H, m), 5. 37 (2 H, s), 7 6 The paper ΛΛ degree is used in China ’s ) A4 gauge (210X297 mm) 81. 7. 2〇.υ〇ϋίΜϋ) Λ 6η 6 Description of the invention (7 5) 4. 19 (2 H, q). 3. 6 2-3. 7 5 (2 H, m), 2. 6 6 (6 H, s), 2. 4 6-2 . 6 5 (2 H, m), 1. 4 5-1. 6 6 (2 H, m), 1. 18 (3 Η, t), 1. 10-1. 34 (2H, m), 0 . 88 (3H, t) Mass Spectrometry (FAB) 7 9 9 (MH +) Example 5 5

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2-N-butyl-4- [N- (E)-(3-dimethylaminomethyl) acrylamido] -l- [[2,-(trityl-tetrazole-5-yl ) Biphenyl-4-yl] methyl] oxamidine iodide methyl methyl plus methyl, then dissolve in 20 mg and mix 20 mg and stir 4 vinegar g J ffl z3 2 gas carbonyl aH oxygen &quot; acid dicarboxyl slM -Up to 5 and the agent is dissolved and the autoclave is reduced and the time is reduced to 5 times. If the consumer cooperation of the Central Bureau of Economy and Economy of the Ministry of Economic Affairs is printed and dried, the acid is dried and dried. Residues and residual imitation amines are added with dissolved residues to remove residues and vaporize in the alcohol 2-methyl group of methylformaldehyde gas to obtain amine methyl group-tosylate tricarboxylate (~ 5 2 azole V_. Succinyl 5 methyl-amine azole A tetramethyl-Ν I group 0 allyl to 4-benzyl-like bubble 81. 7. 20, U00ii | c (II) This paper is not used in the "Home Sample Bi (CNS) A 4 regulation (210X297 ¢; 203 along Λ 6 Β 6 5. Description of the invention (76) Physical and chemical properties 1H-NMR (CDC13): δ (ppm) 6. 7 0-7. 9 2 (2 7 H, m), 5 . 9 5-6. 16 (1 Η, m), 5. 4 7 (2 Η, s), 4. 1 1 (2 Η, q), 3. 4 3-3. 5 1 (2 Η, m ), 3.29 (3 Η, s), 2. 52 (6 Η, s), 2. 50-2. 71 (2Η, m), 1. 4 5-1. 6 5 (2 Η, m), 1. 20 (3 Η, t), 1 . 12-1. 31 (2 Η, m), 0.88 (3 Η, t) mass spectrometry (FA Β) 8 1 5 (ΜΗ +) Example 5 6 Me

N ^ NCOCH = CHCH2NMe2 n — Bu-《IT 、 入 C〇2Et

(Please read the notes on the back of the cup first to write this page; install · *? Τ_ line-Ministry of Economic Affairs Central Standards Bureau Beigong &quot; cooperation du printing base alcohol and Kebutane-2 will be amino amine methyl In a-J by boiling, co-ral benzene 10 methyl methylamine methyl dimethyl 3-benzene / IV- tri \) / / VE-// V *. 1 2 oxazolyl τ amine phenyl acetylene allyl After the base ester, the acetic acid carboxyl 5 is dissolved in -B and the Ξ acid--1 ethyl alcohol is dissolved in methyl alcohol-ί-1.眯 Ρ ο H-90 times, this girl's Zhang scales are used in the "« Carbon rate (CNS) T4 specification (210X297 public: ») 81. 7. (1!)

ί, (J Λ 6 Η 6 Fifth, the description of the invention (Π): Bu 5: 〖), get 2-butanenyl-N-methylamino] -ί Bu 〔Ν-(Ε)-(3- Dimethylaminomethyl) propane [〔2 1-(tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-imidazole-5-carboxylic acid ethyl ester 80rag, bubble physical and chemical properties 1H -NMR (CDC13): δ (ppm) 6. 5 0-7. 7 8 (9 H, m), 5.85 — 6. 09 (1 Η, m), 5 4. 15 (2 Η, q) , 3. 3 0-3 3. 26 (3 Η, s). 2. 6 3-2 2. 26 (3 Η, s), 2. 3 7 (6 Η, s), 1. 5 6-1 . 8 7 (2 Η, m), 1. 22 (3 Η, t) 1. 15-1. 38 (2 Η, m), 0.88 (3 Η, t mass spectrometry (FAB) 5 7 1 (ΜΗ +) 4 7 (2 Η, s) 3 5 (2 Η, τη) 8 2 (2 Η, m) \ Please read the precautions and fill in the complete π line, the Ministry of Economic Affairs, the Central Bureau of the Ministry of Economic Affairs, Beigong Consumer Cooperative The standard of the printed paper is used in the "National Standards (CNS) Ή Specification (2 丨 0 father 297 public |) 81. 7. 20.00Uik (ll) Λ 6 Β 6 5. Description of the invention (78) Prescription examples The compound of the present invention is used as a prescription for panacea. Tablet composition 1 ΰ in g tablet Example 3 Compound 7 7 10 Lactose 83.4 Corn starch 18 Hydroxypropylcellulose 4 Calcium carboxymethylcellulose 4 Magnesium stearate 0.6 Total 1 2 0 (mg) The compound of Example 3 7 5 Q g, lactose 4 1 7 g, corn starch 90 g are flowed into a granulation coating device (Ogawara After being uniformly mixed, spray 10% hydroxypropyl cellulose solution with 2QQ grams for granulation. After drying, 0 X element 7 dimensional) ¾ fiber> base plus short, machine-selected ingot sieve punching and sieve back 20 在 经 '所 Η Tiehatake tablets 3 Each magnesium is made into an acid for the purpose of ΗΠ —No-hard mortar and R grams of the Ministry of Economic Affairs Central Standards Bureau K3: industrial consumption ί \ ν cooperation du printing preparation of the original paper of the ingots "scale In use "National" Bi (CHS) T 4 regulations (210X297; ¢) 81. 7. 20.000¾ (II)

Claims (1)

Sixth, the application for patent Fan Garden A: this; η: 7 VJ ¢) 7 No. 8 1 1 06539 patent case of "4-aminoamidoazole derivative" (amended in May 82) 1. One of the following formula (I ) New imidazole derivatives or their preparation Rs is a C2-a alkenyl group which can be optionally substituted by a carboxyl group, an amine group, a Ci-β alkylamino group, a Ci-3 alkane carbonyl group or a Cm 〇 桪 chen aryl group; a Ci-3 alkynyl group or C6- !. The aryloxy radicals are optionally substituted (^-9 courtyard; Ci-a alkyl carbonyl, or formula-(please first «1 please note the back of the page before writing this page • outfit. Ministry of Economic Affairs Printed by Cooperative Society of Co., Ltd. C or hydrogen is 9 RC can be substituted for 1 A alkyl alkane 2 C alkane alkane 7] R -1 I cT o MHC gas I contains -10 or may be C6 group or hydrogen cyanide It is 3 7 4 RRR group residue ester C group aryl sulfonane. This paper standard is applicable to the B Lujia Family Standard (CNS) A 4 specification (210x297 public daughter)% 09 Λ 3 Α7 Β7 C7 D7 VI. Application Patent Fanyuan 2 ^ If the application is a new class of imidazole derivatives or their cleavage-tolerant salts of Patent Fanyuan Item 1, the ester residue is C i alkyl-A2-0-C-X-R or the following formula Base: —CH- Y R8 A2 is Ci-β alkylene, X is oxygen or single bond, and Re is (: 丄 -3 alkyl or C 3_1β alkyl. .2-n-butyl-4- [Ν-methyl-Ν- ( 3-methylbutenyl) amino] -ΙΕ [2 '-(1Η-tetrazol-5-yl) biphenyl-4-yl] methyl] -1Η-imidazole-5 -carboxylic acid or its pharmaceutical Salts are allowed. • 2-n-Butyl-4- [Ν-methyl-Ν- (3-methylbutenyl) amino] -1-[[2 ^ (1Η-tetrazol-5-yl) Biphenyl-4-yl] methyl] -1H-quinazole-5-carboxylic acid 1-ethyl gas carboxy gas ethyl ester or its pharmaceutically acceptable salt. .2-n-butyl-4- [Ν-methyl- Ν -(3-methylbutenylamino) amino] -1-[[2 '-(1Η-tetrazol-5-yl) biphenyl-4-yl] methyl] -1Η-imidazole-5 -carboxy Acid 1- (cyclohexyloxycarbonyl ethyl ester or its pharmaceutically acceptable salts.... A method for preparing novel imidazole derivatives of the following formula: -------------- ^ ------ -装 ------. 玎 --- ^ —0 (Please read the precautions on the back before filling this page) Printed by the Ministry of Economic Affairs, Bureau of Standards, 3 Industrial and Consumer Cooperatives 4 R 2 The size of this paper is in accordance with the Chinese National Standard (CN ’S) A 4 specifications (210 X 297 g H. 6. Apply for a patent. Yuan · Ji This method of making is as follows: amine AT B7 C7 D7 R4 reacts with the carboxylic acid or its reactive derivative of the formula Rs _C〇2 Η (the symbol in the above formula is as defined in item 1 of the patent application scope). A method for preparing novel azole derivatives as follows: // ° R ‘This method of making the following formula amine The Ministry of Economic Affairs t Central Sassafras Bureau of Consumer Cooperation Du Yin made with the carboxylic acid or its reactive derivatives of the formula Y-A1 -C〇2 Η to produce imidazole derivatives of the following formula, ... .................... (.................... ¾ ........ ..................... ίτ.ί ....................... Φ ( Please read the precautions on the back before filling in this page) This paper size is applicable to the China National Standard (CNS) Τ4 specifications (210x297 public) 3 A 7 巳 7 C7 D7 6. Scope of patent application 0 (Please read the precautions on the back first, and then be able to make a hundred copies). .. Order &lt; • Green. The Ministry of Economic Affairs Central Bureau of Industry and Fisheries Cooperative Printing and Printing-Y (Y is halogen) alkylation Reagent reaction (in the above formulas, RV is Cl-3 alkyl, other symbols are as defined in item 1 of Shenzhuang Patent Fan Garden). — 4 The size of this paper is applicable to China National Standard (CNS) T4 (2’10 father 297 gong) 6. Patent application Fan Ji 9. A method for preparing novel azole derivatives of the following formula A7 B7 C7 D7 κι R Η This preparation method is to deprotect the compound of the following formula R ‘(In the above formula, R + is Ce-1 () 硪 珲 aryl group Ci-a alkyl group, other symbols are as defined in the first paragraph of the application for patent model garden). 10. A method for preparing novel azole derivatives of the following formula: MR R4 This preparation method is to treat the ester compound of the following formula with acid or alkali (please read the precautions on the back and then fill in this page) • Install, • Order system R4 .Line. This paper scale is suitable for CNS Ψ4 specifications (210x297 mm) A7 B7 C7 D: Six. Patent application (RP in the above formula is a gaseous C, _17 ester residue Carboxyl group of esterification, other symbols are as defined in Item 1 of the patent application country). 11-An angiotensin II antagonist as a antagonistic composition • Contains novel azole derivatives or pharmaceutical acceptable salts and excipients such as No. 1 of Shenzhao Patent Fanyuan. 12 For example, the pharmaceutical composition of item 11 of the patent application is used to treat blood pressure or chronic heart failure. -------------- ί --------- Pretend ------ '玎 --- Lonely Marriage (Please read the notes on the back before filling in this Page) The Ministry of Economic Affairs has printed the paper standard for the Beigong Consumer Cooperative to use the Chinese National Standard (CNS) A 4 specifications (210 2 &lt; 297 public goods)