UA67730C2 - Anthranilic acid derivatives as multidrug resistance modulators - Google Patents

Abstract

Anthranilic acid derivatives of formula (I) wherein each of R to R9 is an organic substituent, n is 0 or 1, m is 0 or an integer of 1 to 6, q is 0 or 1, X is a direct bond, 0, S, -S-(CH2)p- or -О-(СН2)р- wherein p is from 1 to 6 and Ar is an unsaturated carboxylic or heterocyclic group, and the pharmaceutically acceptable salts thereof, have activity as inhibitors of P-glycoprotein and may thus be used, inter alia, as modulators of multidrug resistance in the treatment of multidrug resistant cancers, for example to potentiate the cytotoxicity of a cancer drug. (I).

Description

Description of the invention

According to the invention, compounds are proposed that are useful as modulators of resistance to many therapeutic agents (SBLZ), in particular, SBLZ, which is caused by the excess production of P-glycolrotein (P-gp), the method of their production, and pharmaceutical and veterinary compositions containing them.

The resistance of tumors to treatment with some cytotoxic agents is an obstacle to successful chemotherapy treatment of cancer patients. The tumor may become resistant to the cytotoxic agent that was used in the previous treatment. A tumor may exhibit intrinsic or implanted 70 resistance to a cytotoxic agent that has not been previously exposed to it and that is not related in structure or mechanism of action to any agent used in the previous treatment of the tumor. Similarly, some pathogens may become resistant to a pharmaceutical agent that was previously used to treat diseases or disorders that these pathogens exacerbated. Pathogens can also develop intrinsic or instilled resistance to a pharmaceutical agent that has not previously been affected. Examples of this effect 72 include multidrug-resistant forms of malaria, tuberculosis, leishmaniasis, and amoebic dysentery. These phenomena refer to collective (to many therapeutic means of resistance (SBL3Z).

The most common form of SBLZ is caused by the excessive production of P-pp, a protein on cell membranes that can reduce the accumulation of the drug in cells by pumping it out. It was shown that this protein is the main cause of SBLZ of cancer cells (Vesk MU.T., Viospet. RNagtasoi., 1987, 36, 2879-2887).

In addition to cancer cells, p-glycoprotein has been found in many normal human tissues, including the liver, small intestine, kidney, and blood-brain endothelium. P-glycoproteins can play a role in limiting the absorption of foreign toxic substances through biological barriers.

Therefore, in addition to their ability to increase the sensitivity of cancer cells to cytotoxic agents, inhibitors

Р-pi can be expected to increase absorption during oral administration of some drugs and improve their transfer through the blood-brain barrier. Gee)

Indeed, it was shown that the use of the p-gp inhibitor cyclosporine enhances the absorption of acebutalol and vinblastine in the intestines of rats by 2.6 and 2.2 times, respectively | Tegeo, T. ei ai. U. Rpagt. Ripagtasoi, 1996, 48, 1083-1089), while mice with a p-gp gene deficiency in SBLZ showed a 100-fold increase in sensitivity to the pesticide ivermectin with a toxic effect on the central nervous system | Zspipkei, A.N. ei ai., SeiI, 1994, p. 77, 491-5021. In addition to an increase in the level of the therapeutic agent in the brain, the mice showed an increase in the level of the therapeutic agent in many tissues and a decrease in excretion.

The disadvantages of the therapeutic agents recently used for the modulation of SBLZ, called resistance-modifying agents (MSZ3), are that they often show insufficient pharmacokinetic characteristics and/or are toxic at the concentrations required for modulation of SBLZ. 3o It is now shown that a series of derivatives of anthranilic acid exhibits inhibitory activity against p-gp and therefore can be used to get rid of the resistance of tumors and pathogens to many therapeutic agents. They also have potential applications for improving the absorption, distribution, metabolism, and elimination characteristics of some therapeutic agents. "

According to the invention, a compound derived from anthranilic acid of the formula (I) C is proposed; ; V s o yiv A Z 6 4 p Ag NMU ee» M SNU dz t mnoi kE Ve

AND

Ge») oyu in which, - each of B, B! and B2, which are the same or different, - H, C--Salkyl, OH, Si-Salkoxy, halogen, nitro group, or - and M(KTOr 1), where each of BO and B"!, which are the same or different, - H or C-Svalkyl, or B' and B, attached to c 20 adjacent positions of ring b, together form methylenedioxyl or ethylenedioxyl;

BZ - H or C.-Svalkyl with B/- C.-Svalkyl or K7- -СНо- or -СНоСН»-, which is attached (i) to position 2 of ring B with the formation of a 5- or b--linked saturated nitrogen-containing ring , fused to ring b, or (ii) to a position on ring a that is adjacent to the position of X when it is a single bond, thus forming a saturated 5- or 22-membered nitrogen-containing ring fused to ring a ;

GF) VR-N, ON or S.-Svalkil; 7 X - direct connection, O, 5, -5-(СНо)р- or -0-(СНо)р- where p-1-6; 28- H, Si-Svalkil or Si-Svalkoxyl; in 4-0 or 1;

Ag - unsaturated carbocyclic or heterocyclic group; each of K'/ and BU, the same or different, is a substituted or unsubstituted H, Si-Swalkil,

C.-Sbalkoxyl, hydroxyl, halogen, phenyl, -MNON, nitro group, group M(B'9B7), which is defined above, or group 5B2, where K 2 is H or C.-Svalkyl, or B" and 8, when located on adjacent carbon atoms, 65 form, together with the carbon atom to which they are attached, a benzene ring or methylenedioxyl;

BZ is a phenyl or an unsaturated heterocyclic group, each of which is substituted or unsubstituted by S.i-Svalkyl, OH,

C.-Sulfoxyl, halogen, C.sub.3-C.sub.cycloalkyl, phenyl, benzyl, trifluoromethyl, nitro group, acetyl, benzoyl or M(B'9B'), which is defined above, or two substituents on adjacent positions of the rings of the specified phenyl or heterocyclic group together form a saturated or an unsaturated 6b-membered ring, or methylenedioxyl; n: or 1; and t or 1-6; or a pharmaceutically acceptable salt thereof.

Group X is attached to any of the positions 2-6 of the ring not occupied by B 9. It is better when it is attached to the position

C or 4. In the best series of compounds, KU is in position 2, and X is in position C or 4 of ring a. When X is in position Z or 4 of ring a, RU can also occupy position 5. Given the free rotation of ring a, position 6 is equivalent to position 2.

The best value is t-0 or 1-3, better 1 or 2. The best value is 4-1.

The S.i-Svalkil group can be linear or branched. C.--Svalkyl, of course - C--Svalkyl, for example, methyl, ethyl, propyl, i-propyl, n-butyl, b-butyl or t-butyl, halogen - E, CI, Bg or I, better - E, SI or Wu.

C.i-Svalkyl can be substituted usually by one or more halogen atoms, for example, 1, 2 or 3. It can be perhalogenated, for example, with trifluoromethyl.

The C-Swapcoxyl group can be linear or branched. Of course, it is C--Cylalkyl, for example, it is methoxy, ethoxyl, propoxyl, i-propoxyl, n-butoxyl, b-butoxyl or t-butoxyl. t-1-6, and of course, 1, 2 or 3. An unsaturated carbocyclic group is, of course, a Cb-C-ocarbocyclic group containing at least one unsaturated bond, for example, such an S-Siraryl as phenyl or naphthyl. An unsaturated heterocyclic group is, of course, a 5- or β-ene heterocycle with at least one unsaturated bond containing one or more heteroatoms selected from M, 5, and O, optionally fused to a benzene ring or to a second such 5- or with a 29-membered heterocyclic ring. Gee)

An unsaturated heterocyclic group can be, for example, furan, thiophene, pyrrole, indole, isoindole, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, pyridine, quinoline, quinoxaline, isoquinoline, thienopyrazine, pyran, pyrimidine, pyridazine, pyrazine, pyrinic or triazine, and may be unsubstituted or substituted with one or more substituents, for example, OH, halogen, such a C-Salkyl, which may be unsubstituted or substituted, e.g., OH, halogen, such as C3, C1-Sulfoxy, a nitro group and amino group M(B 987) which is defined above. m

The preferred heterocyclic group represented by B 9 includes at least one nitrogen atom, the heterocyclic group represented by Ag includes at least one nitrogen or sulfur atom. In the best series of compounds p-O, and K7 is represented by -СНоСН»-, which is attached to position 2 or 6 of the b ring, forming a tetrahydroisoquinoline group with the b ring. Otherwise, n-1, and B" is represented by -CH»o-, which is attached to position 2 or 6 of ring B, forming a tetrahydroisoquinoline group with ring b.

In the other best series of compounds t-1, X is a simple bond attached to position C or 4 of ring a, and B. 7 " is represented by -SiNo-, which is attached to position C or 4 of ring a, forming with ring a tetrahydroisoquinoline group. Otherwise, t-0, X is a simple bond attached to position 3 or 4 of ring a, and 7 - c is represented by -СНоСНо-, which is attached to position 3 or 4 of ring a, forming a tetrahydroisoquinoline group with ring a. and"? Ag is preferably a benzene, naphthalene, thiophene, thienopyrazine, pyridine, pyrazine, indole or furan ring. c, is preferably a quinoline, isoquinoline, quinoxaline, pyridine, pyrazine, oxazole, (o) isoxazole, isothiazole or thiazole group It is best when it is quinolin-3-yl, quinoxalin-2-yl, pyrazin-2-yl, pyridin-2-yl, pyridin-3-yl, oxazol-4-yl or thiazol-4-yl.

It's best when E, B! Yes? independently selected from H, OH, S.-Svalkoxyl and nitro group, or K- H, and B! and

Che 2 attached to positions 2 and 3, C and 4, 4 and 5 or 5 and 6 of the BY ring together form methylenedioxyl or oz 20 ethylenedioxyl. o According to the best aspect of the invention, anthranilic acid has the formula (Ia):

IN!

Go)

VI with g 4 M - (SN-M

F) with her Y N | и 3 МН о во А св) и дя 60 5 рии 21 : гдци : 31 ди : гдци вякий КК" and К-", the same or different, are hydrogen or methoxyl, К" and К"", the same or different, independently selected from H, CH3, CE3, E, SI, Bg, MNo, MO", MNON, methoxy, hydroxyl and phenyl; or BZ! and B"! located on neighboring carbon atoms, together with these atoms form a benzene ring or methylenedioxyl. 65 B - 2-furanyl, 3-furanyl, 2-thiophene, 3-thiophene, 2-indolyl or 2-benzofuranyl or a ring of one of the following formulas (II), (PG) or (IM):

BI

Kk

M M. OV 81 Me ki 4 VE! and 91 M (I) in" SH Kk (m in which B 9! and КЙ, the same or different, are independently selected from H, C.-Alkyl, which can be linear or branched, C3-Secylisoalkyl, phenyl, benzyl, CEz .

VV! and 2", the same or different, each - hydrogen, methyl or methoxyl, or KU! and KU! located on adjacent carbon atoms, together with the pyridine ring to which they are attached, form a quinoline or in 5,6,7,8 - tetrahydroquinoline ring; B and B, the same or different, each - hydrogen, methyl or propionyl, or B 191 and B11 located on adjacent carbon atoms, together with them form a benzene ring.

B/21-H, C-C alkyl, C 3-C cycloalkyl, phenyl, benzyl or acetyl; geOaboyi1, and 8-1, 2 or 3; or a pharmaceutically acceptable salt thereof. 8-1-3, and - better 1 or 2.. In the best series of compounds of formula (Ia) g-1, 8-2, B! and B are each methoxyl, B?! - 2-quinoxaline group, 3-quinoxaline group, 2-pyrazine group or 3-pyridine group, each of which may be unsubstituted or substituted.

According to another aspect of the invention, anthranilic acid has the structure (A): c 5 » 9 c (o)

In k- x ped y

Ag H z Z sho g» y v!

In the book KU,

And her too

Ov (A) so in which it- (a) each of BC, BC! and K?, the same or different, selected from H, OH, MO", M(B'OB"), halogen or

C.-C. alkyl, or K - H, and B and B? with the carbon atoms to which they are attached, together form methylenedioxyl or ethylenedioxyl, provided that K, B" and B? are not all represented by H, but each of BZ, 5 kb, o

КТ, в8, в, Аг, Х and т are defined above for formula (I); or (b) each of B, B and 2, the same or different, is H or methoxyl, and each of KU, 22, 29, B", 28, VU, Ag, X and t is defined above. " 20 According to another aspect of the invention, anthranilic acid has the structure (B): with 05 с с и Е. and (B - Or ) and where B, K!-83, 5-2, Ag and n are defined above for formula (1). c 50 According to another aspect of the invention, anthranilic acid has the structure (C): in (4) o KE

Xh

In Kk with I no in

In many in (F; A, (C) name) and 13 rB ro every K, K/-KU, KU-KU, Ag, X and t are defined above for formula (1).

According to another aspect of the invention, anthranilic acid has the structure (0): 60 z 3 y o y v . in x in!

Ag R; SNa/p' 7 d2 de 5 Sh

VZ MN I B b5 A c. yu F)

in which B, B 1-27, Ag, t and n are defined above for formula (I), and X, which is in position З or 4 of ring a, is defined above for formula (1).

In the best series of compounds of formula (I), K7 - S.-Svalkil. Preferably, each of B, VE and VC? selected from H, OH or methoxyl.

KV is attached to ring a in any of positions 2-6. Of course, 27 is attached in position 2 of ring a.

Examples of preferred compounds according to the invention are given below. s (8) «c) so cha cha (Se) shi s z (22) -I -I o 50 (42)

F) name) 60 b5

Chemical name Compound Mey (2-14-(2-(6,7-dimethoxy-3,4-dihydro-IN-isoquinolin-2-yl)-ethyl-phenylcarbamoyl)-phenyl)-amide 2-chloro-quinoline -3-carboxylic acid (2-44-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)"ethyl-phenylcarbamoyl)-phenyl)-amide 4-hydroxy-7- trifluoromethyl-quinolin-3-70 carboxylic acid (2-(4-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|- 9594 phenylcarbamoyl)-thiophene-3 -yl)-amide of quinoline-3-carboxylic acid 75 (2-(A4-(2-4(6,7-dimethoxy-3,4-dihydro-IN-isoquinolin-2-yl)-ethyl)-phenylcarbamoyl) -4-dimethylamino-phenyl)-amide of quinoline-3-carboxylic acid (2-14-(2-(6,7-dimethoxy-3,4-dihydro-THI N-isoquinolin-2-yl)-ethyl-phenylcarbamoyl) -4-dimethylamino-phenyl)-amide of quinoxaline-2-carboxylic acid 20 (2-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl-9597 phenylcarbamoyl )-thiophen-3-yl)-amide of quinoxaline-2-carboxylic acid in (3-14-(2-(6,7-dimethoxy-3,4-dihydro-IN-isoquinolin-2-yl)-ethyl|- 9600 cm phenylcarbamoyl)-pyridin-2-yl)-amide of quinoxaline-2-carboxylic acid 4-hydroxyquinoline-3-carboxylic acid (2-14-124(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl-9606 phenylcarbamoyl)-phenyl)-amide o 30 so (3-14-12-(6,7-dimethoxy-3,4-dihydro-1-isoquinolin-2-yl)-ethyl-9608 phenylcarbamoyl)-4-methyl-thiophen-2-yl)-amide quinoxalin-2-carboxylic acid y-(3-414-H2-(6,7-dimethoxy-3,4-dihydro--1A-isoquinolin-2-yl)-ethyl|- 9609 tk 35 phenylcarbamoyl)-4- methyl-thiophen-2-yl)-amide of quinoline-3-carboxylic acid (2-(4-42-((3,A-dimethoxy-benzyl)-methyl-amino)-ethyl)-phenylcarbamoyl)- | 9612 "quinoxaline-2-carboxylic acid phenyl)-amide - 40 s (2-(4-42-((3,4-dimethoxy-benzyl)-methyl-amino|-ethyl)-phenylcarbamoyl)- | 9613 "with phenyl |-amide of quinoline-3-carboxylic acid 12-12-(3,4-dimethoxy-benzyl)-1,2,3,4-tetrahydro-isoquinoline-7-butylcarbamoyl-phenyl)-amide of quinoxaline-2-carboxylic acid

B. (2-14-(.2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl-9615-phenylcarbamoyl)-4-methylsulfanyl-phenyl)-amide quinoline- of 3-carboxylic acid 2 oquinol (4-44-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-thiophen-3-yl) -amide n-3-carboxylic acid m-(4-414-12-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl)-9617 o phenylcarbamoyl)-thiophene-Z3 -yl)-b-methyl-nicotinamide

HF (2-44-12-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethylsulfanyl|- | 9621 phenylcarbamoyl)-phenyl)-amide of quinoline-3-carboxylic acid bo ( Quinoline-3-carboxylic acid 3-44-(2-(6,7-dimethoxy-3,4-dihydro-IN-isoquinolin-2-yl)-ethyl|-9ab2a2 phenylcarbamoyl)-pyrazin-2-yl)-amide b5

(2-(4-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethoxy|- 9623 phenylcarbamoyl)-phenyl)-amide of quinoline-3-carboxylic acid 95 ( 2-44-(2-(6,7-Dimethoxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|- 9625 phenylcarbamoyl)-Phenyl)-amide of quinoline-3-carboxylic acid (2-44-(2-(I,3-dihydro-isoindol-2-yl)-ethyl-1-phenylcarbamoyl)-phenyl)-amide 70 quinoline-3-carboxylic acid (2-14412-(6,7-dichloro- 3,4-dihydro-IN-isoquinolin-2-yl)-ethyl-1-ab28 phenylcarbamoyl;)-phenyl)-amide of quinoline-3-carboxylic acid (2-(4-(2-17,8-dichloro-3,4 12-14-(2-12-43,4-dimethoxy-phenyl)-ethyl|-methyl-amino )-ethyl)- 9530 phenylcarbamoyl)-phenyl)-amide quinoline-3-carboxylic acid that H2-(4-(2-((3,4-dimethyl-benzyl)-methyl-amino|-ethyl|-phenylcarbamoyl)- 9631 phenyl-amide of quinoline-3-carboxylic acid (2-44-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethoxy|- 9632 ch phenylcarbamoyl)-phenyl) -amide of quinoxaline-2-carboxylic acid o (2-13-12- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl-9633 phenylcarbamoyl)-phenyl)-amide quinoline-3-carboxylic acid o (2-(4-(2-(7 -nitro-3,4-dihydro-IN-isoquinolin-2-yl)-ethylI-phenylcarbamoyl)-so phenyl)-amide of quinoline-3-carboxylic acid Kk 2- (2-44-(2-(6,7- dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl-1-9635 m phenylcarbamoyl)-phenyl)-amide of methyl-thiazole-4-carboxylic acid (Ce)

H2-(4-42-((3,4-dimethoxy-benzyl)-ethyl-amino|-ethyl)-phenylcarbamoyl)-phenyl|-amide quinoline-3-carboxylic acid (2-(4412-(6,7- dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl-9638 "phenylcarbamoyl)-phenyl)-amide of 2-methyl-oxazole-4-carboxylic acid 2 s "" (2-(4-12- ((3-isopropoxy-4-methoxy-benzyl)-methyl-amino)-ethyl)- 9639 " phenylcarbamoyl)-phenyl|-amide of quinoline-3-carboxylic acid

F 75 (2-(4-42-(methyl-(3,4,5-trimethoxy-benzyl)-amino|-ethyl-9640 phenylcarbamoyl)-phenyl|-amide of quinoline-3-carboxylic acid -I -1 (2 -(4-42-|butyl-(3,4-dimethoxy-benzyl)-amino|-ethyl)-phenylcarbamoyl)- 9641 su phenyl-amide of quinoline-3-carboxylic acid c (2-(4-12-(4 -butoxy-3-methoxy-benzyl)-methyl-amino|-ethyl)- 9642 phenylcarbamoyl)-phenyl-amide of quinoline-3-carboxylic acid 25 12-(4-12-(3,4-difluoro-benzyl)-methyl -amino|-ethyl)-phenylcarbamoyl)-9643 o phenyl)|-amide quinoline-3-carboxylic acid ko (2-(4-42-C2,3-dihydro-benzo (1,4) dioxin-b-ylmethyl) -methyl-amino |- 9645 in ethyl)-phenylcarbamoyl)-phenyl)-amide quinoline-3-carboxylic acid b5

(2-х4-(2-(4-isopropoxy-3-methoxy-benzyl)-methyl-amino|-ethyl-9646 phenylcarbamoyl)-phenyl-amide of quinoline-3-carboxylic acid

H2-(4-(2-((3-hydroxy-4-methoxy-benzyl)-methyl-amino|-ethyl-9647 phenylcarbamoyl)-phenyl)|-amide of quinoline-3-carboxylic acid (2-14-I3- (68,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-9648 to propoxy)-phenylcarbamoyl)-phenyl)-amide quinoline-3-carboxylic acid (2-(4- Quinoline-3-carboxylic acid 12-((4-hydroxy-3-methoxy-benzyl)-methyl-amino|-ethyl)- 9649 phenylcarbamoyl)-phenyl|-amide (2-44-12-(6,7-dimethoxy Quinoline-3-carboxylic acid -3,4-dihydro-1H-isoquinolin-2-yl)-ethyl-2-methyl-phenylcarbamoyl)-phenyl)-amide (2-414-12-(6,7-dimethoxy-3 ,4-dihydro-IN-isoquinolin-2-yl)-ethyl|-2-methoxy-!96551 phenylcarbamoyl)-phenyl)-amide of quinoline-3-carboxylic acid (2-(4-11(3-isopropoxy-4- methoxy-benzyl)-methyl-amino|-methyl)-phenylcarbamoyl)-phenyl|-amide of quinoline-3-carboxylic acid c o (2-13-(2-(6,7-dimethoxy-3,4-dihydro-1H -isoquinolin-2-yl)-ethyl-phenylcarbamoyl)-phenyl)-amide of 5-methyl-pyrazine-2-carboxylic acid o zo (2-44-I2-(6,7-dimethoxy-3,4-dihydro-1H -isoquinolin-2-yl)-1-methyl-ethyl|- 9654 phenylcar bamoyl)-phenyl)-amide of quinoline-Z3-carboxylic acid o cha (2-14-42-M(4-dimethyl amino-benzyl)-methyl-amino|-ethyl-cha phenylcarbamoyl)-phenyl-amide quinoline-Z- carboxylic acid (Ce) (2-(4-42-(3-butoxy-4-methoxy-benzyl)-methyl-amino-ethyl | - 9656 phenylcarbamoyl)-4,5-dimethoxy-phenyl-amide of quinoline-3-carboxylic acid « (2-44-12-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)- ethylI-2-methoxy-| -isoquinolin-2-yl)-ethyl)-2-methyl- 3658 phenylcarbamoyl)-phenyl)-amide of pyrazine-2-carboxylic acid

F

-1 (2- 1А4-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-2-methoxy-phenylsagrotoyl)-phenyl)»amide pyrazine-2- carboxylic acid -I oyu 070 (2-413-13-(6,7-dimethoxy-3,4-dihydro-IN-isoquinolin-2-yl)-propyl|- 9660 o phenylcarbamoyl)-phenyl)-amide quinoline-3 -carboxylic acid

M-(2-(4-1(3-Isopropoxy-4-methoxy-benzyl)-methyl-amino|-methyl)-9651 phenylcarbamoyl)-phenyl|-nicotinamide

F) I5-chloro-2-(4-|(3,4-dimethoxy-benzyl)-methyl-amino|-ethyl 9563 pF phenylcarbamoyl)-phenyl-amide of quinoline-3-carboxylic acid in (2-(4-( 2-(7,8-dihydro-5H-(1,31-dioxolo 14,5-91 isoquinolin-b-yl)-ethyl|- 9664 phenylcarbamoyl)-Pphenyl)-amide of quinoline-3-carboxylic acid b5

(2-(4-(2-(6,7-diethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|i- 96565 phenylcarbamoyl)-phenyl)-amide of quinoline-3-carboxylic acid ( 6-(4-H2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl)|- 9566 phenylcarbamoyl)-thieno (2,3-53 pyrazin-7-yl) -amide of quinoline-3-carboxylic acid

Г2-(4-42-((3,4-dimethoxy-benzyl)-methyl-amino|-ethyl)-phenylcarbamoyl)-4,5-| 9667 0 difluoro-phenyl-amide of quinoline-3-carboxylic acid (2-(4-42-((3,4-dimethoxy-benzyl)-methyl-amino|-styl)-phenylcarbamoyl)- | 9668 5-methyl-phenyl -amide of quinoline-3-carboxylic acid (2-(4-12-((3,4-dimethoxy-benzyl)-isopropyl-amino|)-ethyl)-phenylcarbamoyl)-phenyl-amide of quinoline-3-carboxylic acid (2 -(4-42-((3,4-dimethoxy-benzyl)-methyl-amino|-ethyl)-Phenylcarbamoyl)- | 9660 20). β-nitro-phenyl)-amide of quinoline-3-carboxylic acid 2-( A4-Isopropyl-benzoylamino)-M-12-(6,7-dimethoxy-3,4-dihydro-1H- 9304 isoquinolin-2-yl)-ethyl-benzamide 2-(4-Isopropyl-benzoylamino)-M- T2-(6,7-dimethoxy-3,4-dihydro-1H-a405 o isoquinolin-2-yl)-ethyl-b-chloro-benzamide 2-(4-Isopropyl-benzoylamino)-M-(2-(6 ... d 9350 - imethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl-4-chloro-benzamido chn 2-(4-Isopropyl-benzoylamino)-M-(2-(6,7-dimethoxy-3 , dihydro-1H-9401 i-o isoquinolin-2-yl) ethyl)-3-chloro-benzamide, 2-(4-Isoprop yl-benzoylamino)-M-(2-(6,7-dimethoxy-3,4-dihydro-1H-9663" di isoquinolin-2-yl)ethylI-5-bromo-benzamide from p. 2-(4-Isopropyl-benzoylamino)-M-(2-(6,7-dimethoxy-3,4-dihydro-1H-9349-» isoquinolin-2-yl)-ethylI-4-fluoro-benzamide p 15 2 -(4-Isopropyl-benzoylamino)-M-(2-(6,7-dimethoxy-3,4-dihydro-1H-9398 isoquinolin-2-yl)-ethyl|-3-methyl-benzamide -I -I 2 -(4-Isopropyl-benzoylamino)-M-(2-(6,7-dimethoxy-3,4-dihydro-1H-9399 c» 70 isoquinolin-2-yl)-ethyl|-3-methoxy-benzamide o 2 -(4-Isopropyl-benzoylamino)-M-(2-(6,7-dimethoxy-3,4-dihydro-TIN-9424 isoquinolin-2-yl)-ethyl|-3-hydroxy-benzamide 2-(4- Isopropyl-benzoylamino)-M-(2-(6,7-dimethoxy-3,4-dihydro-1H- 9420

IF) isoquinolin-2-yl)-ethyl|-4-nitro-benzamide t 2-(4isopropyl-benzoylamino)-M-H2-(6,7-dimethoxy-3,4-dihydro-1H-9435bo isoquinoline-2 -yl)-ethyl|-4-amino-benzamide b5

2-(4-Isopropyl-benzoylamino)-M-(2-(6,7-dimethoxy-3,4-dihydro-1H-9432 isoquinolin-2-yl)-ethyl|-5-phenyl-benzamide 9 H2-( 6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl-amide 3-(4- 9410 isopropyl-benzoylamino)-naphthalene-2-carboxylic acid 2-(4-Dimethylamino-benzoylamino) -M-(2-(6,7-dimethoxy-3,4-dihydro-IN-0 isoquinolin-2-yl)-ethyl|-benzamide 2-(4-Propyl-benzoylamino)- M-(2-(6 ,7-dimethoxy-3,4-dihydro-1H-9297 isoquinolin-2-yl)-ethyl|-benzamide from 2-(4-Pentyl-benzoylamino)-M-(2-(6,7-dimethoxy-3, 4-dihydro-1H- 9395 isoquinolin-2-yl)-ethyl|-benzamide 2-(4-Cyclahexyl-benzoylamino)-M-(2-(6,7-dimethoxy-3,4-dihydro-1H- 9331 isoquinoline) -2-yl)-ethyl|-benzamide (2-(2-(6,7-dimethoxy-3,4-dihydro-1IN-isoquinolin-2-yl)-ethylcarbamoyl|- 9294 phenyl)-amide biphenyl-4- carboxylic acid (2-H2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethylcarbamoyl1-9295 o phenyl)-amide naphthalene-2-carboxylic acid 12-(2-( 6,7-dimethoxy-3,4-dihydro-IN-isoquinolin-2-yl)"ethylcarbamoyl-9302 o phenyl)-amide benzo|1,3|dioxol-5-carbo of a new acid with 2-(4-Diethylamino-benzoylamino)-M-(2-(6,7-dimethoxy-3,4-dihydro-IN-9310-isoquinolin-2-yl)-ethylI-benzamide y- (Ce) 2-(4-t-Butyl-benzoylamino)-M-(2-(85,7-dimethoxy-3,4-dihydro-18-isoquinolin-2-yl)-ethyl|-benzamide « 2-Benzoylamino-M- I12-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-1l)- 935 - c t90 | ethyl I|-benzamide . 2-(4-Bromo-benzoylamino)-M-(2-(6,7-dimethoxy-3,4-dihydro-1-isoquinoline-2-yl)-ethyl-benzamide p 15 2-(4 -Nitro-benzoylamino)-M-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline- | 9381 2-yl)-ethylI-benzamide -I - 2-(4-Phenoxy-benzoylamino) -M-(2-(6,7-dimethoxy-3,4-dihydro-1H-c) isoquinolin-2-yl)-ethyl-benzamide

Shk 2-(4-Benzoyl-benzoylamino)-M-(2-16,7-dimethoxy-3,4-dihydro-1H-9427 isoquinolin-2-yl)-ethyl|-benzamide 2-(4-Benzyl-benzoylamino )-im-(2-(6,7-dimethoxy-3,4-dihydro-1H-Zd42 o isoquinolin-2-yl)-ethyl)-benzamide t 2-(4-Cyclohexyloxy-benzoylamino)-M-(2 -(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-benzamide b5

2-(4-Benzyloxy-benzoylamino)-M-(2-(6,7-dimethoxy-3,4-dihydro-1H- 9460

Isoquinolin-2-yl)-ethyl|-benzamide (2-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethylcarbamoyl-9377 phenyl)-amide pyridine-2- carboxylic acid

M-12-12-(6,7-Dimethoxy-3,4-dihydro-IN-isoquinolin-2-yl)-ethylcarbamoyl|- 9359 70 phenyl)-nicotinamide

M-12-(2-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)"-ethylcarbamoyl|- 9384 phenyl)-isonicotinamide 12-(2-(6,7-dimethoxy- 3,4-dihydro-1H-isoquinolin-2-yl)-ethylcarbamoyl|- 9391 phenyl)-amide of pyrazine-2-carboxylic acid 12-12-(6,7-dimethoxy-3,4-dihydro- 1H-isoquinoline- 2-yl)-ethylcarbamoyl-9347 2-phenyl)-amide of quinoxaline-2-carboxylic acid (2-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethylcarbamoyl-9383 phenyl)-amide of isoquinoline-1-carboxylic acid c (2-I12-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethylcarbamoyl-9385 o phenyl)-amide quinoline-2- carboxylic acid (2-(2-(6,7-dimethoxy-3,4-dihydro-IN-isoquinolin-2-yl)-ethylcarbamoyl|- 9389 phenyl)-amide of isoquinoline-3-carboxylic acid o co 12-( 2-4(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethylcarbamoyl|- 9397 Kc phenyl)-amide of quinoline-3-carboxylic acid cha 12-(2-(6,7 -dimethoxy-3,4-dihydro-1-isoquinolin-2-yl)u-ethylcarbamoyl|- 9365 s phenyl)-amide of thiophene-3-carboxylic acid 12-(2-(6,7-dimethoxy-3,4- dihydro-1H-isoquinolin-2-yl) -ethylcarbamoyl|- 9367 « phenyl)-amide of 1H-indole-2-carboxylic acid - c (2-414-12-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl )|- 9531 from phenylcarbamoyl)-phenyl)-amide of quinoline-2-carboxylic acid (2-14-12-(6,7-dimethoxy-3,4-dihydro-IN-isoquinolin-2-yl)-ethyl|- 9542

F phenylcarbamoyl;-5-hydroxylamino-phenyl)-amide of quinoxaline-2-carboxylic acid -I - (2-414-HT2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)- ethyl-c) 70 phenylcarbamoyl)-4-methyl-phenyl)-amide of quinoxaline-2-carboxylic acid c (2-14-I2-(6,7-dimethoxy-3,4-dihydro-IN-isoquinolin-2-yl )-ethyl-phenylcarbamoyl)-4-hydroxy-phenyl)-amide of quinoxaline-2-carboxylic acid 7 (2-44-(2-(6,7-dimethoxy-3,4-dihydro-1IN-isoquinolin-2-yl )-ethyl- 95 (F) phenylcarbamoyl)-5-nitro-phenyl) amide of quinoxaline-2-carboxylic acid t (2-(4-(2-(6,7-dimethoxy-3,4-dihydro-IN-isoquinoline) -2-yl)-ethyl/- 9561 690 | phenylcarbamoyl)-5-trifluoromethyl-phenyl)-amide of quinoxaline-2-carboxylic acid b5

(2-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl-9562 phenylcarbamoyl)-5-Fluoro-phenyl quinoxaline-2-carboxylic acid 2 (2- Quinoxaline-2-carboxylic acid 14-(2-(6,7-dimethoxy-3,4-dihydro-THN-isoquinolin-2-yl)-ethyl|- 9564 phenylcarbamoyl)-3-fluoro-phenyl)-amide (2 -(4-(2-(6,7 dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|- 9568 16 phenylcarbamoyl)-4-fluoro-phenyl)-amide of quinoxaline-2-carboxylic acid 2-14-(2-(6,7-dimethoxy-3,4-dipdro-1H-isoquinolin-2-yl)-ethyl|- 9573 phenylcarbamoyl)-4,5-dimethoxy-phenyl)-amide quinoxalin-2- carboxylic acid ( 15 (2-14-12-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl-954 phenylcarbamoyl)-phenyl)-amide quinoline-3-carboxylic acid ( ( 2-14-(2-(6,7-dimethoxy-3,4-dihydro-IN-isoquinolin-2-yl)-ethyl-9574 phenylcarbamoyl)-4-fluoro-phenyl)-amide of quinoline-3-carboxylic acid c 25 (2-(4-(2-(6,7-dimethoxy-3,4-dihydro-1H-isox inolin-2-yl)-ethyl-9576 o phenylcarbamoyl)-4,5-dimethoxy-phenyl)-amide quinoline-3-carboxylic acid (6-44-(2-(6,7-dimethoxy-3,4-dihydro - 1IN-isoquinolin-2-yl)-ethyl-9578 o 30 phenylcarbamoyl)-benzo (1,3) dioxol-5-yl)-amide of quinoline-3-carboxylic acid SO (2-44-12-(6, 7-dimethoxy-3,4-dihydro-14-isoquinolin-2-yl)-ethyl-9581-35-phenylcarbamoyl)-5-nitro-phenyl)-amide of quinoline-3-carboxylic acid "so (2-14-124 (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl-9584 phenylcarbamoyl)-4-methyl-phenyl)-amide of quinoline-3-carboxylic acid « 40 (2-14-( 2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|- 9588 8 s phenylcarbamoyl)-5-methyl-phenyl)-amide quinoline-3-carboxylic acid from (2 Quinoline-3-carboxylic acid -14-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl-15-phenylcarbamoyl)-4-chloro-phenyl)-amide

F

-1 (2-14-(2-(6,7-dimethoxy-3,4-dihydro-IN-isoquinolin-2-yl)-ethyl|- 9586 phenylcarbamoyl)-5-chloro-phenyl)-amide quinoline-3 -carboxylic acid -I syu 70 (2-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl-9589 o phenylcarbamoyl)-5-amino-phenyl) -amide of quinoline-3-carboxylic acid (2-14-12-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl-9545 phenylcarbamoyl)-phenyl)-amide quinoline-2 -carboxylic acid (F) (2-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl- 9590

GF phenylcarbamoyl)-phenyl)-amide of 5,6,7,8-tetrahydroquinoline-3-carboxylic acid bo (2-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2- yl)-ethyl- 9472 phenylcarbamoyl)i-phenyl)-a2amide of pyridine-2-carboxylic acid b5 m-(2-44-(2-(6,7-Dimethoxy-3,4-dihydro-IN-isoquinoline-2- yl)-ethyl|/- 9482 phenylcarbamoyl)-phenyl)-nicotinamide

M-(2-14-(2-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl-9483 phenylcarbamoyl)-phenyl)-isonicotinamide (2-14-(2- Pyrazine-2-carboxylic acid (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|- 9493 o phenylcarbamoyl)-phenyl)-amide

B-methyl-pyrazine-2-carboxylic acid (2-414-12-(6,7-dimethoxy-3,4-9527 dihydro-1H-isoquinolin-2-yl)-ethyl1-phenylcarbamoyl)-phenyl)-amide tv 1000 M4(2-14-12-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl/|- 9557 phenylcarbamoyl-phenyl)-b-methyl-nicotinamide

Mm-(2-(4-(2-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl)|- 9582 phenylcarbamoyl)-Phenyl)-b-methoxy-nicotinamide 5 -propionyl-pyrazine-2-carboxylic acid (2-14-(2-(6,7-dimethoxy-3,4-95569 dihydro-1H-isoquinolin-2-yl-ethyl-phenylcarbamoyl)-phenyl)-amide in 2 -benzoylamino-M-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-c ethyl|-phenyl!-benzamide and) 2-benzoylamino-M- (4 -(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-9511 ethyl|-phenyl)-4-methyl-benzamido so 2-Benzoylamino-M-14-(2 -(6,7-dimethoxy-3,4-dihydro-IN-isoquinolin-2-yl)-ethyl|-phenyl-5-methyl-benzamide 2-Benzoylamino-M- (4-(2-(6 ,7-dimethoxy-3,4-dihydro-14-isoquinolin-2-yl)-9512 o ethylI-phenyl)-b-methyl-benzamide 2-(2-Fluoro-benzoylamino)-M-14-(2-( 6,7-dimethoxy-3,4-dihydro-1H-9489 "isoquinolin-2"yl)-ethyl|-phenyl)-benzamide 2 with "2-(3-Fluoro-benzoylamino)-M-14-(2 -(6,7-dimethoxy-3,4-dihydro-1H-"isoquinolin-2-yl)-ethyl)-phenyl)-benzamide in GO 244. Fluoro-benzoylamino)-M-(4-12-(6, 7-dimethoxy-3,4-dihydro-TH-9501 is also isoch inolin-2-yl)-ethyl|-phenyl)-benzamide - 2-(2,A4-Difluoro-benzoylamino)-M-14-12-(6,7-dimethoxy-3,4-dihydro-1H-9513) 070 isoquinolin-2-yl)-ethyl|-phenyl)-benzamide o 2-(2,6-Difluoro-benzoylamino)-M-14-(2-(6,7-dimethoxy-3,4-dihydro-1H- 9514 isoquinolin-2-yl)-ethyl|-phenyl)-benzamide o 2-(2-Chloro-benzoylamino)-M-14-12-(6,7-dimethoxy-3,4-dihydro-1H- 9494 q isoquinoline -2-yl)-ethyl-phenyl)-benzamide in 2-(3-Chloro-benzoylamino)-M-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) )-ethyl|-phenyl)-benzamide b5

2-(4-Chloro-benzoylamino)-M-14-12-(65,7-dimethoxy-3,4-dihydro-1H-9495 isoquinolin-2-yl)-ethyl)-phenyl)-benzamide and 2-( 2-Methyl-benzoylamino)-M- 14-(2-(6,7-dimethoxy-9 4-dihydro-1H-9497 isoquinolin-2-yl)-ethylI-phenyl)-benzamide 2-(3-Methyl-benzoylamino )-M-414-(2-(6,7-dimethoxy-3,4-dihydro-1H-70 isoquinolin-2-yl)-ethyl-phenyl-benzamide 2-(4-Methyl-benzoylamino)-M-14 .-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenyl)-benzamide and 2-(5-Methoxy-benzoylamino)-KI-14-( 2-(6,7-dimethoxy-3,4-dihydro-1H-8477 isoquinolin-2-yl)-ethyl1-phenyl)-benzamide 2-(3-Methoxy-benzoylamino)-M-14-12-(6, 7-dimethoxy-3,4-dihydro-1H-9517 isoquinolin-2-yl)-ethyl|-phenyl-benzamide 2-(4-Methoxy-benzoylamino)-M-14-12-(6,7-dimethoxy-3 ,4-dihydro-1H-951 isoquinolin-2-yl)-ethyl|-phenyl)-benzamide sc e-(2-Hydroxyl-benzoylamino)-M-14-(2-(6,7-dimethoxy-3,4 -dihydro-1H- 9535 o isoquinolin-2-yl)-ethyl)-phenyl)-benzamide 2-(3-Hydroxyl-benzoylamino)-M- 14-(2-(6,7-dimethoxy-3,4-dihydro -1H- 9549 o 3o Isoquinolin-2-yl)-ethyl|-phenyl)-benz honey 2-(4-Hydroxyl-benzoylamino)-M-14-12-(8,7-dimethoxy-3,4-dihydro-1H-9559 isoquinolin-2-yl)-ethyl1-phenyl)-benzamide - ( se)

Ester of acetic acid and 2-(2-14-H2-(6,7-dimethoxy-3,4-dihydro-1H-9534 isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenylcarbamoyl)-phenyl "

Ester of acetic acid and 3-(2-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-C isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenylcarbamoyl)-phenyl with Ester of acetic acid and 4-(2-414-(2-(6,7-dimethoxy-3,4-dihydro-NH-9548 isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenylcarbamoyl)-phenyl

Ф 2-(2-Trifluoromethyl-benzoylamino)-M-14-12-(6,7-dimethoxy-3,4-dihydro- | 9523 - 1nNAzoquinolin-2-yl)-ethyl|-phenyl)-benzamide - 2- (3-Trifluoromethyl-benzoylamino)-M-14-12-(6,7-dimethoxy-3,4-dihydro- (3-Dimethylamino-benzoylamino)-4- 14-(2-(6,7-dimethoxy-3,4-dihydro-9556 1H-isoquinolin-2-yl)-ethyl|-phenyl)-benzamide o 2-(4 -Isopropyl-benzoylamino)-M-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-9447 isoquinolin-2-yl)-ethyl-phenyl-benzamide o 2-(4-Cyclohexyl-benzoylamino )-M-14-12-(6,7-dimethoxy-3,4-dihydro-1H- | 9461 60 isoquinolin-2-yl)-ethyl-phenyl)-benzamide b5

(2-14-12-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl-9470 phenylcarbamoyl)-phenyl)-amide of naphthalene-1-carboxylic acid (2-14- 12-(6,7-dimethoxy-3,4-dihydro- I H-isoquinolin-2-yl)-ethyl-9476 phenylcarbamoyl)-phenyl)-amide of naphthalene-2-carboxylic acid 2-(3,4-Dichloro- benzoylamino)-M-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-9536b isoquinolin-2-yl)-ethyl1-phenyl)-benzamide 2-(3,4-Dimethyl-benzoylamino )-M-14-12-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl1-phenyl)-benzamide (2-44-12-(6,7-dimethoxy -3,4-dihydro- TH-isoquinolin-2-yl)-ethyl» 9471 phenylcarbamoyl)-phenyl)-amide of thiophene-2-carboxylic acid (2-14-(2-(6,7-dimethoxy-3,4 -dihydro-1IN-isoquinolin-2-yl)-ethyl|- 9492 r. phenylcarbamoyl)-phenyl)-amide of thiophene-3-carboxylic acid

Compounds of formula (I) can be produced by a method that includes: a) treatment of aminobezamide of formula (MI) o) c , also o

Ah H sik KE (U o where Ag, B and EZ are defined above, and 7 is a group of co

In and -

Same sleep B -

EE t M St a

In M B (o; det, p, a, K, 21-65 and X defined above, with a carboxylic acid of the formula 29-СООН or with its activated derivative, in which KZ is defined above, or 5) treatment of a compound of the formula (XII) « o - cho p t 6 I

A lot of A

F o) -1 oyu -1 where Ag, B?, B2-KU, X, d and t are defined above, with the amine of the formula (XX) 54 3 (95) 50 B is also VI! in

Gi") ev p v?

H 00) where B, B!-B7 and n are defined above, and optionally by removing any optionally substituted protecting group present, and/or optionally by converting one compound of formula (I) into another compound of formula (I ),

HF) and/or, if desired, by converting one compound of formula (I) into a pharmaceutically acceptable salt thereof, and/or, if desired, by converting a salt into a free compound of formula (1).

According to a variant of method (a), the carboxylic acid of the formula K?-COOH is commercially available, or it can be prepared as described in example bA below. The acid can be activated, like its corresponding anhydride K 9 СОСИ, which can be bought or made from a free carboxylic acid of the formula E9-СООН by treatment with thionyl chloride. Alternatively, Vo-soon carboxylic acid can be activated with cyclohexyl-M-(2-morpholineethyl)-carbodiimide methyl-p-toluenesulfonate and 1-hydroxybenzotriazole, or 2-chloro-1-methylpyridinium iodide. 65 Aminobenzamides of the general formula MI can be prepared in one of three ways, illustrated below by Scheme 1, where each of 7, Ag, B' and BZ is defined above. The first route involves the direct coupling of an appropriately substituted commercially available anthranilic acid IM with an amine of formula IX (step ii) and is described in more detail in Example 4A below. The starting amine of formula IX can be prepared as described in Example 1A below.

The second route involves the coupling of an appropriately substituted commercially available nitrobenzoic acid I and subsequent reduction of the nitro group to an amino group (steps i and i), which are described in more detail in examples 2A and ZA, respectively, below. The third pathway involves 4 stages, starting with the commercially available aminoester MII. This path is described in more detail in Example 5 below.

Scheme 1 7 o

In a dream at 7 p.m

Ag U she DAM v Ag new alkyl sho Mo, vi Mo; Ag c) about V

In SON 7 in a stage) and in the beginning. SA) in M n ra

AND

EE m MN"

And the compound of the general formula and

In process variant (b), the amine of formula XX is a known compound, or it can be prepared from known starting materials by conventional methods of organic chemistry, for example as described in example 3. Bromide intermediate of formula XI! produced by treating the corresponding hydroxy compound of the formula CHMII with a brominating agent. Suitable brominating agents include M-bromosuccinimide. The hydroxy compound of formula XM can be prepared as illustrated in Scheme 2. The reactions of Scheme 2 are described in more detail below in Example 7.

Scheme 2 about that

X (SOR. in o

Chun 67 s that F ho Ye "in Mo hu! o u o o - cha v! M y he zno" (Se)

NE i" (n) " 0) 7 SNUKOR shchi 7 x z z" Ag Nv : in tn KhMI 75 de. yes

F e (o, -I v! X snu-on - I M Ch t

Нв 9 Kк МН Ю (42) - ХУ ote I bromination to compounds of the formula ХІІ о The starting amino derivative of the formula ХІ, in which P is a protected hydroxyl group, is made from the corresponding protected nitro derivative by reduction, for example, treatment with hydrogen in ethanol in the presence of platinum dioxide . Protected nitroderivatives are obtained by treating an unprotected nitroderivative with protecting groups supplying the P group. 60 Step (i) is usually performed by the reaction between compounds X and XIM in the presence of a base, for example, triethylamine. The resulting compound is restored at stage (i), for example, under the conditions described above, for the production of compound XII, with the preparation of an intermediate compound of formula XU.

Stage (iii) includes treatment of the compound of the formula XM with the compound K9-SOCIi in an organic solvent in the presence of a base to form the compound of the formula XM, which is deprotected in stage (im), and the resulting deprotected derivative 65 of the formula XMIII is treated with a brominating agent in stage (M), obtaining the required compound of the formula XI.

Compounds of formula (Ia) can be produced by a method that includes:

(a) treatment of aminobenzamide of the formula MIP! at

With , | Etc

H in m) MN, where B! and VE"! defined above, and if necessary, as an option, protected, and 7 - group in! (snud СХ,

AND

/5 where r, 8, B! and VK?! defined above, a carboxylic acid of the formula ЕЗ1-СООН or its activated derivative, in which 2?! defined above, or (B) treatment of the compound of formula (XI!) sozNn

МН ободу SCH, where VE?! defined above, with the amine of the formula (IX) o di!

Mev S, Fr

And so de g, 8, B! and V! defined above, with the formation of a compound of formula (Ia), in which both B! and B"! - hydrogen, cha or (c) treatment of azalactone of the formula (XII!) - o (Se) (ХР) (9)

J

May h

BI : , but) c where K"" is defined above, the amine of the formula (IX )

In" . and?

MN" (SNi)dt M v r 45 I ah) - where r, 8, V! and V! defined above, with the formation of a compound of formula (Ia), in which both B! and B"! - hydrogen, and optionally, by removing any optionally substituted protecting group present, and/or, optionally, by converting one compound of formula (Ia) into another compound of formula (Ia), and/or, optionally, by converting 50 of one compound of formula (Ia) into a pharmaceutically acceptable salt thereof, and/or, optionally, by converting the salt into a free compound of formula (Ia). -COOH is commercially available or can be prepared as described in Example 6B below.The acid can be activated, such as its corresponding anhydride K 51.SOCI, which can be purchased or prepared from the free carboxylic acid of the formula KU!-COOH by treatment with thionyl chloride.

Alternatively, the v-soon carboxylic acid can be activated with methyl-l-toluenesulfonate

HF) cyclohexyl-BI--2-morpholineethyl)-carbodiimide and 1-hydroxybenzotriazole, or iodide 7 2-chloro-1-methylpyridinium.

Aminobenzamides of the general formula MI! can be obtained in one of two ways. The first way involves the reduction of the corresponding 2-nitrobenzamide, for example, by treatment with hydrogen in the presence of platinum dioxide. 2-nitrobenzamide can be prepared by treating 2-nitrobenzoic acid, optionally activated, with an amine of formula IX described above. The preparation of the intermediate of formula Mi" is illustrated by Scheme 3 below. Steps (i), (ii) and (ii) of this scheme are described below in Examples 28, 3B and 48, respectively, and step (ii) is described in Example 48. Preparation of amine IX' described in example 18. b5

Scheme Z ku son t ? 7- 1 Kk more - 56565«6--- - - - ve Mo (replacement of IX) Nn

In the 2nd day of the MO» MI her

WHO! and I o 710 EU you Y: - 5 - t M (and amine IX) N

CT MN"

IN! MN Ush?

In process variant (B), the intermediate of the formula X" was produced by hydrolysis of the corresponding methyl ester, which was prepared by treating commercially available methyl anthranilate with acid chloride in the presence of triethylamine in dichloromethane. This stage is described in Example 6 below.

In process variant (c), the azalactone of the formula X is produced by treating commercially available anthranilic acid with acid chloride of the general formula B?!-SOCI in pyridine or a mixture of pyridine and dichloromethane at 0"C for 3-8 hours.

A compound of formula (I) can be converted into a pharmaceutically acceptable salt, and the salt can be converted into the free compound by conventional methods. Salts can be mono- or bis-salts. Bis- or double salts can be formed in the presence of two basic nitrogen atoms in the structure of the compound of formula (I). Suitable salts include c pharmaceutically acceptable salts of inorganic or organic acids, examples of inorganic include d) hydrochloride, sulfate, and orthophosphate, and organic (p-toluenesulfonic, methanesulfonic, mucoid, and succinic. Bis-salts include, in particular, bis-hydrochlorides and bis-mesylates .

Optical conversion of a compound of formula (I) into another compound of formula (I) can be carried out by conventional methods.

For example, a compound of formula (I) containing an esterified hydroxyl group such as -OSOMe can be converted into a compound of formula (I) containing a free hydroxyl group by hydrolysis, for example, alkaline. with

A compound of formula (I) containing a free hydroxyl group can be converted into a compound of formula (I) containing an esterified hydroxyl group by esterification, for example, by reaction with a suitable carboxylic acid, chloride or acid anhydride. uh-

A halogen-containing compound can be converted into an aryl-containing compound by Suzuki coupling (Miuatsga M., Mapadit, Zylgisi A., Zupii.Sottip., 1981, 11, 513). A compound of formula (I) containing a nitro group can be converted into a compound of formula (I) containing an amino group by reduction, for example, treatment with hydrogen in the presence of platinum dioxide as a catalyst under suitable conditions.

Cancer cells that show resistance to many therapeutic agents, which are classified as SBLZ-cells, show a decrease in the intracellular accumulation of the therapeutic agent in comparison with the corresponding drug-sensitive cells. As it was indicated, the experiments with the use of SBLZ-cell lines showed that SBLZ is often associated with an increase in the expression of plasma membrane protein (P-gp), which is able to bind the therapeutic agent. It can be thought that P-gp functions as a pump that pumps out many hydrophobic compounds, and a transfection study using cloned P-gp has shown that its overexpression can confer a SBLZ-phenotype to cells, see, for example, App. Kew. Viospet., 1989, 58, 137-171.

The main function of P-gp in normal tissues is to remove intracellular toxins from cells. It

Me. suggests that overexpression of P-gp may play a clinical role in multidrug resistance. -I In many forms of human cancer - leukemias, lymphomas, sarcomas and carcinomas, an increase in the level of m-RNA or protein R-p has been found. Indeed, in some cases, an increase in the level of P-pp was determined during biopsy of tumors after

Sh- repetition of chemotherapy. 2) 20 It was shown that the inhibition of P-gp function in P-gp-mediated SBLZ leads to the general accumulation of the anticancer drug in cells. For example, verapamil, a well-known calcium channel blocker, has been shown to sensitize SBLZ cells to the Vinca alkaloids ip miigo and ip mimo/Sapseg. Kezv., 1981, 41, 1967-1972. The proposed mechanism of action involves competition with the anticancer agent for binding to P-gp. A number of structurally incompatible resistance modifying agents (DRAs) acting by this mechanism have been described, such as tamoxifen (Moimadex:ICI) and related compounds, as well as cyclosporin A and derivatives.

GF) Derivatives of anthranilic acid of formula (I) and their pharmaceutically acceptable salts (hereinafter referred to as compounds according to the invention) were identified by biological tests as inhibitors of P-pp, which can be used to modulate SBLZ, in particular, caused by P-gp. The results are shown below in example 1. As P-gp inhibitors, compounds according to the invention can be used as modifying SBLZ means, or MSZ. Compounds according to the 60 invention can modulate, for example, reduce SBLZ or get rid of it, especially when it is mediated by P-pp.

The compounds according to the invention can therefore be used to implement a method of enhancing the cytotoxicity of agents that are cytotoxic to cancer cells. This method includes, for example, the application of one of the compounds according to the invention to cancer cells when studying the effect of a cytotoxic agent on cancer cells. In this way, it is possible to enhance the therapeutic effect of a chemotherapeutic or antineoplastic agent. The resistance of cancer cells to a cytotoxic agent during the course of chemotherapy can be weakened or eliminated.

The compounds according to the invention can also be used for the implementation of a method of treatment of diseases in which the corresponding pathogen detects SBLZ, especially when it is mediated by P-pp, for example, SBLZ-forms of malaria (Riaztodist Taisiragit), tuberculosis, leishmaniasis and amoebic dysentery. Such a method includes, for example, the use of one of the compounds according to the invention (separately, simultaneously or sequentially) with a therapeutic agent to which the pathogen detects SBLZ3. This is how you can enhance the therapeutic effect of the medicinal product against

SBLZ-pathogen.

A human or animal suffering from a tumor can be treated for resistance to a chemotherapeutic agent 70 by a method comprising administering one of the compounds of the invention in an amount effective to enhance the cytotoxicity of said chemotherapeutic agent. Preferred examples of chemotherapeutic or antineoplastic agents in the context of the invention include Vinca alkaloids such as vincristine and vinblastine, anthracycline antibiotics such as daunorubicin and doxorubicin, mitoxantrone, actinomycin O, taxanes such as taxol, epipodophyllotoxins such as etoposide and plicamycin.

Compounds according to the invention can also be used to implement a method of improving the characteristics of absorption, delivery, metabolism and/or elimination of therapeutic agents, which includes the use by a patient separately, simultaneously or sequentially of one of the compounds according to the invention and the indicated therapeutic agent.

In particular, this method can be used to enhance penetration into the central nervous system, or to enhance absorption when taken orally.

Compounds according to the invention can, for example, be used to implement a method of facilitating the passage of a medicinal agent through the blood-brain barrier, as well as in the treatment of AIDS or AIDS-related complex. If such treatment is necessary, a person or an animal can be treated by a method that includes their use of one of the compounds according to the invention.

The compounds of the invention can be used in various dosage forms, for example, for oral administration such as tablets, whether or not coated with sugar or a coating, capsules, solutions and suspensions, and for parenteral (intramuscular, intravenous or subcutaneous) administration. according to the invention it is therefore possible to i) apply by injection or infusion. The dosage depends on various factors, including the age, weight and condition of the patient and the route of administration. However, the usual dose adapted for each route of administration when a compound according to the invention is administered to an adult alone is 0.001-5mg/kg, most often (0.01-5mg/kg body weight. Such doses can be given, e.g. , 1-5 times a day by bolus infusion, infusion over several hours and/or repeated use. and,

Anthranilic acid derivatives of formula (I) or their pharmaceutically acceptable salts are formulated for use by M as pharmaceutical or veterinary compositions, which also include pharmaceutically or veterinary acceptable carriers or diluents. The compositions are made by conventional methods and used in a pharmaceutical or edible veterinary form. Therefore, the proposed means for use as modulators of SBLZ, which include any of the compounds according to the invention.

The compounds according to the invention can be used in any conventional form, for example:

A) Orally, for example, as tablets, coated or not, dragees, lozenges, aqueous or oily suspensions, liquid solutions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or "elixirs". Compositions intended for oral use can be prepared by any person skilled in the art of manufacturing pharmaceutical compositions, which may contain one or more agents selected from

And the group that includes sweeteners, flavors, dyes and preservatives to obtain pharmaceutical perfect and pleasant preparations.

Tablets contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients,

Which are suitable for the production of tablets and which can be, for example, inert diluents, such as calcium and sodium carbonates, lactose, dextrose, sucrose, cellulose, corn or potato starch or calcium and sodium phosphates; granulating and disintegrating agents, for example, corn starch, alginic acid, alginates or sodium starch glycolate; binders, such as starch, gelatin or gum arabic; lubricants, for example, silicon dioxide, calcium or magnesium stearates, stearic acid or talc; 5p effervescent mixtures; dyes, sweeteners, wetting agents such as lecithin, polysorbates or lauryl sulfate. o Tablets can be uncoated or coated in known ways to delay disintegration and o absorption in the gastrointestinal tract, and therefore have an effect for a long time. For example, it is possible to use such abalizing materials as glycerol mono- or distearate. Such preparations can be produced by known methods, for example by means of mixing, granulation, tableting, coating with sugar or film. 5B Compositions for oral use may be presented as hard gelatin capsules in which the active ingredient is mixed with a solid inert diluent such as calcium phosphate or carbonate or (F) kaolin, or as soft gelatin capsules in which the active ingredient is alone or its mixed with an aqueous or oily medium such as peanut or olive oil or liquid paraffin.

Aqueous suspensions contain the active material in a mixture with auxiliaries, which are suitable for the production of aqueous suspensions. Such auxiliaries are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxymethylpropylcellulose, sodium alginate, polyvinylpyrrolidone tragacanth and gum arabic; dispersing or wetting agents may be natural phosphatides such as lecithin or condensation products of alkylene oxide with fatty acids such as polyethylene oxide stearate or condensation products of ethylene oxide with long chain aliphatic alcohols such as 65 Heptadeethyleneoxyethanol or such condensation products of ethylene oxide with partial esters of fatty acids and hexytolane hydride in, for example, polyoxyethylene sorbitol monooleate.

These aqueous suspensions may also contain one or more preservatives, for example, ethyl- or n-propyl-p-hydroxybenzoate, one or more coloring agents such as sucrose or saccharin.

Oil suspensions can be created by suspending the active ingredient in a vegetable oil such as peanut, olive, sesame or coconut or a mineral oil such as liquid paraffin. Oil suspensions may include thickeners such as beeswax, solid paraffin or cetyl alcohol.

Sweeteners and flavoring agents can be added to obtain a pleasant oral preparation. Compositions can be protected by adding such antioxidants as ascorbic acid. In dispersible powders and granules suitable for making aqueous suspensions by adding water, the active ingredient is mixed with dispersing or wetting agents, suspending agents and one or more preservatives. Suitable dispersing or wetting and suspending agents are mentioned above. You can also introduce sweeteners, flavors and dyes.

Pharmaceutical compositions according to the invention can also be oil-in-water emulsions. The oil phase can be a vegetable oil, for example, olive or peanut oil, or a mineral oil, for example liquid /5 paraffin, or a mixture thereof. Suitable emulsifying agents may be natural gums such as gum arabic and tragacanth, natural phosphatides such as soy lecithin, and esters and partial esters of fatty acids and hexitol anhydrides, such as polyoxyethylene sorbitol monooleate, or such condensation products of ethylene oxide with said partial esters of fatty acids and hexitol anhydrides, such as polyoxyethylene sorbitol monooleate. Emulsions may also contain sweeteners and flavors. Syrups and elixirs 2o Can be made with sweeteners, for example, glycerin, sorbitol or sucrose. In particular, syrup for diabetics can contain as a carrier only a product, for example, sorbitol, which is not metabolized in the body to glucose, or is metabolized to it in a small amount.

Such compositions may also include a demulsifier, preservative, and sweetening and flavoring agents.

B) Parenterally, i.e. subcutaneously, intravenously, intramuscularly or intrasternally, or by means of infusion, in the form of sterile injectable aqueous or oil-based suspensions, which can be created by methods known to those skilled in the art, using suitable dispersing or wetting agents and suspending agents means which i) was mentioned earlier. Sterile injectable preparations may also be solutions or suspensions in a non-toxic parenterally suitable diluent or solvent, for example as a solution in 1,3-butanediol.

Acceptable media and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, solvents and suspending media usually use sterile fixed oils. For this, you can use any soft non-volatile oils, including synthetic mono- or diglycerides. In addition, such fatty acids as oleic are used in preparations for injections. M

C) Inhalations in the form of aerosols or spray solutions.

D) Rectal, in the form of suppositories, which is made by mixing the medicinal agent with a suitable edible non-irritating medium, which is solid at normal temperature, but liquid at rectal temperature, and therefore, when used, the medicinal agent melts and releases the medicinal agent. Such materials are cocoa butter and polyethylene glycol.

D) Locally, in the form of creams, ointments, jellies, lotions, solutions or suspensions.

Daily doses can vary widely, they must be adapted to individual needs in each specific case. In general, acceptable daily doses for adults are in the range of 2-200 mg, although the upper limit may be exceeded in some cases. The daily dose can be taken as a single 7-3) dose or divided into separate doses. . Next, the invention is illustrated by examples. and?" Example 1: Testing of compounds of formula (I) and their salts as modulators of SBLZ

Materials and methods Mouse mammary gland carcinoma cell line EMT6 and SBLZ-resistant subline LYA? 1.0

Cultivated in KRMI 1640 medium containing 1075 fetal calf serum and 2 mM glutamine at 372C in

He») 596 CO» Cells were subcultured between 1:200 and 1:2000 in the case of the parental cell line and between 1:20 and 1:200 in the case of the SBLZ-resistant subline after trypsinization (0.259o trypsin, 0.µg/l EDTA) .

Sche 1. Analysis of the accumulation of the therapeutic agent -I AK 1.0 cells were seeded 48 hours before the analysis in 96b-cell impermeable plates (Sapregta RaskKaga).

The assay medium includes a mixture of tritiated daunorubicin (DR) (0.9 MCI/ml), cytotoxic agent o, and labeled DR (2MM). Compounds of formula (I) were serially diluted with medium within the concentration range of 0.508nM-10cCM. The cells were incubated at 377°C for 71 hours, then washed and the radioactivity absorbed by the cells was determined. The absorption results were expressed as IR, and 10095 was taken as the absorbance observed in the presence of the known MOH verapamil at a concentration of 100 mM.

The results are shown in Table A below.

F) name) 60 b5

Table A

Mo Yikwo Compound (NM)

Accumulation 9591 shi: SU PI Z GP 0.087 write you pi ku LISH tyu Go 9596... 01320 9600 0.199 9606 9608 | God is4shchshchish or 0.431 9612 0.087 9613 0.098 0.278 0.213 2 9616 0116 0113 9621 77770453 Shchshchshchkh (6. 9622 0.207 9623

And 779634 CC | 6.85 to them 7779635 6 sh KkSK | 0.669 --4 9656 0841101 - 7739638... |. 9639

F

-And -And at 50 o

F) about 65

9640 70194 Ж юКМж 1 ши 0.0019 719642 7 703413 9643 704 С 79645 17 70179777 9646 1 7029556Жж 7779547 | 7003333 96248 0.038 0 9649 0.188 9650. 7 006 szhzh6sh IZ 9651 11771110 005 9659 «K 0.064 19653 0.490 965417... 013550777 ly nn tes 0.596 5. | 0188 (0.343 9658 7729977. 03 КЖ "| со 9354 now: и Кк 77938501. 08 усхЮ 777 9401...Й.Й.ЙUB.Й.ЙЙЙЙУКББ30 ДФ ЙБ| M 7793564! 34 ShshchD 9349 se) 9398 9399 Ba 78BB94 17 25 779420. | . (UI 19 | « 9435 2 9432 that 94107173 ;» shi y: shi k LYN 35339997 DYU | MZ-- - yuk----- 9395

No. 9331 9294 777704 - 9295 70398 9 / 9302 777150. 9334 o 9351 80 o 9380 7.09 g "'Z 9426 50698 2 24yush ( 9427 9442 10 o le 065 sh 7

PF) pc YN YN s 9377 BV o 9359 65

9347 777730 9 9383 tt 9585 9389 718 "RK 9397 plyny ky PIV U YN 70 9367 ppl10.1 7 7e531 0010035 M / te 17177703 9543 leva. 30717777 709877 ev 071 ob1705 071 o1700

OBO 770024 to5v4. 0020707177309 9568 0.017

M 9573 0.0095 BGN. 12707000 005 9571 tora 9574 YMIMsh0019. 98576 0.064 9578 0.084 s 951 7410935 Sh o 9584 9588 0.094 9593 001477 9586 to o zo 9589 9545 08 o 9590 0.097 m- 9472 11105 | Kk 9485 9483 t) 94931777 005 9527 ..YIM0052.D F 9557. 01011 0015

OBYAO « i I - 5 86 55 (62 Z p. 9510

From" BT 9512 88577 tv489,0117000705 -8503- 1708

F teo 11770042 - de13 9514 J. 095 sh ZKZhf2|'i - 9494 se 70 9495 1105 M 8496 o 9497 16000371 9503 yours 01010711 006 9517 I .7ЙЙyMsh04 B 5yuzhshf5 охов | 9595 945 TO5BO 00117726 non: 7 TIRES FAULT IN 65

9461 7718. and 9476 9536 1045 1.195387 | ...YUyuYUR SO (ZP 9471 779492... 1.10... tv -- - - - 93986 | 0.14 2 ShDshshBBK |! 9515 9539 | 02 94686 5479 our shYy 9567 0 .i..016.... 9572 60053 ЮЖ Ж ЖХКш 9577 9585 2. Enhancement of doxorubicin toxicity (a) Selected compounds of formula (I) were tested for their ability to enhance the toxicity of doxorubicin for AK 1.0 cells. concentration of doxorubicin (0.34 MM), which alone is non-toxic for AB cells. (In 1.0o. After 4 days of incubation with doxorubicin, reproduction was measured by colorimetric analysis with sulforhodamine B (ZKkepap ei am U. Mai. Sapseg Ipvi. 82, 1107-1112, 1990). The results are summarized in Table B. (b) Cells were cultured for 4 days with doxorubicin (0.2563 NM-17.24 MM) at a fixed concentration of each compound. Proliferation was measured as described in ZKepap et al., see ref. IR, concentration required to reduce proliferation by 5095 relative to control (no treatment) for doxorubicin alone and with each compound was determined and used to calculate the amplification index (PI): m

IP- IC of doxorubicin

Ikaa doxorubicin plus EMMA -

The results are shown in tables C1 and C2

Table B

Compound Mo Toxicity Toxicity

Compounds of the Cytotoxic (ICoo km) agent " (ICoo sm)

A- 5 05 A 5 o'clock 17 65 -

I 94056. 1...yuzhschf22. | Yuk 008 with | 798354. | 8071 5 0155. and 79394 Her 10 | 0 and? (22) -I -I at 50 (42)

F) name) 60 b5

9349 B 21777644 government office 9435 tvo 704 9432 vysh SZYINYNYNY PODYV c; ZY 8 Sptltevb 3231-4035 15037 9297 yav 20001777 083 theses 02320718 7177105 1 9331 9295 av 02030717 057 9310

Potezvy 03303170 0011317 005 9351 8 171877 10 9380 I 40077 17 05 G KzhSHF6

Pototazai 22175115 goodbye. 02120110 006 9457 writes t YN POLONYN GNN 9445 ny x PI PL EH ZLYY

Gte4va. 702717778857333313330008 9347 35 00706 15 9383 4017770 9385 poynonve tup nin TYNY 9389 tvo 7083 ny: ZY PI t ZY PO U: ZON tebia. 2Z2031777777777155.17 7705 9531 0.005 9542 0.014 Tawa3 2107708 07708 208 20 Z5BA 00017771 0051 TEV 1 2 1 77 70861 0.00 28... | 0.0034 9573 0.0004 s 00077 25 Bl tva 71700008 (5) 9574 Goa 1 0005 9576 I...sh0985 | 0.0018 9578 I 6.08 .6D.BBMK | 0.0014 9581 | 031. yushzhkhzhi o.0038 9584 | 86 7 sh with 0.015 and ZBa -5--555 0005-37-37 o 93593 76 17770005 9586 s 9589 poteavav 2832310 ShO 60 th- 9590 and ShЮШ02020217777777 60057 5472 zav 7Ш777777772775 Sh776|

Naked 7717 7 8 5 7 1 lov z5 Gootadva 17777790 00531 is; tey 71777457 0007 tey. 37717901 005 cash. 30303173 04910008 1 7779456 | ЮюЮюЮююююююЮ.50.ЮЙ..БЙ | B.YM003.Y.B 1. « teo 21021778 1 005 ev. 231407 1777005 9489 o 10057 0 Ped 1 tvo 17 0008 8 s ZO 83000017 004 ;" sty 2 5 1L« A 2 (ON la 5 2 .I, 25 ( | « f049 2 5 NA-30- 2712 0087 -a- RA 5 00 o o

Fo -A- 55-2. 6 5 005 Z

A-y 1 7 7 717 74073 -- 004 and A- 85252521 2807331 - 005 тя5- 185 5 О6« « Z -i te 23 35 285 -55- - 6 6 5 pita 71756

MIZZ5557665 0.0005 se 70 rttlevYa 11 - 5 5355565 5-5 tva 14801110 m - vy 5 1 58 11 0065 p-va 115 03010083 8-x 53177385 1 0075... /

MA- i y5 - zh- 7772011 0095... ditch. 77771773 56531 3 0015 9538 55252538 1770773 0014 9471 pita 17773002

F) Gtvayaa 31173301 0002.6..Д 1

ready 30117071 10017 o ho tvab6 01100301303601.1.yu6yu 005..6YUyu Zhmzhsh/ 9567 0.028 9572 7 z0ISH02031 777004 in GlteBu. 30177377 | 0.060035 9585 77777989 2 ЧтБ )3 0.022 65

Table C1

Index of increase of MSZ

Concentration: about 9594 and 601 | 307 | 159 1 2595 145 12891193! | 1.45 70 9596 I Z54 | 1311 44 | 268. 9597 AND 878 | 551 | 382 80 9600 25511981 YY YY "7 96508 178 | 1318 | 60 | 31 | 67 9609 I 68 | 19 | 74 | 34 | 14 9612 | и71 | 145 | 95! | 11 9613 | 1685 | 97 | 361 | 4 | Z 9 Because | 32 | 9 GG 2 9815 175 | 85 | 23 | 9. 9616 ) 185) 7431142! / from o817 | 81 | 151 4 | 15 9621 | 25 | 44 ! 1613 10 9622 I 79 1 46 | 15 | 8 1 18 9625 I. 60 | 7 | 4 | her

GG lov | 27 | 8 41 115 9630 | 26 | 6 | 2 | 1

And 9631. | 67 | 20 | 9 |! t 9632 I. 8 127|811 9633 | 13.7 | 34 | 13 1 16 g o65 7 | 5118 7 | 7 Huh! hey | 8636 (| 13. | 46 | 22 | | 26 9638 26 | 15111 1177 (o) 7779639 | 136 | 78 | 34 Her | 26 779640 238 | 46|25| | 1 9641 |162 | 46 | 17| | 15 9642 I 14 | 25| 1921 | 109 | o 1779643 | 67 | 24 | 15 | | 10 zo Her, 9645 | 72 | 21 | 153 | | 10 so 9646 I 48 | 13 | 111 | 10 9647 I 6 1 1 G m

And 9648 | | | 34 | 1! 16

And 9649 | 66 | 60 | 46 | | 53 | "and

And 9650 | 33 | 14 | With ! |! With oBBi oo | AG 1177111 so 9652 and 76 | 1812 1 9655 | 65 | 37 | 13 | | 18 9660 | 14 121111 Yi! 9661 | 195 | 711 38 | 1.2 9663 1 89 1741801 | 50 / « 9664 | 116 | 37 | 1981 1 lo HER 79665 | 50 | 285 | 7 her! 14 - with 9667 shi i PIV PIV POLO 9668 ki POLYA KO PON NOVO "z 9669 shi pyv PA PON M y 9677 | ГГ 117711

Ge) -I -I s 50 "2 (F) ko bo 65

Table C2

ЗО0 НМ | 100 10 M

M

7778304 30 1 177 9405 ///861 | her 79354 | 20 G.Yu. ЮЙИС1 9394 | 19 | /! 93849 | 22. |. Sh MD ( 9424 | 37 | / " ГГ 9420 | 25 | Б Z«Х.| | / syu GP 9297 | | 16 1 9395 2 g 1 1 11 9331 129 HER 40 | her her 9994 7118 | | her 8295. | | 16 | | HER 9426 | 65 | / | /

And 9427 | 32 | 14 | ! t» Goescho | 67 | 210 1 17777177 9459 | 112 | 45 8460 | 36 | 18 | | 1 9531 | | t60 |150| 720 | 30

GG. 95429 .| (BE | 160 1128, | ЖФ Ж юХЩфКзФ

And 779543 | | 150 | 150 120 | 24 th 18554 | her |90Ї and her 79541 | (| 160 |160| 150 | 75 and e5v1 | (G.Yu sh BZHKh 1001 60 | 14 952 | |! |831 60 | 40 9554 | .ЮЮ.Ю 1129Ї 1. and 18568. | / 881 60 | 23

GG 9vU3 | 1 11001 94 | 83 | p. 251 BAD. | 1 150 11201 67 | 15

ГГ 7ло5/1 her 1 1100100 | with 8 | (about) 9574 | | |84| 60 | 16 79576. i 1 280 225 | 7/8 7 79581 |; HER | |3001| 090 / ote 17023031, 1736 12 o zo Golevvv Her 1. yu M. 686 | so 9593. | | | 5/7 |6 79586. | | | | 6 | 5 | M 795898 | Shhsh| | 111 79590... Her. her G (14 2 | them- 7 8483 | 24 | 14 zv (M - 8493. |200| 851761 M 1. s 719527 1120 | 103 | 50 | 11 15. 778557. |. 1. 1001 11 9456 |.. 12 01 7177

GG. le510 | 267 | 120 | 12|! 7 lion: | 214 | 120 121 | /| "

Go 78489 | 3031 192 | 771 YuyuYudsch ZV « 78500 | 300 97155 | -o 0 GOevot 177 177183 168119 sh YuK«I (s 79514 | 1201 40 | | |.

And 79454 | 1481 38 | 17 her "» Go 9495 5 | ovi | 15) 13 " | 79496 825 | 254 | 19 16. 9497 | 2001 52 | | | in 79503 77 | 36 | She eats her

GOlev4 1267. 150 | 34| ДщЩ 1 БЖ Щ Ж 4 b» 79477 63 | 29! 79517. | 120, 40 and 79518 | 240 120; 79535. | | 128 381 -I 9447 | 340 1 40 | | |. 78461 | 30 1 13 g 7 s". 70 I want | 7901 26 GG 1 1 9476 | 136 | 83 | | |. . lake 9536 |. 1 128 | 391.yuYu.YUYYUY |. 9538 | 1 128 43

Iii 9471 | 230) 15 GG 1

G. 9539. | | 128 35. Yud ShM. 9466 | 60 | 30 | | | K. 29 See eBb | 1 11518 17 9572 | | |831 5 | 2 (F, to the left. 01771151 1826 yuyu | 95855 | | | 72 | 13

C. Enhancement of the toxicity of various cytotoxic agents Enhancement indices for a selection of compounds using different cell lines and different cytotoxic agents, with the exception of doxorubicin, were measured as described above for doxorubicin, the results are summarized in Table 0. b5

Table Yu

The increase index of the Ministry of Health

Concentration:

Compound Me! Line | Cytotoxicity of 30 nm cells of бБбя |276оАЮ такея| PbB | I | 8

VI ey Pobiovn PByy МН МН 4

And 9596 Sh|2780А0| Taxol. | 743 | 160 | 35

We are members of NGO NINI NOV 4 9597 12780АБИ Taxolo | 2070 1497

Pooiy shso Poiai PoY SHVI NI 4

Me 4 4 4 ur pt 4 z614 |NBULH! Takol | 11 | 11 | K|/

Example 1A Production of amines of the general formula (IX)

Amines of general formula (IX) were prepared as shown in the table below,

Table 1 g u t I Ge

THEM Their method. sha en o

IX.4 Method IX.F

Oros below nm 67 | "in)

ИХ.В он ССС Method ИХ. Uosha 07 below i) drank cha

IX.1 o. Method 1X.1

I Goly below Che

NA me Y se)

IX.3 o. manual IH.3 odu nm "OMe"

IH.K for help. IH.K

SGS below 2s on Me Ohm

IX.1 Me SS manual. IX.1 z» n below

Mn,

IH.t me o help. THEIR. t e SH; and oaya below

F vedy -I iH.p r ! at. method IX.p - and IX.O SOS method IX.O about 50 mi, and Me below

Х.р. THEIR. r nya

Their method, 99

OMe to her o in du lav FI OoMe 6o Mo: Mn; IXH 40 Reductive amination of 3,4-dimethoxybenzaldehyde was carried out as described in method 2B(M), obtaining an intermediate secondary amine. Alternatively, this amine can be prepared by reacting veratrilamine with methyl chloroformate followed by reduction of the carbamate with lithium aluminum hydride. A mixture of amine (3.76 g), 4-nitrophenethyl bromide (4.78 g) and sodium carbonate (3.3 g) in 25 bml of acetonitrile was refluxed for 3 hours. Treatment with water after cooling gave 1.75 g of orange oil.

The nitro group was reduced in ethanol in a hydrogen atmosphere over platinum dioxide as a catalyst, obtaining 1.3 g of amine IX.bB.

The method of IX s b you purely om om Ж | Ome

Zk OMe nm , IH. c - : a mixture of 4-nitrothiophenol (1.00g, 6b.44mmol), 1,2-dibromoethane (1.39ml, 2.5 equivalents) and potassium carbonate (2.22g, 2.5 equivalents) in 15ml acetonitrile stirred at room temperature for 30 minutes.

Intermediate bromide (0.8 g, 47905) was obtained by treatment with water and fractional crystallization.

A mixture of bromide (0.336bg, 1.28mmol), 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.294g, 1.2v8mmol) and potassium carbonate (0.372g, 2.1 equivalents) in 1Oml of acetonitrile heated under reflux for 3 hours. Treatment with water and flash chromatography (ethyl acetate/hexane) gave the desired tertiary amine (0.236g, 49965).

To a suspension of tertiary amine in 2 ml of ethanol, 0.3 ml of concentrated NS, 0.151 g of iron were added and heated to 802C for 2 hours. Treatment with water gave amine IX.c as a gum-like substance (0.195 g, 90905).

Method IX.a It was carried out similarly to method IX.c using p-nitrophenol as a starting material.

The reduction of the nitro group in this case was carried out in ethanol in a hydrogen atmosphere over platinum dioxide as a catalyst.

The method of IH.e

Their method. ee sch on on OMe en OK o A i)

Me o Me o Me oMe ' oMe su ov that | rome or rve e ni Me IIIHe cha

Carbonate was added to a solution of 1-methyl-6b,7-dihydroxy-1,2,3,4-tetrahydrozoline hydrobromide (1.00 g, 3.84 mmol) in 25 ml of a mixture of acetone/water (4:1) with stirring. sodium (0.611 g, 5.7 mmol), the mixture was cooled to - 0"C and benzyl chloroformate (0.6 ml, 4.19 mmol) was added, then allowed to warm to room temperature and stirred for 2 days. The mixture was filtered and the filtrate was concentrated under vacuum, the resulting aqueous solution was poured into 8 ml of ethyl acetate, the organic phase was washed with water (3 x 4 ml), brine (40 ml), dried over magnesium sulfate and concentrated under vacuum to obtain a brown oil, which was purified by flash chromatography (510). hexane/ethyl acetate 1:1) to give benzyl carbamate (0.817 g) as a white foam. "

To a solution of benzylcarbamate (2.74g, 8.75mmol) in 100ml of THF, sodium hydride (6095 dispersion, 2.10Gg, shsh s 5Ommol) and methyl iodide (27.25ml, 44O0mmol) were added, then 5Oml of DMSO was added and heated under reflux and overnight, then poured into 200 ml of ethyl acetate and 100 ml of water, the organic phase was extracted, washed with water (3 x 4 O ml), brine (40 ml), dried over magnesium sulfate and concentrated under vacuum to obtain a brown oil, which was purified by flash chromatography (5 hexane/ethyl acetate 2:1) to give the dimethoxy intermediate (2.7 g) as a yellow crystalline substance.

Gee! The benzylcarbamate group was cleaved by dissolving the intermediate (2.7 g, 8.6 mmol) in 27 mL of a mixture of methanol/dichloromethane (1:11) and reducing it with palladium on activated carbon (0.7 g) for 4 days at

Atmospheric pressure and at 27.5 kPa during the next 12 hours. Filtration and reduction in vacuo gave the crude secondary amine (1.89g) as an orange oil.

The amine was further reacted with 4-nitrophenethylboromid and reduced by method IX.B amine IX.e was obtained as an orange solid. c Method IX.E in 05

Seoul ul 5500 ve su SU their mn,

GF! mo; A mixture of 4-nitrophenethylamine hydrochloride (0.77 g, C, mmol), o,-dibromo-o-xylene (1.00 g, C3, mmol) and potassium carbonate (1.83 g, 13.3 mmol) in 20 ml of acetonitrile was heated under reflux for 2 hours.

Treatment with water and flash chromatography (595 methanol in dichloromethane) gave the desired tertiary amine 60 (0.297g, 2996).

The nitro group was reduced in a mixture of methanol and dichloromethane in a hydrogen atmosphere over platinum dioxide as a catalyst and purified by flash chromatography (5% O, hexane/ethyl acetate), obtaining amine IX. (0.297 g, 2990). b5

Their method. 9 years

OD ste MO - SSO! | Ome

Their. 8 me

A mixture of 3-nitrophenethyl alcohol (2.11g), methanesulfonyl chloride (2.44ml, 2.5 equivalents) and triethylamine (1.7bml, 2 equivalents) in dichloromethane was stirred at 0"C for 4.5 hours. Treatment with water gave the desired mesylate (2.27g, 7395) as a yellow solid.

6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.13 g, 1 equivalent) and potassium carbonate (3.2 g, 2.5 equivalents) and heated at 1007C for 4 hours. Treatment with water gave the tertiary amine (1.49 g, 4795) as a yellow oil.

The nitro group was reduced in a mixture of ethanol and dichloromethane in a hydrogen atmosphere over platinum dioxide as a catalyst, obtaining IX.d (1.11 g).

Their method. oh he ome he dO what; co; co; | sn SSS sly cm nn, IH. in

A mixture of 3-nitrophenol (10g, 72mmol), epichlorohydrin (11.2ml, 144mmol) and potassium carbonate (10g, 72mmol) in M,M-dimethylformamide was stirred at room temperature for 18 hours. Treatment with water gave the intermediate epoxide (10.8 g, 7795) as a whitish crystalline substance.

A mixture of epoxide (1.09g, 5.mmol), 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (21g, Ge! 9.mmol) and potassium carbonate (1.3g, 9.mmol) in 20 ml of tetrahydrofuran was stirred at room temperature for 72 hours. Treatment with water and purification by flash chromatography (ethyl acetate) afforded the desired alcohol (0.39g, 5090) as a white solid.

Hydrogenation of the nitro group was carried out by method IX.Yu, obtaining amine IX.p.

Method IH.i (av) zo so, sosi o ,- Se ni - o) ak so so b Me i om o Me i o Me ih u o Me Y son

S Foe od - zv sy meshi s o te OMe SSS

St. M.O.M. under Navevnu "

Me Me Iha

A solution of 3-methyl-4-nitrobenzoic acid (5.0 g, 0 mmol) and thionyl chloride (1 ml) in 100 ml of toluene was heated under reflux for 3 hours, then cooled overnight and the mixture was evaporated, followed by azeotropic distillation with toluene. and hexane gave chloride (quantitatively) as a whitish substance with a low melting point.

To diazomethane, (which was prepared from an excess of M-methyl-M-nitrosotoluene-p-sulfonamide, as described in Modea! 85

Rgasiisa! Ogdapis Spetivig, 4th edition, p. 293) added Zml of triethylamine. The mixture was cooled in an ice bath and

Hydrochloric anhydride in diethyl ether was added slowly. After 2 hours, acetic acid was added until the release of nitrogen stopped. The mixture was filtered, concentrated in vacuo and the residue dissolved in diethyl ether, washed with saturated ammonium chloride, aqueous potassium carbonate and brine, dried over sodium sulfate, and reduced until crystallization began, which was continued in the refrigerator, and then 2) 20 filtered, yielding 2.03 g of diazoketone as pale brown crystals.

A solution of diazoketone (2.0 g, TOmmol) in 1 ml of ethanol was heated under reflux, obtaining a brown solution, to which a solution of argentum benzoate (0.125 g, 0.54 mmol) in 2 ml of triethylamine was slowly added. The mixture turned black and nitrogen was released. Subsequent portions of argentum benzoate were added until the evolution of nitrogen stopped, and heated under reflux for another 55 minutes. Mixture 29 was filtered through brownmillerite and concentrated in vacuo to a brown liquid, which was purified

HF) by flash chromatography (51%, 59% hexane in ethyl acetate) to give the desired ethyl ester (1.46 g) as a yellow liquid. Ethyl ester (1.35g, 6b,0b5mmol) was dissolved in 1,4-dioxane (bbml) and water (20ml) was added until cloudiness was reached, then GIONONE 20 (0.762g, 17mmol) was added and the mixture was stirred at room temperature overnight. . The mixture was acidified with hydrochloric acid, extracted three times with VOml dichloromethane, dried over magnesium sulfate and concentrated in vacuo to give the desired acid (0.633 g) as orange crystals.

A mixture of acid (0.630g, 8.23mmol) and 1-hydroxybenzotriazole hydrate (0.546g, 4.04mmol) in 30ml DMF was stirred at room temperature for 10 minutes. 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (0.78g, 4.04mmol) was added followed by dicyclohexylcarbodiimide (0.667g, 3.2mmol) and stirred at room temperature overnight, then the filtrate was filtered concentrated in vacuo, treated with dilute hydrochloric acid and then with dilute sodium hydroxide solution, extracted with dichloromethane, washed the organic phase with water and brine, dried with sodium sulfate, and evaporated the solvent in vacuo to give a yellow residue, which was purified by flash chromatography (510 5, hexane/ ethyl acetate 1:1), obtaining the desired amide (0.7bg) as a whitish crystalline substance. The nitro group was reduced by method IX.B z

Ra/activated C (5O0mg). Purification by flash chromatography (5105, hexane/(ethyl acetate 1:1)) gave the intermediate amide (0.695g) as a white foam. The amide (0.730g, 2.15mmol) was recovered by adding, with stirring, a solution in 100ml of tetrahydrofuran to a suspension of lithium aluminum hydride (0.244 g, 6.433mmol) in 5 ml of tetrahydrofuran at room temperature, then heated under reflux for 2 hours, then cooled and carefully 7/0 added 0.5 ml of water in 20 ml of dichloromethane, magnesium sulfate was added, stirred for 10 minutes, filtered and the filtrate was evaporated in a vacuum, obtaining the desired amine IX.i (0.661 g) as a whitish crystalline substance.

Method IX.i Using 3-methoxy-4-nitrobenzoic acid as a starting material, amine IX.I was obtained by method IX.1.

The method of ХК ССС is TS I we and OMme MO; SSS a O chn, me ome YH.K

A mixture of amine (0.336g, 1.61mmol), 4-nitrobenzyl bromide (0.289g, 1.34mmol) and potassium carbonate (0.277g, 2.01mmol) in 50ml acetonitrile was stirred at room temperature for 2.5 hours. Treatment with water gave the desired intermediate, the nitro group of which was reduced by method IX.0, obtaining IX.k as a yellow oil (0.380 g).

Method IH.I Me Me SO

Me M OoMe tambourine otsi vv sch od E --- Z om Ge! Me ome o

M --- - omMe su OMe nm (there are 7 of them

A mixture of 2-(4-nitrophenyl)propionic acid (5.0g, 2bmmol) and thionyl chloride (3.75g, 52mmol) in Zbml of toluene was heated under reflux for 2 hours, then cooled and the solvent was evaporated in a vacuum to obtain chloride anhydride. Hydrochloric anhydride (5.47 g, 2 mmol) was dissolved at 0"C in dichloromethane, and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (37 g, 24 mmol) and triethylamine (5.4 ml, 0 mmol) were added to this solution. in. was stirred for 7 hours and acid/base treatment and flash chromatography (195 methanol in h-dichloromethane) gave the desired amide (4.09g, 5695).

The nitro group was reduced in a mixture of ethanol and dichloromethane in a hydrogen atmosphere over a Ra/activated C as ise) catalyst, and the amide was reduced to the desired amine with lithium aluminum hydride in tetrahydrofuran.

Method IX.t oMme ome ome 5-h bosom ny h o pt FO - fu pt - wound vovoh

OmMe p o; Me and? in

S IH.t

Mn,

Isovanillin was alkylated with iodobutane, and then reductive amination was carried out by method 2B(im), obtaining

Me. intermediate secondary amine, the reaction of which with 4-nitrophenethyl bromide in acetonitrile, and then hydrogenation of the -I nitro group in a hydrogen atmosphere over platinum dioxide as a catalyst, gave the desired amine IX.t. "The way of ИХп -и 1 -- г - ны omv I And what

Mo, ono" y - ro --- o AY Mo; so i Go) OME ome --- oche NAH 99 about them ?

HF) Mesylate was prepared from 4-nitrophenethyl bromide by method IX.d4. A mixture of mesylate (1.0 g, 4.1 mmol) and sodium cyanide (0.40 g, 8.2 mmol) was stirred in 25 ml of DMSO at 907C for 7 days. Treatment with water gave the desired nitrile (0.651 g, 9190).

Nitrile (0.615 g) was heated under reflux in 25 ml of 1.5 M sodium hydroxide solution for 5 hours. 60 By treating with water, an intermediate carboxylic acid (0.548 g) was obtained, which was converted into an anhydride by treatment with thionyl chloride in toluene, and then by reaction with b,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, an amide was obtained, the nitro group of which was reduced by method IX.i , receiving amine IX.p. b5

The method of IH.o pe ome and in. ref ОМе mo; Ome mo mo o? me I ome b M

MN. M OMe kn and OMme and IHo and 5

A mixture of 3,4-dimethoxybenzoyl chloride (3.9g, 19.2mmol) and 7-nitro-1,2,3,4-tetrahydroisoquinoline (2.81g, 15.mmol) in 200ml dichloromethane was stirred for 2 hours and filtered. Treatment of the filtrate with water and purification by 7/0 flash chromatography (1-1096 methanol in dichloromethane) afforded the desired amide (3.25g, 4695) as a yellow oil.

The reduction of the nitro group and the amide was carried out by method IX.i, obtaining amine IX.o as a yellow oil. (1.37g).

Method IX.r To

O.M om di

3,4-dimethoxybenzaldehyde and 4-nitrophenethylamine hydrochloride in methanol were mixed with triethylamine for 3 hours. Hexane was then added to precipitate the desired imine and filtered off, then reduced to the secondary amine intermediate using sodium borohydride in methanol. The amine was alkylated by refluxing with 2-iodopropane and potassium carbonate in acetonitrile. Hydrogenation of

Nnitrogroups in a hydrogen atmosphere with palladium on charcoal obtained amine IX.r as a yellow gum-like substance. at

Reference to example 1B: production of amines of general formula IX".

Amines of general formula IX' were prepared as shown in Table 3.

Table Z d" ("in 30. ah)

MN; (сНнуюЮ- С, o g -

Amen | Mr. YOU | Link che

ICH to the drug |x a 2 Compound 3.5 i-o in example Z

ММО-А- 96/20180 « to | n 2 Compound 2.2 w c in example 2

AND MO-A- "» 96/20180

IHS with 2 nn Compound 3.4 in example C (22) МО-А- -И 96/20180 их а0 13 bMeomenizhe 7 их e 1 Compound 2.7 о 70 in example 2

MMO-d- o 96/20180

Il Kk Compound 2.10 in example 2

MO-A-

F) 96/20180 ko I 4 1 Compound (2.3 in example 2 60 MO-A- 96/20180

Production of 3-(6,7-dimethoxy-3.4-dihydro-1H-isoquinolin-2-yl)upropylamine (ХХЯ) b5 sto sto yan

M. M hundred But spo - see

Here we are -- lT3 5 nu t ro

Y I M pl. Their Sol an: 70 A mixture of tetrahydroisoquinoline (5g, 20mmol) and potassium carbonate (9g, bbmmol) in 100ml of dimethylformamide was heated at 1007C for 4 hours. Concentration in vacuo, workup, and concentration afforded the intermediate nitrile (3.68 g) as a pale yellow solid.

A suspension of lithium aluminum hydride (0.280 g, 7.32 mmol) in 25 ml of tetrahydrofuran was added to a solution of the intermediate nitrile (0.600 g, 2.44 mmol) in 5 ml of tetrahydrofuran at 0"C under a layer of nitrogen, stirred for 30 minutes and allowed to warm for 12 hours. to room temperature, then quenched by slow addition of 0.28ml of water, 0.28ml of 2N Mahon and 0.9Uml of water.The mixture was dried over magnesium sulfate, filtered and the organic layer was concentrated in vacuo to give the desired compound IX.a as a yellow oil (0.510g) .

Reference to example 2A: Preparation of 2-nitrobenzamide of the general formula M ome son ome sosi in coor.

Ome MO, oMe Mo, oschI ni Ome IH.t

Sy o M aly er --- Jr

OMe Mo, p 29 A mixture of 4,5-dimethoxy-2-nitrobenzoic acid (7.0 g, 3 mmol) and thionyl chloride (4.5 ml, 2 equivalents) He) was refluxed in 140 ml of toluene for 2 hours, then cooled and the solvent was removed in vacuo to give the chloride as a yellow solid (quantitative yield).

A mixture of hydrogen chloride (0.851 g), triethylamine (1 equivalent) and amine IX.t (1.09 g) in 18 ml of dichloromethane was stirred for 18 hours at room temperature. and (ethyl acetate), obtained the required nitrobenzamide M.13 as a white solid (0.737g). co

Further, in a similar way, using suitably substituted nitrobenzoic acid or nitrobenzoyl chloride m and amine IX, nitro compounds of formula (M) were obtained, which are presented in Table 4.

Table 4 m

Nitrobenzoic "Amine Titrobenzamide U S. 3o I acid or their ix, nitrobenzoyl chloride spoil s zy U I oMe

Mo, So m « 40 sovi rev t (and in) with SS yad dl - MU. "» mo, shk g SOS IHS o SIS Y z oMme 45 bus sosi ih: o sr ke

F S si S,

Mo, mo, UA - and SO IH.e po baki o o m OMe - mo, sok i d) 50 -ho mo, U.5

GotoToi IH.Yi

Mez o o y idu mo, Y Y uv

Mo,

SOS Ih:h o vi se osos mo, ko, ome U?

SOS IH.V he white (F; S Ge du, ko, vo yu still 00 x8 60 b5

Y SOS IC.Yi; see

S roza ko, sab mo, Me U

SOS IR. Z: se vi od 19) where is So Oma U.

SOS IH.K 9.

AC

N y M xx Me oMme mo, Ai mo, U.

So IX.1 me he 7OMe and s o mo y ? so U42 to SOS IH.p - oe

In t o shJuo Kk KAK! 2 Mo,

SOS IK.o o i OMe i ' N i Mo, byu, Ul

E son iv iv ich rova «o, M.16 sch a SO NI IH.a | about iome | in oi S, o d sin il du

Mo, about; call;

SOS fo ICr t

Ge) iy Ome ( I | «v) mo, | | soch | mo, Mov s

Such compounds from the above scheme as M.16 or M.26 can be converted into other compounds of the formula M, M by replacing the halogen with such a suitable nucleophile as a thiol or amino group in such a suitable solvent as M,M-dimethylformamide or acetonitrile. uh-

Sodium thiomethoxide (0.050 g, 0.72 mmol) was added to a solution of M.16 (0.200 g, 042 mmol) in 2 ml of M,M-dimethylformamide and stirred at room temperature for 72 hours, then diluted with ethyl acetate, washed with brine, dried with magnesium sulfate and the solvent was removed in vacuo to give M.18 as a yellow solid (0.190g, 89965).

Nitrobenzamide M.17 was prepared by heating under reflux a mixture of M.26 in acetonitrile with an excess of 4096 of an aqueous solution of dimethylamine for 8 hours. with I SS h M ? iy uv 7

Mr. Ra and SO

Ge») n mo, U417

Sh- Reference to example 2B: Preparation of 2-nitrobenzamides of the general formula MI" - M-(4-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethylI|-phenyl) )-2-nitro-4-trifluoromethyl-benzamide (MI .24) son OMe (95): SOS ha i) all Mo» g Mom S ome ve o di OM

ZBZ52t soy gla

GF) ts ko

GI A mixture of 2-nitro-x,o;o-trifluoro-p-toluic acid (0.25g, 1.0bmmol) and thionyl chloride (0.bml) with bml toluene was heated under reflux for 4 hours, then concentrated in vacuo and by azeotropic distillation with toluene, crude chloride was obtained, which was added to a solution of amine IX.B (0.28g, 0.8v8mmol) and triethylamine (0.18ml, 1.33mmol) in TOml of dry dichloromethane and stirred for 24 hours at room temperature. Further treatment after trituration in ether gave compound M.24 as a whitish powder (0.44).

Further, in a similar way, using an appropriately substituted nitrobenzoic acid M and amine YH, we obtained 65 Nitro compounds of the formula (MI"), which are presented in Table 5.

Table 5

Mitrobenzoin Amino | Pyrobenzamide UIT 00000 er PP

DU chuki fish vi or and somo,

MI".23 o SON IHTU So « pf o DU om o Mo, ero

MI!". 25 sleep IR 4

C Zv as,

AND MI!.26

Owl See ome

KO syu yuyu

SI MO. IN!

And that's it! which

MI!.27 p

Reference to example ZA: Preparation of 2-aminobenzamides of the general formula MI from the corresponding nitro compounds about

UI.12 OMe nir:ROShaevi

M o «t OMe | "in)

In the village

Y Y n | OoMme cha mo, Me

M - o OoMe; (Se)

M U.12 in!

MN, "

A solution of M.12 (0.140 g, 0.000 mmol) in bml of ethanol was purged with nitrogen and 30 mg of platinum dioxide was added, the mixture was stirred at atmospheric pressure under hydrogen for 2 hours, filtered through Seitem and concentrated in vacuo to give MI.12 as white foam (0.126g, 9696), with" Next, aminobenzamides of the formula (MI), which are presented in Table 6, were obtained in a similar way.

Table 6 (22) -I -I o 50 (42)

F) name) 60 b5

Nitro compound |2- Aminobenzamide

In MI

; her о о 25 о зо The method can be applied to obtain compounds containing a sulfur atom.

OmMe so o im cha

M | U y OomMe M cho 2 (Se)

Omg

CS

M OoMe

S and MI.3 "

To a solution of nitrobenzamide U. (147 g, 0.3 mmol) in 2 ml of methanol, we added 0.140 ml of concentrated with diatomaceous earth M.3 (0.147g, 0.30) and 0.140 Her. 0.072g of iron and heated to 802 for 2 hours. The mixture was basified with saturated sodium carbonate solution, extracted with ethyl acetate, dried with magnesium sulfate, and the solvent was removed in vacuo to give a whitish solid, which was purified by flash chromatography (ethyl acetate) to give the desired aminobenzamide MI.Z

X(0.047g, 34905).

Gee! Similarly, the following aminobenzamide was obtained.

OMe -I

M

- o OD OMe (95) 50 ra M o H ml8

Mn, ,

Reference to the example of ZV: Production of 2-aminobenzamides of the general formula MI! 5 2-amino-M-4-(2-(6.7-dimethoxy-3.4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenyl)-benzamide (MIIH.23)

Ome m v dk o Sl y p ume cht23 kt Yae bo va k | oMe

HO

7 what 7 s OmMe tu s 1 Uig23 ! nn ot

WE"

A solution of MI.23 (12g, 260mmol) in 200ml of ethanol and 160ml of dichloromethane was purged with nitrogen and 240mg of platinum dioxide was added, the mixture was stirred at atmospheric pressure under hydrogen for 4 hours, filtered through a sieve and concentrated in vacuo. Recrystallization from methanol gave white crystals of MIiII!.23 (9.6 g).

Next, aminobenzamides of the formula (MI! ), which are presented in Table 7, were obtained in a similar way.

Table 7

UT .24 ССО 70 o rovy 2 oce s u dob iv nm, mI11'!24

UI7.25 x 9 yar,

In, in

UT1I!.25

MI". 26 g o breath

KA in, sch mia,

UpI'26 Fr

U1"7.27: ome o di, and so o in Mn, so

UTII!.27 M

Reference to example 4A: Preparation of 2-aminobenzamides of the general formula MI from the corresponding anthranilic acids

MI.19 OMe more m /more IXa me h

SHYN oMe not) with a M

We know the mind | schi t b» m smn, -I Solution of 3-aminopyrazine-2-carboxylic acid (0.500g, 3,bOmmol), amine IIXa (1,12g 3,bOmmol), -1M-cyclohexyl-M-(2-morpholineethyl )-carbodiimide of methyl-p-toluenesulfonate (1.68 g, 3.9 bmmol), 1-hydroxybenzotriazole (0.486 g, 3.bmmol) and triethylamine (0.591 ml, 3.bmmol) in 30 ml of dry dichloromethane (95) 50 was stirred for 5 days at room temperature. Subsequent treatment with water and recrystallization from ethyl acetate yielded the required MI compound. 19 as a pale yellow solid (0.733G).

Aminobenzamides, which are presented in Table 8, were obtained in a similar way.

F) name) 60 b5

Table B

Anthranilic Amine 2-Aminobenzamide acid in ХХ UT ху ХОН ХХ.а уУ1.24 ві

M sMn, pa them." u1.25 and 0 son,

Because IX.b 1.27 7 -4 chn,

Me Mn, then So IH-b then om Mn,

Reference to example 4B: Production of 2-aminobenzamides of the general formula MI from the corresponding 2o anthranilic acids 2-amino-M-4-(2-(6,7-dimethoxy-3.4-dihydro-1H-isoquinolin-2-yl)-ethyl| -Phenyl)-5-methyl-benzamide (MIIH.12)

Ome

Me son Phi

IF i uva OME s min ih

Mn, | OMe o o C, e "c)

Me M UK? p o

MN; M.

A solution of 2-amino-5-methylbenzoic acid (0.190g, 0.9bmmol), amine IX.p (0.300g, 0.9bmmol), m

M-cyclohexyl-M-(2-morpholineethyl)-carbodiimide methyl-p-toluenesulfonate (0.449g, 1.0bmmol) and 1-hydroxybenzotriazole (0.143g, 1.0bmmol) in TOml of dry dichloromethane were stirred for 48 hours at (Ce) room temperature. Further work-up and flash chromatography on silica gel with methanol in ethyl acetate (2:98) afforded the desired compound MI.12 as a pale yellow solid (0.058G). 2-amino-M-(2-(6.7-dimethoxy-3.4-dihydro-1H-isoquinolin-2-yl)-ethyl|-4-fluoro-benzamide (MYH.07) . | MN them. Me with ?

OMe and ss OMe - and '

E M UPR.07 -I

When stirring, to a solution of M-cyclohexyl-M-(2-morpholethyl)-carbodiimide methyl-p-toluene sulfonate (0.238 g, 0.5 mmol) and 1-hydroxybenzotriazole (0.076 g, 0.5 mmol) in 7 mL of dry dichloromethane was added 2-amino-4-fluorobenzoic acid (0.080g, 0.52mmol) and then triethylamine (0.08ml, 0.57mmol) and amine IX.a (0.200g, 0.5mmol) and stirred for 48 hours at room temperature . Further workup and flash chromatography on silica gel with methanol in dichloromethane (5:95) afforded aminobenzamide MIG.07 as a pale yellow solid (0.057g).

Aminobenzamides presented in Table 9 were obtained in a similar way. (F) Table 9 and acid M" 60 b5 -Ко-

sleep IX'.a o C in So mn, Mn,

UHTTI'Oo1 si YH'.a a SO

Soy ash chn,

Mn,

UiIiI".02 to si so IS .a bme xx g. o va povo mn, Sh chn,

MIII".03 son IX'.a ay 5: IZ 9 KI

Sh pai sha se v cha, Bo

MITI'".04 dream Their .oa 9 C 1 ov and bom

Mn, and si s

UTITI!

And ve popa nn, Shchi s

UTII". o6 Ge) zi SON IK'.a o S

It is the fault of her bath, sleep, sleep, o

UTIKH OV so,n Ih'.a S so gyi zhom,

Mn, nn, -

Oh, she is

UTIiYI!.09 che so and Smt

Хх т

Seen (Se) om chn, Yi n b nn,

MIIII!.10 - . and? (22) - - (95) (42) name) because b5 -D1-

sleep THEM a t me

MN. 2 nn,

MITI!.11 -- their bosoms. this is their rose o, chn, k om Mn,

UII1' .13 dream HO. WITH

СХ about DI ome 7 Toh

E kn,

TUES.

MIn5 to mn, g kn, IZ

UTII'.15 at sleep | IHT SOS 9 and me

And vedy kn, Soya - n

We,

MI111!.16 Ha gospo vn IV rech bi provo (o) snu Mn, nout svat nn,

UTII!.317 "c) n IH O.B fought and Sh so so, s, idu 2 zome

So km

Mn, chn,

WHITI!. 18th century

Dream IZhb.a o sho stos y

And mn, chn, ome

UII1!.19 sleep IX'.s e fo « thing y

SH So and Z

МН, мк, с Mmttt".2a ;» and om and vn, and (o) UTII!b.21 so, IH'.e o and ku im - Su : ey vve

And me -| Many, many

MITI'".22 (95) sb IHT SSS 2 fe o di me sn, Mn, soi n sn, Mn,

MIYITI'.28 s son IR me -x 2 o | draft and MA, p. m" o ts mn,

UTII!.29 60

Reference to example 5: Preparation of 2-aminobenzamides of the general formula MI from the corresponding amino esters

MI b5

8. ssOume (7 in SOMe s So,n g g ---

Mn, other mn o- o- -y o - o is o res pa 70 y; oMe zn o-i

K oh Fa va p 5 and mi. 20 oMe

Mn,

To a solution of methyl 3-amino-2-thiophenecarboxylate (7.56g, 48.1mmol) in 40ml of dichloromethane was added a solution of di-t-butyldicarbonate (11.55g, 52mmol) in 10ml of dichloromethane, and then 4-dimethylaminopyridine (0.6bg, 4.vmmol) and stirred for 4 hours at room temperature, the mixture was diluted with dichloromethane, washed with water, dried over magnesium sulfate and the solvent was removed in vacuo to give a gum, which was purified by chromatography (10905 ethyl acetate in hexane) to give the desired t-butyl carbamate (4 , 40g, 36905).

To a solution of t-butyl carbamate (1.01 g, 3.95 mmol) in 4 ml of tetrahydrofuran and 1 ml of methanol, a solution of sodium hydroxide (0.316 g, 7.0 mmol) in 4 ml of water was added and stirred for 4 hours at room temperature, acidified to pH 4, extracted with ethyl acetate , dried with magnesium sulfate and the solvent was removed in vacuo, obtaining the required acid and a white solid (0.80 g, 83905). (5)

A mixture of intermediate carboxylic acid (0.150g, 0.b2mmol), M-cyclohexyl-M-(2-morpholineethyl)-carbodiimide methyl-l-toluenesulfonate (0.288g, 0.0b8mmol), 1-hydroxybenzotriazole (0.092g, 0.b8mmol) ) and IX.a (0.175 g, 0.5 mmol) in a ml of dry dichloromethane were stirred for 3 days at room temperature, the mixture was diluted with dichloromethane, washed with water and a saturated sodium carbonate solution, dried with magnesium sulfate, and the solvent was removed under vacuum, obtaining a yellow a gummy substance, which was purified by chromatography (silica, ethyl acetate) to give the desired amide as a white foam (0.112g, 33905). co

Gaseous NH! for 10s and - stirred for 1 hour, then basified with sodium carbonate and extracted with ethyl acetate, dried with magnesium sulfate and the solvent removed in vacuo, obtaining the desired aminoamide as a white solid - (0.151g, 91965). (se)

The following amino amides were prepared in a similar way.

Table 10

Starting Amin IX Dinoamide UI « en shii

Me 0 IH.a MI.21 o)

Z h mn, i g IH.a Ui.22

Co

Me, in IV Ut.53

M 5 Ok -I o 20 Reference to example bA: production of acids of the general formula vU-so»n. which are not on sale

I) s (o; o | re - A 2

SI M si M (F) To a hot solution of 2-chloro-3-quinolinecarboxaldehyde (0.500 g, 2.61 mmol) in 7 ml of t-butanol and 12 ml of water

A hot solution of potassium permanganate (0.580 g, 3.67 mmol) in 15 ml of water was added dropwise over 15 minutes, stirred for 1 hour under a reflux condenser, allowed to cool, and the MpO precipitate was washed with water and t-butanol. The pH of the filtrate was adjusted to 5 with 2N CARRIER solution, extracted with chloroform, dried over magnesium sulfate, and the solvent was removed in vacuo to give the acid as a yellow solid (0.210g, 39965).

The desired acid can otherwise be obtained by basic hydrolysis with sodium or lithium hydroxide of a suitable ester such as 2-methyl-thiazole-4-carboxylic acid ethyl ester or 4-hydroxy-quinoline-3-carboxylic acid ethyl ester in such a suitable solvent as 4-dioxane or methanol. 65 Reference to example 6B: production of acids of the general formula К21-СО5Н. u) 4-cyclohexyloxybenzoic acid

Vg ev) he o

J

"boss and - (t - o o

To a solution of methyl-4-hydroxybenzoate (1.0 g, 6.61 mmol) and cyclohexyl bromide (1.62 ml, 13.1 mmol) in 20 ml | | | and dimethylformamide, potassium carbonate (2.26 mg, 16.4 mmol) was added, heated at 100"C for 24 hours, cooled, filtered and concentrated in vacuo. Flash chromatography on silica gel (hexane/ethyl acetate 5:1) gave methyl-4 -cyclohexylbenzoate (0.169g), which (0.162g, 0.6b9mmol) was dissolved in 10ml of 1,4-dioxane and bml of water and lithium hydroxide monohydrate (0.032g, 0.7bmmol) was added, stirred at room temperature /5 for 18 hours and added another 0.032g of lithium hydroxide monohydrate and stirred for another 4 hours. The mixture was added to ethyl acetate, washed with brine, and concentrated to give the desired compound as a yellow solid (0.027g). its) b-methoxy-3-pyridinecarboxylic acid and c)

Me and him

GO- 2 2 sno M sno M

To a solution of b-methoxy-3-pyridinecarboxaldehyde (0.050 g, 0.3 mmol, prepared by the Sotipz apa method

Kiirask, U. Ogd. Spet., 1990, 55, 69-73) in 0.5 ml of t-butanol was added a solution of potassium permanganate (0.081 g) in ml. EM water, stirred for 2 hours at room temperature and added a saturated solution of sodium sulfite until d) disappearance of the purple color, extracted several times with chloroform, gradually acidified with 2H solution

NOAH The chloroform extract was concentrated in vacuo to give the desired compound as a white solid (0.042). ii) 5-propionylpyrazinecarboxylic acid o

Maya SO Me; M. i SbOMe ze) ru p

M M m

M. Son about | I: (Se; m l-

M o "

To a solution of propionaldehyde (0.78 ml, 0.9 mmol) and methyl-2-pyrazine carboxylate (0.250 g, 1.81 mmol) in

07BMl H»BO, at 07C, t-butyl hydroperoxide (70905, 1.0ml, 7.25mmol) and a solution of Rez0O)07NhO c) with (3.02g, 10.U9mmol) in ml of water were simultaneously added, allowed to warm to room temperature and stirred for 2 hours. "» Solid Ma»52O»z was added until the iodine-starch color disappeared, then extracted with dichloromethane and "concentrated in vacuo by flash chromatography on silica gel (hexane/ethyl acetate 85:15) to obtain methyl-5-propionyl-2- pyrazine carboxylate (0.106 g) as a pale yellow solid. The methyl ester was treated with lithium hydroxide monohydrate (0.025 g, 0.5 mmol) in 15 ml of tetrahydrofuran and 0.5 ml of water, stirred at

Me. at room temperature for 2 hours and acidified with 2N Na. 4 hours. The organic phase was concentrated in vacuum, obtaining the desired compound (0.092 g). -1 im) 5,6,7,8-tetrahydroquinoline-3-carboxylic acid son so, and 5-0 U --k

A mixture of 3-quinolinecarboxylic acid (1.73 g, 10.00 mmol) in 20 ml of trifluoroacetic acid was shaken in the apparatus

Parra with 200 mg of platinum dioxide at 70-105 kPa. After 90 minutes, it was filtered and the solvent was removed in vacuo to give an oil which was added dropwise to diethyl ether to give a white solid which

HF) was filtered off and recrystallized from ethyl acetate/hexane to give the desired compound as a white solid (0.770 g). name)

Production of the compound of formula (I) by a variant of method (a)

Method A 60 9616 b5 o no | y r o m Ome ss o OMe m a y M

B I UY.22

MN

70 and | Ome

Id

M c) du Me so 5 n i c) che es HVObI6

M

A mixture of 3-quinolinecarboxylic acid (0.500g, 2.89mmol) and thionyl chloride (0.42ml, 5.8mmol) and 15ml of toluene was heated under reflux for 2 hours, then cooled and the solvent removed in vacuo to give the chloride as a white solid.

Chlorine anhydride (0.041 g, 1.4 equivalents) was added to a solution of amine MI.22 (0.067 g, 0.015 mmol) in 2 ml of anhydrous dichloromethane while cooling in an ice bath and allowed to warm to room temperature and stirred for 18 hours, then diluted with 30 ml of dichloromethane, washed with saturated sodium carbonate solution (2x20ml), dried with magnesium sulfate and the solvent was removed in vacuo to give a solid, which was purified by chromatography (silica, ethyl acetate) to give 9616 as a white solid (0.039G, 4496).

If possible, CO-SOCI anhydride is purchased directly. Other similarly prepared compounds are presented below in Table 11.

Method B about 9653 so about g nos. y, soty tost, y e mn, M OMe | t with A F

Omg

M M sOostosh

МН ОМе о и хнк9BB3

M Me o, c Solution of amine MI.7 (0.165 g), 5-methylpyrazinecarboxylic acid (0.063 mg, 1.2 equivalents), parts of M-cyclohexyl-M-(2-morpholineethyl)-carbodiimide of methyl-p-toluenesulfonate ( 0.162g, 1.0 equivalent) and "1-hydroxybenzotriazole monohydrate (0.051g, 1.0 equivalents) in 15ml of anhydrous dichloromethane were stirred at room temperature for 18 hours, the mixture was diluted with dichloromethane, washed with water and saturated sodium carbonate solution, dried with magnesium sulfate and the solvent was removed in vacuo to give (2) a solid which was purified by chromatography (silica gel, ethyl acetate) to give 9653 as a white solid (0.031g).

Other compounds produced in a similar way are presented below in Table 11. - Method C syu 50 9617

Omg

OD OO

I, O F Me sleep H

M22 59 g U oMe i ; yah

M o) o d oMe i M 60 5 - Nn khn 9617 o U i

М сн, bo 2-chloro-1-methylpyridinium iodide (0.041g, O, 15 mmol) and stirred at room temperature for 7 days, saturated sodium carbonate solution (15 ml) was added and the mixture was extracted with dichloromethane (2x330 ml). The combined organic phases were dried with magnesium sulfate and concentrated in vacuo, followed by flash chromatography (silica gel, ethyl acetate), obtaining 9617 as a white solid (0.011g, 18905).

Other similarly prepared compounds are presented below in Table 11.

Table 11

Amine of formula I Substituent in oxygen Compound of formula

MI in

AND

1.1 at 9591 sy

UI.1 on 9592 ee o

M se

MI.2O sia A 95 yo

Ui1.17 p. A 595

WITH

MI.17 MA 9596

Ex. 2

Ut:35 M Kk 557 se iz o o

Tue. 24 M Ah 9600 from p

M | "in)

Uu1.1 on A 9606 (ze) xx

M -

UI.21 M And it's loud

M ise)

U1.21 and 9609

M "

U1.2 M | zeb12 Z p 7 O

UI.2 9613 h Without

M

Ut1.15 M 8614 from this

Ge") Me

MT.18 96515 -And yo: ! there is also MI.22 A 8516 | and. "2 У1.22 сх с 9617 ио

M Me

E. And 9621 and:

F) no

UI.19 дх 9622 тых име) e 60 MI.4 s A 9623 r ши

MI.5 Z

I r b5 -4v-

UI.v sa 9626 o

M

Ui.a S ze32 ; yo -

M

MI,7? sou 9633 yo

M

MmIi.1 z635 70 iy

X in me

MI.1 A 3538 id obme 15

MI.8 hu A 9648 7

M

Uti5 ybFf A 9850 and. 20 M 1.10 sia 9551 og

M

U1.11 he A se

AND

25 yo:

M (8)

MI.7 M 9653

AND

M Me ut12 still k ze5i (av) 30 o: s u

MI.13 365655 t v.

M

From MI.10 M 3657 is),

With yo

Msme

E. M. A 9658 sh

M

-

U1.10 M A h M i?

MU1.14 s A Z660 is m

Ge") Tue. 11 that 8661 pe -I M

MI.25 A Z653 -I i i:

M

(95)

Mt. 23 with Ah 9Z6Be o yo

M

Tut. 27 hu A 9667

OO

(FI UI.29 yo 9668

I r name) m

MI.28 s A 9669 m

UtI.3o o points 9877 is:

M

65 In these examples, acetonitrile was used instead of dichloromethane at room temperature to reflux.

Example 7: Synthesis of intermediate bromide of Formula XII Bromide of formula XII was prepared in the following way: injury 7a ! ohm M t

Speech 70 naks and language

CO

S o dach lova so

MN about Iya donu about

M

Nn shchi 7 | this is ts o on o /osch o

So MN KhPa Fr

Mn s-x of so 0 Z xx

My-

To an ice-cooled solution of 7a, 4-nitrophenethyl alcohol (5.0 g, 29.9 mmol) and imidazole (2.25 g, 32.9 mmol) in 200 ml of dichloromethane was added dimethylhexylsilyl chloride (b, b ml, 33.2 mmol), and the mixture was stirred for 16 hours at room temperature and diluted with 200 ml of diethyl ether, then the solution was washed with 200 ml of water, 200 ml of 2N HCl and 200 ml of brine, dried with magnesium sulfate and the solvent was removed under reduced pressure, obtaining 76 (10 g) as a yellow liquid. « 7s 400 mg of platinum dioxide was added to a solution of 75 in 250 ml of ethanol, then hydrogen was introduced. The mixture was stirred vigorously for 3 days, filtered through brownmillerite, and the solvent was removed under reduced pressure to give compound 7c (9.88 g) as a yellow liquid. ;" 785 Triethylamine (b,bml, 47.6b4mmol) was added to a solution of 7c (8.78g, 31.75mmol) and 2-nitrobenzoyl chloride (7.1g, 38.11mmol) in 4Oml of dichloromethane cooled to 07С, allowed to warm to room temperature and after 168 hours, it was washed with 40 ml of water, the aqueous phase was extracted twice with 40 ml of dichloromethane. The combined organic phases were dried over magnesium sulfate and the solvent removed under reduced pressure to give a brown resinous solid which was stirred in hexane for 2 hours to give a white solid which was dissolved

Sh- in dichloromethane and filtered through a layer of flash silica gel. The solvent was removed under reduced pressure to give 74 (6 g) as a white solid.

Te 74 was reduced by the method of reduction of 7c in 100 ml of ethanol from 200 mg of platinum dioxide, obtaining compound o Te (4.42 g) as a peach-colored solid. o 77 Triethylamine (2.5 ml, 17.9 mmol) was added to a solution of 7e (4.75 g, 11.0 mmol) and 3-quinoline carbonyl chloride (2.7 g, 14.3 mmol) in 7 Oml of dichloromethane, stirred at room temperature for 16 hours, was poured into 7Oml of dilute sodium carbonate solution, the layers were separated and the organic phase was washed with water, dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain 71 (4.9g) as an off-white solid. 79 Tetrabutylammonium fluoride (1M in THF, (F) 19.2ml, 17.28mmol) was added to a solution of 71 (4.78g, 8.64mmol) in 7Oml of tetrahydrofuran, stirred for 4 days, the solvent was removed under reduced pressure, the residue was dissolved in 100 ml of ethyl acetate, adding enough water to cause the appearance of a precipitate, which was filtered off, washed with water and then with diethyl ether. The residue was azeotropically distilled with toluene and dried in vacuo to give 79 (C g) as a cream solid.

Xa To a solution of 79 (Zg, 7.29 mmol) and triphenylphosphine (3.8 g, 14.58 mmol) in 25 ml of dichloromethane was added

M-bromosuccinimide (2.6g, 14.58mmol) was heated at 509C for 16 hours, cooled and Bml of methanol was added, and diethyl ether was added after 5 minutes until precipitation occurred. The precipitate was filtered and washed with diethyl ether. The residue was dried in vacuo to give XIIa (2.13g) as an off-white solid. 65 Production of compounds of formula (I) by a variant of method (B)

Scheme Z

Hg

M OMe

Mn Me OM n y ef | for () r

XIa M Me

M OoMe o / o seam

KI OMe

N

Mn 9630 about them "-

M

A mixture of Za (0.068g, 0.35mmol), which is a compound of formula (XX) and prepared by the method described below, Xa (0.166g, 0.5mmol), potassium carbonate (0.072g, 0.52mmol) and tetrabutylammonium iodide (0, 1 equivalent) in Zml

M,M-dimethylformamide was stirred at room temperature for 4 days, the mixture was diluted with ethyl acetate, washed with water, dried with magnesium sulfate, and the solvent was removed under reduced pressure to obtain a brown gummy substance. Flash chromatography (silica gel, ethyl acetate) and C recrystallization (methanol/dichloromethane) afforded 9630 (0.043g, 2195) as a white solid. (5)

Compounds of formula (1) were obtained by a similar method.

Synthesis of amine Structure of amine Compound of formula xx of formula XX of formula (I)

CCS see s.E

TGeyesekv, 1996, 37, 5453-5456, see s.B.BSOKKeg, 9629

S, Testganeikgop - 9 teeskegya, 1996, 37, "so 5453-5456 me Me Method for (iii) 8631 in see below"

Method Za(113) 9634

C see below - o c 7 ome Method For (their) eye see below

Ome. ит ' зар ОМе Method За(у) 9639

See for more details Method Za(xi) 9640 ! See below

Me, h ope

Method Za (uiii) 641 - See below

Me and the Method for(s) 9643 her for the Method for(x) 9545 oyu r - :

Method Za(xi) 9646

GF! o see below iy s OMe ime) 60 b5 hvuoMe manual Za(khii 9647 z): ZA Ш 1 Method Za(khih) o | Z o Method Za (khm) z664 soju

The method for (hchi zve5

AHA -o-i oMe tm I n ! oMe t5 Me-. Ahhh

And V. OMe

A solution of triethylamine (7.2 ml, 52 mmol) and homoveratrylamine (1.92 ml, 11 mmol) in 100 ml of dichloromethane was added to a solution of methyl chloroformate (1 ml, 1033 mmol) in 10 ml of dichloromethane, cooled to -782C, the mixture was warmed to room temperature and stirred for 18 hours, then saturated sodium carbonate solution was poured off, extracted with dichloromethane, dried with magnesium sulfate, and the solvent was removed under reduced pressure to give a yellow oil, which was purified by flash chromatography (1956 methanol in ethyl acetate) to give methyl carbamate (2.06 g, 78905), a solution of which (2, 00g, 8.37mmol) in bOml of tetrahydrofuran was added dropwise to a suspension of lithium aluminum hydride (1.59g, 41.ommol) in bOml of tetrahydrofuran, cooled to 0"C, the mixture was allowed to warm to room temperature and stirred for 18 hours. Then, 2, 2 ml of water, then 2 N sodium hydroxide solution and again 2.2 ml of water and magnesium sulfate. After 15 minutes of stirring, the mixture was filtered and the filtrate was concentrated in vacuo to give Zaib i) as yellow oil (1.61g, 99905).

Method of Zakiya) o erue eru su o -- - N

Me Me Me | (ze)

Me me te in: and m

Me 25(i)

A mixture of 3,4-dimethylbenzoic acid (3.5g, 23.33mmol) and thionyl chloride (3.5g, 46.7mmol) in toluene was heated under reflux for 2 hours, then cooled and the solvent was evaporated in vacuo to obtain crude hydrogen chloride like butter Hydrochloric acid was dissolved in 50 ml of dichloromethane and, while cooling in an ice bath, 4095 methylamine solution (18 ml, 10 equivalents) was added, stirred for 48 hours and treated with water to obtain a yellow solid, which was purified by flash chromatography (silicon dioxide, ethyl acetate/hexane) and obtained required amide as a white solid (1.84g, 4990). C c To a solution of amide (1.00 g, 6.133 mmol) in 20 ml of dry tetrahydrofuran was added lithium aluminum hydride (698 mg, 2 c equivalents) and heated under reflux for 3 hours, then cooled and treated with water to obtain a light oil, which was purified by flash chromatography (silica, ethyl acetate) and obtained Zack) as a colorless oil (0.175 g, 19905).

Method of Zation) (22) -I "-

V. ov MO,

He) 50 1,2,3,4-tetrahydroisoquinoline (20.2 ml, 16b1mmol) was added dropwise to 80ml of concentrated H»ZO) at 0"C, and potassium nitrate (17.5g, 173mmol) was carefully added in portions and stirred for 16 hours. , then basified with a concentrated ammonium hydroxide solution, then extracted with chloroform, dried with magnesium sulfate and the solvent was removed under reduced pressure, obtaining a brown oil, which was dissolved in 100 ml of ethanol and concentrated hydrochloric acid was added, the precipitate formed was filtered and 29 recrystallized from methanol, obtaining Zakiiyi hydrochloride) (11,2g, 3390). (FI Ways of Zayim). Za(mi). Za(uiyi). Za(ih). Za(x). Zaikhii. Za(hiyi) and Za(him)

The amines Za(im), Za(mi), Zai(myi), Za(ih), Za(x), Zaihyi), Zaihii) and Zai(chem) were prepared by reductive diamination from acceptable aromatic aldehydes. This involves the reaction of aldehydes with with an amine such as methyl, ethyl or butylamine in a suitable solvent such as methanol or toluene. The resulting imine is reduced to the desired amine by hydrogenation over platinum dioxide in a suitable solvent such as ethanol or lithium aluminum hydride in tetrahydrofuran.

Method Zach) b5 -BO0-

OMe OoMe pnn- c) o

He o 95 N ud OM e

OMe N in XX "M o" - e

Me" MU" on M TV

A mixture of 3-hydroxy-4-methoxybenzaldehyde (1.00g, 6b.57mmol), 2-iodopropane (0.79ml, 1.2 equivalents) and 70 potassium carbonate (1.09g, 1.2 equivalents) was heated under reflux for 5 hours. An intermediate aldehyde was obtained by treatment with water. The desired amine Za(m) was obtained by reductive amination by the Za(im) method. Amen

Zatmii) and Za(xi) were prepared similarly using an acceptable commercially available aldehyde, its reaction with an alkylating agent such as 1-iodobutane or 2-iodopropane, followed by reductive amination to the desired amine.

Method Za(khm) 15 ome he he is SS in OK,

Me o Ii o ;

In ST S

- at 20 A solution of 6.7-dimethoxy-1.2.3.4-tetrahydroisoquinoline hydrochloride (5.00g, 22mmol) in an excess of a mixture of 8Oml of 4890 hydrobromic acid and 04ml of hypophosphateic acid was heated under reflux for 5 hours. The cooled mixture was filtered and washed with methanol and ether to give the desired dihydroxylated compound as a white solid (4.75g, 8895). 25 3.07 g of sodium carbonate was added to its solution in a mixture of acetone/water 4:1 and the mixture was cooled in an ice bath, then 3.0 bml of benzyl chloroformate was added and the mixture was stirred for 18 hours. After filtration, the filtrate was collected and treated with water, and then flash chromatography (hexane/ethyl acetate) gave benzylcarbamate (3.6bg, 6290).

Dibromomethane (0.28ml, 3.99mmol) and potassium carbonate (2.75g, 19.7mmol) were added to a solution of benzyl carbamate (1.00g, 3.34mmol) in BOml of M,M-dimethylformamide and heated at 71007C for 1.5 hours and after cooling and filtering, the filtrate was collected and treated with water followed by flash chromatography (hexane/ethyl acetate, 5:1) to give the required 1,3-dioxolane (0.669g, 64965). co

By hydrogenation in a hydrogen atmosphere over palladium on activated carbon in a mixture of methanol and dichloromethane with m cleavage of benzylcarbamate, the required amine Za(khm) was obtained.

Method Za(khm) - he o i So 0 SYS F o 19 2B(khmi) "a "

Sodium hydride (6095 dispersion in mineral oil, 0.385g, 10.03mmol), iodoethane (6b,bml, 83,bmmol) and - c BbBml of dimethylsulfoxide were added to a solution of the intermediate benzylcarbamate obtained above (0.500g, 1.67mmol) in 1Oml of tetrahydrofuran. refluxed for 18 hours, treated with water, and then flash chromatography twice (hexane/ethyl acetate, 5:11) afforded a yellow oil (0.549g, 9295). Cleavage of benzyl carbamate, as described above, gave the desired amine Za(chmi).

Example 4: Production of compounds of the formula (Ia) by combining an amine of the formula (MI) with an activated acid of the formula ERSOOH (variant of method a) (2) Method A (2-14-I2-(6,7-dimethoxy-3,4-dihydro- 1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)amide - quinoline-3-carboxylic acid (9544) -I o 50 (42)

F) name) 60 b5 o o no yo: SI y: - 2 m

M and 7 Shchi m o M OMe " MYg.23

M

N OMe

M

M n

MA in 9544 «t

M

A mixture of quinoline-3-carboxylic acid (4.00 g, 2 mmol), thionyl chloride (3.5 g, 46.7 mmol) in toluene was heated under reflux for 2 hours, then cooled, the solvent was evaporated in vacuo and triturated in hexane to give solid crude hydrogen chloride (4.15g). To a suspension of hydrogen chloride (2.64 g, 14 mmol) in 100 ml. EM of anhydrous dichloromethane was added while cooling in an ice bath amine MIP.23 (4 g, 9, Zmmol), allowed d) to warm to room temperature and stirred for 1 hour. Dilute potassium carbonate solution was added and the mixture was extracted three times with chloroform, the combined organic phases were dried with magnesium sulfate and evaporated until crystallization began. The same volume of diethyl ether was added and allowed to crystallize to give a yellow solid which was purified by flash chromatography (silica, ethyl acetate/hexane) to give 9544 as a white solid (5.4g). with

Other similarly prepared compounds are presented in the table below. If possible, purchased hydrogen chloride VU'SOSI was used. -

Method in (2-(4-(2-(6.7-dimethoxy-3.4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)amide with furan-3z-carboxylic acid (9526) oMe o d- - Bon and M o - o schi OMe

M UI". 23 and OMe in s MN; ch o and OoMe a dy

M n v!

F 9526 nih -i Ge) o -I sy

A solution of 3-furanic acid (0.019g, 0.17mmol), amine MG.23 (0.075g, 0.17mmol), o cyclohexyl-M-(2-morpholineethyl)-carbodiimide methyl-p-toluenesulfonate (0.079g, 0, 19 mmol) and 1 o -hydroxybenzotriazole monohydrate (0.025 g, 0.19 mmol) in 5.0 ml of dry dichloromethane were stirred for 18 hours at room temperature, saturated roseol was added and the mixture was extracted twice with 25 ml of dichloromethane, the combined organic phases were dried with magnesium sulfate and evaporated in vacuum Flash chromatography (silica gel, 290 methanol in ethyl acetate) and recrystallization from ethyl acetate afforded 9526 (0.018g) as a yellow solid. (F) Other compounds obtained in a similar way are presented in the table below. g Method C (2-14--2-(6.7-dimethoxy-3.4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-b-methylnicotinamide (9557) 60 b5

OMe ho Son S «jo OMe sn M Upg. 23 and M

N OMe

M

DI

70 and: n

MN

9557 0 | and:

He sleeps

Triethylamine (0.0 bml, 0.34 mmol) was added to a solution of b-methylnicotinic acid (0.047 g, 0.34 mmol) and amine MIG.23 (0.075 g, 0.17 mmol) in 5.00 ml of anhydrous dichloromethane, and then iodide 2- chloro-1-methylpyridinium (0.044g, 0.17mmol), stirred for 18 hours at room temperature, 15ml of saturated sodium carbonate solution was added and the mixture was extracted with dichloromethane twice in 30ml portions, the combined organic phases were dried with magnesium sulfate and evaporated under vacuum. Flash chromatography (silica gel, 2906 methanol in ethyl acetate) and trituration in ethyl ether gave 9557 (0.008 g) as a white solid.

Method O 2-(4-isopropyl-benzoylamino)-M-(2-(6,7-dimethoxy-3.4-dihydro-1H-isoquinolin-2-yl)-ethyl|-3-methylbenzamide (9398) ch son 2 siyu (8) o ОМе - МАХИ 5 зщи ООМе . N so

M.N., University of Eng.O8 Shchi

Me

OoMe and AH and

M (Se) and OME

Nn

MN

Me in h 9398 8 s. ,» To a suspension of 4-isopropylbenzoic acid (5.00g, ZOmmol) in 5O0ml of toluene, thionyl chloride (5ml) and 1 drop of dimethylformamide were added and heated under reflux for 2 hours, then cooled and the solvent was evaporated in vacuo, obtaining crude hydrogen chloride (5, 5d) as yellow oil. This chloride anhydride (o) (0.068g, 0.37mmol) was added to 100ml of anhydrous dichloromethane while cooling in an ice bath, amine M.o8 - (0.110g, 0.3mmol) and 2M sodium hydroxide solution, allowed to warm to room temperature and stirred vigorously for 5 hours, the mixture was extracted twice with 15 ml of ethyl acetate, 15 ml of brine, dried with magnesium sulfate and evaporated in a vacuum. Flash chromatography (silica gel, 2906 methanol in ethyl acetate) and trituration at 50 in ethyl ether afforded 9398 (0.016g) as a white solid. A second portion of the desired compound (0.015 g) was obtained by crystallization of the remainder of the mother liquor. (ze) Other compounds obtained in a similar way are presented in Table 12 below.

F) name) 60 b5

Table 12 p now we pinni pishna zho na aa nannya pishini

Azmin of the formula Ko U kislop Slosyuye Compound of the formula.

UTIIb.02 item x 9405 sn, y kt

MIT1".09 | 9359 utII 01 A 9355 sia 1 sn,

Yat Ob | x 5355

KE aa

UTIT.0i - x 9331 o

UTII her t A 3334 i s don, (8) and Sh (av)

UTTI":01 OH A 9380

Gee)

Hg

Utti7b1 s g 8381 v.

MO, che

UtIITbi oi /o A 5455 so

Gee)

UTITt" 01 x 5427 7 "

UTIiTb1 sa A 5442 Z7Z s uttiI oi -h A 9459 . this is

UiIi7o1 ke B 5460

Yeoo

F UT" .01 M 3377 -I yo -1 YATI o huzn A 5359 that o shchiii.o1 se 8381 "2 this:

UTII" 01 chapter A 8381

And Iv

UTII". 01 M 9347 would be in vo i (F. se

ІІІ.0І cha 8383 ko i

These r still bo

UTII 01 Kori Tori 5385

WITH

UtIi oi se z389 b5 -BA-

UTII.0i SO 93957 pas

UTtITTo1 K z365

She is at 5 uttI 61 I 93657

M

H

UTIIT.23 M 9531 po

M and Oct

UitI 18 o'clock A 5571 ob

M.Sc

UTtI" 35 5578 o z: Fo 2 zvo: o utIi 23 M g i 9545 yo v

UTIiI 23 of A i- r

M (Se)

UtIi 123 tia V 5475 yo - . and"

Ge") -i -i (95) "2 ko bo b5 -5B-

tii 25 he A 5482 and UiIii.53 also A z483

R her .23 S A 2493 yo.

UitI!:23 Me A 5527 and skh r

M ssn,

UTIi". 23 se A 5582 "their

M OMe

Leviticus 7:23 and A z5BZ

M sn, o yo » uUtIIi.23 There are 9489 of them that o

UTIIT23 SCHE A 5509 oh,

UTIIT.23 A Z5Oi (av) 3o "7Х

E so t. E x 5

UTIIIT.23 9513 to them; in

IS

UtIt 23 E AH 8514 (Se) in - . and"

Ge") - and - and (95) "2 ko bo b5 -5Bb-

MIII'.23 s A 9454 tu

IS

MIII'.23 "o A 94956 si

MITiT. 23 sn, A 5503 and,

UTII'.23 "xx A 9504 sn,

UI11'.23 ОМе А 9477

MIII1'". 23 in A 9517 p

UYTI.23 "oh A 9518 o

Ome

MITI". 23 ososn, z534 no o

UT .23 -- 7ObOSN A 35240 (ze)

Co

MU1I1I!.23 And took him from the trees,

And what in - . i" (22) -i -i (95) (4e) ko) 60 65

In ', MM

And at

MY1'.23 A z447

Mo sn,

UIIII.2 9461

And 615

UIt1".23 -x A 9470 ko utIi!.23 ik A 3476 utIii.23 shchi x z536 -

MITI". 23 A 9538

PI

under the neck

UTIi". 23 Sho A for 7 and 8 p

UIIII". 23 A 95492 o / u v

UTIII 723 N A 8515 -25 o

IN

Utii1 1.23 o'clock A z539 o'clock -- h

UiIi719 A 9166 rch- o (Se) tt 151 kb A « 79 I 572 Z : A 9 s and y zy NESLY

UttIt. 26 yo A 3577 . and? | M

UIIII". 22 A 5585

Example 5: Interconversion of compounds of formula (Ia)

Me. Compounds of formula (Ia), which were prepared by the method of example 4, were converted into other compounds of formula (Ia) as described below. ()

Ш- 2-(2-hydroxy-benzoylamino)-M-14-(2-(6,7-dimethoxy-3.4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenyl)-benzamide (9535)

ОМе (95) вв 62 о ди оме ОМе ! SH

So 9534 a uva OM chn

Sodium hydroxide (0.003g, 0.077mmol) in 0.bml of water was added to a solution of 9534 (0.035g, 0.0bmmol) in 2ml of methanol and stirred for 2 hours at room temperature , and then heated under reflux for 3 hours, added sodium hydroxide 0.18 mmol) and heated under reflux for another 3 hours, cooled and acidified with 2M NOSI and then partially alkalized with saturated sodium bicarbonate solution. The mixture was extracted twice with 25 ml of ethyl acetate, washed with 30 ml of brine, the combined organic phases were dried with magnesium sulfate, filtered and concentrated in a vacuum. Chromatography (silica gel,

ethyl acetate) gave 9535 (0.019g, 58905) as a white solid.

Compounds 9540-9549 and 9548-9559 (iii) 2-(4-isopropyl-benzoylamino)-M-(2-(6.7-dimethoxy-3.4-dihydro-1H-isoquinolin-2-yl)-ethyl|- 5-phenylbenzamide (9432)

OomMe o 2 pana om ro 9: s o b e o ! and MN 9432 o

Phenylboronic acid (0.005g, 0.038mmol) and tetrakis(triphenylphosphine)palladium in 0.bml of dimethylethylene glycol and sodium carbonate solution (2M, 0.04ml,

O,Ommol) and heated under reflux for 3.5 hours, cooled and added 1 Oml of water. The mixture was extracted twice with 1 ml of ethyl acetate, washed with 2 ml of water and dried with magnesium sulfate, then filtered and concentrated in a vacuum. Chromatography (silica gel, ethyl acetate) gave 9432 (0.015Gg, 75905) as a white solid. (ii) 2-(4-isopropyl-benzoylamino)-Im-(2-(6.7-dimethoxy-3.4-dihydro-1H-isoquinolin-2-yl)-ethyl|-4-amino-benzamide (9435)

M.

Se "sha ome el i Zome om Mn Sh o 9420 na "chn o 9435 dov sh o

Platinum dioxide (0.005g) was added to a solution of 9420 (0.047g, O0.08bmmol) in 2ml of methanol and 2ml of ethyl acetate.

The mixture was stirred at atmospheric pressure under hydrogen for 18 h, filtered through silica gel (1095 methanol in ethyl acetate) and concentrated in vacuo to give 9435 (0.042 g, 9595) as a yellow powder. (m) ozo (2-(4-I2-(6.7-dimethoxy-3.4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-5-hydroxyamino-phenyl)amide of quinoxaline-2-carboxylic acid (9542) Fr

OMe cha

Ge S, oMe a: o du i-

N ----w

ZB o nn - ov cm Ge;

M o 7 non M o zho 9542

M and "

Platinum dioxide (0.004g) was added to a solution of 9541 (0.0387g) in 25ml of ethanol and 25ml of dichloromethane. The mixture was stirred at atmospheric pressure under hydrogen for 18 hours, filtered through silica gel and concentrated in vacuo. Trituration in ethyl acetate and three times in diethyl ether gave 9542 (0.029g, 8090). as a yellow solid. and?" Example 6: Preparation of compounds of formula Ia) with testing of groups (c) 2-(4-isopropyl-benzoylamino)-M-(2-(6.7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl) -3-hydroxy-benzamide

Ge" (9424) is made by the method according to scheme 4. son oMe. o Oma - pi KAM dn. In oMe and OMe -| ns zha Mn, ! mig29(v-N) c. with MIR. 30

Mn i So oMe twoM5o s still dow that 9424

F)

GI Operation (i) A solution of commercially available 3-hydroxyanthrpanilic acid (0.324g, 2.12mmol), amine YX a (0.500g, 2.12mmol), cyclohexyl-M-(2-morpholineethyl)-carbodiimide methyl-p-toluenesulfonate (0.987g, in 2.33mmol), 1-hydroxybenzotriazole monohydrate (0.315g, 2.33mmol) and triethylamine (0.32ml, 2.44mmol) in 20ml of dry dichloromethane were stirred for 3 days at room temperature. Treatment with water followed by flash chromatography (silica gel, 295 methanol in dichloromethane) and trituration in diethyl ether afforded MIIG.29 (0.174g) as an orange solid.

Operation (its) A solution of MSh (29 (0.170 g, 0.4 mmol), imidazole /(0.034 g, 0.5 mmol) and 65 t-butyldimethylsilyl chloride (0.076 g, 0.50 mmol) in 10 ml of dimethylformamide was stirred for 3 days at room temperature Then imidazole (0.093 g, 1.37 mmol) and t-butyldimethylsilyl chloride (0.206 g,

1.37 mmol) and stirred for 4 hours. Treatment with water followed by flash chromatography (silica gel, 290 methanol in ethyl acetate) afforded MIIG.ZO (0.142g) as a yellow oil. Operation (ii) Triethylamine (1.12ml, 8.04mmol) and amine MIG.30 (1.57g, 3.24mmol), with stirring and cooling in an ice bath, were added to

A solution of 4-isopropylbenzoyl chloride (0.738 g, 4.04 mmol) in 1 mL of anhydrous dichloromethane was allowed to warm to room temperature and stirred for 18 hours, then poured into 5 mL of saturated sodium carbonate solution and extracted twice with 7 mL of dichloromethane. The combined organic phases were dried with magnesium sulfate and concentrated in vacuo. Flash chromatography (silica gel, 290 methanol in ethyl acetate) obtained 2-(4-isopropyl-benzoylamino)-3-(t-butyldimethylsilanyloxy)-M-(2-(6,7-dimethoxy-1,2,3,4- tetrahydro-naphthalene-2- and 70 l)-ethyl|-benzamide (0.367g) as a cream solid.

Operation (im) 1.0M solution in tetrahydrofuran of tetrabutylammonium fluoride (0.6Zml, 0.bZmmol) while cooling in an ice bath was added to the solution of 2-(4-isopropyl-benzoylamino)-3-(t-butyldimethylsilanyloxy)-M-(2 -(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalene-2-yl)-ethyl|-benzamide (0.365 g, 0.5 in 8 mmol) in 20 ml of tetrahydrofuran, stirred for 30 minutes, then /5 It was poured into 30 ml of saturated ammonium chloride solution and extracted twice with 50 ml of ethyl acetate.

Flash chromatography (silica gel, 296 methanol in ethyl acetate) afforded 9424 (0.220g) as a light yellow solid. (in). Quinoxaline-2-carboxylic acid 2-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|I-phenylcarbamoyl)-4-hydroxy-phenyl)-amide (9554) was made by the method according to scheme 5. but a dream (V and u

Fe OMe

M in your dream, Su oMe sch na , oh IS Ge)

ОМе (и) ий я о ру о tvomz5o.

M,

So mig.32 sme so o gu» o still - she. (2 -

MN -- ve ON, 9554 (Te)

TO ssh and 4. . 2. "

Operation () to a solution of commercially available 5-pdroxyanthrpanilic acid (1.0g, b.54mmol) in 40ml of dimethylformamide while stirring and cooling in an ice bath was added imidazole (1.8g, 26.1mmol) and -t-butyldimethylsilyl chloride (3 .95g, 26.1mmolmmol), the mixture was allowed to warm to room temperature and stirred for 18 hours. Treatment with water gave 2-amino-5-(t-butyldimethylsilanyloxy)-benzoic acid (1.74 g), which was used in operation (ii) without purification.

Operation (ii) 2-amino-5-(t-butyldimethylsilanyloxy)-benzoic acid (1.6g) from operation (ii), amine IXZh.r (1.87g, 6b,00mmol), M-cyclohexyl-M-( 2-morpholineethyl)-carbodiimide methyl-p-toluenesulfonate (2.79g, 6.bmmol) and (o) 1-hydroxybenzotriazole monohydrate (0.89g, b, b.mmol) were dissolved in B50ml of anhydrous dichloromethane and - stirred for 3 days at room temperature temperature Treatment with water and flash chromatography (silica gel) gave MI .31 (0.443g) as a yellow foam. -i Operation (iii) 2-quinoxaloyl chloride (0.67g, 0.35mmol) was added to a solution of 50% triethylamine (0.1Oml, 0.72mmol) and amine II" (0.200g, O, 28mmol) in 1Oml of anhydrous dichloromethane, the mixture was allowed to warm to room temperature and stirred for 18 hours. Treatment with water and m) flash chromatography (silica gel, 290 methanol in ethyl acetate) gave (4-t-butyldimethylsilanilox)-2-14-(2 -(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amidhinoxaline-2-carboxylic acid (0.183 g) as a yellow foam. 22 Operation (im) 1.0 M solution in tetrahydrofuran of tetrabutylammonium fluoride (0.67 ml, 0.67 mmol) at

Gee! (4-g-butyldimethylsilanyloxy)-2-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)- phendelyl)-amide of quinoxaline-2-carboxylic acid (0.150g, 0.21mmol) in 1Oml of tetrahydrofuran was stirred for

30 minutes, then poured into 20 ml of saturated ammonium chloride solution and extracted twice with 30 ml of ethyl acetate. The combined organic phases were washed with 30 ml of water, 30 ml of brine, dried with magnesium sulfate and concentrated in vacuo. Flash chromatography (silica gel, 2906 methanol in ethyl acetate) and trituration in diethyl ether afforded 9554 (0.032g) as a yellow solid. (with). Quinoline-3-carboxylic acid (5-amino-2-(4-(2-(6.7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amide ( 9589) made by the method according to scheme 6. 65 Scheme 6

OMe seboASSV

M --- nm Mo, Zh gu OMe hv nim oMe o vna OMe

SO to Mn MO, nen-ya « vooso SSS o ev ome (im) zov, shk o MN, UPG.33 OMe dev

M seam. "MN MN

M that in -Vchoso----" V " N, 9589 p

Operation (ii) A solution of 4-amino-2-nitrobenzoic acid (0.96g, 5.3mmol), amine IX.LB (1.65g, 5.3mmol), o

M-cyclohexyl-M-(2-morpholineethyl)-carbodiimide methyl-p-toluenesulfonate (2.46 g, 5.8 mmol) and 1-hydroxybenzotriazole monohydrate (0.79 g, 5.6 mmol) in 15 ml of anhydrous dichloromethane were stirred for 18 hours at 20-257"С. 15 ml of water were added and three 15 ml extracts were made with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. Trituration in diethyl ether and flash chromatography (silica gel, 1095 methanol in dichloromethane) gave the intermediate nitroamine (0 ,42g) as an orange solid

Operation (ii) A solution of the product from operation (ii) (0.42g, 0.8v8mmol), di-t-butyl dicarbonate (0.24g, 1.1mmol) and M,M-dimethylaminopyridine (0.005g, 0.04mmol) in 15 ml of anhydrous dichloromethane was stirred for 1 hour in an ice bath, the mixture was allowed to warm to room temperature and stirred for the next three hours. 15 ml of potassium carbonate solution was added and extracted three times with 1-5 ml of dichloromethane. The combined organic phases were dried with magnesium sulfate and concentrated in vacuo. Chromatography (silica gel, 2.590 methanol in dichloromethane) gave the intermediate protected nitroamine (0.37).

Operation (ii) 1095-palladium on charcoal (0.035g) was added to a solution of the product from operation (ii) (0.35g, 0.1 bimol) in 5ml of ethanol and 5ml of dichloromethane. The mixture was stirred at atmospheric pressure under hydrogen for 18 hours, filtered through Seitem, and concentrated until crystallization began. After cooling the product with amine MIIG.32 (0.19g) was obtained as a yellow crystalline substance.

Operation (im) Amin MP 82, (0.192ml, 0.35mmol) while cooling in an ice bath was added to a suspension of quinoline-3-carboxylic acid chloride (0.150g, 0.21mmol) in 3ml of anhydrous dichloromethane, stirred for 30 minutes, the mixtures were then allowed to warm to room temperature and stirred for a further 18 hours. 30ml of potassium carbonate solution was added and 30ml of chloroform was extracted. The organic phase was washed 4 times with water, dried with magnesium sulfate and concentrated in a vacuum. Trituration in anhydrous diethyl ether and recrystallization from methanol and dichloromethane gave Bos-protected 9589 (0.19 g) as a cream solid. -I Operation (M) The solution of the compound from operation (im) (0.078g, O0.11mmol) was stirred for 3 days in a mixture of 20ml of 5N NOI and 25ml of ethanol, made alkaline with a saturated solution of potassium carbonate and extracted three times with 5Oml of dichloromethane. The combined organic phases were dried with magnesium sulfate and concentrated in vacuo. o Flash chromatography (silica gel, 2.596 methanol in dichloromethane) and recrystallization from methanol/dichloromethane afforded the desired compound, 9589 (0.015 g) as a light brown solid.

Example 7: Production of compounds of formula (Ia) from methyl anthranilate (variant of method B)

The path to compounds of formula (Ia) through an intermediate is given by scheme 7.

Scheme 7

F) name) 60 b5

SOZHmMe soma dream start

МН» МН МН х , 2 g. Hi obi hi chi

ОМе о ра

Her and Y OMe are written by ay

Ge; BA

The reaction at room temperature of commercially available methyl anthranilate X with chloride of the formula

VRSOSI in the presence of triethylamine with dichloromethane as a solvent for 1-14 hours gave intermediate 72 of the general formula (ХІ), the hydrolysis of which was carried out by treatment with sodium hydroxide in a methanol/water mixture under reflux for 1-5 hours. By acidifying the mixture of NSI, intermediate acid (XII) was obtained.

The production of the final product of formula (Ia) was carried out by combining this acid with amine IIX a. 1.1 equivalent of 1,1-carbonyldiimidazole was added to a solution of the intermediate acid in tetrahydrofuran and the mixture was stirred at room temperature for 71 hours. Then 1.0 equivalents of amine IIH.a and 2.6 equivalents of pyridinium p-toluenesulfonate were added. The resulting mixture was heated under reflux for 56 hours and cooled. After removal of the solvent and treatment, the product was purified by flash chromatography on a silica gel column. The compounds produced by this general route are collected in Table 13.

Table 13 ri 0000 - stshzht VM session mon sem

Y o ia Compounds of the formula syny nin och o

A СХ se OmMe («in) sn, n nn so dov 9304 im cha sa i o SSS (se) their pe min oMe

Kk ro Nn chn « 9 Fi 9294 - -- F . nos nresa o soE-ome (22) Plural

Ge) - and in 9302 it is -I about AS from Oman

MN

Gays From two at 8295

GF). ka Example 8: Production of compounds of Formula (IV) using azalactones of the general formula (HIPI) (variant of method c) 60 b5 son I ee -MY | oh and NOT peace

Om a (U av | yati 70 " Shh M OMe -1 M n ky

Ж Zі я о КЕ 19 The reaction at 02C of commercially available anthranilic acid with anhydride of the general formula VR'SOSI in pyridine or its mixture with dichloromethane for 3-8 hours yielded the intermediate azalactone of the formula (CHP).

By treating this intermediate with amine IXa in toluene under reflux in the presence of p-toluenesulfonic or camphorsulfonic acid for 14-24 hours, compounds of the general formula (Ia) were obtained. The final product was purified by flash chromatography on a silica gel column. The compounds produced by this general route are listed below.

OoMe 6) ra, s i OoMe (8)

MN

9310 c) (c)

S g. cha o OME s ra,

M OMe

N "

MN shi s y o) y? 9297 (22) -I Example 9: Production of salts

Hydrochlorides of compounds of formula (I) were produced by treating solutions of the compounds in tetrahydrofuran with 2-molar NOS and followed by ultrasonic treatment until a clear solution was formed. The solvent was removed under vacuum, and the remaining 20 oz of the solution was sublimed to obtain the hydrochloride salt. Otherwise, hydrochlorides were produced by passing gaseous NSI through a solution of the corresponding free base in tetrahydrofuran, followed by evaporation to dryness. Example 10: Pharmaceutical compositions

Tablets weighing 0.15 g, each of which included 25 mg of the compound according to the invention, can be produced in the following way.

Composition for 10,000 tablets compound according to the invention (250g) lactose (800g) corn starch

GF) (415g) talc powder (30g) magnesium stearate (5g) sugar The compound according to the invention, lactose and half of corn starch were mixed and the mixture was passed through a sieve with holes of 0.5 mm mesh. 10 g of corn starch was suspended in 9 UOml of hot water and the resulting paste was used for powder granulation. The granulate was dried and crushed into small particles on a sieve with 60 holes of 1.A4 mm mesh. The residue, talc and magnesium stearate were added, mixed gently and pressed into tablets.

Example 11: Characteristics of compounds of formula (I)

The compounds produced in examples 2-9 were characterized by mass spectrometric, microanalytical means, proton NMR, and in some cases by infrared spectroscopy. The results are summarized in the table below. b5

Claims (18)

The formula of the invention 1. A compound that is an anthranilic acid derivative of the formula (I) V. M Z kh nin d 70 Ag ni /ya And her Sn/p with B in mnoi in I: A o in which each of K, B and in, the same or different, means H, Si-Svalkil, OH, C-Svaloxyl, halogen, nitro, or M(B'9B), where each of CO and B", the same or different, means H or C-Svalkyl, or B! and B attached to adjacent positions of ring B, together form methylenedioxyl or ethylenedioxyl; BZ - H or C.-Svalkyl; B" means C.-Svalkyl or KK" means -СНо- or -СНХСН»-, which is attached either (i) to position 2 of ring B with the formation of 5- or b--membered saturated nitrogen-containing ring fused to ring b, or (ii) to a position on ring a adjacent to the position of X when it is a single bond, thus forming a saturated 5- or 6-membered nitrogen-containing ring , fused with ring a; in 25 - H, OH or S.-Svalkyl; cm X - direct bond, o, 5, -ЗА(СНо)р- or -0-СН»)р-, where p - 1-6; o 29 - H, C.-Svalkyl or C.i-Svalcoxyl; 4-0 or 1; Ag - unsaturated carbocyclic or heterocyclic group; o each of B/ and B8, however ovish or different, means H, S.i-Svalkil, which is replaced or not replaced, C.-Saloxyl, hydroxyl, halogen, phenyl, -MNON, nitro group, group M(B 98), which is defined above, or group o ЗА2, where B" - H or C.-Svalkyl, or B" and BZ, when they are located on neighboring carbon atoms, they form, together with He, the carbon atom to which they are attached, a benzene ring or a methylenedioxyl substituent; M VZ - phenyl or an unsaturated heterocyclic group, each of which is substituted or unsubstituted by S.i-Svalkyl, OH, C-S-Croxyl, halogen, C3-S-cycloalkyl, phenyl, benzyl, trifluoromethyl, nitro group, acetyl, i-benzoyl or M(B ОВ), which is defined above, or two substituents on adjacent positions of the ring of the specified phenyl or heterocyclic group together form saturated or unsaturated 6b-membered ring, or methylenedioxyl; n: beans; a « t - 0 or 1-6; or a pharmaceutically acceptable salt thereof. and with 2. The compound according to claim 1, which differs in that it has the structure (A): т о 6 : 4 3 Кк 75 век Як дну. and Ge) 3 T/l of M Ag N y (with Y in! V. VE many in - And d? what about in (A) m) in which (a) each of B, C! and BK, the same or different, means H, OH, MO», Ш(В98 7), halogen or Co-Svalcoxyl, or K means H, and B! and B2 with the carbon atoms to which they are attached together form methylenedioxyl or ethylenedioxyl, provided that VK! and K2 do not mean H, but each of KU, E?, K9, c", 8, KU, Ag, X and t is defined by GF) according to claim 1, or 7 (b) each of P, B! and VC, the same or different, means H or methoxyl, and each of BZ, 5, 29, c", 8, c, Ag, X and t is defined according to claim 1. in C. The compound according to claim 1, which differs in that it has the structure ( C): b5 c? IF) 1 V Kk M M tsh; Ah N ve p v! 1 Kk MN in in? and A (B) o v where B, B!-83, K5-K9, Ag and n are defined according to claim 1. 4. The compound according to claim 1, which differs in that it has the structure (C): ВЗ , 0) В 7 Хх В M еще Ni- в Аг Н t 20. g 2 V Mn in V? KE A c in which (o) VE, 87-83, 25-29, Ag, X and t are defined according to claim 1. 5. The compound according to claim 1, which differs in that it has the structure (0): Кк , о) З : о З 6 4 6 4 ! so 7 )54 Kk M x H 3 - 3 2 I Ag H 1 - 1 M СН» claim 2 v2 Vo 5 I - VZ Mn V Kk (Se) Y O Vo | (0) in which B, B 1-89, Ag, t and n are defined for formula (I), and X, which is in position C or 4 of ring a, is defined according to claim 1. 6. The compound according to claim 1, which differs in that it is an anthranilic acid derivative of the formula (Ia): - с в!! , . and (F) with B31 with E! 4 - F M TU (СН 5 H -I A! МН -1 В 6 A (a) so and Od" s in which B! and 22, the same or different, mean hydrogen or methoxyl, B! and B" are the same or different, independently selected from H, CH3, CE3, E, SI, Bg, MNo, MO", MNON, methoxyl, hydroxyl and phenyl; or B! and B", located on adjacent carbon atoms, form together with these atoms benzene ring or methylenedioxyl substituent, B! means 2-furanyl, 3-furanyl, 2-thiophene, 3-thiophene, 2-indolyl or HF) 2-benzofuranyl or a ring of one of the following formulas (II), (PI) or (IM : bi , Vi 81 Be 60 Kk 7 I! ' 91 A Kk (Z in" PP) B (ХУ) in which B9! and B/, are the same or different, independently selected from hydrogen, Si-Svalkilu, which can be linear or 65 branched, C3-Seccycloalkyl, phenyl, benzyl, trifluoromethyl, E, SI, Be, Ov, MO", dimethylamino- or diethylamino group, acetyl or benzoyl; or VU! and VY, located on neighboring carbon atoms, form together with these atoms are a benzene ring or a methylenedioxyl substituent, B! and VU, the same or different, each it means hydrogen, methyl or methoxyl, or BU! and BU! located on neighboring carbon atoms, together with the pyridine ring to which they are attached, form a quinoline or 9,6,7,8-tetrahydroquinoline ring structure, ВО and В! same or different, each means hydrogen, methyl or propionyl, or B'Ya! and B, located on adjacent carbon atoms, together with them form a benzene ring, B/21- H, C.-Salkyl, C.sub.3-C.sub.cycloalkyl, phenyl, benzyl or acetyl, heEOaboys, and in 1,2 or 3, or its a pharmaceutically acceptable salt. 7. The compound according to claim 6, which differs in that in formula (Ia) r - 1, 8 - 2, both B! and B?! mean methoxyl, and KK?! means a 2-quinoxaline, 3-quinoline, 2-pyrazine or 3-pyridine group, each of which may be substituted or unsubstituted. 19 8. The compound, which is (2-(4-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amide 2-chloroquinoline -Z-carboxylic acid, (2-(4-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amide 4-hydroxy- 7-trifluoromethylquinoline-3-carboxylic acid, (2-(4-12-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-thiophen-3-yl )-amide of quinoline-3-carboxylic acid, (2-(4-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-4-dimethylaminophenyl )-amide of quinoline-3-carboxylic acid, (2-(4-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-4-dimethylaminophenyl )-amide of quinoxaline-2-carboxylic acid, Ge) (2-(4-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-thiophene -3-yl)-amide of quinoxaline-2-carboxylic acid, (3-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)- Pyridin-2-yl)-amide of quinoxaline-2-carboxylic acid, o (2-(4-I2-(6,7-dimethoxy-3,4-dihydro-1H -isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amide co 4-hydroxyquinoline-3-carboxylic acid, (3-14-I2-(6,7-dimethoxy-3,4-dihydro-1H- isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-4-methyl-thiophen-2-yl)-amide - quinoxaline-2-carboxylic acid, - (3-14-I2-(6,7-dimethoxy-3, Quinoline-3-carboxylic acid 4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-4-methyl-thiophen-2-yl)-amide, o (2-(4-2-((3 ,4-dimethoxybenzyl)-methyl-amino|-ethyl)-phenylcarbamoyl)-phenyl|-quinoxaline-2-carboxylic acid amide, (2-(4-2-((3,4-dimethoxybenzyl)-methylamino|-ethyl) -phenylcarbamoyl)-phenyl|-amide of quinoline-3-carboxylic acid, « 12-(2-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-7-ylcarbamoyl|-phenyl)-amide - quinoxaline -2-carboxylic acid, c (2-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-4-methylsulfanylphenyl)-amide with » quinoline-3-carboxylic acid, (4-4-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-thiophen-3-yl)- quinoline-3-carboxylic acid amide, M-(4-14-(2-(6,7-dimethicone) si-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-thiophen-3-yl)-b-methylnicotinamide, -I (2-(4-I2-(6,7 -dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)u-ethylsulfanyl|-phenylcarbamoyl)-phenyl)-amide of quinoline-3-carboxylic acid, 7 (3-14-(2-(6,7- dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-pyrazin-2-yl)-amide oz 20 quinoline-3-carboxylic acid, (2-(4-(2-( 6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethoxy|-phenylcarbamoyl)-phenyl)-amide of quinoline-3-carboxylic acid, (2-14-I2-(6,7 -dimethoxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amide quinoline-3-carboxylic acid, (2-14-I2-(1,3 -dihydroisoindol-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amide of quinoline-3-carboxylic acid, HF) (2-(4-(2-(6,7-dichloro-3,4-dihydro-1H -isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amide of quinoline-3-carboxylic acid, o (2-(4-I2-(7,8-dichloro-3,4-dihydro-1H-isoquinoline -2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amide of quinoline-3-carboxylic acid, 60 12-I4-(2-42-(3,4-dimethoxyphenyl)-ethyl|-methyl amino)-ethyl)-phenylcarbamoyl|-phenyl)-amide of quinoline-3-carboxylic acid, (2-(4-2-((3,4-dimethylbenzyl)-methylamino|-ethyl)-phenylcarbamoyl)-phenyl|-amide quinoline-3-carboxylic acid, (2-(4-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethoxy|-phenylcarbamoyl)-phenyl)-amide quinoxalin- 2-carboxylic acid, because (2-13-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amide quinoline-3- carboxylic acid, (2-14-I2-(7-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amide quinoline-3-carboxylic acid, (2- 2-Methylthiazole-4-carboxylic acid (4-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amide (2-(4 Quinoline-3-carboxylic acid -2-((3,4-dimethoxybenzyl)-ethylamino|-ethyl)-phenylcarbamoyl)-phenyl|-amide, (2-(4-I2-(6,7-dimethoxy-3,4 -dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amide of 2-methyloxazole-4-carboxylic acid, 70 (2-(4-2-(3-isopropoxy-4-methoxybenzyl)- methylamino|-ethyl)-phenylcarbamoyl)-phenyl|-amide quinoline-3-ka carboxylic acid, (2-(4-22-(methyl-(3,4,5-trimethoxybenzyl)-amino|-ethyl)-phenylcarbamoyl)-phenyl)|-amide quinoline-3-carboxylic acid, (2-(4 Quinoline-3-carboxylic acid -2-(butyl-(3,4-dimethoxybenzyl)-amino|-ethyl)-phenylcarbamoyl)-phenyl|-amide, (2-(4-2-(4-butoxy-3-methoxybenzyl )-methylamino|-ethyl)-phenylcarbamoyl)-phenyl|-amide of quinoline-3-carboxylic acid, (2-(4-2-(3,4-difluorobenzyl)-methylamino|-ethyl)-phenylcarbamoyl)-phenyl|- Quinoline-3-carboxylic acid amide, (2-(4-2-(2,3-dihydrobenzo|1,4|dioxin-6-ylmethyl)-methylamino|-ethyl)-phenylcarbamoyl)-phenyl|-quinoline-3-amide -carboxylic acid, (2-(4-2-(4-isopropoxy-3-methoxybenzyl)-methylamino|-ethyl)-phenylcarbamoyl)-phenyl|-amide quinoline-3-carboxylic acid, (2-(4-2- (3-Hydroxy-4-methoxybenzyl)-methylamino|-ethyl)-phenylcarbamoyl)-phenyl|-amide of quinoline-3-carboxylic acid, (2-A4-I3-(6,7-dimethoxy-3,4-dihydro- 1H-isoquinolin-2-yl)-2-hydroxypropoxy|-phenylcarbamoyl)-phenyl)-amide of ch quinoline-3-carboxylic acid, (2-(4-2-(4-hydroxy-3-methoxybenzyl)-methylamino|- ethyl )-phenylcarbamoyl)-phenyl|-amide of quinoline-3-carboxylic and) acid, (2-14-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|- 2-methylphenylcarbamoyl)-phenyl)-amide of quinoline-3-carboxylic acid, o z o (2-14-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|- 2-Methoxyphenylcarbamoyl)-phenyl)-amide of quinoline-3-carboxylic acid, and (2-(4--7(3-isopropoxy-4-methoxybenzyl)-methylamino|-methyl)-phenylcarbamoyl)-phenyl|-amide M quinoline -3-carboxylic acid, (2-13-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amide y- 5- methylpyrazine-2-carboxylic acid, "o (2-14-12-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-1-methylethyl|-phenylcarbamoyl)-phenyl)-amide quinoline-3-carboxylic acid, (2-(4-2-(4-dimethylaminobenzyl)-methylamino|-ethyl)-phenylcarbamoyl)-phenyl|-amide quinoline-3-carboxylic acid, « (2-(4-2- ((3-butoxy-4-methoxybenzyl)-methylamino|-ethyl)-phenylcarbamoyl)-4,5-dimethoxyphenyl|-amide from c quinoline-3-carboxylic acid, . (2-14-12-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-2-methoxyphenylcarbamoyl)-phenyl)-amide 5-methylpyrazine-2-carboxylic acid, (2-14-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-2-methylphenylcarbamoyl)-phenyl)-amide pyrazine-2-carboxylic acid, Ge" (2-(4-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-2-methoxy-phenylcarbamoyl)- phenyl)-amide of pyrazine-2-carboxylic acid, Ш-(2-13-3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl|I-phenylcarbamoyl)-phenyl )-amide -I of quinoline-3-carboxylic acid, IM-(2-(4--K(3-isopropoxy-4-methoxybenzyl)-methylamino|-methyl)-phenylcarbamoyl)-phenyl|-nicotinamide, about I|b -chloro-2-(4-2-((3,4-dimethoxybenzyl)-methylamino|-ethyl)-phenylcarbamoyl)-phenyl|-amide of quinoline-3-carboxylic acid, (2-(A4-I2-(7 ,8-dihydro-5H-(1,3|dioxoloy|4,5-d|isoquinolin-b-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amide quinoline-3-carboxylic acid, (2-(4- I(2-(6,7-diethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amide of quinoline-3-carboxylic acid, F) (6-14- (2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-thieno|(2,3-B|pyrazin-7-yl) -amino acid of quinoline-3-carboxylic acid, (2-(4-2-((3,4-dimethoxybenzyl)-methylamino|-ethyl)-phenylcarbamoyl)-4,5-difluorophenyl|-amide in quinoline-3- carboxylic acid, (2-(4-2-((3,4-dimethoxybenzyl)-methylamino|-ethyl)-phenylcarbamoyl)-5-methylphenyl|-amide quinoline-3-carboxylic acid, (2-(4-2- ((3,4-dimethoxybenzyl)-isopropylamino|-ethyl)-phenylcarbamoyl)-phenyl|-quinoline-3-carboxylic acid amide, 65 (2-(4-2-((3,4-dimethoxybenzyl)-methylamino|- ethyl)-phenylcarbamoyl)-5-nitrophenyl|-amide of quinoline-3-carboxylic acid, 2-(4-isopropylbenzoylamino)-M-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-benzamide, 2-(4-isopropylbenzoylamino)-M- (2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-b-chlorobenzamide, 2-(4-isopropylbenzoylamino)-M-(2-(6,7- dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-5-chlorobenzamide, 2-(4-isopropylbenzoylamino)-M-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-4-chlorobenzamide, 2-(4-isopropylbenzoylamino)- M-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl| -3-chlorobenzamide, 2-(4-isopropylbenzoylamino)-M-(2-(6, 7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-5-bromobenzamide, 2-(4-isopropylbenzoylamino)-M-(2-(6,7-dimethoxy-3,4- dihydro-1H-isoquinolin-2-yl)-ethyl|-4-fluorobenzamide, 2-(4-isopropylbenzoylamino)-M-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2- yl)-ethyl|-3-methylbenzamide, 70 2-(4-isopropylbenzoylamino)-M-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-3-methoxybenzamide, 2-(4-isopropylbenzoylamino) -M-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl)|-3-hydroxybenzamide, 2-(4-isopropylbenzoylamino)-IM-(2-( 6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl I-4-nitrobenzamide, 2-(4-isopropylbenzoylamino)-M-(2-(6,7-dimethoxy-3,4 -dihydro-1H-isoquinolin-2-yl)-ethyl|-4-aminobenzamide, 2-(4-isopropylbenzoylamino)-IM-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2 -yl)-ethyl|-5-phenylbenzamide, 3-(4-isopropylbenzoylamino)-naphthalene-2-carboxylic acid (2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-amide, 2-(4-dimethylamino-benzoylamino)-M-(2-(6,7- dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-benzamide, 2-(4-propylbenzoylamino)-M-(2-(6,7-dimethoxy-3,4-dihydro-1H- isoquinolin-2-yl)-ethyl|-benzamide, 2-(4-pentylbenzoylamino)-M-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|- benzamide, 2-(4-cyclohexylbenzoylamino)-M-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-benzamide, 12-(2-(6,7- dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethylcarbamoyl|-phenyl)-amide of diphenyl-4-carboxylic acid, 12-(2-(6,7-dimethoxy-3,4-dihydro-1H Naphalin-2-carboxylic acid -isoquinolin-2-yl)-ethylcarbamoyl|-phenyl)-amide, 12-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)- ethylcarbamoyl|-phenyl)-amide of benzo|1,3|dioxole-5-carboxylic acid, 2-(4-diethylaminebenzoylamino)-M-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline) -2-yl)-ethyl|-benzamide, (8) 2-(4-t-butylbenzoylamino)-M-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) -ethyl|-benzamide, 2-benzoylamino--(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl)|-benzamide, 2-(4-bromobenzoylamino)- IM-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-benzamide, ozo 2-(4-nitrobenzoylamino)-M-(2-(6, 7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-benzamide, 2-(4-phenoxybenzoylamino)-M-(2-(6,7-dimethoxy-3,4-dihydro- 1H-isoquinolin-2-yl)-ethyl|-benzami d, o 2-(4-benzoylbenzoylamino)-M-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-benzamide, M 2-(4-benzylbenzoylamino) )-IM-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-benzamide, 2-(4-cyclohexyloxybenzoylamino)-IM-(2-(6, 7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-benzamide, i- 2-(4-benzyloxybenzoylamino)-M-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-benzamide, «o 12-(2-(6, Pyridine-2-carboxylic acid 7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethylcarbamoyl|-phenyl)-amide, IM-42-(2-(6,7-dimethoxy-3,4 -dihydro-1H-isoquinolin-2-yl)u-ethylcarbamoyl|-phenyl)-nicotinamide, M-42-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)u -ethylcarbamoyl|-phenyl)-isonicotinamide, pyrazine-2-carboxylic acid 12-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)u-ethylcarbamoyl|-phenyl)-amide , " 12-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethylcarbamoyl|-phenyl)-amide of quinoxaline-2-carboxylic acid, . 12-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethylcarbamoyl|-phenyl)-amide isoquinoline-1-carboxylic acid acid, 12-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethylcarbamoyl|-phenyl)-amide quinoline-2-carboxylic acid, 12-(2-(6 ,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethylcarbamoyl|-phenyl)-amide of isoquinoline-3-carboxylic acid b, 12-(2-(6,7-dimethoxy-3,4 -dihydro-1H-isoquinolin-2-yl)-ethylcarbamoyl|-phenyl)-amide of quinoline-3-carboxylic acid, Ш- 12-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline- 2-yl)-ethylcarbamoyl|-phenyl)-amide of thiophene-3-carboxylic acid, -I 12-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethylcarbamoyl| -phenyl)-amide.- 1H-indole-2-carboxylic acid, o (2-(4-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|- phenylcarbamoyl)-phenyl)-amide o quinoxaline-2-carboxylic acid, (2-14-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)- Quinoxaline-2-carboxylic acid 5-hydroxyamino-phenyl)-amide, Quinoxaline-2-carboxylic acid (2-14-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-4-methyl-phenyl)-amide, F) (2-14-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-4-hydroxyphenyl)-amide of quinoxaline-2-carboxylic acid , (2-14-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-5-nitro-phenyl)-amide in quinoxaline-2-carbon acid, (2-14-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-5-trifluoromethylphenyl)-amide of quinoxaline-2-carboxylic acid, Quinoxaline-2-carboxylic acid (2-4-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-5-fluoro-phenyl)-amide , 65 (2-4-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-3-fluoro-phenyl)-amide quinoxaline-2-carbon acids Quinoxaline-2-carboxylic acid (2-4-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-4-fluoro-phenyl)-amide , (2-14-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-4,5-dimethoxyphenyl)-amide of quinoxaline-2-carboxylic acid , (2-(4-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amide of quinoline-3-carboxylic acid, (2 Quinoline-3-carboxylic acid -4-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-5-fluoro-phenyl)-amide, 70 Quinoline-3-carboxylic acid (2-4-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-4-fluoro-phenyl)-amide , (2-14-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-4,5-dimethoxyphenyl)-amide of quinoline-3-carboxylic acid , (6-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-benzo|1,3|dioxol-5-yl)- amide of quinoline-3-carboxylic acid, (2-14-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-5-nitro-pheny l)-amide of quinoline-3-carboxylic acid, (2-14-12-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-4-methyl- phenyl)-amide of quinoline-3-carboxylic acid, (2-14-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-5-methyl- phenyl)-amide of quinoline-3-carboxylic acid, (2-(4-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-4-chloro -phenyl)-amide of quinoline-3-carboxylic acid, (2-(4-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-5- chloro-phenyl)-amide ch quinoline-3-carboxylic acid, (2-4-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-5 -amino-phenyl)-amide i) quinoline-3-carboxylic acid, (2-(4-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl )-phenyl)-amide of quinoline-2-carboxylic acid, o z o (2-(4-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl) -phenyl)-amide of 5,6,7,8-tetrahydroquinoline-3-carboxylic acid, and (2-(4-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl )-ethyl|-phenylcarbamoyl)-phenyl)-amide M pyridine-2-carboxylic acid, M-(2-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) )ethyl|-phenylcarbamoyl)-phenyl)-nicotinamide, i-M-(2-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl) )-phenyl)-isonicotinamide, "o (2-(4-12-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amide pyrazine -2-carboxylic acid, (2-(4-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amide 5-methylpyrazine- 2-carboxylic acid, "M-(2-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl|-phenylcarbamoyl)-phenyl)-6-methylnicotinamide, with c IM-(2-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl|-phenylcarbamoyl)-phenyl)-6-methoxynicotinamide, . 5-propionylpyrazine-2-carboxylic acid and? (2-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amide, 2-benzoylamino-M-(4- (2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenyl)-benzamide, 2-benzoylamino-M-(4-(2-(6,7- dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenyl)-5-methylbenzamide, Ge» 2-benzoylamino-M-(4-(2-(6,7-dimethoxy-3, 4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenyl)-4-methylbenzamide, 2-benzoylamino-M-(4-(2-(6,7-dimethoxy-3,4-dihydro-1H- isoquinolin-2-yl)-ethyl|-phenyl)-6-methylbenzamide, Ш- 2-(2-fluorobenzoylamino)-M-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline) -2-yl)-ethyl(1|-phenyl)-benzamide, -I 2-(3-fluorobenzoylamino)-M-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2- yl)-ethylI|-phenyl)-benzamide, 2-(4-fluorobenzoylamino)-M-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethylI| -phenyl)-benzamide, o 2-(2,4-difluorobenzoylamino)-M-(4-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|- phenyl)-benzamide, o 2-(2,6-difluorobenzoylamino)-M-(4-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phen yl)-benzamide, 2-(2-chlorobenzoylamino)-M-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl1|-phenyl)-benzamide, 2-(3-chlorobenzoylamino)-M-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl1|-phenyl)-benzamide, 2-(4- chlorobenzoylamino)-M-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenyl)-benzamide, 2-(2-methylbenzoylamino)-M- (4-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenyl)-benzamide, F) 2-(3-methylbenzoylamino)-M-(4 -(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenyl)-benzamide, ka 2-(4-methylbenzoylamino)-M-(4-(2 -(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenyl)-benzamide, 2-(2-methoxybenzoylamino)-M-14-(2-(6,7 -dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl(1|-phenyl)-benzamide, in 2-(3-methoxybenzoylamino)-M-14-(2-(6,7-dimethoxy-3 ,4-dihydro-1H-isoquinolin-2-yl)-ethyl(1|-phenyl)-benzamide, 2-(4-methoxybenzoylamino)-M-14-(2-(6,7-dimethoxy-3,4-dihydro- 1H-isoquinolin-2-yl)-ethyl(1|-phenyl)-benzamide, 2-(2-hydroxybenzoylamino)-M-14-(2-(6,7-dimethoxy- 3,4-dihydro-1H-isoquinolin-2-yl)-ethyl(1|-phenyl)-benzamide, 2-(3-hydroxybenzoylamino)-M-14-(2-(6,7-dimethoxy-3,4-dihydro -1H-isoquinolin-2-yl)-ethyl(1|-phenyl)-benzamide, 2-(4-hydroxybenzoylamino)-M-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline- 2-yl)-ethyl|-phenyl)-benzamide, 65 2-(2-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl )-phenylcarbamoyl)phenyl acetic acid ester, Acetic acid 3-(2-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenylcarbamoyl)phenyl ester, 4-(2- Acetic acid 14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenylcarbamoyl)phenyl ester, 2-(2-trifluoromethylbenzoylamino)-M- 14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenyl)-benzamide, 2-(3-trifluoromethylbenzoylamino)-M-14-(2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenyl)-benzamide, 2-(3-dimethylaminobenzoylamino)-M-4-(2-(6,7- dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenyl)-benzamide, 2-(4-isopropylbenzoylamino)-M-(4-(2-(6,7-dimethoxy-3, 4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenyl)-benzamide, 70 2-(4-cyclohexylbenzoylamino)-M-14-(2-(6,7-dimethoxy-3,4-dihydro- 1H-isoquinolin-2-yl)-ethyl|-phenyl)-benzamide, (2-(4-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|- phenylcarbamoyl)-phenyl)-amide of naphthalene-1-carboxylic acid, (2-(4-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)- hair dryer yl)-amide of naphthalene-2-carboxylic acid, 2-(3,4-dichlorobenzoylamino)-M-4-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)- ethyl|-phenyl)-benzamide, 2-(3,4-dimethylbenzoylamino)-M-14-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethylI|- phenyl)-benzamide, (2-(4-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amide thiophene-2-carbo acid, (2-(4-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amide thiophene-3-carboxylic acid, ( Furan-3-carboxylic acid 2-(4-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amide, (2-( 4-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amide of 1H-indole-2-carboxylic acid, sc (2-( 4-I2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amide of benzofuran-2-carboxylic acid, and) 2-(4- cyclohexylbenzoylamino)-M-I(3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl)|-benzamide, 2-(4-cyclohexylbenzoylamino)-M-(2- (3.4-d hydro-1H-isoquinolin-2-yl)-ethyl|-benzamide (2-14-I3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl|-phenylcarbamoyl)- phenyl)-amide ozoquinoxaline-2-carboxylic acid, 12-I4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-phenylcarbamoyl|-phenyl)-amide oquinoxaline-2 -carboxylic acid M (2-14-I2-(3,4-dihydro-1H-isoquinolin-2-yl)-ethyl|-phenylcarbamoyl)-phenyl)-amide quinoline-3-carboxylic acid, 12-I4-(6 ,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-phenylcarbamoyl|-phenyl)-amide quinoline-3-carboxylic acid, "o or its pharmaceutically acceptable salt. 9. A composition for pharmaceutical or veterinary use, comprising a pharmaceutical or veterinary carrier or diluent, and a compound according to claim 1 or 6 as an active agent. 10. The method of obtaining the compound according to claim 1, which differs in that "aminobenzamide of the formula (MI) from c (6); From re Ag H 8 -I where Ag, B" and Z are determined according to claim 1, and 7 - group - VZ Ko s" 70 x sv g Z v! o voy and tm tgsnih , v? also V where t, p, a, K, 27-85 and X are defined according to claim 1, treated with a carboxylic acid of the formula B 9-COOH or its 25 activated derivative, in which KO is defined according to claim 1; and/or, if desired, convert one compound of the formula (F) (I) to another compound of formula (I), or, if desired, convert one compound of formula (I) into its GI pharmaceutically acceptable salt, and/or, if desired, convert the salts into a free compound of formula (1). 11. The method of obtaining the compound according to claim 1, which differs in that in the compound of the formula (XII): b5 0 , Х сн 7 IF 2 Кк "М че а Пи Аг Нн це 6 В Мне 70 о в де Аг, В?, 29-KU, Х, д and т determined according to claim 1, treated with amine of formula (ХХ): E., in B! In M sn," p in? H (XX) where B, B!-B7 and n are defined according to claim 1, and optionally, remove any present, optionally substituted protecting group, and/or, optionally, convert one compound of formula (I) to another compound of the formula (His), and/or, if desired, convert one compound of the formula (I) into its pharmaceutically acceptable salt, and/or, if desired, convert the salts into a free compound of the formula (1). 12. The method of obtaining the compound according to claim 6, which differs in that the aminobenzamide of the formula MI" o c ! 31 r o М H "c) zo vam) MH, as where B! and E"! determined by claim 6, and as an option, protected, and 7 - group cha B! ; С F (Se) (СН»)» M v! And where r, 8, B'! and B?! defined according to claim 6, treated with a carboxylic acid of the formula B 2!-СООН or its « 70 activated derivative, where 2 is defined according to claim 6; and/or, optionally, convert one compound of formula () to another compound of formula (I), and/or, optionally, convert one compound of formula (I) into a pharmaceutically acceptable salt thereof, and/or, optionally , convert salts into a free compound of formula (1). и"? 13. The method of obtaining the compound according to claim 6, which differs in that the compound of the formula (XII!) is treated with an amine formulas (IX) with V. « WE, (СНзЮ- С, Ф) I (ХХ) o de g, 5, V! and B?! defined according to claim 6, and/or, optionally, convert one compound of formula (I) into another compound of formula (I), and/or, optionally, convert one compound of formula (I) into its pharmaceutically acceptable salt, and /or, if desired, convert the salts into a free compound of formula (1). 14. The method of obtaining the compound according to claim 6, which differs in that the azalactone of the formula (XII!) b5 (ХХ (c) and AK - M vo! where ВР! has the above value, are treated with amine of the formula (ХХ) ВЕ! ; МН» (СНО); M v 1 T х) 19 where r, 5, В"! and VK defined above, and optionally, remove any optionally substituted protecting group present, and/or, optionally, convert one compound of formula (Ia) into another compound of formula (Ia), and/or, optionally, convert one compound of formula (Ia) into its pharmaceutically acceptable salt, and/or, if desired, convert the salts into a free compound of formula (Ia). 15. The compound according to claim 1 or 6, which differs in that it is intended for use in a method of therapeutic treatment of humans and animals. 16. The compound according to claim 15, which differs in that it is intended for use as an inhibitor of P-glycoprotein. 17. The compound according to claim 15, which is characterized by the fact that it is intended for use as a modulator of resistance to multiple therapeutic agents, to enhance the cytotoxicity of a chemotherapeutic agent, to enhance the therapeutic effect of a therapeutic agent directed against a pathogen resistant to multiple therapeutic agents, c or improvement absorption, distribution, metabolism or elimination characteristics of the therapeutic agent. at 18. The compound according to claim 15, which differs in that it is used in the production of medicines for use as a P-glycoprotein inhibitor. "c) Zo so cha cha (Se) - with . and? (o) -I -I o) 70 (42) ime) 60 b5