TWI251589B - N7-substituted xanthine derivatives - Google Patents

Abstract

This invention is related to novel theophylline derivative wherein has the formula I, II, and III as follow. The R1 present; the wherein R2 selected from three groups as follow; wherein R4 selected from four group as follow formula, wherein R3 selected from the follow groups, halogen, OH saturated straight chain C1-3 alkyl group, saturated straight chain C1-3 alkoxyl group, or combined the above groups with hydrogen. The n value is 1, 2, or 3.

Description

1251589 IX. INSTRUCTIONS: The industry is profitable. The invention is a type of theophylline structure. 4 Biosynthesis has adenosine (adenosine) accepting ion channel permeability II and formula in effect And increase the potassium background. Glandular r udenosine) plays an important role in the cell's energy metabolism, and is considered to be an important cell messenger for cells to produce specific biochemical reactions that lead to physiological responses. It is expected that the heart rate will slow down, the income will be reduced (4), and the blood vessels will expand in the * tube. In the middle of the system, the glandular sputum inhibits the release of neurotransmitters, resulting in a sedative effect and an anti-spasmodic effect. In addition, it can regulate the release of renal renin and inhibit the agglutination of platelet 'regulating lymphocyte turnover', which leads to the inhibition of fat decomposition of fat cells. The pharmacological effects of Adenosine vary according to the morphology of the cells on the different cells; Acceptance and naming are derived from the 1978 Bumstock in Pharmc〇1〇gy Renah, No. 24, 1251, vol. 5, pp. 9-9, 511. This nomenclature system is based on the pharmacological properties of glandular phenanthrene. Can be divided into? 1 acceptor, sputum acceptor; if the relative pharmacological properties of the acceptor is aden〇sine > MgADpg ATP, and the relative pharmacological sage of the P2 acceptor is atp^adi>-;AMP>adenosine 〇

Pi acceptors can be further divided into Αι, 2 receptors; according to the literature published by Calker et al. in 1979, the adenosine receptors are divided into two types: adenylyl cyclase. Ai accepts) m inhibits adenosine 3,5,_Cycuc •monophosphate, cyclic aMP. The report states that the inhibitory effect of Αι receptor-adjusted adenylate cyclase has been found in brain, fat cells, cardiac muscle cells, smooth muscle cells, and testicular pills. A: The recipient stimulates the production of adenosine 3,5,monocyclic monophosphatase. A? The recipient can stimulate the activation of adenylate cyclase in many parts of the brain, including the hippocampus, striatum, cerebral cortex, and liver and blood platelets. There are some specific tissues that have both ~ and human 2 receptors, including fat cells, cardiomyocytes, and smooth muscle cells. The activation of adenosine receptors is thought to be dominated by G proteins, regardless of whether adenosine 61251589-induced inhibition or stimulating gland ___(adenylate cydase) requires the binding of a glyphus (GTP) p agonist to & or A The binding of G-proteins caused by the body is still unclear. However, the effect of A! acceptor-induced inhibition of A2 receptors on the scales of the A2 receptors is GI-protein. And & protein, this can reasonably be the plate between the glycoprotein G and the gland (v) (four) (iv). In this mold filament, the binding of the agonist to the & acceptor results in activation of the a subunit of the & protein and subsequent isolation from the sputum pool. The gland protein is directly activated by the Gsa protein: g: acid cyclase. Conversely, accepting the activity promotes the live b of the Gi egg, resulting in the segregation of the secondary (4) and subsequent release of the Gia protein to inhibit adenylate cyclase (10) cydase). The special G protein and the thief-receiving body, in addition to the current known association via adenylate cyclase, are not yet known. In some studies, a series of adenosine isoforms were used to determine the classification of the receptor subtypes. In the 接受ι receptor, the order of action was R_PIA>adenosine>NECA; in the A2 receptor, This order is NECA>adenosinegR-PlA. Since adenosine receptor activation is 1251589, the effector system is not only via adrenal cyclase, so the order of the drug effect is widely differentiated from the recipient subtype. Adopted. Adenosine receptors were divided into four subtypes in the recent study by Linden, J. A, A2a, A2b and A3 (Trend J. Pharmacol Sci. VoU5 PP.298-306, chest), 4 and ~ can stimulate the gland ¥adenylyl cyclase, Uang, BT. et al. reported A; cardioprotective effects in myocardial hypoxia (P]X) G Natl Acad Sd. Vd.95, pp. _, touch); Based on the affinity of yang]neca, the acceptor is further divided into high affinity 4 and low affinity A2b, while adenosine itself has stronger affinity for ^ than & The ventricular cells produced by anaerobic, g-grow-free cultured silk cells produce about $2 ovulations, and the sacs are released by ventricular cells to prevent 1 D of 1 ^ in hypoxia and continue to protect for about Μ minutes, but their effects Machine change = still unclear. Liang, BT. et al. lack of research suggests that the A3 receptor can be regarded as a heart-turning escort--the treatment direction. The I25l589 adenosine receptor has the following effects on the blood vessels: eg Collis, MG et al. Stimulation ^ accepts the effect of inhibiting the contraction of the left atrium of the guinea pig (price · J · Vol.78, ρρ · 207-212, 79S3), stimulation A〗 a receptor will cause coronary artery dilatation, stimulation of A2b receptor will relax the aorta (Martin PL , / 2), because the stimulation of A? receptor will make e-AMP increase the mouth, so it can also relax the trachea, according to C〇His, mg et al. in 1982, Volume 76, Issue 381 to 387 The literature published on the page states that adenosine can relax the trachea because it stimulates the A2a receptor. According to Fumkawa S. et al., 1993, r. J. Pkzrmflco / Vol. 236, pp. 255-262 The published literature states that 'stimulation A: the receptor causes vascular and tracheal smooth muscle relaxation. It is related to the opening of atp_sensitive Κ+ channel. Previously, the chemical synthesis of adenosine agonist was mainly in adenosine structure. Modification of the first, second and third places, or The ribose hydroxyl (0H) in the structural formula is removed, or the ribose is replaced by another five-membered ring (Ueeda, M. et al 1990; Chern, JW et al 1991; Matsuda, A. et al 1992; Tao3 PL. Et al 1993 ) 〇9 1251589 Methyxanthine drugs such as: theophylline, caffeine, etc. are antagonists of a (jen〇sine) receptor. There are many literatures. It is described that the drug is modified by the thiol-xanthine-based drug. The carbon chain is added to the first, third, seventh, eighth and ninth positions of the methyxanthine class to investigate the adenosine (acjen〇sine). Effects, found that new compounds in addition to tracheal relaxation (Takagi, κ. to α /. / 9 continent; Miyamoto, Κ · ei α /. 7993; Peikov, Ρ · ei α / 7995); for adenosine acceptance The body still belongs to the antagonist (Muller, CE. ek/. 7卯3). The object of the invention is to disclose a formula I having the theophylline structure.

10 1251589 The present invention further utilizes various pharmacological experiments to confirm that the genus of the genus genus and the genus of the genus genus has the activity of accepting aden sine receptors and the permeability of the bell-ion tube. This 1st is based on the formula and the derivative of the formula m, and the addition of the necessary bribes to bribe into various pharmaceutical combinations*, with the effect of the secret receptor, and the potency of potassium ion pipeline. Table 1. Description of mass spectrometry and hydrogen nuclear magnetic resonance spectroscopy data of compounds 4, 5, and 6 of Table 1. Table 2 Mass spectrometry and hydrogen nuclear magnetic resonance spectroscopy data of compounds 7, 8, and 9 Table 3 EC5 〇, pD2 (-logEC50) values Table 4 Αι, 八2% of the receptor antagonist. , ρ〇2 (_1〇gEC5.) value pattern illustrates the synthesis method of the structure of the formula I in Fig. 1. The synthesis method of the structure of the formula II, III, Fig. 3 Compound 1. Structural formula Fig. 4 Compound 1. 8-German tea Test (8-PT) heartbeat, blood pressure reaction 1251589 Figure 5 compound 1, 8-benzylophylline (8-PT) heartbeat, blood pressure reaction a · · control group b ... lmg / kg of compound 1 c. ...2mg/kg Compound 1 d...3mg/kg Compound 1 Figure 6. Heartbeat, blood pressure response of compound 1, 8-mercaptophylline (8-PT) Figure 7 Gland 4, 8-meridyl test ( 8-ΡΊΓ) heartbeat, blood pressure response Figure 8 adenosine, 8-benzylophylline (8-PT) heartbeat, blood pressure response a··· control group b...l mg/kg gland moss c...·2 Mg/kg adenosine d...3 mg/kg adenosine Figure 9 adenine, 8-octyl tea test (8-PT) heartbeat, blood pressure response Figure 10 atrial contractile force response A., a... compound 1 c···xanthine analog (XAC) b...8-octyl theophylline (8-PT) d_··pretreatment 10·5 Μ theophylline Β··· a···compound 1 b. ..3,7-biguanidyl small propyne xanthine (DMPX) c. .. 8-(3-chloroethene) coffee (CSC). d...pretreatment 10·5 (alloxazine) C... a ...compound 1 b···tetraethylamine (TEA) c··· 10·6M glyburide 12 1251589 Figure 11 Adenosine on the atrial atrial effect A·· a· ·. neck ^ Gan Hbenzylophylline (8-PT) c···xanthine analogue (XAC) d ···Pretreatment of 10·5 Μ theophylline. B".a···adenosine b...3,7-bismethyl small propyne xanthine (DMPX) c··· 8-(3-chloro group Ethylene) curry (CSC) d··, pretreatment 10·5Μ squirting (alloxazine) C...a···adenosine·b···tetraethylamine (TEA) c···pretreatment ΙΟ· 6 Μ 降 降 图 图 图 图 图 图 图 图 图 图 图 图 图 图 图 图 图 图 图 图 图 图 图 图 图3,7-bismethyl-1-propyne xanthine (DMPX) c. .. 8-(3-chloroethene) coffee (CSC) d···pretreatment 1CT5M 洛喷 (alloxazine) _ C·. · a·,·Compound 1 b···tetraethylamine (TEA) c···Pretreatment 10·6M glyburide 13 1251589 Figure 13 Effect on trachea A·· a. · ·>^^甘b· ··Pre-treatment 8_; base tea test (8-PT) B...a·.·adenosine c...8_(3-chloroethylene) curry (CSC) b...3/7-biguanyl Small propyne jaundice (DMPX) d···pretreatment 10·5]νϋ_ (alloxazine) C...a···adenosine b···tetraethylamine (TEA) c... Figure 16. Effect on vascular relaxation A., a...Compound 1 b...8-benzyl theophylline (8-PT) c···xanthine analog (XAC) ά· ··Pretreatment 10·5ΜTheophylline Β...a...Compound 1 b."3,7-Dimethyl-small alkyne scutellaria (DMPX) c".8_(3-gas-vinyl) coffee (CSC) d ···Pretreatment 10·5Μ卩all (alloxazine) Xin C.·. a...Compound 1 b···Tetraethylamine (TEA) c···Pretreatment 10·6ΜYellose 14 1251589 Figure I5 Adenocarcinoma A!, A2 receptor drop-off effect A·· a. ·^^g b...8_benzyl theophylline (8_PT) c···xanthosamine analogue (XAC) d··. Do not deal with 105 Β Β Β... a.·· adenosine b...3,7_ big fluorenyl small propyne jaundice (DMPX) c··· 8-(3-chloroethene) coffee (CSC) d ···Pre-treatment 10·5Μ^σ well (alloxazine) C".:a···adenosine·b··.tetraethylamine (TEA) c·.·pretreatment 10·6Μ superior hypoglycemic. Figure 16 ·The role of adenosine Ai, Α2 receptor a...Compound 1 b···Adenosine analogue (NECA) c· · ·Details of adenosine invention

The present invention discloses a compound of formula I, formula II and formula III having the theophylline structure, 15 1251589

, r4 can be arbitrarily selected

N_N- Ν Ν - / Ν , R3 can choose halogen, trans-base (〇Η), saturated ΐ-3 carbon number linear chain, alkyl, saturated state. 1-3 carbon number linear oxy group Alkyl group, or both sulfhydryl groups and one of the above substituents; η is a natural number 丨, 2, 16 1251589 is a derivative of the formula i, which is a synthetic method as shown in FIG. The tea is dissolved in the inhomogeneous dimercaptodiamine (the wind 仏

Dimethylformamide, DMF), was placed in a _11 gamma}^_1* stirred oxime and then added with a chlorinated alkyl acid, concentrated under reduced pressure, and recrystallized to give a purified white crystalline intermediate C. The intermediate product was then dissolved in absolute ethanol, and bicyclohexane carbodiimide (N', N'-Dicydohexylcarbodiimide, DCC) was added and stirred overnight. After purification under reduced pressure and recrystallization, a purified derivative can be obtained. The preparation is a derivative of the main structure in which the number of alkyl groups of the chlorinated alkyl acid is sufficient to determine the η value of the structure of formula I. That is, a ruthenium chloride acid is added to obtain a compound of the formula I having a value of 1; a chlorinated propionic acid is added, and the η value is 3. Another method for synthesizing a derivative of the formula I is by a tea assay which is soluble in an assay of a mono-S-amp; amine (DMF) and then added to a ketone (y_butyrolactone) to form theophylline butyric acid (Theophylline-7- Butyric acid). The reaction solution was concentrated under reduced pressure by adding bicyclohexyl fluorite-imine (DCC). Compound 1 was obtained by allowing the concentrated liquid to stand. 17 1251589 A derivative of the formula II is a synthetic method as shown in Fig. 2, which is prepared by dissolving theophylline in decyl alcohol for reflux, and then adding 1,2-dibromoethane. The intermediate product A can be obtained by adding sodium hydroxide to continue the reaction. The intermediate product A is dissolved in decyl alcohol for reflux, and intermediate product B can be obtained by adding piperazine. The intermediate product B is dissolved in decyl alcohol and refluxed, and the purified derivative can be obtained by adding N-Benzylpiperazine, 2-Furoyl Chloride ^ Benzenesulfonyl chloride ^ Alpha-Toluenesulfonyl chloride, Etiioxylbenzenesulfonyl chloride, Hydroxylbenzenesulfonyl chloride according to the needs of the product. The derivative having the main structure of Formula III is a synthetic method as shown in FIG. 2, which is prepared by dissolving theophylline in decyl alcohol for reflux, and then adding dibromodecane (1,2-dibromoethane) to react. The sodium nitrite is further reacted to obtain the intermediate product A. The intermediate product A is dissolved in methanol for reflux, and the l-Phenylpiperazine, l-(2_Pyrimidyl) piperazine, 1_(2-Pyridyl) piperazine, l can be further added according to the product 1251589, respectively. -(2-Chlorophenyl)piperazine, 1_(m_Chlorophenyl)piperazine, l-(4-CMorophenyl)piperazine, N-Benzylpiperazine continue to react to obtain a purified derivative. The above synthesized products were subjected to purification, crystallization, and physical and chemical data such as elemental analysis, mass spectrometry (MS), infrared spectroscopy (ir), hydrogen nuclear magnetic resonance spectroscopy, private fox, CDCy, and ultraviolet absorption (uv). The effect of pharmacological activity is assessed in a suitable mode to determine the activity of the compound. The compound of the present invention is added to various excipients, carriers, or diluents as necessary, and pharmaceutically acceptable ingredients are added to the composition: the preparations can be administered orally. The rectal administration of the solid dosage form , liquid sputum dosage form, face _ road money injection _, sewing the affected area of the person ^ dosage form. These _ _ _ _ _ _ _ _ _ _ _ _ _

I, acid 1, disintegration agent such as vitamins, ethanol, glycerin, etc., and can be made into tablets or filled with sputum. Make the hair and compound liquid: dissolve with two salts _ women _ (10) ΡΗ ^ ^ 19 1251589 Add auxiliaries, emulsifiers to make injections or other liquid agents. The compound of the present invention or a pharmaceutically acceptable addition salt of an acid may be blended with various bases. The formulation method may also be formulated into an ointment. The pharmaceutical composition prepared by using the compound of the present invention as a main component can be applied to the main ingredient of a mammal, and the dosage can be formulated according to the symptoms, usually from 100% to 300 mg per person per time, three times a day. Left fish straight, jump, blood pressure test tube test with 50% absolute alcohol (absolute alcohol) and 1 〇 ° /. Propylene glycerol dissolves compounds! Then, add 4%% of physiological saline, which are respectively configured as 2 mg/lml, 4 mg/lml, 6 mg/lmU% absolute alcohol, 10% glycerol (pr〇pylene glyCer〇l), 4% After mixing with physiological saline, it is used as a control medium solvent; adenosine (ac^en〇sine) is dissolved in physiological saline; 8-phenyltheophylline (8-PT) is dissolved in 60% absolute alcohol, and then added 4 〇% 〇·2 ΜSodium hydroxide (Na〇H) in an aqueous solution, configured to 1 mg/ml, 20 1251589, 200-300 g male rats (Wistar strain), 4 〇mg/kg sodium phenobarbital (pentobarbital sodium) abdominal abdomen incision, and inserted into the catheter to make the experimental secret can breathe smoothly. The femoral vein was intubated with a polyethylene tube (ΡΕ50) with an inner diameter of 〇·58 mm and an outer diameter of 驰97 to facilitate the administration of the drug in the experiment; and the three-way stopcock was used (3_way st 〇pc〇ck ), one end is connected to the syringe containing the medicine; the other end is connected with the syringe containing the physiological saline, and after the medicine is given, a small amount of physiological saline can be injected immediately to prevent the drug from staying in the polyethylene tube (PE50) The tube affects the accuracy of the experiment. The left femoral artery is also intubated with a polyethylene tube, also using a three-way stopcock, one end with a heparin solution, which can be used to clear the tube when there is a plug in the polyethylene tube; the other end is connected to the disposable diaphragm dome (Disposable Diaphragm Dome, TA1019), and then received a transfer, the magnified person, and finally recorded by the recorder systemic arterial pressure, mean arterial pressure, and heart rate, the drug's assessment of blood pressure and heart rate in rats. After the different doses of compound 丨 and adenosine were administered via the femoral vein, the differences in heartbeat and i-pressure were compared. The antagonist of 〇·5 mg/kg 八妾妾 receptor (8_PT) was first administered from the femoral vein for 15 minutes, then 21 1251589 was administered to the compound i′ and the antagonist was not given to the heart. Make a difference. The Lilin solution was used as a control group.

Result 10 15 Wistar rats with normal blood pressure were anesthetized with sodium phenobarbital, and the fetus was administered in divided doses of l.Oj.UOmg/kg. Compound 1 as shown in Figure * and Figure 5 can cause heartbeat for up to about 30 minutes. Slowing and sustained blood pressure lowering response, this heartbeat slowed down and the downside was positively correlated. If it is .5哗他4 Receiver antagonist (8_PT) · After the fecal vein is deducted for a few minutes, then compound i can be administered. It can be seen from Figure 6 that the slowing of heartbeat and the reduction of blood pressure of compound i are significantly inhibited. Using the solvent system as a control group, it can be found that the solvent will cause a drop in blood pressure and heart rate, but the blood pressure will return to normal in a short period of time, and the obtained compound of the limbs will be subtracted from the data obtained by the injection of the solvent system. The vehicle system does not affect the effect of Compound 1 on blood pressure and heartbeat persistence. The same experiment was carried out with 1 〇, 2 〇, 3 〇mg/kg adenosine (adenosine), and it was found from Fig. 7., Fig. 9 and Fig. 9 that the heartbeat slowdown and the pressure reduction effect caused by glandular bud were also & Phenyl tea test (8-PT) inhibition. 22 1251589 The isolated atrium, soap tube and guinea pig compound 1 were dissolved in 100% absolute alcohol at a concentration of 1〇·2; ^, diluted with a double strip of water to a concentration of 1〇-8; The gland moss is washed twice with water > valley angle, and the degree is 1〇2]y['Dilute to the concentration of 10 times with ^_次德德水][〇·8 Μ ; R(一)_ PIA is 100% Absolute alcohol dissolution, the concentration is 丨胪乂, diluted to 10 times with the second steaming water to a concentration of 1 〇 8 Μ; 8-benzyl tea test (8 _ phenyltheophylline) dissolved in 80% absolute alcohol, then add 20% ο Μ Μ Μ Μ Μ , , Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Dissolved in distilled water, the concentration is 2]^, diluted with 10 times of double distilled water to a concentration of ΙΟ·3 Μ; 3,7-bis-mercaptopurine jaundice (357-dimetliyl-l-propargyl xanthine, DMPX) Dissolved in 100% absolute alcohol at a concentration of 1〇·2 Μ, diluted to 10:2 with distilled water to 10? The degree is 1〇3 Μ, 8-(3·«chloroethylene) π non (g_(3_. chlorostyryl) caffeine, CSC) is dissolved in dimercapto DMS0 at a concentration of 1 〇-2 Μ, to two Distilled water is diluted 10 times to a concentration of 10-3 μ; alloxazine is dissolved in 100% absolute alcohol at a concentration of 10-2 ¥, diluted to a concentration of 1 〇·3 with twice » * distilled water Hey. TEA is dissolved in a second distilled water solution of 23 1251589 at a concentration of 1 M. Glibend-de is dissolved in water by a second steaming, the concentration is 1G_2M, and 1 (8) times of the second water is used to the concentration of irM. (1) Day-by-body left heart-wide experiment: 芩 B Blmks (1%5) and Kaumann β α/· (1980) research methods and slightly modified, take the weight of 350~500 grams of guinea pigs, hit the head hard Make it faint, then cut the carotid artery to bleed, then immediately cut the chest, quickly take the whole heart out and put it at room temperature (20~25. 〇 has a mixture (95/〇2 + 5% C〇2) In the physiological saline solution (Leb's), the left and right fragrant atrium is separated. The left atrium that does not spontaneously pulsate is obtained from the isolated atrium of the guinea pig, and the ends are clamped by a frog heart clip, and one end is fixed at the other end and connected at the other end. Force transducer, recording left atrial isotope contraction tension by C0ULB0URN AT-High_Speed Videograph, placed in tissue bath of 10 ml of physiological saline (Kreb's) solution The temperature is maintained at 325 C, and the square wave with a wave width of 5 msec slightly larger than the threshold voltage (threshold voltage; 1 _ volt) stimulates the left atrium to cause a contraction reaction. The stimulation frequency is 〇·5 Ήζ, resting tension 〇·5 g Heavy. After balancing (60 minutes) The following experiment was performed. 24 1251589. Completion of cumulative concentration-response curves: To assess the activity of the test compound for adenosine receptors, each left atrium was equilibrated (6 〇 minutes), Add the drug to accumulate the concentration from 1 Ο·7 成为 to 1 M. Observe the inhibition caused by different concentrations of the test compound, and find the ec5 〇, _ maximum reaction half value (ahalfmaximal

r*eSp〇nSe;-l〇g EC5t), abbreviated as yang 2 value). 1〇-5 Μ Αι accepts the antagonist; A2 receptor antagonist; potassium channel blocker 1〇·2 Μ tetraethylamine (TEA), 10-6 优 glibenclamide (Tetmethylammonimn, TEA) After glibenclamide) is treated with ex vivo tissue, the concentration of compound 丨 or gland is added to accumulate from 10·7Μ to Κ).4Μ. Observe the effects of the above-mentioned inhibitors on the protection of the compound or the adenine (arsine).

The guinea pig is removed from the atrium, and after the atrium is stabilized, the sputum is added to the compound, so that the concentration is increased from 10.7.M to 1 〇.4 ^: the contractile force of the cumulative correlation is reduced. If first / generating agent..., receptor antagonist 25 1251589 ίο^ Μ theophylline, xanthine analog (XAC), 8-phenyl theophylline (8-ΡΤ); into the receptor antagonist 3, 7-bis-decyl-small propyne xanthine (DMPX), (3-chloroethylidene) coffee (CSC), 10-5 alloxazine pre-treatment for 30 minutes, then accumulate compound 1 so that The concentration increased from 1〇-7 μ to 10·4Μ, and it was found that the effect of compound 1 on the reduction of atrial contractility was significantly inhibited by the antagonist of the four-synchronized body; if the potassium-subchannel blocker was first 10-2 Μ four Amine (ΤΕΑ), 1〇-6 gli glibenclamide pretreatment for 30 minutes, then accumulate compound 1 to make the concentration from 10, accumulate to 1G4M, such as the reward compound 丨 caused by the reduction of heart pure contraction The role is _ _. These filaments show that the compound has a reduction in atrial fibrillation, and its mechanism may be related to the progeny channel and is associated with glandular adhesion. _ 丨 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ (2) guinea pig isolated trachea experiment:

Day 2 gas weight 350 cut the carotid artery bloodletting, ~ 5 grams of guinea pig, then immediately cut the chest cavity to stun the guinea pig, along the neck, remove the 26 1251589 trachea (about 4 cm long), placed Room temperature (about 22~25. 〇£: in a petrol dish (95% 〇2 + 5% C02) in physiological saline (Kreb, s), cut into the _, then cut the trachea into Each turn has three to four cartilage % knots (the spiral of the cartilage segmen, which is aliquoted (Constantine, 1965)' clamped at both ends, one end fixed to the bottom, and placed in 20 ml of physiological saline (Kreb) , s) in the tissue bath, the temperature is maintained at 32.5 ° C, the other end is connected to the power transducer (f〇rce transducer), via the recorder (go 孓 幽 却 ― ―

Videograph ) Record the isometric contraction tension, and the specimen was given a tensile force of 15 g. After the equilibration, the following experiment was performed. One (cumulative concentration reaction* line: In the experiment, the trachea should be washed with physiological saline (Kreb, s) for 20 minutes repeatedly). After re-equilibration (about 1 hour), spontaneous tension can be obtained (〇, Dormell and Wanstall, 1974; Walter ei ei α/·, 1984), then, by 10-6; ^ coughing and pulling 〇 11〇 1) to stimulate tracheal contraction, adding drugs to make the concentration from 1〇·9Μ to 1〇-5Μ. The inhibition by different concentrations of test compound was observed. Find EC5. , pD2 (alialfmaximalresponse; -logEC5.) value. Further, the antagonist of 27 1251589 of Baguang receptor; the antagonist of A2 receptor; after body tissue: 'potassium ion fine (4) pretreatment is 10_5M.

It is 1〇’5Μ. Separately the effect of these antagonists on the inhibition of glandular or glandular.

Result The guinea pig isolated trachea caused contraction by the order M嗔跋 (carbach〇1). After the tracheal contraction reached a steady state, the compound 丨 was cumulatively added, so that the concentration was accumulated from 109M to l〇-5M′, which could produce dose-related correlation. The trachea is slack. If you first use the antagonist of the Bayi receptor, 1〇-5 μ tea, xanthine analog (XAC), 8-benzyl theophylline (8-ΡΤ); Α2 receptor antagonist 3,7 - bis-mercapto-small propyne xanthine (DMPX), 8_(3_ chloroethene) coffee (esc), 10_5 ox 耕 (alloxazine) pre-treated ex vivo tissue for 30 minutes, then accumulate compound 1 so that The concentration was accumulated from 1〇-9 到 to 10_5 Μ, and it was found that the tracheal relaxation of Compound 1 was inhibited by the antagonist of the octa receptor; if the potassium channel blocker was first used, 1 〇·2 Μ tetraethylamine ( TEA), ΙΟ·6 Μ . After glibenclamide pretreatment for 30 minutes, compound 1 was added to accumulate the concentration from ΙΟ·9 到 to 10 55 Μ, as shown in Figure 12, compound 1 gas 28 l25l589 f Song he works as a __ a few loose (four) material slip _ reading compound 1 has a straight line, and now the ion pass A1, eight 2 receptor antagonists no Mingzi Tongshi resistance coffee only have a gasification tube loose tube to the trachea There is a slight loose _; peptide related. As shown in Figure 13, the inhibition of adenine is only a potassium relaxation effect.

Take 300-500 grams of Wistar atmosphere, forcefully knock out the head from the head, and then bleed from the carotid artery, quickly remove the thoracic aorta, and place it on the cold physiological salt (Krebs) to carefully remove the fat connective tissue around the blood vessel wall. Then cut the thoracic aorta into a ring of about 5_ long, with two "self, the type of white gold wire up and down through the chest wire ring to fix the upper aorta

Placed in 10 ml, 3rc with 95% 〇, -1 C〇2 mixture in the tissue tank, one end is fixed at the bottom of the tissue trough, and the other end is connected to a pressure displacemet transducer (UGO BASILE, Model) 7004, Italy c〇ntract.〇n }; The specimen was given 1 gram of tension and the experiment was performed after 60 minutes of equilibrium. 29 1251589 (1) Evaluation of vasodilatation: Add 3χ10·6 Μ norepinephrine (n_n_ne) test to the tissue trough The activity of the thoracic aorta, after the thoracic aorta shrinks to equilibrium, the 'adrenalin is washed away, and then 3x10]y [曱 adrenaline causes contraction of the thoracic aorta, depending on the contraction response After _% 'to be shrunk to equilibrium, a good concentration of test compound (waves accumulated from 3xl 〇-9M to 10-5M) was observed, and the effects of different concentrations of test compounds on isolated blood vessels were observed. Find the %. , the maximum response half value ^ (PD2) value. Then, the contact agent of the Al acceptor; the acceptor of the a2 acceptor; after the potassium ion channel blocker is pretreated with the ex vivo tissue, the compound sputum or the gland moss is added to accumulate the concentration from 3xl 〇 _9M to 1 〇 -5M. Observing the above-mentioned antagonistic surface inhibitory concentrations of the compound to read the brain caused the lion (4) effect.

Result

The isolated thoracic aorta of Wistar rats caused contraction with 3χ1〇·6 IV [norepinephrine). After the vasoconstriction reaches a steady state, Compound 1 is cumulatively added, and the concentration is accumulated from 3χ1〇·9Μ to 1〇-5m, which can produce 30 1251589 dose-related vasorelax. If you first accept the antagonist of Αι 5 Μ theophylline, xanthine analog 乂 from 〇, 8 benzyl tea test (suppressing); 8.2 receptor antagonist 3,7-bismethyl small Propyne xanthine (dmpx), cardiochlorinated ethylene (CSC), ΙΟ·5 Μ 耕 (all〇xazine) After treatment of the in vitro tissue for 3 minutes, accumulate compound 丨 to make the concentration from 3χ1〇 _9 Μ accumulated to l〇-5M, and it was found that there was no obvious inhibition of vascular relaxation of compound 1. If potassium ion channel blocker IQ·2Μtetraethylamine (tea) and 106M giibenciamide were used first After 3 minutes of treatment, Compound 1 was further accumulated to accumulate the concentration from 3χ10·9Μ to 1〇·5Μ. • The vasorelaxation effect of Compound 1 was significantly suppressed by Fig. 14·. Some results show that Compound 1 has a direct relaxation of vascular smooth muscle, and its relaxation may be related to potassium channel. Gland ^: has a slight relaxation effect on blood vessels, as shown in Figure 15, Ar, A, receptor antagonists have no obvious inhibition, only potassium channel blockers have vascular relaxation that inhibits glandular moss

use. ...A number of turtles and complex combination (adenosinejg town torbindingp special eaten thoughts (1) preparation of cell membrane (under 4t:): 31 1251589 Reference Ciaraldi β α/· (1978) 'Petrus β α/· (1988 And the method of Muzzin β α/· (1992) was modified to place the Wistar rat brain tissue

Ice cold 250 mM sucrose / 50 mM Tris / 1 mM MgCl2, pH of the Tris buffer solution, followed by separation of brain tissue such as cerebral cortex, striatum and weighing it Placed in a 2 〇 volume of ice-cold triacetin-based sputum buffer solution, homogenized with p〇lytron, 15 seconds each time, after mashing for 3 to 4 times, the homogenized solution is pressurized and filtered with gauze. The filtrate was centrifuged for 12 minutes (7 〇〇g), the supernatant was centrifuged for 12 minutes (10, (8) 〇g), and the second supernatant was centrifuged for another 15 minutes (29,000 g). The resulting pellet is resuspended in as little volume as possible of the trihydroxy guanamine decane buffer solution, followed by

Brodford (1976)'s method of using bovine serum albumin as a standard, protein assay dye assay, and protein content in the membrane, and then diluted with trishydroxylethane buffer solution The protein concentration was maintained at 2 〇〇 to 250//g per 1 〇〇 y 1 solution. (2) Binding assays: Modified according to the method of Porzig et al. (/卯2), Petrus et al. (1988) AMnzzin 32 1251589 et al (7974), taking loomembranes, 100 //1 (0.5 nM)[3H]DPCPX or 100//1( 5 nM)[3H]CGS 21680, 1〇〇//1 different concentrations of compound 1 (1〇-9¥4〇-51\/[), with The final volume was 500//1, and the mixture was shaken at 25t for 60 minutes. After the reaction was completed, 1 liter of ice-cold Tris buffer solution was added to terminate the binding reaction. Then, using Millipore filtration manifold and Whatman GF/C glass fiber for rapid filtration, and then rinsing with 15 ml of ice-cold triacetin-based sputum buffer solution, and drying the filter paper together with cell membrane at 60 ° C for 2 hours, then adding A 4 ml liquid scintillation counter was used to determine the radioactivity intensity using a Beckman LS6500 rackbeta liquid scintillation counter.

Result: The cerebral cortex and striatum isolated from the brain tissue of Wistar atmosphere have adenosine 8 and A2 receptors (Tao β Liu 3), and compound 1 via selective binding to adenosine A! acceptor [3H ] DP〇PX and adenosine A acceptor [3H]CGS 21680 compete for binding, and as shown in Fig. 16, it was found that Compound 1 has the function of binding adenosine\ and octa receptor 33 1251589. Comparing the competitive binding of adenosine and adenosine analogue (NECA), it was found that the binding of adenosine Ai acceptor necA > adenosine > compound 1, binds to the role of adenine a2 acceptor NECAK complex 1 > adenosine. Example 1 Synthesis of Compound 1 5 g of bismuth oxide steel (NaOH) was dissolved in an appropriate di-n-methylformamide (DMF). 1 mol of theophylline was dissolved in the above solution and placed in a m_e heater for stirring. After the solution was completely clarified, 3 mol of butanone lactone (丫-biityralactone) was further added to react at 17 (TC for 8-10 hours. After completion of the reaction, concentration under reduced pressure gave crude white crystals; The crystallized white crystal, ie, theophylline-7-butyric acid, can be obtained by repeated recrystallization from ethyl acetate. Hydrogen nuclear magnetic resonance spectrum iH-NMR (DMSO 〇 δ: 8.03 ( s, H, COOH ), 4.25 ( d, H, CH), 4.22 ( d, H, CH), 3.20 ( s, 6H, 2xCH3), 2.13 ( s, 2H, CH2), 2.11 ( s, 2H, CH2), 2·00 (s , 2H, CH2). 34 1251589 'Infrared spectrum analysis IR (KBr): Vmax has a hydroxyl group (〇H) absorption at 3500 cm·1, and an amine group at 3350 〇11-1 absorption) at 1710〇 114 has absorption of carbonyl (-COO-) UV absorption UV (CH3OH): λΜΑΧ (logs): 205 (3.66).

Anal· ( C24H35N604) C, H, N. Next, theophylline-7-butyric acid was dissolved in absolute ethanol and dissolved at 60 ° C; three times the molar amount of bicyclohexane carbonized imine (N, Nf-Dicyclohexylcarbodiimide, DCC) was added. Stir at 60 ° C overnight in a mantle heater. Thereafter, the reaction solution was concentrated under reduced pressure. The concentrated liquid is allowed to stand to obtain a crude solid crystal. After several recrystallization steps with ethyl acetate, the purified compound can be obtained. The structural formula is shown in Fig. 3, which is C24H35〇4N6. Mass Spectrometry MS (FAB+) : M/S472 (M+H+) Hydrogen Nuclear Magnetic Resonance Spectroscopy iH_NMR(DMSO_d6) δ: ( s5 1H,NH )5 8·31 ( s,1H,8-H ),5·59 (d ,H,CH), 5·55 Κ Η,CH),3·31 (s,6Η,2xCH3 ),2.51 ( s5 2Η,CH2 ), 2·5〇( s,2H,CH2 ),2·49 ( s, 2H, CH2), 1.73-1.01 (m5 22H, cyclohexyl H) ° 35 1251589 Example 2 Synthesis of Intermediate A: 20 hr of tea was placed in a 5 〇 _L three-necked flask to class 100 mL The hazelnut decomposition 'returns, and then adds 〇·4 曱 曱 ( (dibromoethane) with constant stirring and heating. After c reaction, add a n hydrogen

Sodium oxide 125 ml, stirring reaction for 3 minutes, stirring for 3 to 5 hours to obtain intermediate product A 〇 Bayification Example 3 Synthesis of compound 4

10 mmol (mmol) of intermediate product a was placed in a 5 〇〇mL three-necked flask dissolved in 100 mL of decyl alcohol, refluxed, and then added with mM pipiperazine and stirred for heating (6). After the reaction, stirring was continued for 3 _ 5 hours. It can be obtained only with compound .4. The mass spectrometry (MS) and hydrogen nuclear magnetic resonance spectroscopy (in-NMR, CDC13) data are shown in Table i. Example 4 Synthesis of Compound 5 10 mmol (mm〇l) of intermediate A was placed in a 5 (8) mL three-necked 36 1251589 bottle dissolved in 100 rnL of decyl alcohol, refluxed, and then 3 Torr milliliters i_(2- Pyrimidyl)piperazine is continuously stirred and heated at 60 ° C for reaction, and the compound 5 is obtained by continuously stirring for 3-5 hours. The mass spectrometry and hydrogen nuclear magnetic resonance spectrum data are shown in Table 1. Example 5 Synthesis of Compound 6 10 mmol (mmol) of intermediate A was placed in a 500 mL three-necked flask to dissolve in 100 mL of decyl alcohol, refluxed, and then 30 mmol of 1-(2-Pyridyl) was added. Piperazhie was continuously stirred and heated 6 (after the TC reaction, stirring was continued for 3-5 hours to obtain compound 6. The mass spectrum and hydrogen nuclear magnetic resonance spectrum data are shown in Table 1. Example 6 Synthesis of Compound 7. Take 1 〇 millimolar ( The intermediate product A of mmol) was placed in a 500 mL three-necked flask, dissolved in 100 mL of decyl alcohol, refluxed, and then added with 30 mmol of 1-(2-Chlorophenyl) piperazine. Stirring was continued for 60 ° C. Stirring was continued. Compound 7 was obtained in 5 hours. The mass spectrum and nitrogen nuclear magnetic resonance spectrum data are shown in Table 2. 37 1251589 Example 7. Synthesis of Compound 8 10 mmol of intermediate product A was placed in a 500 mL three-necked flask and dissolved in 100 mL of methanol. , refluxing, and then adding 30 millimoles of l-(m-Chlorophenyl) piperazine, stirring and heating at 60 ° C, continuing, stirring: mixing for 3-5 hours to obtain compound .8. Mass spectrometry, hydrogen nuclear magnetic resonance spectrum data As shown in Table 2. Example 8 Synthesis of Compound 9 Take 10 millimoles The intermediate product A was placed in a 500 mL three-necked flask and dissolved in 1 mL of methanol, refluxed, and then added to 30 mM 丨 _ (4_

Oilorophenyl)piperazine was continuously stirred and heated 6 (after the TC reaction, stirring was continued for 3-5 hours to obtain Compound 9. The mass spectrum (MS) and hydrogen nuclear magnetic resonance spectrum data are shown in Table 2. Example 9 Synthesis of Compound 10 Take 10耄The intermediate product A of Mohr was placed in a 500 mL three-necked flask and dissolved in .100 mL of decyl alcohol, refluxed, and then added to 3 Torr of mil. 38 1251589 N-Benzylpiperazine was continuously stirred and heated to 6crc reaction, and stirring was continued for 3-5 hours to obtain a compound. Example 10. Synthesis of Intermediate B. Take millimolar (mmol) of intermediate A in a 500 mL three-necked flask, dissolve in 100 mL of decyl alcohol, reflux, and add 30 mmol of piperazine. Stirring and heating at 60 ° C, stirring for 5-10 hours to obtain intermediate B 〇 Example 11 Synthesis of compound 11 10 mmol (mmol) of intermediate B was placed in a 500 mL three-necked flask and dissolved in 100 mL of decyl alcohol. After refluxing, adding 30 mmoles of α-Bromodiphenylmethane, stirring and heating at 60 ° C, stirring for 6-10 hours, the compound 11 can be obtained. Example 12 Synthesis of Compound 12 39 1251589 10 亳 mol (blood nol) )of Product B is placed between 500mL 100mL three-necked flask to dissolve Yue alcohol, reflux, then we add 2-Furoyl mmol 3〇

Chloride is continuously stirred and heated at 60 ° C, stirring is continued for 6-10 hours to obtain compound 12 〇 Example 13 Synthesis of compound 13 is taken in the middle of 10 mmol (mmol). Product B is placed in a 500 mL three-necked flask at 100 mL 曱The alcohol is dissolved, refluxed, and 30 millimoles is added.

After the Benzenesulfonyl chloride was continuously stirred and heated at 60 ° C, the compound 13 was obtained by continuously stirring for 640 hours. Example 14 Synthesis of Compound 14 10 mmoles (mmol) of Intermediate B was placed in a 500 mL three-necked flask, dissolved in 10 Q mL of methanol, refluxed, and then added with 30 mL of Alpha-Toluenesulfonyl chloride. After the reaction, the compound 14 can be obtained by stirring for 6-10 hours. Example 15 Synthesis of Compound 15 1251589 10 mmol (mmol) of intermediate B was placed in a 5 〇〇mL three-necked flask, dissolved in 100 mL of decyl alcohol, refluxed, and then added with 3 Torr of Ethoxylbenzenesulfonyl chloride. After the reaction at 60 ° C, stirring can be continued for 6-10 hours to obtain Compound 15. Example 16 Synthesis of Compound 16 10 mmol (mmol) of Intermediate B was placed in a 500 mL 3-neck flask and dissolved in 100 mL of decyl alcohol to reflux, followed by 3 Torr.

Hydroxylbenzenesulfonyl chloride Continuously smashed and heated at 60 ° C. After the reaction, the compound 16 was obtained by a 6-10 hour drop. 41 1251589

Compound MS (Scan FAB+) iH-NMR (CDCi3) 4 368.44 5: 3.41 (s,3H5NCH3) '3.59(s,3H,NGH3) 2.84 (t, 2H, NCH2) 4.45 (s, 2H, NCH2) .2.67 ( t,4H,2XCH2) 3.17 (t, 4H, 2XCH2) 6.84-6.92 (m, 3H, 3XAr-H) 7.24-7.28 (m, 2H, 2XAr-H) 7.67 (s, la imidazole-H) 5 370.41 5 : 3.40(s,3H,NCH3) 3.59 (s,3H, NCH3) 2.83 (t, 2H, NCH2) 4.64 (s, 2H, NCH2). 2.57 (t, 4H?2XCH2) 3.79 (t54H52XCH2) 6.46-6.51 ( M3 1H, Ar-H ) 8.28-8.30 (m, 2H, 2XAr-H) 7.73 (s, 1H, imidazole-H) 6 369.43 (5: 3.41 (s, 3H, NCH3) 3.59 (s, 3H, NCH3) 2.83 (t, 2H, NCH2) 4.45 (s, 2H, NCH2) 2.83(1, 4H, 2XCH2) 3.51 (t, 4H, 2XCH2) 6.59-6.65 (m, 2H, 2 X Ar-H) 7.43-7.51 ( m, 1H, Ar-H ) 8.16-8.19 (m, 1H, Ar-H) 7.68 (s, 1H, imidazole-H ) 1251589 Table 2 7 402.88 (5: 3.60(s,3H5NCH3) 3.42 (s, 3H, NCH3) 4.45 (t,2H, NCH2) .2.82 (s,2H,NCH2) 2.70 (t, 4H,2XGH2) 3.04 (t, 4H,2XCH2) 6.97-7.01 (m, 2H, 2XAr-H) 7.27-7.36 (m, 2H, 2XAr-H) 7.69 (s, 1H, imidazole-H) 8 402.88 (5: 3.41 (s, 3H, NCH3) 3.59 (s, 3H, NCH3)·· 3.83(t,2H,NCH2) 4.45 (s, 2H, NCH2) 2.64 (t, 4H, 2X CH2) 3.15 (t, 4H,2XCH2) 6.74-6.85 (m,3H, 3XAr-H) 7.13-7.17 (m, 1H, Ar-H) 7.65 (s, 1H; imidazole-H) 9 402.88 (5: 3,39(s,3H) , NCH3) 3.57 (s, 3H, NCH3) 2.82 (t, 2H, NCH2) 4.43 (s, 2H, NCH2) 2.64 (t, 4H, 2XCH2) 3.10(t, 4H, 2XCH2) 6.77-6.8 l.(m , 2H, 2XAr-H) 7.15-7.19(m, 2H, 2XAr-H) 7.65 (s, 1H, imidazole-H )

43 1251589 Table 3 Compound Substituent Blood Pressure Drop (mm/Hg; iv 2mg/kg in rat, n-6) 1 /—〇R.=—CH, CH, CH, COOC ..., H-〇55 ± 4.8 2 /—〇R = —CH.CHXOOC 50 ± 5.3 3 N—〇R.= — CHiCOOC^ XNH-〇45 ± 5.1. i 4 . v nCn^3 30 ± 4.2 ί 5 r~\ N Fly. N N. -< 》 • ^ N-7· 47 ± 3.8 6 /~\ N-\ i R4- j . 53 ±4.9 7 R,= OT-0 丨25 ± 3.6 Cl i 8 R,= NCN:0 1 28 ± 3, α 丨9 R corpse. CM 3〇± 2.8 10 long two. N^N—35 ± 3.3

44 1251589 Compound substituent blood pressure drop (mm/Hg; iv 2mg/kg in rat, n=6) 11 R- ΓΗ/〇R“—(3) will... 30 士2.S 12 〇〇¥ -c^J 28 ± 3.5 13 ^ 1-0 0 35 Soil 3.9 14 r2- ^ 0 40 ± 3.4. 15 R2- S —(Q-〇C2H5 0 43 ± 3.7 16 R2 ^~0"〇H 0 41 ± 2.9

HX

N

N

O^N

N 0 01⁄2 H3C\n

Ch3 ΓΓ CH,

II

CH,

III 45 1251589 Table\Binding adenosine acceptor 4 'adenosine acceptor a2 A, !A2 compound & (Ki3 nM) (IC5〇5nM) (Ki, nM) (IC5〇3nM). Ratio adenosine 丨 782 7 2180士48 49,500士610 66,600士2,100 63.30 Adenosine analogue (NECA) 48.81 ± 4 136 soil 5 154 ± 6 207 ± 10 3.16 Compound 1 3.660 ± 52 10,200 340 158 士士 8 213 士 13 0.04

46

Claims (1)

1251589 X. Patent application scope: 1. A theophylline derivative of the following chemical formula with adenylate effect and blood pressure lowering Ch3 2· - a tea test derivative of the following chemical formula with glandular efficacy and money reduction. 0 people A,〉 ch3 ^CH2CH2C00C ' XNH ο 3·—A theophylline derivative with adenosine-induced and hypotensive lower doses 47 1251589 〇 CHXOOC /丄》 0人广 N ch3 4· A theophylline derivative of the following chemical formula with adenylate effect and blood pressure lowering Ch3 5. A theophylline derivative of the following chemical formula with adenylate-induced and hypotensive blood pressure 48 1251589 6·-the theophylline derivative of the following chemical formula with adenylate-induced and hypotensive blood pressure CH3 〇 7·The following chemical formula tea derivatives with gypical acid-efficiency and blood pressure lowering a theophylline derivative of the following formula having adenosine-induced and hypotensive blood pressure 49 1251589 Ch3 9· A theophylline derivative of the following chemical formula with adenylate-efficacy and blood-reducing Ch3 10. A theophylline derivative having the following chemical formulas with adenylate effect and blood pressure lowering 50 1251589 11. A theophylline derivative of the following chemical formula with adenylate effect and blood pressure lowering 12· A theophylline derivative of the following chemical formula with adenylate-induced and hypotensive blood pressure 0 〇CH2CH2—NN — S—1 ~\ · H3Cx ANW II \=/ · N T" \ 〇丄JL》 0人广 N ch3 〇13. A theophylline derivative of the following chemical formula with adenylate-induced and hypotensive blood pressure 51 1251589 ο ^CH3 J I / N人N人N ch3 〇 14· A theophylline derivative of the following chemical formula with adenylate effect and blood pressure lowering 15. A theophylline derivative of the following chemical formula with adenylate effect and blood pressure lowering 52 1251589 16. A pharmaceutical composition having adenosic acid-acting efficacy and blood pressure lowering, which comprises a therapeutically effective dose as claimed in the above-mentioned patent application! The tea of item 15 to claim 1 and the pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. Η·- kind as the scope of patent application! The tea test derivative of item 15 is used for the manufacture of a drug having adenosine-efficiency and blood pressure reduction. 18·-The method of making tea touches of the following chemical formula I, H3CN Ch3 wherein, 53 1251589 ch2 ch2cooc ^ \Nhh〇Ο ——CH〇CH2CH2 COOC ^ Rl is selected from NNH-〇\ , Ν-^D -ch2 COOC and 'NH0, the method comprises the following steps: (a) The tea of formula IV is reacted with a halogenated alkyl acid of the formula X-(CH2)mC00H in a solvent under a catalyst. H.CN, into IV To obtain the intermediate product C of the following chemical formula V, 54 1251589 (CH2)mC00H V wherein x is an il element, m is an integer from 1 to 3, (b) the intermediate product c of the above formula v is dissolved in a solvent with a bicyclic burnt carbodiimide (Ν', N, -dicyclohexylcarbodiimide) to give the theophylline derivative of the above formula I. 19. The method of producing the theophylline of the following chemical formula according to claim 18, wherein the solvent in the step (a) is dimethyldiamine (N, N-dimethylf〇nnaniide). 20. Manufacture the following chemical formula as described in item 18 of the patent application! The method of tea derivation of the organism 'where the test agent in step (4) is _1. T 21. The method for producing the following chemical organisms as described in claim 18, wherein the solvent in the cattle ~, the slaves ~ I, the base v. yl^(b) is anhydrous ethanol. 22. A method for producing a tea derivative of the following chemical formula, 55 1251589 Ο CH2CH2CH2C00C[ N-O NH〇 The process comprises the steps of: (a) reacting the theophylline of the following chemical formula IV with a butanone (γ-buty ro ac tone) in a solvent under a base catalyst, 56 1251589 wherein x is a halogen 'in is an integer of 3 to obtain a crude crystal tea to determine butyric acid; (b) the above-mentioned crude crystal tea is tested for butyric acid by recrystallization and recrystallization and recrystallization to obtain Purified tea, butyric acid (10) _ymne-7-_); (c) reacting the above-mentioned labyric acid with a bicyclic carbodiimide (9), N-dicyclohexylcarbodiimide, to obtain the tea of the above formula j Test the derivative. 23·If you apply for the patent scope f 22, you will be able to manufacture the following chemical formulas! The method of detecting the street is biological, wherein the recrystallization solvent in the step (6) is ethyl acetate. A method of producing a tea-derivative derivative of the following Chemical Formula 1 as described in claim 22, wherein the solvent in the step (c) is anhydrous ethanol. 25. The method of producing a tea quarantine organism of the following chemical formula I according to claim 22, wherein the reaction in the step (8) is carried out at 2 G to 1 Torr. ^ 26· - Method for producing tea chemo-touch of the following chemical formula π, NRs CH2CH2^n [CN ch3 57 II 1251589 The process comprises the steps of: (a) reacting the theophylline of the following chemical formula IV with 1,2-dibromoethane 58 1251589 (1,2-dibromoethane) in a solvent. Η IV to produce intermediate product A of the following chemical formula VI H3cnη people CH2 CH2 Βγ CH, VI (b) The intermediate product A of the above formula VI is reacted with a piperazine in a solvent to produce an intermediate product B of the formula VII, 59 1251589 (C) The compound VII of the chemical compound VII is dissolved in a compound of μ 、, +, πτ, and 以 以 以 产生 产生 产生 产生 产生 产生 产生 产生 产生 产生 产生 产生 产生 产生 产生 产生 。 。 。 。 。 。 。 。 。 Han et al., in the method of manufacturing the following chemical organisms as described in claim 26, in which the solvent in the cattle treading, the southern double-middle repentance c) is methanol. The method for producing the following chemical organisms described in Item 26 of the patent dry circumference is carried out in Fuzhong, Bovine 'I's Alkali'. /, the reaction in 4 (a) is in the presence of a catalyst. The method of manufacturing the following formula I, as described in claim 28, wherein the reaction of the reaction in step ω The method of producing the following organisms as described in claim 26, wherein the reaction in the step (6) is carried out at a temperature of from C1 to 1251589. 31. The method of producing the theophylline derivative of the following chemical formula I, as described in claim 26, wherein the reaction in the step (c) is carried out at a temperature of from 20 to 100 degrees Celsius. 32. A method of producing a tea derivative of the following chemical formula III, Where R4 is selected from CI 61 1251589 This process comprises the following steps: (a) The following chemical formula IV is reacted in a solvent with 1 2--, 1,2-dibromoethane CH IV To produce intermediate product A of the following chemical formula VI, CH3 VI (6) The intermediate product A of the formula VI is reacted with a compound of the formula Η-1 in a solvent to produce the tea derivative of the above formula III. 33. The method of producing the following chemical organisms as set forth in claim 32, wherein the solution used in the step (4) (6) is a remedy of 62 何 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 62 A process for the theophylline derivative of the formula I, wherein the reaction in the step (a) is carried out under a base catalyst. 35. A method of producing the theophylline derivative of the following formula I, as described in claim 34, wherein the catalyst in step (a) is NaOH. 63