TW307760B - Piperazinedione derivatives having activity as multi-drug resistance modifying agents - Google Patents

Abstract

A piperazinedione of general formula (I) (see claim 1): in which R1 is selected from: - hydrogen; - agroup of formula -COR3 -(NH)t -COR3 in which t is 0 or 1 and R3 is selected from (i) (see claim A): in which v is 0 or 1 when t is 1 and v is 1 when t is 0; and in which n is 0, 1, 2, or 3 at least one of n and m being other than 0, and either: (a) R4 is H or C1-C6 alkyl and R5 is C1-C6 alkyl optionally substituted by one or two phenyl groups, the phenyl group or groups being optionally substituted by one or two C1-C6 alkoxy groups; or (b) R4 and R5, together with the nitrogen atom to which they are attached, form a heterocyclic group selected from (1) to (4) (see claim 1,2,3,4) in which R6 and R7, which are the same or different, are H or C1-C6 alkoxy, or R6 and R7 together form a methylenedioxy group; Y is O or -NR8 in which R8 is C1-C6 alkyl or a phenyl group optionally substituted by CF3; (ii) -NH-(CH2)p-Z (B) in which p is 1 or 2 and Z is C2-C6 alkenyl or a phenyl group otpionally substituted by C1-C6 alkoxy; and (iii) (see claim C) in which R9 is C1-C6 alkyl, pyrimidinyl or a phenyl group optionally substituted by C1-C6 alkoxy; and (iv) (see claim F) in which w is 1, 2 or 3 and L is a heterocyclic group of formula (1) as defined above; - a group of the formula (D): (see claim D) in which each of R10 and R11, which may be the same or different, is C1-C6 alkyl; and - a group of formula (E): (see claim E) in which s is 0 or 1 and each r, which may be the same or different, is 1, 2 or 3 and L is a heterocyclic group of formula (1) as defined above; and R2 is hydrogen or a group of formula -COR3 as defined above, provided that one or R1 and R2 is hydrogen and the other is not hydrogen; and the pharmaceutically acceptable salts thereof have activity as modulators of multi-drug resistance.

Description

A7 B7 is printed by the Beigong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. 5. Description of the Invention (i) The present invention can be used as a compound with multidrug resistance (MDR), its preparation method and the compound The composition for veterinary use and veterinary use. Swelling «Resistance to treatment with a cytotoxic agent is an obstacle to successful chemotherapy for cancer patients. A swollen one can gain resistance to the cytokine agent used in the previous treatment. A tumor may also exhibit intrinsic resistance or cross-resistance to cytotoxic agents that have not been previously exposed to it. The toxin is not related to any toxin agents used in previous treatments in structure or mechanism of action. By analogy, a certain pathogen can acquire resistance to drugs that were previously used to treat a disease or condition caused by that pathogen. Pathogens can also exhibit intrinsic resistance or cross resistance to agents that have not previously been exposed to them. Examples of this effect include the multi-drug resistant forms of malaria, tuberculosis, Leishmaniasis and amoebic dysentery. These phenomena can be collectively referred to as multidrug resistance (MDR). As discussed in more detail later, a cell membrane glycoprotein (P-gp) image has two mechanisms that constitute MDR. P-gP has the property of binding to drugs. A medicament with the ability of MDR can also be used to promote the transmission of phlegm through the vascular barrier, and to treat AIDS and AIDS-related complications. The lack of viscosity of drugs currently used for MDR (called resistance regulators or RMAs) is often associated with poor pharmacokinetic patterns and / or toxicity at the concentration required by MDR. At present, a series of piperazine dione derivatives having multidrug resistance activity have been found. Therefore, the present invention provides a piperdione derivative having the formula (I): -8-This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) (please read the precautions on the back before filling in this Page) • 4-pack. Order 307760 A7 B7 Ο

5. Description of the invention (2 (I) wherein R1 # is selected from:-Hydrogen (A) wherein when t is 1, V is 0 and when tso, 7 is 1; and wherein η is 0 or 1 and m is 0, 1, 2 or 3, at least one of η and π is not 0, or (a) R «is} | or (: 1- (: 8 alkyl, and V is optionally 1 or 2 ^ -Cb alkyl substituted by phenyl, the phenyl or phenyl nursery can be optionally substituted with 1 or 2 alkyl gas nursery; or (b) R «and rs together with the cyanide atom to which they are attached form a choice Miscellaneous from (1) to (4):;. F — ^ lτ ^ (Please read the precautions on the back before filling out this page)-The base of formula _ (NH) tC〇R3, where t is 〇 Or 1 and R3 is pseudo-selected from

⑴ Printed by the Ministry of Economic Affairs Central Bureau of Accreditation Consumer Cooperatives «.

(1)

-N

Y (2 This paper uses the Chinese National Standard (CNS) Α4 specification (210Χ297mm). V. Description of the invention (

A7 B7

Η (3) (4) where Rs and R7, which may be the same or different bases, are 11 or (: 1-(^ alkane or R7 and together form a methylene digas; Y is 0 or -NRe, Where Re $ Cl_CB alkyl or a phenyl group optionally substituted by CF3; (ϋ)

-NH— (CH2) “Z (B) where P is 1 or 2 and Z is a Cz-Cb bond group or a phenyl group optionally substituted by a Ci-Ce hospital gas group; (iii)

-N N—R9 (C) where Rsgh-Ce alkyl, pyrimidinyl or a phenyl group optionally substituted by Ci-Cs alkyl gas; and (iv) -ν (ZΧ ° η 七

F --- J ---.--- f- I installed-(please first «read the notes on the back and then fill out this page). Order the consumer cooperation cooperation printed by the Central Bureau of Economics and Trade of the Ministry of Economic Affairs where w is 1, 2 or 3 and L are the heterogeneous groups of formula (1) as defined above; -The base of formula (D): R10 〇 ~ 〇Η2〇Η (ΟΗ) —CH2-Ν SR11 (D) which may be the same Or Rin and R11 of different groups are Ct-Ce alkyl and -formula (E) -based garden; -10 This paper size is applicable to China National Standard (CNS) A4 specification (210X297mm) s〇776〇 A7 B7 V. Description of the invention (4) Printed by the Beigong Consumption Cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs

E where s is 0 or 1 and may be the same or different, r is 1, 2, 3 and L is a hetero group of formula (1) as defined above; and R2 is hydrogen or the formula -COR3 as defined above, One of them is hydrogen and the other is not hydrogen; or a pharmaceutically acceptable salt. -It can be linear or branched alkyl. Ci-Cs alkyl groups are usually b-C4 alkyl groups such as methyl, ethyl, propyl, i-propyl, η-butyl, secondary butyl or tertiary butyl. Ci-CB alkoxy is usually a Ct- "alkane of methoxy, ethoxy, propanyl, i-propanyl, η-butanyl, secondary butanyl or tertiary butanyl When R1 is the base of formula-(NH) t-COR3, t can be (3 and in this example R1 is formula -COR3. And the integer v is 1 in formula (A). When R3 is formula (A) ), Η is usually 1 and b is 0, 1, 2 or 3, or η is 0 and m is 2. R4 and Rs can be as defined in (a), in this case R * is better It is a methyl group (: 1-〇8 alkyl group. Rs is preferably a methyl group or ethyl group.-% Alkyl group, the last sulfonic atom may be unsubstituted or substituted by 1 or 2 phenyl. Furthermore, the phenyl yes are unsubstituted or substituted with 1 or 2 methyl groups. For example, Rs may be diphenylmethyl, 2-2-diphenylethyl or 3,4-di Methyphenethyl. In addition, R * and Rs can also be as defined in (b). When R * and R * together form Zachen (1), it is generally the same as R7, and is preferably 氲Or methoxy or together form a methylenedioxy group. When R * and Rs together form a compound (2), Y is 0 or -HRa, where Re is preferably methyl, phenyl or 3-trifluoro Methyl phenyl. When R3 is of formula (B) In the case of Z, Z is preferably vinyl, prop-1-enyl-11-The size of this paper is applicable to China National Standard (CNS) A4 specification (210X297mm) ----: ---; --- f — 装 — (Please read the precautions on the back before filling in this page) Order A7 B7 i, the invention description (5) or prop-2-enyl, or be 1 Or a phenyl group substituted by an alkyl group, preferably a methyl group. The preferred benzene cut box is substituted by methoxy with 3,4-di. When R3 is a plaque of formula (C), R3 is pseudo Preferably selected from methyl, ethyl, pyrimidinyl and phenyl, the phenyl group is substituted by a methoxy iCi-Cs alkyl group at the 2, 3 or 4 position, and preferably 4-methoxy Phenyl. When R1 is the base of formula (D), Ri «and RM are generally the same and preferably both are methyl. When R1 is the base of formula (E), s can be 0 and in this In the example, Ri has the formula-(CH2) rL. In formula (E), the substituents M and R7 in the complex are generally the same and preferably both are Η or methyl group or together form a methylene dioxy group In the first embodiment of formula (I), where t = 1 and R1 is hydrogen and Ra is the formula as defined above -COR3 base garden, where R3 is the base of formula A. In the second embodiment of formula (I), Ra is hydrogen and R1 is the formula-COR3 base garden as defined above, where R3 is formula (A) Group, the group of formula (B), wherein Z is vinyl or phenyl substituted by an alkyl group, or the group of formula (C), wherein R * is methyl, pyrimidinyl or phenyl. The phenyl substituted by alkoxy is preferably 3,4-dimethylmethyl phenyl. In the formula (A) in the above first and second embodiments, it is preferable that η is 0 and b is 2 or η is 1 and Β are 0, 1 or 2, or (a) !? 4 *. -. Alkyl and Rs are (^-(: 8 alkyl. (1)) 1? * And the terminal C is substituted with 2 phenyl unsubstituted phenyl or 1 phenyl substituted with C / Cb alkylamino {^ And the N atom to which it is connected together form a heterocyclic ring selected from the base of formula (1), wherein R8 and R'7 are both 11 or (: 1-(: 15 alkoxy, or wherein R < * and R7 together form a methylenedioxy group; (2) where Y is 〇 or -NR8, where -12-the original paper wave scale is used in China National Standardization (CNS) A4 specification (210X297 mm) n. M In m ml nmn,. t issued (please read the precautions on the back before filling out this page) A7 B7 printed by the Consumer Labor Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs V. Description of the invention (6)

Re is methyl, phenyl or trifluoromethylphenyl; (3); and (4). Preferably, R4 is methyl and R5 is diphenylmethyl or 2- (3,4-dimethylmethylphenyl) ethyl, or R4 and R5 together form another heterocycle (1), where 1? 8 and ΙΓ are both Η or both OMe or together form a methylene dioxy group. Preferred examples of the compound of formula (1) are as follows: 1- (4-((32,62) -6-benzylidene-1-methyl-2,5-dioxo-3-pyridinium 11 Qinyl) Methylbenzaldehyde) -4- (2-pyridyl) oxazine (90 2 2) 1- (4-((32,6 2) -6-benzylidene-1-methyl-2,5 -Dioxo-3-piperidinyl) methylbenzyl) -4-methylpiperidine, hydrogen hydride (9 05 2) I- (4-((3Z, 6 Z) -6 -Benzylidene-p-methyl-2,5-dioxo-3-piperazinyl) methylbenzyl) -4- (4-methylphenyl) piperazine, hydrochloride (9071) II -Allyl-4-((3Z, 6Z) -6-benzylidene-p-methyl-2,5-dioxo-3-piperazinyl) methylbenzylamine (9070) 1- (2 -Diphenylmethylmethylaminoethyl) -4-((32,6 2) -6-benzylidene-1-methyl-2,5-dioxo-3-salazinylene) methyl Phenylbenzylamide, gasification (9076) -13-This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (21〇Χ 297 mm) II ^ ---.- It —installed ----- -Subscribe ------ Γ1-7 (please read the notes on the back before filling in this page) Printed 307760 at _B7_ at the Central Sample Bureau of the Ministry of Economic Affairs _B7_ V. Description of the invention (7) Μ _- (2 -(1,2,3,4-tetrahydro-2-isoquinolinyl) Ethyl) -4-((3Z, 6Z) -6-benzylidene-1-methyl-2,5-dioxo-3-piperidino) methylbenzamide, hydronitride ( 9116) &-( 3,4-Dimethyl phenethyl) -4-((3Z, 6Z) -6-benzylidene-1-methyl-2, 5-difluoro-3-arylene Acetoyl) methylbenzylamine (9117) also- (4- (4-phenyl-1-piperazinyl) methylphenyl) -4-((32,6 2) -6-benzylidene -1-Methyl-2,5-difluoro-3-piperidinyl B), methylbenzylamine, hydroformide (9104) M _- (2- (4-Methyl-brazinium ) Ethyl) -4-((3Z, 6Z) -6-benzylidene-1-methyl-2,5-dioxo-3-piperazinyl) methylbenzylamine (9007) L -(2-morpholinoethyl) -4-((3Z, 6Z) -6-benzylidene-1-methyl-2,5-di «generation-3-piperidinyl) methylbenzyl Acetylamine, hydrocyanide (9 053) 1- (4-Benzolinephenyl) -4-((32,62) -6-benzylidene-p-methyl-2,5-di Ethyl) methylbenzylamine, hydrogen «compound (9 054) 1- (4- (2- (1,2, 3,4-tetrakis-cold-diazofluoren-2-yl) ethyl ) Phenyl) -4- ((3Z, 6Z) -6-benzylidene_p-methyl-2,5-difluoro-3-qinylene) methylbenzamide (9080) _____- 14 -___ This paper uses Chinese national standards again (CNS) A4 specification (210 X297mm) ----:-; --- f-installed ------ ordered ------ f again (please read the note on the back ^ item first (Fill in this page) Ministry of Economic Affairs, Central Bureau of Standards, Beigong Consumer Cooperative Du Printing Pack A7 B7 V. Description of Invention (8) 1- (4- (1,2, 3,4-Tetrahydro- / 3-di-deuterofluorene- 2-yl) methylphenyl) -4-((3Z, 6Z) -6-benzylidene-1-methyl-2,5-difluoro-3-piperidyl) methyl benzoylase Amine (9096) 1- (4- (2- (4-phenyl-1-ethenyl) ethyl) phenyl) -4-((32,62) -6-benzylidene-1-methyl -2,5 -Dioxo-3-arylene) methylbenzylamine (9103) 1- (4- (2- (1,2,3,4-tetrakis-2-isoquinoline Group) ethyl) phenyl) -4-((3Z, 6Z) -6-benzylidene-1-methyl-2,5-difluoro-3-piperidinyl 11) methyl benzoyl Amine (9 0 6 5) tL- (4- (2- (4- (3- (tricyanomethylphenyl) -1-Vanyl B Qinyl) ethyl) phenyl) -4-((32,62 ) -6-benzylidene-p-methyl-2,5-difluoro-3-piperazinyl) methylbenzaldehyde amine (9049)

Hr (4- (2- (4- (4- 氱 phenyl) -4-sacrylic group) ethyl) phenyl) -4-((3Z, 6Z) -6-benzylidene-1 -Methyl- 2,5-dioxo-3-piperazinyl) methylbenzamide (9079) M _- (4- (2- (6,7-dimethoxy-1,2, 3,4-Tetrahydro-2-isoquinolinyl) ethyl) phenyl) -4-((32,62) -6-benzylidene-1-methyl-2,5-dioxo-3 -Piperidinyl) methylbenzylamide (9 006) ___-15 ~ ____ This paper method is applicable to the national standard (CNS) A4 specification (210X297 mm) --- τ --- ·- -f ------ 1T ------ f (please read the precautions on the back before filling in this page) A7 B7 " --------- i. Description of invention (9) 1 -(2- (6,7-dimethylamino-1,2,3,4-tetrakis-2-isoquinolinyl) ethyl) -4-((3Z, 6Z) -6-benzylidene -1-Methyl-2,5-difluoro-3-piperidinyl) methylbenzaldehyde amine (9008) 1- (4- (6,7-dimethylamino-1,2,3, 4-tetrahydro-2-isoquinolinyl) methylphenyl) -4-((32,62) -6-benzylidene-1-methyl-2,5-dioxo-3-methylenepipe Azinyl) methylbenzylamide, hydrochloride (9 0 64) (3Z, 6 Z) -6-benzylidene-3- (4- (3-dimethylamino-2-hydroxypropenyl) ) Benzylidene) -1-methyl-2,5-piperdione (9 0 2 3 ) (32,62) -6-benzylidene-3- (4- (2- (6,7-dimethylamino-1,2,3,4-tetrahydro-2-isoquinolinyl) B Group) benzylidene) -1_methyl-2,5-pyrazinedione (9115) H- (4- (2- (6,7-dimethoxy-1,2,3,4-tetra氲 -2-isoquinolinyl) ethyl) phenyl) -3-((32,62) -6-benzylidene-1-methyl-2,5-difluoro-3-methylene piperidine Base) methylbenzylamide, hydrochloride (9051) Printed by the Beigong Consumer Cooperative of the Central Bureau of Economic Development of the Ministry of Economic Affairs (please read the precautions on the back before filling in this page) Gas-1,2,3,4-tetrakis-2-isoquinolinyl) methylphenyl) -3-((32,62) -6-benzylidene-1-methyl-2,5 -Dioxo-3-iminozinyl) methylbenzaldehyde amine (9128) -16- Chinese paper standard (CNS) A4 specifications (210X297 mm) for the paper size of this paper A7 B7 307760 V. Description of invention (10 ) iL- (2- (6,7-dimethylamino-1,2,3,4-tetrakis-2-isoquinolinyl) ethyl) _ 3-((3Z, 6Z) -S-Asia Benzyl-1-methyl-2,5-difluoro-3-oxazinylene) methylbenzamide (9136) 11- (2- (3,4-dimethoxyphenethyl) methan Amino) ethyl) -3-((32,62) -6-benzylidene-1-methyl-2,5-difluoro-3-oxazinylene) methylbenzamide 9137) tL- (4- (2- (3, 4-dimethylphenethyl) methylamino) ethyl) phenyl) -3- ((3Z, 6Z) -6-benzylidene-1- Methyl-2,5-difluoro-3-piperazinyl) methylbenzamide (9138) 11- (4- (2- (4-phenyl-1-piperazinyl) ethyl) Phenyl) -3-((32,62) -6-benzylidene-1-methyl-2,5-dioxo-3-piperazinyl) methylbenzylamine (9083) 1- (4- (3- (6, 7-dimethylhexyl-1,2,3,4-tetrahydro-2-isoquinolinyl) propyl) phenyl) _3 _ ((32,62) -6- Benzylidene-1-methyl-2,5-dioxo-3-pyridazinyl) methylbenzamide, chlorinated compound (9161) H- (2- (2,2-diphenylethyl Group) methylaminoethyl) -3- ((3Z, 6Z) -6-rylenyl-1-methyl-2,5-dioxo-3-imino group) methylbenzamide (9163) -17- This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (21〇X 297 mm) ---- Γ--: --- Γ ▲ — I (Please read the notes on the back first (Fill in this page again) Order A7 B7 printed by Beigong Consumer Cooperative of Central Central Bureau of Economic Affairs V. Invention Description (11) (3Z, 6Z) -6-benzylidene-3- (4- (4- (2- (6,7-dimethoxy-1,2,3, 4-tetrahydro-2-isoquinolinyl) ethyl) benzyloxy) benzylidene) -Bumethyl-2,5-piperazinedione (9176) (3Z, 6Z) -6-benzyl-3- (3- (4- (2- (6,7-dimethylamino-1,2 , 3,4-tetrahydro-2-isoquinolinyl) ethyl) benzyl «benzyl) benzylidene) -1-methyl-2,5-piperazinedione (9177) 1- (4-(( 32,62) -6-benzylidene-1-methyl-2,5-dioxo-3-piperazinyl) methylphenyl) -4- (2- (6,7-dimethoxy -1,2,3,4-tetrakis-2-isolinyl) ethyl) benzamide (9190) bu (4-((32,62) -6-benzylidene-1-methyl -2,5-dioxo-3-piperazinyl) methylbenzaldehyde) -4- (6,7-dimethylamino-1,2,3, 4-tetrahydroisoquinolinyl) Methylpiperidine (9 200) The compound of formula (I) can be contained in an organic solvent containing age, the 1-acetoyl-3-benzylidene-4-methyl-2 of formula (II) , 5-piper B Qin Er copper m · Is mV 11 — ^ ϋ ίΛΜΛ ϋ— flu ..T outfit (please read the precautions on the back before filling this page)

1. Printed by Beitong Consumer Cooperative of 1T Central Bureau of Standards, Ministry of Economic Affairs.

Prepared by the method of aldehyde treatment of the following formula (III): -18-The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297mm) 5. Description of the invention (12 rvR1 0HCAx ^ \ r2 A7 B7 (m) Ministry of Economic Affairs The Central Bureau of Samples and Consumables prints the R1 and R2 as defined in formula (I) and converts the resulting compounds into their pharmaceutically acceptable salts as appropriate. The appropriate ϋ contains sulfonic acid Absolute, sodium monobasic acid, benzyl sulfonate, sodium hydride, potassium t-butoxide and triethyl atmosphere. Suitable organic solvents include dimethyl formaldehyde amine (DMF), tetrahydrofuran (THF) and potassium t-butoxide In the example of t-butanol and its mixture. When DMF is used as the solvent, the temperature is generally between 0 and the temperature of the flow, for example, when the acid rake is used as the test, the temperature is 8QX: to 95t : When sodium hydride or t-butadiene potassium is used as the ore, the reaction mixture is generally heated from 0Ό to room temperature or 45t. The reaction time can be 1 to 4 hours, such as 2 to 3 hours. Compound of formula (II) It can be prepared according to the method described in the following Reference Example 1. The compound of formula (III) can be prepared from commercially available starting materials according to a known method For split preparation, the specific starting materials and methods used depend on the persistence of aldehydes. For example, aldehydes of formula (III), where one of R1 and R * is hydrogen and the other is The above-defined formula -COR3 base blue, the aldehydes can be derived from the compound of formula (IV) in organic solvents (where one of RU and RM is hydrogen and the other of ΓΥ " 11 (iy) is 40 011, (: (^ (Where $ is halogen) or-(: 0 (0 (: 01? ') (Where !? -19 This paper scale is applicable to the Chinese National Standard (<: Yang) 84 specifications (210 Torr 297 mm) γ —installed ------ ordered ------ f, ^ 17 (please read the notes on the back before filling this page) A7 B7 printed by the Industrial and Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs V. Description of the invention (13) is Ct-Cs alkyl)) prepared by treatment with oxygen of the formula H-R3 (where R3 is as defined above); when R11 or R * 1 is -COOH, the anti-molecular It can be carried out in the presence of erbium. When R11 or Ϊ? 21 is -COOH, suitable coupling agents include 1,3-dioxenyl diimide and 1-ethyl-2- (2-? Morphoethyl) sulfonated diiminemethyl-p-toluenesulfonate and 2-amino-1-methylpyridine Anchor iodide. When R11 or Rai is a -COX or-(: 0 (0 [: 01? ') Base garden as defined above, the reaction may optionally be present in the presence of a tertiary ammonia such as Et 3 N or pyridine. The preferred solvent is diazomethane. The activated compound of formula (IV) (where Ri 1 or RM is -COX or -CO (OCOR ') can be selected from the conventional methods in organic synthesis. Compound (IV) (wherein R11 or Rai are carboxy-C00H, respectively). For example, a compound in which R11 or R21 is -COX can be prepared by treating a carboxyl compound with a halogenating agent such as SOC12, PC13, oxalane, or PC1S. 1? 11 or 1? 21 is-(: 0 (() (: 0 !? ') compound can be prepared by treating the carboxyl compound in the presence of tertiary ammonia with Ci-Cs alkyl benzoate, As in the presence of Et3N. Treated with EtOCl or iBuOCOCl. In this example, it is generally convenient to directly treat the resulting mixture with ammonia H-R3. When R3 is the base of the above formula (A) (where η is 1 and v When 1), oxygen H-R3 can correspond to the nitro compound of formula (V) (where B, R4 and N ° 2-0fCHiN ^ RS (V)

Rs is prepared as defined above in formula 00). This original reaction can be used in methanol-20-this paper uses the Chinese National Standard (CNS) A4 specification (210X297mm) (please read the precautions on the back before filling this page)-install. Order the Ministry of Economic Affairs Printed 307760 A7 B7 by Bureau Cooperative Consumer Cooperative V. The description of invention (14) is properly carried out using iron powder and concentrated a-acid, which is generally in the cascade. In addition, this reaction can also be carried out using hydrogen and the rake catalyst located on the master. The compound of formula (v) can be used in an organic solvent containing a base by the compound of formula (VI) (where n is as defined in formula (V) and X is halogen) by

Ammonia of formula (VII) (where R4 and π images are as defined in formula (A) above) is prepared by R4 H— ((VII) R5. The organic solvent is generally DMF or ethyl sperm, and the general test & K2C03. The temperature is generally from room temperature to 1QOTC, such as from 60T: to 80t :. The mule time is generally 1 to 30 hours, such as 2 to 24 hours, and generally about 8 to 12 hours. When R3 is the base defined by the above formula (A) (where η is 0 and v is 1), ammonia H-R3 can be guessed from the original formula (VIII) (where β is 1, 2 or 3 and

R4 and R5 are prepared as defined in formula (A) above). This reaction can be carried out in glyoxyl dimethyl ether containing LiAlH * at a temperature between 40¾, generally from Ot: heating to room rent, such as from 0 to 20T. Other H-R3 atmospheres can also be prepared by conventional methods using similar starting materials or commercially available S. The formula (VIII) can be guessed in an organic solvent containing sickle, by combining the compound of formula (VII) as described above with the compound of formula (X) (where X is halogen and · as in formula (-21-this paper size applies China National Standard Car (CNS) A4 specification (210X297mm) ------- γ --- installed ------ ordered ------ f / 丨: -.I r (please first Read the precautions on the back and fill in this page) A7 B7 15 5. Description of the invention (.NCfCHz-

-X -1 (X) as defined in VIII)). A suitable solvent is acetonitrile. Available experience is K2C03. The reaction is generally carried out under pseudo-flow temperature of the solvent for 1 to 30 hours, such as 1 to 20 hours. The aldehyde of formula (III) (where R1 is the base of formula (D)) can be used in an appropriate solvent

OHC

(XI) -------- f I installed-*. (Please read the precautions on the back before filling in this page) The R1D and R11 printed by the Central Bureau of Industry and Commerce, Beigong Consumer Cooperative as above Defined) to prepare for processing. Such solvents include aqueous THF. Next, the compound of formula (XI) is prepared by first treating 4-hydroxybenzaldehyde with 1.5M bream hydroxide and then with epinitrohydrin. The reaction is generally carried out at about 501C for about 5 hours. The aldehyde of formula (III), wherein R1 is the base plaque of formula (E) (where r is 2 (compound 5.1)), can be prepared by the method described in Reference Example 5 below. The corresponding aldehydes (where r in formula (E) is 1 or 2) can be prepared by a similar method, but using 4-¾-methylbenzoic acid or 4- (3-bromopropyl) benzoic acid instead of the starting material 4- (2-bromoethyl) benzoic acid. The aldehyde of the formula (III) can also be prepared by treating the nitrile corresponding to the formula (XII) with formic acid and (χιι) Raney Nei, as described in the following Reference Example 7-22-This paper size is applicable to China Standard (CNS) Μ specification (210X297mm) Printed A7 _B7_ printed by the employee consumer cooperative of the Central Bureau of Economic Affairs of the Ministry of Economy V. Description of the invention (16) The compound of formula (I) can be converted into a medicinal compound by a known method Accept the salts and convert the salts to free compounds. Suitable salts include those made with pharmaceutically acceptable inorganic or organic acids. Examples of inorganic acids include hydrogen acid, acid and orthophosphoric acid. Examples of organic acids include p-toluenesulfonic acid, methanesulfonic acid, galactaric acid and oxalic acid. Compared with the corresponding sensitized cells, cancer cells that exhibit multi-resistance are called MDR cells, and their intracellular drug accumulation is reduced. Researches have been carried out on MDR cell glands derived from living cells, and it has been found that MDR is often combined with the enhanced performance of drug-binding cell membrane glycoproteins (P-gp). The P-gp system acts as an outflow pump for many hydrophobic compounds, and the P-gp is screened with pure strips to carry out the transformation and dyeing studies. It has been found that excessive expression of P-gP can make cells become MDR phenotypes: see Ann. Rev. Biochem. 5A 137-17 1 (1989). The function of P-gp in normal cells is to send out endotoxin from cells. There is evidence that excessive performance of Jianqian P-gP can play a role in multi-drug resistance. In many human pruritus types-leukemia, lymphoma and malignant tumors. P-gP BRNA or protein increase has been measured. Furthermore, in some cases, it has been found that «in the swollen box living group that has relapsed after chemotherapy, the amount of P-gP will increase. Inhibition of the role of P-gp in P-gP occult MDR has been shown to lead to a net accumulation of anti-cancer cells in cells. For example, the conventional seal channel blocker Verapaail has been shown to make MDR cells resistant to the periwinkle organism Kaminwe (see descriptions outside the law and thigh meat: Manchu Research. 41.1967-1972 (1981)) ^ The The mechanism of action proposed in the literature includes competition with anti-pruritus to bind P-gp. The range of non-structural anti-heavy agents that act with this mechanism includes such as -23-This paper scale is applicable to China National Standard (CNS) A4 specification (; 210X 297 mm) --- ^ ---.- --Λ— 装-(Please read the precautions on the back before filling in this page) Order 307760 A7 B7 5. Description of the invention (17) tan〇j (ifen (N (Jvaldex: ICI) and related compounds, and Cyclosporin A And its derivatives. (Please read the precautions on the back before filling this page) The compound of formula (I) and its pharmaceutically acceptable salts (hereinafter referred to as "the compound of the invention"), tested in biology Zhongji has found that it has the activity of adjusting multi-drug resistance. The test results are listed in Table 3 below. The compound of the present invention can therefore be used as a multi-drug resistance regulator, that is, the resistance resistance agent, Or RMA ^ The compounds of the present invention can modulate poly-resistance, for example, reduce or eliminate them. The compounds of the present invention can therefore be used in a method of strengthening cell lineage agents, the toxic agents are agents that are cytotoxic to swollen cells. One method involves, for example, when exposing the gall cells to the cell in question In the case of toxic agents, one of the compounds of the present invention is administered to swollen cells. The therapeutic effect of chemotherapeutic or inhibitory swollen agents can thus be enhanced. Multidrug resistance of tumor cells to cytotoxic agents during chemotherapy can be reduced or eliminated. The Ministry of Internal Affairs and Communications, Beigong Consumer Cooperatives printed the compounds of the present invention can also be used in the treatment of diseases with pathogens that exhibit multiple resistance, such as multi-drug resistant paralysis (Plasmodium falciparum), Tuberculosis, Leishmania disease, and amoebiasis, etc. This method involves, for example, administering the compound of the present invention (separately, simultaneously, or mine) together with an agent that exhibits multiple resistance to the pathogen. The therapeutic effect of the agent can be strengthened. Human or animal patients suffering from sleeping boxes can be treated by including a method of administering a compound of the present invention to a swelling that is resistant to chemotherapy. The compound of the present invention pseudo-intensifies the The effective amount of cytotoxicity of chemotherapeutic agents is administered. Examples of chemotherapeutic or pharmacological agents for suppressing frost cream include, for example, Changchun Xinyu and Chang-24. (〇 ~ 5) Eight 4 specifications (210 to 297 mm) A7 B7 printed by the Beigong Consumer Cooperative of the Central Bureau of Economic Development of the Ministry of Economic Affairs 5. Description of the invention (18) Periwinkle bioassay such as spring flower test; such as daunorubicin and Anhuisu's anthracyxline resistance; actinomycin D; taxanes such as yew yeast: epipodophyllotoxins such as podophyllotoxin and plicanycin. Furthermore, humans suffering from diseases with multiple pathogen resistance Or an animal, which may include a method of administering a compound of the present invention to treat the resistance of the pathogen to a therapeutic agent. Examples of such diseases include malaria (Xiaqiu malaria Xin), tuberculosis, Leishmania Disease and amoebic dysentery. MDR can also be used to deliver drugs through the cerebrovascular barrier, as well as the treatment of AIDS and AIDS complications. The compounds of the present invention can therefore be used in methods for promoting drug delivery through cerebrovascular barriers, and in the treatment of AIDS and AIDS-related complications. Human or animal patients in need of such treatment can be treated by a method comprising administration of a compound of the present invention. The compounds of the present invention can be administered in different dosage forms, for example, orally in the form of tablets, capsules, dragees or film tablets, liquid solutions or suspensions, or injected parenterally intramuscularly, intravenously or subcutaneously. The compounds of the present invention can therefore be administered by injection or infusion. The dosage depends on various factors, including age, weight, patient status, and route of administration. However, when a compound of the present invention is administered by unicast to an adult, the amount of W used in each administration route is generally 0.001 to 50 Bg / kg, and the most commonly used dose is 0. Heavy) Fan Garden. This amount can be administered by, for example, infusion of pills 1 to 5 times a day, infusion for several hours, and / or repeated administration. The dioxone diketone derivative of formula (I) or its acceptable salt is acceptable -25-This paper uses the Chinese National Standard (CNS) A4 specification (210X297mm) (please read the back Matters needing attention and fill in this I)

, tT The Ministry of Economic Affairs, Central Bureau of Standardization and Printing Co., Ltd. Beigong Consumer Cooperative Printed A7 B7 V. Description of the invention (19) Formulated as a composition for medicinal or veterinary use, the composition also contains a lotus or an animal The load is thin! Or diluted _. The composition is generally pseudo-prepared by the following conventional method and administered in a medicinal or medically acceptable manner. Therefore, an agent containing any one of the compounds of the present invention can be used as a multi-drug resistance regulating agent I. For example, a solid oral form may contain a diluent such as milkweed, vinegar, sucrose, cellulose, corn flour, or potato starch co-existing with the active compound; such as dihydrated silicon, talc, stearic acid, Lubricant of magnesium stearate or calcium and / or polyethylene glycol; such as starch, gum arabic, gelatin, methyl cellulose, carboxymethyl cellulose, or polyvinylpyrrolidone binder; such as starch, brown algae A crushing agent for acid, alginic acid or sodium starch glycolate; a foaming mixture; a dye; a sweetener; a moisturizer such as lecithin, polysorbate, lauryl sulfate. The preparation of these forms can be made in a conventional manner, such as by mixing, granulating, tabletting, sugar coating, or film coating processes. Liquid Qiang dispersions for oral administration can include syrups, emulsions and suspensions. The syrup may contain, for example, sucrose or sucrose with glycerin and / or glycyrritol and / or shanol as a carrier. More specifically, the syrup administered to patients with diuresis may contain as a carrier only a product such as glucagon, which does not metabolize to glucose or only a very small amount of glucose. Suspensions and emulsions may contain, for example, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylvinyl, or polyvinyl yeast as carriers. Suspensions or solutions for intramuscular injection may contain co-existing active compounds such as anhydrous water, olive oil, ethyl oleate, secondary enzymes such as malonylase, and if necessary, a suitable amount of caine Hydrogen cyanide compounds etc. can be used _ 2 6 ~ This paper size is applicable to China National Standard (CNS) A4 specification (210X297mm) ----- · --f I installed ------ order- ----- (Please read the precautions on the back before filling in this page) Α7 Β7 Printed by the Beigong Consumer Cooperative of the Central Bureau of Samples of the Ministry of Economic Affairs V. Invention Instructions (20) Accepted publications. Some compounds of the present invention are insoluble in water. These compounds can be coated in lipids to make sacs. The invention can be further illustrated by the following examples. Reference Example 1: Buethynyl-3-benzylidene-4-methyl-2,5-hemazindi_m_ 1,4-diethylbenzyl-2,5-a®B is dicopper ( As described by Marcuccio and Elix in Aust. J. Chea, 1 984, 3 7, 1 7 9 1) (25.Og, 126 BlDOl) at 130t :, DKF (2 0 0 πl), with three Treatment with amine (17.6lll, 126 naol) and benzaldehyde (13.0 Bl, 126 nmol). After 4 hours, the mixture was cooled to room temperature and poured into ethyl acetate (10Q0 »1) and rinsed with brine three times. Any solid food formed in this step must be filtered out. The filtrate was dried with MgSO * and the solvent I was removed under reduced pressure. The residue was recrystallized from an ethyl acetate / hexane solution to obtain 11.78 g (38%) of 1-ethenyl-3-benzylidene-2,5-piperidinedione. The final compound was placed in a DMF: hexane (1: 5) solution, treated with NaH and Mel and heated to room temperature to obtain the title compound in 57% yield. Participants are energetic ;? ： There is a defeat in the future. Even a cage is prepared with Η-IPamine-27-This paper uses the Chinese National Standard (CMS) Α4 specification (210X297mm) (please read the precautions on the back before filling in this Page) • Installed and ordered * ". 307760 A7 __B7 5. Description of the invention (21)

I— nn t ^ ni 1 ^ 1 ^^^ 1 L 1 ^ 1 (please read the precautions on the back before filling this page) 2.1 Place 4-bromoethylnitrobenzene (2a) under 801C & 2 (: 03 in DMF was treated with buphenylpiperazine for 8 hours. Compound 58c with a yield of 58% was obtained. Then 2c Kojihara, which was treated with male powder and concentrated sulfuric acid under reflux in MeOH 3 hours. The desired amine 2.1 can be obtained with a yield of 40%. Following a similar synthesis route, but using 4-bromoethylnitrobenzene or 4- (3-Austrapropyl) nitrate as needed Substitute 4- (2-bromoethylnitrobenzene) with benzene, and replace 4-phenylsulfazine (2 b) with the appropriate compound of formula (VII) When preparing these other amines, the conditions used in each step are as described above for the preparation of 2.1, but in the preparation of amine 2.9, the original step is to use the fi under Psi in the yeast and support Yu Shuo. In the case of amine 2.4, in the example of amine 2.4, the nitro-genogenous pyridine is accompanied by the hydrogenolysis of 4-aminophenyl to obtain amine 2.4. -28-This paper method standard is applicable to China National Standard (CNS) A4 (210X 297mm)

, TT Printed by the Ministry of Economic Affairs, Central Bureau of Samples and Printing Co., Ltd. S07760 A7 B7 Printed by the Industrial and Consumer Cooperatives affiliated to the Central Bureau of Standards of the Ministry of Economy V. Description of the invention (22) g_1 Compound (IV) N〇 > —OtCHiiraf where a is: Compound VII Amine H-R3 (N °) 2 hci.hn ^ A〇Mq Guang Ya ~ (2.2) 2 ». Οο (2.3) .2 (2.4) 2 0 ^ 0 Η, h (2-5); ^ '—Binding f 〆1. (Please read the precautions on the back first and then fill out this page) The paper size is applicable to China National Standard (CNS) A4 specification (2! 0X 297mm) 307760

A B 5. Description of the invention (23)

--7 ---: --f —installation ------ order ------ f'4 — '(please read the notes on the back before filling out this page) Zhen Gong, Central Bureau of Standards, Ministry of Economic Affairs The size of the paper printed by the consumer cooperative is applicable to the Chinese National Standard (CNS) Μ specification (210 '297 g ** A7 B7

OMe Fifth, the invention description (24) Participate in the case of the old people: 2

HcmN ^^ 〇Me 3a OMe 3.1 Combine 6,7-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride (3 a) in acetonitrile containing K2C03 with I flow down for 24 hours. Compound 3b can be obtained in 92% yield. Next, 3b was treated with LiAlH * in glyoxygen dimethyl ffi at room temperature overnight. Then raise the temperature to 40¾ and hold the ore for 30 minutes. The amine 3.1 with a yield of 98% can be obtained. Following a similar synthetic route, but if necessary, the conditions of the first step were neglected and the appropriate compound of formula VII was substituted for 3a. Table 2 shows examples of other H-R3 amines prepared. ——.--- ^ —— f 丨 installed ------ order ----- γ ring |; (please read the precautions on the back first and then fill out this page) Cooperative printing-31 This paper bearing standard is applicable to China National Standard (CNS) A4 specification (210X 297mm) 307760 A7 B7 Printed by Beigong Consumer Cooperative of the Central Standardization Bureau of the Ministry of Economic Affairs 5. Description of invention (25) ^ __ 2 Type VII Chopsticks for the first step of the compound. Amine H-R3 (No) ΗΝ ^ ΝΜβ K2C〇3, ClCHjCN, CHjCN reflux 20h / \ Ji NMe Η2Ν ^^ \ __ / (3.2) H_N 、 / Ph CH 、 Ph K2C〇 3 C1CH2CN, CH3CN reflux '24h Me 1 H2N ^^, 〇 <, Ph (3.3) oo K2C〇3 cich2cn, ch3cn rush 24h H2N ~ oo (3.4) HC 丨 HΝ ^ Λ ^ 〇Μβ K2C〇3 C1CH2CN , ch3cn torrent 24h nrrOM (3-5) ΓΥ〇Μβ K2C〇3, C1CH2CN ch3cn reflux 4h ^ γ0Μ · Ηι »« ^^ Ν ^^ Λ !! χΛ.0Μβ Um (3.6〉-^ --- ,-γ I installed-- (please read the precautions on the back before filling in this page) Order-32 -This paper uses the Chinese National Standard (CNS) A4 specification (210X297mm) A7 B7 5. Description of the invention (26 # 考 奋 皤 甎 4 ·: 黧 他 anti-SH-IP: »靱 备 1. (3,4- 二Oxygen-phenylethyl) methylamine

4a 〇 Λ

4b

MeNH

(Please read the precautions on the back before filling out this page)-Pack · 4.1 Treat 2- (3,4-dimethylmethylphenyl) ethylamine with CHO2Cl2 containing triethylamine at -78t with MeOCOCl and Heat to overnight. Compound 4b can be obtained in 9% yield. Treat 4b in Ot :, THF, treat with LiAlH * and heat to room temperature overnight. A compound 4.1 with a yield of 91% can be obtained, which can be used as a starting amine for compound 2.9 in Reference Example 2. 2. ΗζΝ- (ΠΗρ) a-NMp-nHaf: HPhz 2,2-diphenylethylamine was treated with (CF3C0) 20 in Et2O at 0υ for 1 hour. The obtained quantitative yield compound (Ph) 2-CH-CHa-MHCOCF3 was treated with KH and then with Mel and 13-crown-6 at room temperature for 24 hours at 0 * C in THF to obtain the yield 91% of (Ph) 2-CH-CH2-NMeCOCF3. The resulting compound was treated with 2M NaOH in alcoholic fermentation for 2 hours under a wine stream to obtain (Ph) 2-CH-CH2-NHMe with a yield of 81%, and then it was applied to the Chinese National Standard (CNS ) A4 specification (210X 297mm) Printed by the Ministry of Economic Affairs, Central Bureau of Standards and Services, Zhengong Consumer Cooperative, printed by the Ministry of Economic Affairs, Central Bureau of Standards, and Beige Consumer Cooperatives. The treatment was carried out for 24 hours under the stream to obtain (Ph) 2-CH-CH2-NMe-CH2CN with a yield of 83%. When this compound was used in glyoxyl dimethyl ether at room temperature, LiAlH * Liyuan was used for 2 hours to obtain 90% yield of standard amine (compound 4.2).

4.3 Place compound 4c in CHZC12 containing 2-amino-1-picoline anchor iodide and triethylamine, with 6,7-dimethylamino-1,2,3, 4-tetrahydroisoquine Treatment. The solution was heated to room temperature overnight. Ke »Compound-34 with a yield of 93%-This paper scale is applicable to the Chinese National Standard (CNS) A4 ^ t grid (210X 297mm) (Please read the precautions on the back before filling this page) 307760 A7 B7

Me〇2C

OMe

V. Description of the invention (2S compound 4d, treated with trifluoroacetic acid in diazomethane at room temperature for 30 minutes. After being developed with acetone, compound 4e with a yield of 10% can be obtained. Compound 4e under 10¾, In THF, treated with LiAlH * and left overnight to warm to room temperature. The compound 4.3 with a yield of 75% can be obtained. Example of the gangster douwei R: Lu 5.1 Xiyu prepared H02C ^^^ 5a

Me02C ^^^ — ^ ---.--- r I installed ------ ordered ---- ΓΊΙ: (please read the precautions on the back before filling in this page) Central Bureau of Standards Printed by Beigong Consumer Cooperative

DC

HOCH

5d-35 — The paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) A7 B7 V. Description of the invention (29) Compound 5a is treated under CH2N2 for 7 hours under 01 in THF. 5b with a yield of 98% is available. Next, compound 5b was treated with 6,7-dimethyl «yl-1,2,3,4-tetrahydroisoquinoline hydronitride in DMF containing K2C0 3 at room temperature for 5 days to produce 5c with a rate of 56%. Compound 5c was broadcast in the THF at room temperature for 1 hour by LiAlH * treatment for 5 days (yield 80%). Then it was treated with CH2Clj§ solution of NaOAc buffer and pyridinium europium chlorochromate (PCC) in CH2H2 at room temperature for 16 hours. Compound 5.1 was obtained in 25% yield. Participant Fen_Li fi: formula (T Π ^ Lu Ai's method of preparation 1 is listed in Table 3 below, the aldehydes of formula Ilia by 3-methyl benzoic acid in Ot: under, containing 2-child- 1-Methylpyridine anchor iodide in CH2Cla was prepared by treatment with the appropriate amine H-R3 (prepared by one of Reference Examples 2 and 3). The reaction was heated to room temperature overnight. Table ·? : Type: TTTa ^ Pavement (Ilia) nn In ii ^ f n-^ — ^^ — ^ 1 SHIV m · HI. * 0¾. (Please read the note on the back ^ item first and then fill in this page). Printed by the quasi-bureau of negative labor consumer cooperatives η ohc / ^^ \ cor3 (Hla) -36-The paper scale is applicable to the Chinese National Standard (CNS) A4 grid (210X297mm). B. Invention description (30) R3 corresponds to the amine Hf ^ 6-1 rry9 ^ 2.2 6.2 j0p-〇Nph 2.1 6.3 JCCC 2.7 S .4 2.9 S.5 〇τγ〇Μ · 3.5 6 .SM ·! 3.6 * 6.29 Ve Ph —NHy ^ X ^ N ' ^ \ ph 4.2 m II m-----I person- .-- ί I (please read the precautions on the back before filling in this page) Order the printing method of the Ministry of Economic Affairs, Central Bureau of Industry and Commerce, Beigong Consumer Cooperative The β type shown in Table 4 below is provided by combining 4-formaldehyde benzoyl The chlorinated compound is treated with CH-C12 containing triethylamine at 0 ° C and treated with the appropriate amine H-R3. In the example of aldehyde S. 32, 4-carboxybenzaldehyde is used to replace 4-methylbenzylacetate. Compound and 2-chloro-Bttidine iodide can be added to the reaction mixture. The reaction is heated to room temperature overnight. The amine pseudo is prepared by one of Reference Examples 2 and 3, or is a commercially available product -37-This paper scale is universal Chinese National Standard (CNS) Α4 specification (210X297 mm) 307760 A7 87 V. Description of invention (31) Constitution 4: Type TTTh ^ Lu Americium, C〇R3 〇HCja nib Central Ministry of Economic Affairs R3 printed by Rongju Bureau of Staff Consumer Cooperative corresponds to amine H-R3 β.7 -ΝΗ 人 J 2 · 2 '6.8 / \ _NH ~ NWNMe 3.2 6.9 rrv0Me 3.1 • 6.10 -〇〇Section products 6.11 / ~ Λ _Γ ~ \ Commercially available products 6.12 -Ν ^ ΝΜβ \ ^ / Commercially produced 5r 6.13 ~ eight-ΝΗ \ __ / Coin-sold products 6.14 _νη ^ λν /-^ 0 λ = / \ _ν Commercially available products 6.15 χΤ〇Χ: 2.7 6 .IS ^ 00 -N „iJ 2.3 38. The size of this paper is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) — i — ^ 1 —binding {mu (please read the back first Note to fill out this page) V. description of the invention (32) A7B7 Ministry of Economic Affairs Central Office staff standard rate consumer cooperatives printed

-39-This paper uses the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ---; ---.--- r -installed ------ order ----- -Ti (Please read the precautions on the back before filling in this page) 307760 Α7 Β7 V. Description of the invention (33) Method 3 Treat the compound of formula (XI) as defined above at room temperature in THF with an aqueous solution of HNMea for about 2 hour. The following formula (ΙΠ) can be produced with a yield of 91%. 〇HC ^ 0H 〇

N:, Me 'Me 6.28 Fang Nong 4. The compound 5d described in Reference Example 5 was treated with 4-hydroxybenzaldehyde in THF containing triphenylphosphine and diethyl azide carboxylate under 0Ό The aldehyde of the following formula (III) was obtained with a yield of 40%. Printed by the Beigong Consumer Cooperative of the Central Ministry of Economic Affairs

The aldehyde of the following formula (III) can be produced with a yield of 50%.

OHC

6.31 40-The size of this paper is applicable to the Chinese National Standard (CNS) Α4 specification (210Χ297 ong) ---; ---, --- r I installed ------ ordered ------ fi ( Please read the notes on the back first and then fill out this page) A7 B7 5. Description of the invention (34) Laofenfenyou; Example 7: Road 7.1 Xixi Yueho2c

CIOC

7a 7b

Br 7c

OMe

N OMe 7d

OMe-: ---; --f I installed ------ order ----- eight "(please read the precautions on the back before filling in this 1) Beigong Consumer Cooperative of the Central Bureau of Economic Affairs of the Ministry of Economic Affairs Print

OHC

7.1

N OMe -41-This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (2 丨 OX 297mm) A7 B7 V. Description of invention (35) Use 7a in toluene with SO Cl2 and a catalytic amount DMF was treated under reflux for 4 hours. The obtained compound η was treated with 4-aminobenzyl mash in CHZC12 containing triethylamine at 01C. The reaction mixture was heated to room temperature overnight. Using flash chromatography (1: 1 hexane: ethyl acetate) to obtain 7c with a yield of 33%, it was taken in acetonitrile containing K2C〇3 with 6,7-dimethyl «yl-1,2 , 3,4-Tetrahydroisoquinoline was treated under the stream for 18 hours. By flash chromatography (ethyl acetate containing 10¾ methanol), a 7d yield of 25% can be obtained. Treat 7d with formic acid and 50% Raney water slurry at reflux for 2 hours. Aldehyde can be obtained with a yield of 71% 7.1 Ο Cell storage example 1: Formula (〇 compound Xi prepared equipment will refer to the 1-ethynyl-3-benzylidene-4-methyl-2,5- By treating the aldehydes prepared in one of the reference examples 5, 6 or 7 in the DMF containing Cs2C03 at a temperature of 80 to 90T under the temperature of 80 to 90T, the compounds of formula I listed in Table 5 can be prepared. -; ---.--- f I installed ------ ordered ------ ^ α (please read the precautions on the back before filling in this page) Printed by the Cooperative Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs The size of the paper used is in accordance with the Chinese National Standard (CNS) Α4 specification (210Χ297 mm) 307760 A7 B7 V. Description of the invention (36) The compound of formula I printed by Beigong Consumer Cooperative of the Central Bureau of Economic Development of the Ministry of Economic Affairs 6.7 9006 S.8 9007 6.9 9008 6.10 9022 6.28 9023 β .11 9049 S. 1 9051 6.12 9052 5.13 9053 S _ 14 9054 β. 15 9064 β. IS 9065 6.17 9070 6.13 9071 6.19 9076 δ.20 9079 β .21 9080 6.2 9083 G. 22 909S Β. 23 9103 6.24 9104 5.1-9115 β. 25 9116 6.25 9117 6.3 9123 6.5 9136 6.6 9137 β .4 9133 6.27 9161 β.29 9163 6.30 9176 β .31 917 7 7.1 9190 β .32 9200 '-ίBinding τ " (Please read the precautions on the back before filling in this page) -43-This paper wave scale is applicable to China National Standards (CNS) Α4 specification (210Χ 297mm) Economy Printed A7 _B7_ by the Ministry of Central Provincial Bureau of Labor and Consumer Cooperative V. Description of the invention (37) Compound 9 05 2, 9 0 7 1, 9 0 7 S, 9116, 9104, 9 05 3, 9 0 5 4, 90 64 And 9051 in the final step, by making the gaseous HC1 bubble through the solution of each compound in THF to convert each compound to its hydrochloride alpha The acid salt (rather than the free acid) was subjected to the biochemical test described in Example 3. Fen_Example;?: Lozenges weighing 0.15 g each and containing 25 ng of the compound of formula (I) or its lozenges It can be prepared according to the following method: For 10.OQO ingot cutting compound of formula (I) or its salt lactose (8Q0 g) corn starch (415 g) talc (3Q g) magnesium stearate (5 g) Mix the compound of formula (I) or its salts, lactose and half of corn starch. Next, the mixture is forced to pass through a sieve of Q.5 BB mesh size. Corn starch (10 g) was suspended in warm water (90 ml). The resulting slurry was used to granulate the powder. The resulting granules were dried and crushed into small pieces on a sieve with 1.4 · β mesh size. Add the remaining amount of starch, talc and magnesium stearate and mix carefully to make lozenges. The size of this paper is applicable to China National Standard (CNS) A4 (210X297mm) -j binding J · ^-.. 1 (please read the notes on the back side and fill in this page first). A7 B7_____ printed by Industrial and Consumer Cooperatives V. Description of the invention (3δ) Example 3: Test of the compound of formula (I) and its salts as MDR regulators Gland AR 1.Q at 37C, 5% (: 02, cultured in RPMI 1640 medium containing 10% fetal bovine blood and 2 ηΜΜ glutamic acid. In the role of trypsin (0.25% trypsin, 0.2 gl〃, EDTA) after the cells are transferred between the parental cell gland in the case of 1 to 2 00 and 1 to 20 00, and in the case of the MDR resistant para gland in the case of 1 to 2 0 And 1 to 2QQ transfer for sub-transplantation. 1. Box storage experiment inoculated AR 1.0 cells into 96 opaque culture dishes (Canberra. This analysis medium contains a flooded velvet serotonin (DNR), A mixture of cytotoxic agent and unlabeled DNR (0.3 u Ci / ml; 2 / iM). Dilute the compound of formula (I) to 5 with analytical medium To the concentration range of ΙΟΟιιΜ. Before washing and measuring the radioactivity attached to the cells, the cells were cultured at 37P for 1 hour. The results are expressed in% of the maximum accumulation volume, of which 100% of the storage mole refers to the concentration 100 In the presence of, the measured accumulation may be IC50. The results obtained are shown in the following Table 6. This paper is again applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) ---; ------ -f I installed ------ order ------ f / (please read the notes on the back before filling in this page) 5. Description of the invention (39) ^ __ Q. A7B7 Central Sample Bureau of the Ministry of Economic Affairs Industrial and consumer cooperatives print compound numbers ICs a (u Μ) Maximum accumulation (%) Accumulation Dong 9006 0.4 9007 30% 9003 3.0 9022 7.0 9023 30% 9049 20% 9051 0.15 9052 100 9053 50 9054 32% 9064 0.3 9065 6 90 7 0 S 9071 5 9076 44% 9079 30 9030 18% 9033 2 9095 «20% 9103 20% 9104 5 9115 5 9116 4 9117 5 9123 3 9136 Q .9 9137 2 9133 0.8 9161 20% 9163 2.0 917G 1.000 9177 X.750 9190 0. 350 9200 L. 700 -46-The paper is suitable China National Standard (CNS) A4 specification (210X 297mm)-^ ---, --f I installed ------ ordered ------ f. ^ (Please read the notes on the back first Please fill out this page again) A7 B7 Printed by the Consumers ’Cooperative of the Central Bureau of Economic Development of the Ministry of Economic Affairs 5. Description of the invention (40) 9 Intensive determination of the compound of formula (I) in AR 1.0 cells by Ai Biao Ability to be toxic. In the initial proliferation analysis, the compound was titrated to Axin (0.86%), which had a fixed degree of silylate, and it was not toxic to AR 1.0 cells in the presence of a single mole. After 4 days of cultivating with anhuisu, the colorimetric sulphorhodaBine B analysis was used to determine the proliferation phenomenon (Skehan eJL a ±; J. Natl. Cancer Society. Ϋ pp 1 1 0 7- 1 1 1 2 (1 9 9 0)) . The results are shown in Table 7. Compounds that make AR 1.Q cells sensitizing to Q.86 township anhuisu without congenital toxicity were selected for further study. In the presence of a fixed concentration of the compound of formula (I) at the maximum secondary toxicity concentration measured by the preliminary experiment, Xihao was prepared for 4 days with the concentration of Q.Ql ηΜ-5 0 Qing's A Huisu. Ske han eJL a_L, k c ± L. Described the quantitative proliferation. The IC5tI (the concentration required to reduce the proliferation of the untreated control group by 50%) and the ICu obtained by adding the compound of formula (I) to estimate the enhancement index (PI): ICso PI when the anemone is alone = —- ICSD results when A Huixue plus RMA are shown in Table 8: ---: ---.--- f I installed-- (Please read the notes on the back first Please fill out this page again)

A This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (2 丨 0X297mm) 5. Description of the invention (41) Discarded 7 A7B7 Printed compound number 'Compound and M' Thrombosis (ICso u Μ) (ICso u Η) 900S 2 0.04 9008 10 2.0 9022 35 0.3 9023 10 5.0 9049 2 0.2; 9051 2 0.01 9053 40 4.0 9054 50 30 90S4 2 0.01 9055 2 0.2 9070 40 4.0 9071 6 0.2 9079 2 1.7 9083 3 0.1 9104 40 0.05 9115 60 2.0 911S 8 1 9117 a, 3 9123 10 2 913S 13 2 9137 12 · 4.5 9138 a 1.0 9163 10 0.5 9176 10 0.2 9177 15 0.5 9190 15 0.05 9200 13 0.3 -48-This paper size is applicable to China National Standards (CNS) A4 (210X 297mm) ^-t I binding ------ Z (please read the precautions on the back before filling this page) 5 Description of the invention (42) A7 B7 Qu servant. Refer to the servant group number (i.e. RMA under the MU) 9006 1000 9022 5 9049 15 9051 2000 9064 750 90GS 15 9071 4 9079 3 9104 17 913δ 25 9138 333 9163 5.7 9176 300.0 9177 75.0 9190 75.0 (measure d at: 0.3μΜ) 10.0 (measured at 0.1μμ) 3.3 (measured at: 0.03μΜ) 1.4 (measured at 0.01μΜ) ------- · --- r -¾ clothing ----- -1T ------ ^ (Please read the precautions on the back before filling in this page) The paper printed by the Ministry of Economic Affairs Central Bureau of Customs and Industry Beigong Consumer Cooperative is applicable to the China National Standard Falcon (CNS) A4 specification (210X297 C7) A7 307760 B7 V. Description of the invention (43) Dou Ali 4: The compounds and salts prepared by Examples 1 and 2 of Taixin Xixi compound are described by mass spectrometry, microanalysis and proton nmr technology Its special. These results are described in Tables 9 and 10: (please read the notes on the back before filling this page) The Central Standard Falcon Bureau Employee Consumer Cooperative printed this paper. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) A7 B7 V. Description of the invention (44 ϋ ,, —d Printed micrographics analysis surface of the Beigong Consumer Cooperative of the Central Bureau of Economic Development of the Ministry of Economic Affairs 1 68.26 6.42 9.81 · 68.09 6.44 9.81 64.3 5.80 11.6 66.0 5.30 10.3 Estimated value 68.39 6.46 9.97 64.3 5.85 12.0 66.1 5.35 10.3 OX: z 〇zr z knock nnr data *. 2.35 (6H.S). 2.41 (lH.dd). 2.57 (lH.dd). 2.99 (3H.s). 4.02 ( 2H.m). 4.08 (lH.m). 7.00-7.03 (3H.m). 7.28-7.42 (8H.m). 7.95 (lH.b) 2.75 (3H.s). 2.88 (3H.s). 3.10-3.30 (4H.bs). 3.35 (4H.bs). 6.85 (lH.s). 7.12 (lH.s). 7.32-7.40 (5H.m). 7.48 (2H.d). 7.65 (2H. d). 10.30 (lH.bs) 2.96 (3H.s) 3.40 (4H.bs). 3.99 (4H.bs). 6.98 (lH.s). 7.20 (lH.s). 7.43-7.56 (7H.in ). 7.82 (2H.d). 7.89 (2H.d). 8.12 (2H.d) 10.43 (lH.s). 10.83 (lH.s) solvent / magnetic field oo rr o d-DMSO / 300MH2 1 i Ό Mass spectrometry data ____1_U_ Chess I 〇〇 UJ FAB + Mass (strength) 422 (100) oo ·-* lT) " W * 'w »< n < n cn 509 (40). 508 (45). 331 (35). 178 (100) Molecular formula C? 4H2; N304 C2SH26N4〇3 HC1 i C3UH2iN404 HC1 No. 1 9023 9052 9054 (please read the precautions on the back before filling out this page) This paper size uses the Chinese National Standard (CNS) A4 specification (210X 297 mm ) Fifth, the invention description (45) 3! Then A7 B7 Ministry of Economic Affairs Central Standards Bureau employee consumption cooperative printed lH m «r data 2.87 (3H.s). 2.89-3.23 (8H.m). 3.73 (2x3H.s ), 4.20-4.54 (2H.m). 6.78 (lH.s). 6.82 (lH.s), 6.88 (lH.s). 7.09 (lH.s). 7.20-8.07 (13H.m). 10.30 ( lH.s). 10.62 (lH.s). 11.01 (lH.bs) 2.35 (3H.s), 2.49-2.73 (lOH.m). 3.02 (3H.S). 3.59 (2H.m). 7.07 ( lH.s). 7.28-7.44 (6H.m). 7.50 (2H.d). 7.86 (2H.d) 2.76-2.90 (6H.m). 3.02 (3H.s). 3.61-3.70 (4H.m ). 3.85 (2x3H.s) .6.55 (lH.s). 6.64 (lH.s). 6.94 (lH.bs). 7.07 (lH.s). 7.27-7.43 (6H.rn). 7.47 (2H. d). 7.85 (2H.d) 3.02 (3H.s). 3.35-4.07 (8H.m). 6.56 (lH.t). 7.08 (lH.s). 7.29-7.43 (6H. «i). 7.50 (2H.d). 7.55 (2H.d). 8.83 (2H.d) 2. 64-2.75 (6H.m ;, 2.87 (2H.m). 3.04 (3H.S). 3.23-3.31 (4H.ni). 7.04-7.10 (3H.m). 7.12 (lH.s) 7.23-7.42 (9H.m). 7.55 (2H.d). 7.59 (2H.d). 7.78 (lH.s). 7.96 (2H.d) 2.86 (3H.s). 2.92-3.18 (6H.m). 3.36 -3.48 (2H.in). 3.73 (2x3H.s). 4.22-4.55 (2H.m). 6.78 (lH.s). 6.82 (lH.s). 6.89 (lH.s). 7.09 (lH.s ), 7.28-8.14 (13H.m) 10.29 (lH.s). 10.69 (2H.bs) i volume / magnetic field 1 d6-DMSO / 400MHz Έ O i · — C0C13 / 400MHz go § C0C13 / 400MHz d6-DMSO / 400MHz quality clamp data mode 丨 00 LU LU UJ oo UJ C / l UJ quality boy (strength) 643 (100) 474 (100) 567 (100) 1.495 (20) .331 (100) 680 (100) 643 (22). 348 (30). 206 (100) Molecular formula C39H38N205 C33H34N405. 28 " 2 八 〇3 CJ9H3aNAHCl 9006 9007 9008 9022 9049 9051 ^ * ^ 丨 binding f- ^ (please read the precautions on the back and then fill out this page) This paper size is easy to use Chinese National Standard (CNS) A4 specification (210X297 Mm) 307760 A7 B7 V. Description of invention (46) Printed by Beigong Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs

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(Please read the precautions on the back before filling out this page) This paper uses the Chinese National Standard (CNS) A4 (210X297mm). The Central Sample Bureau of the Ministry of Economic Affairs of the People ’s Consumer Cooperative printed the B7. Invention Description (47) Male a C 3 = '-ο 1.62 (2Η.ιη). 1.88-2.04 (2H.m). 2.40-2.82 (8H.m). 2.89 (3H.s). 4.77 (lH.s). 6.87 (lH .s). 7.09 (lH.s). 7.17-7.80 (17H.m). 8.02 (2H.d). 10.19 (lH.s) 2.64-2.90 (8H.m). 2.86 (3H.s). 3.68 (2H.S). 6.88 (lH.s). 6.90-7.04 (2H.m). 7.10 (lH.s). 7.22-7.48 (9H.m). 7.72 (4H.m). 8.00 (2H. d). 10.19 (lH.s). 10 67 (lH.s) 2.74 (3H.s). 2.70 (2H.m). 2.80 (2H.m). 3.58 (2H.s). 3.70 (2H.s ). 6.88 (lH.s). 6.90-7.05 (2H.m). 7.10 (lH.s). 7.20-7.50 (9H.m). 7.65-7.80 (4H.m), 8.00 (2H.d). 10.27 (lH.s). 10.62 (Ills) 2.5-2.6 (6H.m). 2.75 (2H.m). 2.85 (3H.s). 3.11 6.75 (lH.t). 6.88 (lH.s). 6.90 (2H.d), 7.1 (lH.s). 7.2 (3H.m). 7.28-7.49 (7H.m). 7.75 (3H.m). 8.1 (2H.d). 10.15 (lH.s). 10.6 (lH.bs) 2.5 (4H.m), 2.85 (3H.s). 3.11 (4H.in). 3.5 (2H.s). 6.75 (lH.t). 6.88 (lH.s). 6.90 ( 2H.d). 7.1 (1H, S) .7.2 (3H.m). 7.28-7.49 (7H.m). 7.75 (3H.in). 8.1 (2H.d) 2.90 (3H.s). 3.0-4.8 (lOH.m). 6.86 (lH.m s). 7.11 (lH, s). 7.15-7.50 (9H.ni). 7.68 (2H.d). 7.96 (2H.d). 8.77 (lH.bs). 10.34 (lH.bs). 10.42 (lH .b) 5? w inverse fSl Έ 〇〇δ υο »fsj g rr g 1 1 oo on g 1 NJ i 〇 ^ 3- g 1 d6-DMSO / 400HHz Pvj X ◦ r ~ o CJ m irrigation. as« h »* U1 LU ►—-tb— * _ 揃 s vo CO v〇LD 1 ·· _ ·. c〇o • w · &t; —t cnj un CO § C \ JC \ J U3 608 (15). 291 (100) 612 (87). 175 (100) »of— * > M > · co in SS 0: = ¾ ί = 1 〇δ ozg iT 5 m 1 o GO o a > s O 'sr— * cn ^ " A cn (please read the precautions on the back before filling in this page) The size of this paper is applicable to the Chinese National Standard (CNS) A4 specifications (21 〇X 297 mm) ^ 07760 A7 B7 V. Description of invention (48 economy Ministry of Central Bureau of Standardization and Accreditation Bureau employee consumption cooperative printed 鲡 α C ◦ · 'ε < η < — ·. CO χ: • · t. Γ " Ί VJ3 -W / 1 /) cr jd • * Γ ^ Ν , * Gongyi Gong CM 4- > · r—4 • w »r ^». · * _✓ 1 < v〇 · < 〇rr x: co o «f—4 · CO W ~ CO • · · CNj s CO · (/)*〇.<s〇 ♦ * x: 3ric .CO · — CNJ υΊ 〇) 'CO O 工 O GO • n · n r- »« ~ • CNJ * · -M .SO «Π · · IC Engineering CM -Π C \ J · >» ✓ ✓ cn cn * 〇— ON Engineering L〇 • cn · ♦ C \ J '― ^ r * ^. -L〇s t. O 00 Q Ό 3: · " «3 * —M- ^. w {/) 〇 • 工 ～ CO — CM ^ < — ♦ 1 /) • · · rc ⑺ < ^ 〇— ZC 'CO > 〇〇-^ * nw v ") CP > E, Gong; £ • < s〇CTi CM — ^ · -w > " S • CTs (/ J r -♦ ^ < sO * L〇S · 3: · • C * " 5 < — * P's »X: ^ · • ^ r * co / ^-N fT ~) C \ J LH · · CSJ · Ν «〇 \ ~ 工 • CNJ-· C \ J '― ^ · * " ·»' (/ > C / l CO C \ i., Un m: • r— ♦ rW c \ i < n 'w- 1 /) T: ^ CO CO < yi O ✓ · 3 = CO 〇 * »^ -4 OW * • * 〇 ~ \ cm cm ~ on Lf)» ·. · un zc s 1,0 r— ♦ f «—4 C2 · * " · Gong 00 03 co · 〇 " \ w 工 〇) co * CO X3Z · • C \ ir— " 4 ***% c \ j ^ w S uO O 2: ca r- ~ 4 CM CO LO • · -GO S t / t / jr ^. t ~ T!, Nm / Sw / -S ^ > 2 • U1 C \ j ~ cn 工 ， cr > tn l〇co rc • * 1 1 '(^ η Ό ^ ⑦ Ln σ > co • «· CO CM < Τ» ^ Γ * »« »lD • s« · f " T * ^ £ · * s〇S '• VX jJ Z; cm · σ > -¾- · W Worker C \ i one: C f— ♦ Γ-Ή 〇 > -wr »>--— · * GO '. • 03 CD · L〇CM CO CM r-. 〇CNJ UD BU CO CO ca 〇T) CNJ ^ 'rs «<« — κ S (/) cy > ^ 3T 3: ^ X: s π s — Yiyi Gong lD CTi ^ 3- r * ^ C \ J Ό '― ^ 〇 > CM Γ0 Γ ^. CM I c \ i ^ r >. ^ ¢ / 7 »ί / > " Ο, S _Q CM--CNJ --o 工 工 cn: rx: -ΓΟ CNJ * ^ r— ♦ C \ i > — * (^ «» > — · »> * _ ✓ un un CT3 • LO cr > 2 〇〇om · ^^ c * 1 Π r- * i * 〇t / i, * r- * «N | (« —s oi or co r—4 < n < — ♦ UO. O > · · Jz • 00 t / 1 Γ ** · · — * n ^ • CM C〇 ^ GO L〇S ⑦ S Π U3 □ £ 卜 · * 〇 £ · »r— < · > w« — >-»— S > w» * · " · »Gonggong 00 nc \ j * —i * 〇〇 · -TJ- zc -U1 U1 · C \ j ^ p * ^ ^» • cj ^ σ > un c \ j one'vO 々C \ J 〇 > C \ J (T3 > vO ~~ s' —— · · NS x—v 工 工 n: S 々C \ l O —. ~ · · * x LO ryj Ln ^ CSJ ^ ^ CM • 〇cp O oo V £) ~ 〇〇 · * — · ~ ΙΠ · • · Engineering C \ J (/) 1— * • Γ * · »* Engineering m · WU〇 1. ε Ο · Ο X ♦ CNJ ^ >-& quo t; s Nw / U1 < y) ·. · — 工 S Ό · —, • · »—« · r * · * ·. x: · ^ r vo co «w > CO c • Pn. O CO ~ ♦ cm ^ ε i ε ui · LTi. • Engineering, Industrial Engineering o • ^ 3- r—4 5S W inverse ivj i 〇 ^ ― · Ο CJ rsj § ^ r 1 rsj ioo 5 > § o N4 5 O 々r — · N-* r ~ 〇 «r G. Fsj Έ 〇 ^ rr— * o» W class W. ►—t ►— · LU t ~ -4 ϋΟ UJ h— · S moo O CNJ fH * »—» w〇〇CM — 1 * " " · in > -N〇un «—i / '« ― / a > un C \ jr ^. un cm / «— s § 奈奈 L〇cr > O ") -* ^ 1 P ^. (-^ LH VO if—H CM 3 »o M '4 σ > CM UJ or ^» ^ > o in ιΛ f-1 (M ci *%% t- »2? 5 c ^ 1 m r- * 1 '< ON L〇3 cn g GPi GO CNJ v〇n》 _ * σ' »I m IIII n L. inmn I-- 丁 I __ n«, 1 0¾. i 1. (Please read the precautions on the back before filling out this page) This paper size is applicable to China National Standard (CNS) A4 (21 ο X 297 mm) 307760 A7 B7 5. Invention description (49)

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Printed by the Ministry of Economic Affairs, Central Bureau of Standards, Employee and Consumer Cooperatives, ΠΑΓ data agent / magneto-contrast I x 〇〇〇 quality braid number trout: chess-style k · »* UJ quality" (strength> 620 (32) 1 molecular formula 1 C3? H40N4 〇5 9200 7 5 The size of this paper is applicable to the Chinese National Standard (CNS) A4 specification (210X297mm) ^ --- suspicion--r- 坤 衣 ------ tr (Please read the precautions on the back first Fill in this page)

Claims (1)

0 6. Patent application scope 1. A piperazine dione derivative of formula (I): (I) wherein R1 is pseudo-selected from: -argon-formula- (NH) t-COR3 group, where t is 0 Or 1 and R3 is selected from: (Please read the notes on the back before filling this page) ⑴ (A) Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs where t is 1, V is 0 and when t is 0, V is 1; Or 3, at least one of η and m is not 0, or (a) R4 is an alkyl group, and R5 is a Ct-Cs alkyl group optionally substituted with 1 or 2 phenyl groups, the phenyl or phenyl group The group is optionally substituted with 1 or 2 alkoxy groups; or (b) R4 and R5 together with the nitrogen atom to which they are attached form a heterocycle selected from (1) to (4): -N Y (2) (3) (4) This paper scale is applicable to the Chinese National Standard (CNS> A4 specification (210X 297 mm) -58- 307760 A8 Β8 C8 D8 The scope of patent application can be the same or different base Rs and R7 are H Or C1-CS alkoxy or Rs and R7 together form a monomethylene group; Y is 0 or -NR8, where Ra is Ci-Cs alkyl or a phenyl group optionally substituted by CF3, (ii ) -NH— (CHa) —Z (B) where p is 1 or 2 and Z is (: 2-(^ alkenyl or a phenyl group optionally substituted by a Ct-CB alkane group; (Π i ) -NN- (C) where 1 to 3 are Ci-cs alkyl, pyrimidinyl or a phenyl group optionally substituted by Ci-CB alkoxy; and (iv) a N (F) where W is 1, 2 or 3 and L is a heterocyclic group of formula (1) as defined above;-a group of formula (D): R10 —O-CH2CH (0H) —CH2—N> R11 (D) Printed by the Employee Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, where R1Q and R11, which can be the same or different bases, are both Ci-Cs alkyl groups: and-groups of formula (E); -CH where s is 0 or 1 and may be the same or different, r is 1, 2, 3 and L is a heterocyclic group of the formula (丨) as defined above; -S9-cns) a4 «^. (210x297 ^ *) Central Ministry of Economic Affairs The Bureau of Standards ’Staff Consumer Cooperative printed Α8 Β8 C8 D8 π, the scope of patent application and R2 is hydrogen or the formula -COR3 'as defined above, where one of Ri and Ra is hydrogen and the other is not hydrogen; or one Pharmaceutically acceptable salts. 2. The compound according to item 1 of the patent application scope, wherein R 1 is hydrogen and I? 2 is a group of formula -COR3 as defined in item i of the application patent scope, wherein R 3 is a group of formula A. 3. The compound according to item 1 of the patent application scope, wherein R 2 is hydrogen and R 1 is a group of formula -COR 3 as defined in item 1 of the patent application scope, wherein R 3 is the base of formula (A), formula (B) base group, wherein Z is a vinyl group or a phenyl group substituted with two C! -Cs alkoxy groups, or a group of formula (C), wherein R2 is a methyl group, a pyrimidinyl group or a phenyl group. 4. The compound according to any one of items 1, 2 and 3 of the patent application scope, wherein in formula (A), η is 0 and m is 2, or η is 1 and m is 0, 1, 2 or 3 , Or ri is 1 and m is 0, and or alkyl and P.Ct-Cs alkyl, the terminal C atom of which is substituted by 2-value unsubstituted phenyl or a phenyl substituted by ^ -daggeroxy Substituted; or (b) R4 and R5 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group of formula (1), wherein R7 and R7 are both hydrogen or both alkoxy, or together form a sub Methylenedioxy; (2) where Y is 0 or -NR8, where R8 is methyl, phenyl or trifluoromethylphenyl; (3); and (4) Ο 5. According to item 1 of the patent application scope Compounds, wherein R2 is hydrogen and R1 is a group of formula (D) or (E) as defined in item 1 of the patent application scope. β. — A compound whose pseudo-selection is selected from: -60-This paper wave scale uses the Chinese National Standard (CNS) Α4 wash grid (210X29? mm) ---; --- · --- "-installed- (Please read the precautions on the back before filling this page) A8 B8 C8 D8 printed by the Beigong Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs VI. The scope of patent application meridian 4-methyl_2,5_dioxo_ 3_piperazinyl) methylbenzyl) -4- (2-pyrimidinyl Qin (9〇22) ^ (^. (^, ^ Bu bu arylene-Bu methyl- 夂 ^ two gas generation-Bu Ya Piper 0 Qinyl) Methylbenzyl IS group) -4-Methylbenzylamine, hydrogen hydride (9〇52) I- (4-((3Z, 6Z)-6-Sub-yl-1-methyl- 2,5-Difluoro-3-arylene H Qinyl) Methylbenzyl) -4- (4 -Part A | Benyl) piperazine, hydrochloride (9071) · II-allyl _4-((3B, 62) -6-Asia: ¥: yl-1-methyl-2,5-difluoro-3-oxazinyl) methylbenzamide (9070) i- (2-Diphenylmethylmethylaminoethyl) -4-((3Z, 6Z) -6-benzylidene-1-methyl-2,5-difluoro-3-piperazinyl) Methylbenzamide, hydride (9076) • 11 _- (2- (1,2,3,4-tetrahydro-2-isoquinolinyl) ethyl ) -4-((32,6ethyl) -6-benzylidene-p-methyl-2,5-dioxo-3-piperazinyl) methylbenzylamide, hydrochloride (9 116) « „-(3,4-Dimethoxyphenethyl) -4-((3 art, 6 ethyl) -6-benzylidene-p-methyl-2,5-dichloro-3-oxazinylene) methine Benzoamide (9117) _____________- 61 ~ _; _____ This paper size is applicable to China National Standards (CNS) A4 specification (210X297mm) (please read the precautions on the back before filling out this page). Pack. Order 307760 A8 B8 C8 D8 VI. Patent application scope ti_- (4- (4-phenyl-piperazinyl) methylphenyl) -4-((3Z, 6Z) -6-benzylidene-p-methyl-2 , 5-dioxo-3-piperazinyl) methylbenzylamide, hydrochloride (9104) (2-(4-methyl-piperazinyl) ethyl) -4-((3Z , 6Z) -6-benzylidene-methyl-2,5-dichloro-3-piperazinyl) methylbenzamide (9007) (2-morpholinoethyl) -4- (( 3Z, 6Z) -6-benzylidene-p-methyl-2,5-difluoro-3-piperazinyl) methylbenzamide, chloride (9053) N _- (4-morphobenzene Group) -4- ((3Z, 6Z) -6-benzylidene-p-methyl-2, 5 -dioxo-3-piperazinyl) Benzylamide, hydrochloride (9054) tL- (4- (2- (2- (1,2,3,4-tetrahydro- / 3-diazofluoren-2-yl) ethyl) phenyl)- 4-((3B, 62) -6-benzylidene-1-methyl-2,5-digeno_3-piperazinyl) methylbenzamide (9080) d _- (4- (1,2,3,4-Tetrahydro- / S-diazofluoren-2-yl) methylphenyl 4-((3ethyl, (^)-6-benzylidene-methyl-2,5 -Difluoro-3-piperazinyl) methylbenzylamide (9096) ___- 62-_. A paper wave scale is applicable to the Chinese National Standard Falcon (CNS) A4 specification (210X297 mm) ---- --.:---i/y outfit ------ order ------ Γ..Ι--Ί (please read the precautions on the back before filling in this page) Employee of Central Bureau of Standards, Ministry of Economic Affairs Printed by the consumer cooperative 1 hire 1 A8 B8 C8 D8 3〇776〇's patent scope 1- (4- (2- (4-phenyl-1-piperazinyl) ethyl) phenyl) -4- ( (32,62) -6-benzylidene-p-methyl-2,5-dioxo-3-piperidinyl B-qinyl) methylbenzamide (9103) 1- (4- (2- (1, 2,3,4-tetrahydro-2-isoquinolinyl) ethyl) phenyl) -4- ((3Z.6Z) -6-benzylidene-p-methyl-2, 5-dioxo-3- Piperazinyl) methylbenzamide (9065) i- (4- (2- (4- (3-trifluoromethylphenyl ) -1-Enzazinyl) ethyl) phenyl) -4-((3Z, (5Z) -6-Aminylyl-1-methyl-2,5-Dioxo-3-Enzazinyl ) Methylbenzamide (9049) ϋ- (4- (2- (4- (4-chlorophenyl) -4-hydroxypiperidino) ethyl) phenyl) -4-((3 ethyl , 6 ethyl) -6-benzylidene-1-methyl-2,5-dioxo-3-piperazinyl) methylbenzamide (9079) tL- (4- (2-(6 , 7-dimethylamino-1,2, 3,4-tetrahydro-2-isoquinolinyl) ethyl) phenyl) -4-((3Z, 6Z) -6-alkylene-bumethyl- 2, 5-dichloro-3-piperazinyl) methylbenzamide (9006) 1- (2-((3,7-dimethoxy-1,2,3,4-tetrakis -2-isoquinolinyl) ethyl) -4-((3ethyl, 62) -6-ylidene-p-methyl-2,5-dioxo-3-piperazinyl) methylbenzoyl Amine (9008) -63-The standard of this paper is applicable to Chinese national standard (CNS) A4 Washing (210X 297mm) ---: --- 1 --- KI Packing ------ Order --- --- I; M (Please read the precautions on the back before filling out this page) Printed A8 B8 C8 D8 3〇776〇 by the Ministry of Economic Affairs, Central Engineering Bureau, Zhengong Consumer Cooperative's patent application scope JL- (4- (6 , 7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolinyl) methylphenyl ) -4-((; ^, 6ethyl) -6-benzylidene-1-methyl-2,5-difluoro-3 · piperazinyl) methyl》 benzylamine, hydrochloride ( 9064) (3Z, 6Z) -6-benzylidene-3- (4- (3-dimethylamino-2-hydroxypropanyl) benzylidene) -1-methyl-2,5-piperazine Dione (9023) (3Z, 6Z) -6-benzylidene-3- (4- (2- (6,7-dimethylamino-1,2,3,4-tetrahydro-2-isoquin Porphyrinyl) ethyl) benzylidene) -p-methyl-2,5-phthalazine dim (9115) i- (4- (2- (6,7-dimethylamino-1,2,3,4- Tetrahydro-2-isoquinolinyl) ethyl) phenyl) -3-((3Z, 6Z) -6-benzylidene-1-methyl-2,5-dioxo-3-methylenepipe_ Group) methylbenzamide, hydrochloride (9051) 1- (4- (6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolinyl) methyl Phenyl) -3-((3 ethyl, 6Z.) -6-benzylidene-1-methyl-2, 5-difluoro-3- 'piperazinyl) methylbenzamide (9128 ) H- (2- (6,7-dimethylamino-1,2,3,4-tetrahydro-2-isoquinolinyl) ethyl) -3- ((3Z, 6Z) -6- Benzyl-p-methyl-2,5-dioxo-3-piperazinyl) methylbenzamide (9136) -64 * This paper size is applicable to China National Standard (CNS) Α4 specification (210Χ297mm)- --1 — "---- installed ------ ordered ------ Γ ^ (Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 307760 A8 B8 C8 D8 _ ~, patent application scope 11- (2- (3,4-dimethoxyphenethyl ) Methylamino) ethyl) -3- ((3Z, 6Z) -6-benzylidene-bromomethyl-2,5-difluoro-3-piperazinyl) methylbenzamide (9137. ) H- (4- (2-(3,4-dimethoxyphenethyl> methylamino) ethyl) phenyl) -3-((32,62) -6-benzylidene-1- Methyl-2,5-dioxo-3-piperazinyl) Methylbenzamide (9138) 1- (4- (2- (4-phenyl-l-lazinyl) ethyl) Phenyl) -3-((3Z, 6Z) _ 6-benzylidene_bmethyl_2,5-dioxo-3-arylene_yl) methylbenzylamine (9083) 1- (4- (3-(6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolinyl) propyl) phenyl.)-3-((3Z, 6Z) -6- Benzylidene-p-methyl-2,5-dioxo-3-piperidinyl (P-Qinyl) methylbenzamide, hydrochloride (9161) H- (2- (2,2-diphenylethyl) Methylaminoethyl) -3-((3Z, 6Z) -6-benzylidene-1-methyl-2,5-dioxo-3-piperazinyl) methylbenzamide (9163 ) (3Z, 6Z)-(5-benzylidene-3- (3- (3- (4- (2- (6,7-dimethoxy -1,2, 3,4_tetrahydro-2-isosalilinyl) ethyl) noonoxy) meridian) — 丨 _methyl_ 2,5-piperazinedione (9176) This paper The standard is applicable to China National Standard (CNS) A4 see grid (210X297mm) --- 7 ----- winter, 1 pack ------ order ------ f # (please read the back side first Matters needing attention and then fill out this page) Printed and printed by the Consumer Cooperative of the Central Bureau of Prospects of the Ministry S07760 A8 B8 C8 D8 VI. Patent application scope (3Z, 6Z) -6-benzyl-3- (4- (4- ( 2- (6,7-dimethoxy-1,2, 3.4-tetrahydro-2-isoquinolinyl) ethyl) benzyloxy) benzylidene) -p-methyl- 2.5-piper_di_ (9177 ) 11- (4-((32,6ethyl) -6-benzylidene-: 1-methyl-2,5-difluoro-3-piperazinyl) methylphenyl) -4- ( 2-(6, 7-dimethylamino-1,2,3,4-tetrahydro-2-isolinyl) ethyl) benzamide (9190) Bu (4-((3Z, 6Z)- 6-benzylidene-1-methyl-2,5-dioxo-3-piperazinyl) methylbenzyl) -4- (6,7-dimethylamino-1,2, 3,4-tetrahydroisoquinolinyl) methylpiperidine (9200). A pharmaceutical or autumn medicinal composition with multi-drug resistance-adjusting activity, which comprises a medicinal or veterinarily acceptable carrier or diluent and as the main active ingredient, such as patent application items 5, 5 or 6 The compound. 8.-A method for preparing as claimed in the scope of patent application, the method is included in the organic 2, 3 丨 I 4 1 compound is 1-acetoxy-3-benzylidene-4-methyl-2,5-piperazinedione as an aldehyde of formula (111) ---: I-V- -~ Outfit -------- Ordered ------ f Travel (please read the notes on the back first and then fill in this page) OHC Printed by the Cooperative Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (ΠΙ) treatment, in the aldehyde of formula (ΠI), R 1 and R2 are as defined in item 1 of the scope of patent application; and, if necessary, the resulting compound is converted into its pharmaceutically acceptable salts. 66-This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X 297mm) 307760 Α8 Β8 C8 D8 Patent application, such as the first part of the scope of the patent application -1 drug resistance suicide i-ζφ-- Compounds, which can be used as multiple Km nl «— ilflfl tn« HI · · V ^ > 1 m I ^ VJ-^ (please read the notes on the back first-fill in this buy- »Ministry of Economic Affairs Central Standards Bureau under-employment consumer cooperation The size of the paper printed by Du Duan is applicable to the Chinese National Standard (CNS) A4 (2 丨 0X297mm)