RU2195454C2 - Derivatives of anthranilic acid, methods of their synthesis and pharmaceutical composition based on thereof - Google Patents

Abstract

FIELD: organic chemistry, biochemistry, pharmacy. SUBSTANCE: invention relates to novel derivatives of anthranilic acid of the formula (I)

where R¹, R² mean H, alkyl, OH, alkoxy-group, halogen atom, nitro-group, N(R¹⁰R¹¹); R³ means H, alkyl; R⁴ means alkyl or R⁴ means -CH₂- or -CH₂CH₂- that is bound either at position 2 of cycle b completing saturated 5- or 6-membered nitrogen-containing cycle or at position 2 of cycle a with which X is bound by a single bond completing saturated 5- or 6-membered nitrogen-containing cycle; R⁵ means H, OH, alkyl; X means a single bond, O, S, -O--(CH₂)_p- where p is a number from 1 to 6; R⁶ means H, alkyl, alkoxy-group; q is a number from 0 to 1; Ar means phenyl, naphthyl or heterocyclic group containing S or N; each among R⁷ and R⁸ means H, alkyl, alkoxy-group, hydroxy-group, phenyl, -NHOH, nitro-group, N(R¹⁰R¹¹), SR¹²; or each among R⁷ and R⁸ in common with carbon atoms forms benzene or methylenedioxy- -substitute; R⁹ means phenyl or heterocyclic group containing 1 or 2 atoms among O, S or N; n = 0 or 1; m = 0-3. Compounds of the formula (I) show activity as inhibitor of P-glycoprotein and can be used in pharmaceutical composition and for enhancement of cytotoxic effect of chemotherapeutic agent. Also, invention relates to methods of synthesis of compounds of the formula (I) and formula (Ia)

that involve treatment of compound of the formula (VI)

with carboxylic acid, compound of the formula (XII)

with compound of the formula (XX)

, compound of the formula (VIII')

with carboxylic acid, compound of the formula (XII')

with compound of the formula (IX')

and compound of the formula (XIII')

with compound of the formula (IX')

Description

 The invention relates to compounds useful as multidrug resistance modulators (MDR), in particular MDR caused by the excessive production of P-glycoprotein (P-gp), to their preparation and pharmaceutical and veterinary compositions containing them.

 The resistance of tumors to treatment with certain cytotoxic agents hinders the successful chemotherapeutic treatment of cancer patients. The tumor may become resistant to the cytotoxic agent used in the previous treatment. The tumor may also exhibit hereditary resistance or cross (cross-) resistance to a cytotoxic agent that has not been previously used, and this agent is not associated with the structure or mechanism of action with any agent used in previous tumor treatments.

 Similarly, some pathogens may become resistant to pharmaceuticals used in previous treatments for diseases or disorders caused by these pathogens. Pathogens may also exhibit hereditary or cross-resistance to pharmaceuticals that they have not previously been exposed to. Examples of this effect include multidrug resistance forms of malaria, tuberculosis, leishmaniasis, and amoebic dysentery. These phenomena are collectively referred to as multidrug resistance (MDR).

 The most common form of MDR is caused by the overproduction of P-gp in the cell membrane, a protein that can reduce the accumulation of drugs in cells by pumping these drugs. This protein has been shown to be the main cause of multidrug resistance in tumor cells (Beck, W.T. Biochem. Pharmacol., 1987, 36, 2879-2887).

 In addition to cancer cells, p-glycoprotein is found in many normal human tissues, including the liver, small intestine, kidneys and blood-brain endothelium. P-gps are localized in all these tissues in the secretory regions of cells. This localization means that P-gp may 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, P-gp inhibitors increase the oral absorption of certain drugs and improve the movement of drugs across the blood-brain barrier. Indeed, administration of cyclosporin, a P-gp inhibitor, has been shown to increase the intestinal absorption of acebutolol and vinblastine in rats by 2.6 and 2.2 times, respectively (Tereo, T. et al., J. Pharm. Pharmacol., 1966, 48, 1083-1089), whereas a mdr la P-gp gene deficient mouse shows up to 100-fold increased sensitivity to the central neurotoxic pesticide ivermectin (Schinkel, AH et al., Cell, 1994, 77, 491-502). In addition to elevated levels of drugs in the brain, P-gp-deficient mice have been shown to have increased drug levels in many tissues and decreased drug excretion (drug excretion from the body).

 The lack of drugs so far used to modulate MDR, called resistance modifying agents or RMA, is that they often have a poor pharmacokinetic profile and / or are toxic at the concentrations required for MDR modulation.

 It has now been found that a number of anthranilic acid derivatives are active as inhibitors of Pgp, and therefore, they can be used to overcome the multidrug resistance of tumors and pathogens. They are also potentially applicable to improve the absorption, distribution, metabolism and removal of certain drugs.

где каждый из R, R¹ и R², которые являются одинаковыми или различными, обозначает Н, C₁-C₆-алкил, ОН, C₁-C₆-алкокси, галоген, нитро или N(R¹⁰R¹¹), где каждый из R¹⁰ и R¹¹, которые являются одинаковыми или различными, обозначает Н или C₁-C₆-алкил, или R¹ и R², являясь присоединенными в соседние положения цикла

, вместе образуют метилендиокси- или этилендиоксигруппу;
R³ обозначает Н или C_1-6-алкил;
R⁴ обозначает C₁-C₆-алкил или R⁴ обозначает -СН₂- или
-СН₂СН₂-, который присоединен либо (I) в положение цикла

, завершая насыщенный 5- или 6-членный азотсодержащий цикл, конденсированный с кольцом

, либо (II) в положение в цикле

, соседнее тому, с которым связан X, являющийся простой связью, тем самым завершая насыщенный 5- или 6-членный азотсодержащий цикл, конденсированный с кольцом

;
R⁵ обозначает Н, ОН или C₁-C₆-алкил;
Х обозначает простую связь, О, S, -S-(CH₂)_p- или
-O-(CH₂)_p-, где р обозначает целое число от 1 до 6;
R⁶ обозначает Н, C₁-C₆-алкил или C₁-C₆-алкокси;
q обозначает 0 или 1;
Аr обозначает ненасыщенную карбоциклическую или гетероциклическую группу;
каждый из R⁷ и R⁸, которые являются одинаковыми или различными, обозначает Н, незамещенный или замещенный C₁-C₆-алкил, C₁-C₆-алкокси, гидрокси, галоген, фенил, -NHOH, нитро, определенную выше группу N(R¹⁰R¹¹) или группу SR¹², где R¹² обозначает Н или C₁-C₆-алкил, или R⁷ и R⁸, когда расположены на соседних углеродных атомах, образуют вместе с атомами углерода, к которым они присоединены, бензольный цикл или метилендиоксизаместитель;
R⁹ обозначает фенильную или ненасыщенную гетероциклическую группу, каждая из которых незамещена или замещена C₁-C₆-алкилом, ОН, C₁-C₆-алкокси, галогеном, С₃-С₆-циклоалкилом, фенилом, бензилом, трифторметилом, нитро, ацетилом, бензоилом или определенным выше N(R¹⁰R¹¹), или два заместителя в соседних положениях кольца указанного фенила или гетероциклической группы вместе завершают насыщенный или ненасыщенный 6-членный цикл или образуют метилендиоксигруппу;
n обозначает 0 или 1 и
m обозначает 0 или целое число от 1 до 6;
или его фармацевтически приемлемую соль.Therefore, this invention provides a compound derived from anthranilic acid of the formula (I)

where each of R, R ¹ and R ² that are the same or different, is H, C ₁ -C ₆ -alkyl, OH, C ₁ -C ₆ -alkoxy, halogen, nitro or N (R ¹⁰ R ¹¹ ), where each of R ¹⁰ and R ¹¹ that are the same or different, denotes H or C ₁ -C ₆ -alkyl, or R ¹ and R ² , being attached to adjacent positions of the cycle

together form a methylenedioxy or ethylenedioxy group;
R ³ is H or C _1-6 alkyl;
R ⁴ is C ₁ -C ₆ alkyl or R ⁴ is —CH ₂ - or
-CH ₂ CH ₂ -, which is attached either (I) to the position of the cycle

completing a saturated 5- or 6-membered nitrogen-containing ring fused ring

, or (II) to position in the cycle

adjacent to the one to which X is bonded, which is a single bond, thereby completing a saturated 5- or 6-membered nitrogen-containing ring fused to the ring

;
R ⁵ is H, OH or C ₁ -C ₆ alkyl;
X is a single bond, O, S, —S— (CH ₂ ) _p - or
-O- (CH ₂ ) _p -, where p is an integer from 1 to 6;
R ⁶ is H, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy;
q is 0 or 1;
Ar is an unsaturated carbocyclic or heterocyclic group;
each of R ⁷ and R ⁸ , which are the same or different, is H, unsubstituted or substituted C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxy, halogen, phenyl, -NHOH, nitro, the above-defined group N (R ¹⁰ R ¹¹ ) or an SR ¹² group, where R ¹² is H or C ₁ -C ₆ alkyl, or R ⁷ and R ⁸ , when located on adjacent carbon atoms, form together with the carbon atoms to which they are attached benzene cycle or methylenedioxy substituent;
R ⁹ represents a phenyl or unsaturated heterocyclic group, each of which is unsubstituted or substituted by C ₁ -C ₆ alkyl, OH, C ₁ -C ₆ alkoxy, halogen, C ₃ -C ₆ cycloalkyl, phenyl, benzyl, trifluoromethyl, nitro , acetyl, benzoyl or N (R ¹⁰ R ¹¹ ) as defined above, or two substituents at adjacent positions of the ring of said phenyl or heterocyclic group together complete a saturated or unsaturated 6-membered ring or form a methylenedioxy group;
n is 0 or 1 and
m is 0 or an integer from 1 to 6;
or a pharmaceutically acceptable salt thereof.

, не занятом R⁶. Предпочтительно она присоединена в положение 3 или 4. В предпочтительных группах соединений, R⁶ находится в положении 2, и Х находится в положении 3 или 4 цикла

. Когда Х находится в положении 3 или 4 цикла

, R⁶ может альтернативно занимать положение 5. Благодаря свободному вращению цикла

положение 6 эквивалентно положению 2.Group X is attached in any one of positions 2-6 of the cycle

not occupied by R ⁶ . Preferably it is attached at position 3 or 4. In preferred groups of compounds, R ⁶ is at position 2, and X is at position 3 or 4 of the cycle

. When X is in position 3 or 4 of the cycle

, R ⁶ may alternatively occupy position 5. Due to the free rotation of the cycle

position 6 is equivalent to position 2.

 The value of m is preferably 0 or an integer from 1 to 3, more preferably 1 or 2. The value of q is preferably 1.

C ₁ -C ₆ -alkyl group may be linear or branched. Typically, a C ₁ -C ₆ alkyl group is a C ₁ -C ₄ alkyl group, for example a methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl or tert-butyl group. Halogen is F, Cl, Br or I. Preferably F, Cl or Br. A substituted C ₁ -C ₆ alkyl group is usually substituted with one or more halogen atoms, for example 1, 2 or 3 halogen atoms. This may be a perhaloalkyl group, for example trifluoromethyl.

The C ₁ -C ₆ alkoxy group may be linear or branched. Usually it is a C ₁ -C ₄ alkoxy group, for example a methoxy, ethoxy, propoxy, iso-propoxy, n-propoxy, n-butoxy, sec-butoxy or tert-butoxy group. The integer m has values from 1 to 6 and is usually 1, 2 or 3.

The unsaturated carbocyclic group is usually a C ₅ -C ₁₀ carbocyclic group that contains at least one unsaturated bond, for example a C ₆ -C ₁₀ aryl group such as a phenyl or naphthyl group. An unsaturated heterocyclic group is typically a 5- or 6-membered heterocyclic ring with at least one unsaturated bond containing one or more heteroatoms selected from N, S and O, and optionally fused to a benzene ring or to a second such 5- or 6- member heterocycle.

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, purine or triazine group. The above heterocyclic ring may be unsubstituted or substituted with one or more substituents, for example, one or more substituents selected from OH, halogen, C ₁ -C ₆ alkyl, unsubstituted or substituted with, for example, halogen, such as CF ₃ , C ₁ -C ₆ alkoxy, nitro and the above amino group N (R ¹⁰ R ¹¹ ).

Preferably, the heterocyclic group represented by R ⁹ includes at least one nitrogen atom, and the heterocyclic group represented by Ar includes at least one nitrogen or sulfur atom.

, завершая с циклом

тетрагидроизохинолиновую группу. Альтернативно n обозначает 1, а R⁴ обозначает -СН₂-, который присоединен в положение 2 или 6 цикла

, завершая с циклом

тетрагидроизохинолиновую группу.In the preferred series of compounds, n is 0, and R ⁴ is —CH ₂ CH ₂ -, which is attached to position 2 or 6 of the ring

ending with a loop

tetrahydroisoquinoline group. Alternatively, n is 1, and R ⁴ is —CH ₂ -, which is attached to position 2 or 6 of the ring

ending with a loop

tetrahydroisoquinoline group.

, и R⁴ обозначает -CH₂-, который присоединен в положение кольца цикла

, соседнее с положением 3 или 4 соответственно, завершая с циклом

тетрагидроизохинолиновую группу. Альтернативно m обозначает 0, Х обозначает простую связь, присоединенную в положение 3 или 4 цикла

, и R⁴ обозначает -СН₂СН₂-, который присоединен в положение кольца цикла

, соседнее с положением 3 или 4 соответственно, завершая с циклом

тетрагидроизохинолиновую группу.In other preferred series of compounds, m is 1, X is a single bond attached to the 3 or 4 position of the ring

and R ⁴ is —CH ₂ -, which is attached to the position of the ring ring

adjacent to position 3 or 4, respectively, ending with a cycle

tetrahydroisoquinoline group. Alternatively, m is 0, X is a single bond attached at position 3 or 4 of the ring

and R ⁴ is —CH ₂ CH ₂ -, which is attached to the position of the ring ring

adjacent to position 3 or 4, respectively, ending with a cycle

tetrahydroisoquinoline group.

 The Ar group is preferably a benzene, naphthalene, thiophene, thienopyrazine, pyridine, pyrazine, indole or furan ring.

The group R ⁹ is preferably quinoline, isoquinoline, quinoxaline, pyridine, pyrazine, oxazole, isoxazole, thiazole or isothiazole. More preferably, R ⁹ is quinolin-3-yl, quinoxalin-2-yl, pyrazin-2-yl, pyridin-2-yl-, pyridin-3-yl, oxazol-4-yl- or thiazol-4-yl- a group.

, вместе образуют метилендиокси- или этилендиоксигруппу.R, R ¹ and R ^{2 are} preferably independently selected from H, OH, C ₁ -C ₆ alkoxy and nitro, or R is H and R ¹ and R ² being attached at positions 2 and 3, 3 and 4, 4 and 5 or 5 and 6 cycles

together form a methylenedioxy or ethylenedioxy group.

где R¹¹ и R²¹, которые могут быть одинаковыми или различными, каждый обозначает водород или метокси;
R³¹ и R⁴¹, которые могут быть одинаковыми или различными, каждый независимо выбирают из Н, СН₃, СF₃, F, Cl, Вr, NH₂, NO₂, NHOH, метокси, гидрокси и фенила; или R³¹ и R⁴¹, когда расположены на соседних углеродных атомах, образуют вместе с атомами углерода, к которым они присоединены, бензольный цикл или метилендиоксизаместитель,
R⁵¹ обозначает 2-фуранил, 3-фуранил, 2-тиофен, 3-тиофен, 2-индолил или 2-бензофуранил или цикл одной из нижеследующих формул (II'), (III') или (IV'):

где R⁶¹ и R⁷¹, которые могут быть одинаковыми или различными, выбирают из водорода, линейного или разветвленного C₁-С₆-алкила, С₃-С₆-циклоалкила, фенила, бензила, трифторметила, F, Cl, Br, OR¹², NO₂, диметиламино, диэтиламино, ацетила и бензоила, или R⁶¹ и R⁷¹, когда расположены на соседних атомах углерода, образуют вместе с атомами углерода, к которым они присоединены, бензольный цикл или метилендиоксизаместитель.In a preferred aspect, the anthranilic acid of the invention has the following formula (Ia):

where R ¹¹ and R ²¹ , which may be the same or different, each represents hydrogen or methoxy;
R ³¹ and R ⁴¹ , which may be the same or different, are each independently selected from H, CH ₃ , CF ₃ , F, Cl, Br, NH ₂ , NO ₂ , NHOH, methoxy, hydroxy and phenyl; or R ³¹ and R ⁴¹ , when located on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a benzene ring or methylenedioxy substituent,
R ⁵¹ is 2-furanyl, 3-furanyl, 2-thiophene, 3-thiophene, 2-indolyl or 2-benzofuranyl or a cycle of one of the following formulas (II ′), (III ′) or (IV ′):

where R ⁶¹ and R ⁷¹ , which may be the same or different, are selected from hydrogen, linear or branched C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, phenyl, benzyl, trifluoromethyl, F, Cl, Br, OR ¹² , NO ₂ , dimethylamino, diethylamino, acetyl and benzoyl, or R ⁶¹ and R ⁷¹ , when located on adjacent carbon atoms, form, together with the carbon atoms to which they are attached, a benzene ring or methylenedioxy substituent.

R ⁸¹ and R ⁹¹ , which may be the same or different, each represents hydrogen, methyl or methoxy, or R ⁸¹ and R ⁹¹ , when located on adjacent carbons, form, together with the pyridine ring to which they are attached, a quinoline or 5, 6,7,8-tetrahydroquinoline ring system;
R ¹⁰¹ and R ¹¹¹ , which may be the same or different, each represents hydrogen, methyl or propionyl; or R ¹⁰¹ and R ¹¹¹ , when located on adjacent carbon atoms, form, together with the carbon atoms to which they are attached, a benzene ring;
R ¹²¹ is H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, phenyl, benzyl or acetyl;
r is 0 or 1 and
s is 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.

The integer s has values from 1 to 3 and is preferably 1 or 2. In the preferred series of compounds of formula (Ia), r is 1, s is 2, R ¹¹ and R ^{21 are} both methoxy, and R ⁵¹ is 2-quinoxalo group, 3 a quinoline group, a 2-pyrazine group or a 3-pyridine group, each of these groups may be unsubstituted or substituted.

где (a) каждый из R, R¹ и R², которые являются одинаковыми или различными, обозначает Н, ОН, NO₂, N(R¹⁰R¹¹), галоген или С₂-С₆-алкокси, или R обозначает Н, и R¹ и R² образуют, вместе с атомами углерода, с которыми они связаны, метилендиокси- или этилендиоксигруппу, при условии, что R, R¹ и R² не все являются Н, и каждый из R³, R⁵, R⁶, R⁷, R⁸, R⁹, Аr, Х и m имеет вышеуказанные для формулы (I) значения; или
(b) каждый из R, R¹ и R², которые являются одинаковыми или различными, обозначает Н или ОМе, и каждый из R³, R⁵, R⁶, R⁷, R⁸, R⁹, Аr, Х и m имеет вышеуказанные значения.In another aspect, the anthranilic acid of the invention has the following structure (A)

where (a) each of R, R ¹ and R ² , which are the same or different, is H, OH, NO ₂ , N (R ¹⁰ R ¹¹ ), halogen or C ₂ -C ₆ alkoxy, or R is H and R ¹ and R ² form, together with the carbon atoms to which they are attached, a methylenedioxy or ethylenedioxy group, provided that R, R ¹ and R ^{2 are} not all H, and each of R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , Ar, X and m are as defined above for formula (I); or
(b) each of R, R ¹ and R ² , which are the same or different, is H or OMe, and each of R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , Ar, X and m has the above meanings.

где R, R¹-R³, R⁵-R⁹, Ar и n имеют вышеуказанные для формулы (I) значения.In another embodiment, the anthranilic acid of the invention has the following structure (B):

where R, R ¹ -R ³ , R ⁵ -R ⁹ , Ar and n are as defined above for formula (I).

где R, R¹-R³, R⁵-R⁹, Ar, Х и m имеют вышеуказанные для формулы (I) значения.In a further aspect, the anthranilic acid of the invention has the following structure (C)

where R, R ¹ -R ³ , R ⁵ -R ⁹ , Ar, X and m are as defined above for formula (I).

где R, R¹-R³, Ar, m и n имеют вышеуказанные для формулы (I) значения, а X, находящийся в положении 3 или 4 цикла

, имеет вышеуказанные для формулы (I) значения.In another embodiment, the anthranilic acid of the invention has the following structure (D)

where R, R ¹ -R ³ , Ar, m and n are as defined above for formula (I), and X is in position 3 or 4 of the cycle

has the above meanings for formula (I).

In a preferred series of compounds of formula (I), R ⁴ is C ₁ -C ₆ alkyl. Preferably R, R ¹ and R ^{2 are} each H, OH or methoxy.

R⁶ присоединен к любому одному из положений 2 - 6. Обычно R⁶ присоединен в положение 2 цикла

.In the loop

R ^{6 is} attached to any one of positions 2 to 6. Typically, R ^{6 is} attached to position 2 of the cycle.

.

 Examples of preferred compounds of the invention are shown in Table A.

где Аr, R⁷ и R⁸ имеют вышеуказанные значения, и Z представляет фрагмент

где m, n, q, R, R¹-R⁶ и Х имеют вышеуказанные значения, карбоновой кислоты формулы R⁹COOH или ее активированного производного, где R⁹ имеет вышеуказанные значения; или
(b) обработку соединения формулы (XII)

где Ar, R⁵, R⁶-R⁹, X, q и m имеют вышеуказанные значения, амина формулы XX

где R, R¹-R⁴ и n имеют вышеуказанные значения; и, если требуется, удаление любых присутствующих необязательных защитных групп, и/или, если требуется, превращение одного соединения формулы (I) в другое соединение формулы (I), и/или, если требуется, превращение одного соединения формулы (I) в его фармацевтически приемлемую соль, и/или, если требуется, превращение соли в свободное соединение формулы (I).Compounds of formula (I) can be prepared by a process that includes:
(a) processing aminobenzamide of the formula (VI)

where Ar, R ⁷ and R ⁸ have the above meanings, and Z represents a fragment

where m, n, q, R, R ¹ -R ⁶ and X have the above meanings, a carboxylic acid of the formula R ⁹ COOH or its activated derivative, where R ⁹ has the above meanings; or
(b) treating a compound of formula (XII)

where Ar, R ⁵ , R ⁶ -R ⁹ , X, q and m have the above meanings, an amine of formula XX

where R, R ¹ -R ⁴ and n have the above meanings; and, if required, removing any optional protecting groups present, and / or, if required, converting one compound of formula (I) to another compound of formula (I), and / or, if required, converting one compound of formula (I) to a pharmaceutically acceptable salt, and / or, if desired, converting the salt into a free compound of formula (I).

In process variant (a), R ⁹ —COOH carboxylic acid is commercially available or can be prepared as described in the following Reference Example 6A. The acid may be activated in the form of the corresponding acid chloride R ⁹ —COCl. It can be obtained commercially or obtained by treating the free carboxylic acid R ⁹ —COOH with thionyl chloride. Alternatively, R ⁹ -COOH carboxylic acid may be activated by cyclohexyl-N- (2-morpholinoethyl) carbodiimide-methyl-p-toluene-sulfonate and 1-hydroxybenzotriazole, or 2-chloro-1-methylpyridinium-iodide.

Aminobenzamides of general formula VI can be obtained in one of three ways, illustrated by scheme 1 (see the end of the description), where each of Z, R ⁷ , R ⁸ and Ar has the above meanings. The first way involves the direct combination of an appropriately substituted, commercially available anthranilic acid of formula (IV) with an amine of formula IX (step III) and is described in more detail in the following reference example 4A. The starting amine of formula IX can be prepared as described in the following Reference Example 1A.

 The second way involves the combination of a suitably substituted, commercially available nitrobenzoic acid III and the subsequent reduction of the nitro group to an amino group (stages I and II). These steps are described in more detail in the following reference examples 2A and 3A, respectively. The third method includes 4 stages, based on the commercially available amino ester VII. This method is described in more detail in the following reference example 5.

 In process variant (b), the amines of formula XX are known compounds or can be prepared from known starting compounds using techniques conventional in organic chemistry, for example, as described in Example 3. The intermediate bromide of formula II is obtained by treating the corresponding hydroxy compound of formula XVII with a brominating agent. Suitable brominating agents include N-bromosuccinimide. The hydroxy compound of formula XVII can be obtained as illustrated by Scheme 2 (see end of description). The reactions of Scheme 2 are described in more detail in the following Reference Example 7.

The starting amino derivative of formula XIII, in which P is a hydroxy protecting group, is obtained from the corresponding protected nitro derivative by reduction, for example, by treating H ₂ with EtOH in the presence of PtO ₂ . The protected nitro derivative, in turn, is obtained by treating the unprotected nitro derivative with a protective group, which gives group R.

 Stage (I) is usually carried out by reacting together the compounds of formula XIII and XIV in the presence of a base, for example triethylamine. The resulting compound is reduced in step (II), for example, under the conditions described above to obtain compound XIII, to give an intermediate of formula XV.

Step (III) involves treating a compound of formula XV with a compound R ⁹ —COCl in an organic solvent in the presence of a base to give a compound of formula XVI. The latter compound is deprotected in step (IV), and the resulting unprotected derivative of formula XVII is reacted with a brominating agent in step (V) to obtain the desired compound of formula XII.

где R³¹ и R⁴¹ имеют вышеуказанные значения и, если требуется, являются необязательно защищенными, и Z' представляет фрагмент

где r, s, R¹¹ и R²¹ имеют вышеуказанные значения, карбоновой кислоты формулы R⁵¹-COOH, или ее активированного производного, где R⁵¹ имеет вышеуказанные значения; или
(b') обработку соединения формулы XII'

где R⁵¹ имеет вышеуказанные значения, амином формулы IX'

где r, s, R¹¹ и R²¹ имеют вышеуказанные значения; с получением соединения формулы (Iа), где R³¹ и R⁴¹ оба являются водородом; или
(с') обработку азалактона формулы XIII'

где R⁵¹ имеет вышеуказанные значения, амином формулы (IX')

где r, s, R¹¹ и R²¹ имеют вышеуказанные значения, с получением соединения формулы (Iа), где R³¹ и R⁴¹ оба являются водородом; и, если требуется, удаление любых присутствующих необязательных защитных групп, и/или, если требуется, превращение одного соединения формулы (Iа) в другое соединение формулы (Iа), и/или, если требуется, превращение одного соединения формулы (Iа) в его фармацевтически приемлемую соль, и/или, если требуется, превращение соли в свободное соединение формулы (Ia).Compounds of formula (Ia) can be prepared by a process that includes:
(a ') processing aminobenzamide of the formula (VIII')

where R ³¹ and R ⁴¹ have the above meanings and, if desired, are optionally protected, and Z 'represents a fragment

where r, s, R ¹¹ and R ²¹ have the above meanings, a carboxylic acid of the formula R ⁵¹ -COOH, or an activated derivative thereof, where R ⁵¹ has the above meanings; or
(b ') processing a compound of formula XII'

where R ⁵¹ has the above meanings, an amine of formula IX '

where r, s, R ¹¹ and R ²¹ have the above meanings; to give a compound of formula (Ia), wherein R ³¹ and R ⁴¹ are both hydrogen; or
(c ') treatment of azalactone of formula XIII'

where R ⁵¹ has the above meanings, an amine of the formula (IX ')

where r, s, R ¹¹ and R ²¹ have the above meanings, to obtain a compound of formula (Ia), where R ³¹ and R ⁴¹ are both hydrogen; and, if required, removing any optional protecting groups present, and / or, if required, converting one compound of formula (Ia) into another compound of formula (Ia), and / or, if necessary, converting one compound of formula (Ia) into it a pharmaceutically acceptable salt, and / or, if desired, converting the salt into a free compound of formula (Ia).

In process variant (a '), the carboxylic acid R ⁵¹ —COOH is commercially available or can be prepared as described in the following Referential Example 6B. The acid can be activated in the form of the corresponding acid chloride R ⁵¹ -COCl. It can be obtained commercially or obtained by treating the free carboxylic acid R ⁵¹ —COOH with thionyl chloride. Alternatively, R ⁵¹ -COOH carboxylic acid can be activated by cyclohexyl-N- (2-morpholinoethyl) carbodiimide-methyl-p-toluene-sulfonate and 1-hydroxybenzotriazole, or 2-chloro-1-methylpyridinium-iodide.

The 2-aminobenzamides of formula VIII ′ are prepared in one of two ways. The first involves the reduction of the corresponding 2-nitrobenzamides, for example, by treatment with hydrogen in the presence of a PtO ₂ catalyst. 2-Nitrobenzamide, in turn, can be obtained by treating the corresponding 2-nitrobenzoic acid, which is optionally activated, with an amine of formula IX ', as defined above. The preparation of amines of formula IX 'is described in the following Reference Example 1B. The steps to intermediate VIII ′ are illustrated by the following Scheme 3 (see end of description). Steps (I), (II) and (III) of the scheme are described in the following reference examples 2B, 3B and 4B, respectively, and step (III) is described in reference example 4B. The preparation of amine IX ′ is described in Reference Example 1B.

 In process variant (b '), an intermediate of formula XII' is prepared by hydrolysis of the corresponding methyl ester, which in turn is obtained by treating commercially available methyl anthranilate with acid chloride in the presence of triethylamine in dichloromethane. These stages are described in the following reference example 6.

In process variant (c '), an azalactone of formula XIII' is prepared by treating commercially available anthranilic acid with an acid chloride of the general formula R ⁵¹ —COCl in pyridine or in a pyridine / dichloromethane mixture at 0 ^{° C.} for 3-8 hours.

 The compounds of formula (I) can be converted into pharmaceutically acceptable salts by conventional methods, and the salts can be converted to the free compound. Salts may be mono- or bis-salts. Bis salts, or double salts, can be obtained when there are two basic nitrogen atoms in the structure of the compound of formula (I). Suitable salts include salts with pharmaceutically acceptable inorganic or organic acids.

 Examples of inorganic acids include hydrochloric acid, sulfuric acid, and phosphoric acid. Examples of organic acids include p-toluenesulfonic acid, methanesulfonic acid, mucus acid and succinic acid. Bis salts may include, in particular, bis hydrochlorides and bis mesylates.

 The optional conversion of a compound of formula (I) into another compound of formula (I) can be accomplished by conventional methods. For example, a compound of formula (I) containing an esterified hydroxy group, such as -OSOME, by hydrolysis, for example alkaline hydrolysis, can be converted into a compound of formula (I) containing a free hydroxy group. A compound of formula (I) containing a hydroxy group by esterification, for example by reaction with a suitable carboxylic acid, halide or anhydride, can be converted into a compound of formula (I) containing an esterified hydroxy group.

A halogen-containing compound can be converted to an aryl-containing compound by the Suzuki coupling reaction (Miyaura, M., Yanagi, T. and Suzuki, A., Synth. Commun. 1981, vol. 11, p. 513). A compound of formula (I) containing a nitro group can be converted to a compound of formula (I) containing an amino group by reduction, for example, by treatment with hydrogen gas in the presence of a PTO ₂ catalyst. Also, a compound of formula (I) containing a nitro group, by reduction, for example by treatment with hydrogen gas in the presence of a PtO ₂ catalyst under suitably controlled conditions, can be converted into a compound of formula (I) containing a hydroxy amino group — NHOH.

 Cancer cells that exhibit multidrug resistance, referred to as MDR cells, exhibit a decrease in intracellular drug cumulation compared to corresponding drug-sensitive cells. As discussed above, in vitro studies of the obtained MDR cell lines have shown that MDR is often associated with increased expression of a cell membrane glycoprotein (P-gp) having drug binding properties. P-gp is believed to act as a pumping pump for many hydrophobic compounds, and transfection studies using cloned P-gp have shown that its overexpression can produce an MDR phenotype on cells: see, for example, Ann. Rev. Biochem., 58, 137-171 (1989).

 The main function of Pgp in normal tissues is the removal of intracellular toxins from the cell. There is evidence to suggest that overexpression of Pgp may play a clinical role in multidrug resistance. Elevated Pgp mRNA or protein levels have been found in many forms of human cancerous tumors — leukemia, lymphomas, sarcomas, and carcinomas. Indeed, it has been found that in some cases, P-gp levels are elevated in tumor biopsies obtained after relapse from chemotherapy.

 Inhibition of P-gp function in P-gp-mediated MDR has been shown to lead to a general cumulation of anticancer agents in cells. For example, verapamil, a known calcium channel blocker, has been shown to increase the sensitivity of MDR cells to Vinca alkaloids in vitro and in vivo: Cancer Res., 41, 1967-1972 (1981). The proposed mechanism of action involves competition with an anti-cancer agent for binding to P-gp. A number of structurally unrelated stability modifying agents having this mechanism are described, such as tamoxifen (Nolvadex: ICI) and related compounds, and cyclosporin A and derivatives.

 In biological tests, it was found that the anthranilic acid derivatives of formula (I) and their pharmaceutically acceptable salts (hereinafter referred to as “the subject compounds”) have activity as inhibitors of P-gp. They can be used to modulate MDR, in particular P-gp-mediated MDR. The results are shown in the following Example 1. As Pgp inhibitors, the subject compounds can be used as multidrug resistance modifiers, also called resistance modifiers or RMAs. The subject compounds can modulate, for example, reduce or eliminate multidrug resistance, especially one that is P-gp-mediated.

 Therefore, the subject compounds can be used in a method for enhancing the cytotoxicity of an agent that is cytotoxic to a tumor cell. Such a method includes, for example, applying one of the subject compounds to a tumor cell while the tumor cell is exposed to said cytotoxic agent. The therapeutic effect of a chemotherapeutic or antitumor agent can thus be enhanced. The multidrug resistance of a tumor cell to a cytotoxic agent during chemotherapy can be reduced or eliminated.

 The subject compounds can also be used in a method of treating a disease in which the responsible pathogen is multidrug resistant, especially P-gp-mediated multidrug resistance, for example, multidrug resistant forms of malaria (Plasmodium falciparum), tuberculosis, leishmaniasis and amoebic dysentery. Such a method includes, for example, the use of one of the subject compounds with (separately, simultaneously or sequentially) a drug to which the associated pathogenic microorganism exhibits multiple drug resistance. The therapeutic effect of a drug against a multidrug-resistant pathogen can thus be enhanced.

 A sick person or animal having a tumor may be treated for resistance to a chemotherapeutic agent in a manner comprising administering to it one of the subject compounds. The subject compound is administered in an amount effective to enhance the cytotoxicity of said chemotherapeutic agent. Examples of chemotherapeutic or antitumor agents preferred from the point of view of the present invention include Vinca alkaloids such as vincristine and vinblastine; anthracycline antibiotics such as daunorubicin and doxorubicin; mitoxantrone; actinomycin D; taxanes, for example taxol; epipodophyllotoxins, for example etoposide and plicamycin.

 The subject compounds may also be used in a method for improving the absorption, distribution, metabolism and excretion of a therapeutic agent, which comprises administering to the patient, separately, simultaneously or sequentially, one of the subject compounds and said therapeutic agent. In particular, this method can be used to increase the penetration of a therapeutic agent into the central nervous system or increase the oral absorption of a therapeutic agent.

 For example, the subject compounds can be used in a method of facilitating drug delivery across the blood-brain barrier and in the treatment of AIDS or AIDS-related complex. If necessary, a sick person or animal can be treated using a method comprising administering one of the compounds of interest.

 The subject compounds may be administered in various dosage forms, for example, orally, in the form of tablets, capsules, sugar or coated tablets, liquid solutions or suspensions, or parenterally, for example, intramuscularly, intravenously or subcutaneously. Therefore, the subject compounds may be administered 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, usually the dosage for an adult taken for each route of administration, when administered only to the compound of the invention, is from 0.001 to 50 mg / kg, most often in the range from 0.01 to 5 mg / kg of body weight. So the dose can be administered, for example, from 1 to 5 times daily by bolus infusion, infusion over several hours and / or by repeated administration.

 The anthranilic acid derivative of formula (I) or a pharmaceutically acceptable salt thereof is formulated for use in the form of a pharmaceutical or veterinary composition, which also includes a pharmaceutically or veterinarily acceptable carrier or diluent. The compositions are usually prepared by the following conventional methods and are administered in a pharmaceutically or veterinarily acceptable form. Therefore, it is proposed a tool for use as a modulator of multidrug resistance, including any one of the compounds.

The subject compounds may be administered in any conventional form, for example, as listed below:
A) Orally, for example, in the form of tablets, coated tablets, dragees, troches, lozenges, aqueous or oily suspensions, liquid solutions, dispersible powders or granules, emulsions, hard or soft capsules or syrups or elixirs. Oral formulations may be prepared by any method known in the art for the industrial manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives to obtain pharmaceutically sophisticated and accepted preparations.

 Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the industrial production of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, dextrose, sucrose, cellulose, corn starch, potato starch, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example maize starch, alginic acid, alginates or sodium starch glycolate; binders, for example starch, gelatin or acacia; lubricants, for example silicon dioxide, magnesium or calcium stearate, stearic acid or talc; foaming mixtures; colorants, sweeteners, wetting agents such as lecithin, polysorbates or lauryl sulfate. The tablets may be uncoated, or they may be coated by known methods to slow down digestion and absorption in the gastrointestinal tract and thereby provide a long lasting effect. For example, time-delaying compounds such as glycerol monostearate or glycerol distearate can be used. Such preparations can be prepared by known methods, for example, by mixing, granulating, tabletting, sugar coating or coating.

 Oral formulations may also be hard gelatin capsules, where the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or soft gelatin capsules, where the active ingredient is present as such or mixed with water or an oil medium, for example with peanut butter, liquid paraffin or olive oil.

 Aqueous suspensions contain the active substances in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone tragacanth and gum arabic; dispersing or wetting agents may be naturally occurring phosphatides, for example lecithin, or condensation products of alkylene oxide with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, such as heptadecaethylenoxycetanol, or products of condensation of non-ethylene oxides with fatty acids and hexites, such as polyoxyethylene sorbitol monooleate, or products of the condensation of ethylene oxide with incomplete complex esters derived from fatty acids and hexite anhydrides, for example polyoxyethylene sorbitol monooleate.

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

 Oil suspensions can be formulated by suspending the active ingredient in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain thickening agents, for example beeswax, hard paraffin or cetyl alcohol.

 Sweeteners, such as those mentioned above, flavoring agents, may be added to provide a palatable oral preparation. These compositions may be retained by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for preparing an aqueous suspension by adding water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

 The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin, or mixtures thereof. Suitable emulsifiers can be resins of natural origin, for example, Arabian gum or tragacanth, phosphatides of natural origin, such as soya bean lecithin, and esters or partial esters derived from fatty acids and hexite anhydrides, such as sorbitol monooleate, and condensation products of said partial esters and ethylene oxide, for example, polyoxy ethylene sorbitol monooleate. The emulsion may also contain sweeteners and flavorings. Syrups and elixirs can be formulated with sweeteners, for example glycerin, sorbitol or sucrose. In particular, a syrup for diabetics can contain as carriers only products, for example sorbitol, which are not converted during glucose metabolism or which are converted only in very small amounts during glucose metabolism.

 Such formulations may also contain irritant reducing agents, preservatives and flavorings and colorings.

 C) Parenterally, or subcutaneously, or intravenously, or intramuscularly, or intrasterially, or by infusion methods, in the form of sterile injectable aqueous or oily suspensions. This suspension can be formulated in a known manner using the appropriate dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.

 Suitable excipients and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are generally used as a solvent or suspending medium. For this purpose, any mixed fixed oil may be used including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid, find use in the preparation of injections.

 C By inhalation, in the form of aerosols or spray solutions

 D) Rectally, in the form of suppositories, obtained by mixing the drug with a suitable non-irritant excipient that is solid at ordinary temperature but liquid at rectal temperature and therefore will melt in the rectum, releasing the drug. Such substances are cocoa butter and polyethylene glycols.

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

 Daily doses can vary widely and are selected according to individual requirements in each case. Typically, when administered to adults, a suitable daily dose is in the range of about 5 mg to about 500 mg, although if appropriate, the upper limit may be exceeded.

 The daily dose may be administered as a single dose or in divided doses.

 The invention is further illustrated by the following examples.

EXAMPLE 1
Testing the compounds of formula (I) and their salts as modulators of MDR
Materials and methods
An EMT6 mouse mammary carcinoma cell line and an MDR-resistant subline AR 1.0 are grown in RPMI 1640 medium containing 10% uterine calf serum and 2 mM glutamine, at 37 ^{° C.} in 5% CO ₂ . Cells are passaged between 1 in 200 and 1 in 2000 in the case of the parental cell line and between 1 in 20 and 1 in 200 in the case of the MDR-resistant line, after trypsinization (0.25% trypsin, 0.2 hl ^-1 , EDTA).

1. Test for cumulation of the drug
AR 1.0 cells were seeded 48 hours prior to testing in 96-well opaque culture plates (plates) (Canberra Packard). The test medium contains a mixture of tritium-labeled daunorubicin (DNR) (Dannorubicin) (0.3 μCi / ml), a cytotoxic agent and unlabeled DNR (2 μM). The compounds of formula (I) are successively diluted in a test medium in a concentration range from 0.508 nM to 10 μM. Cells are incubated at 37 ^{° C.} for 1 hour before washing and determining cell-bound radioactivity. The results are expressed as IC ₅₀ for cumulation, where 100% cumulation is that observed in the presence of the known RMA verapamil at a concentration of 100 μM.

 The results are shown in table. A1.

2. Potentiation of doxorubicin toxicity
(a) Selected compounds of formula (I) are tested for their ability to potentiate the toxicity of doxorubicin in AR 1.0 cells. In the initial proliferation tests, the compounds were titrated against a fixed concentration of doxorubicin (0.34 μm), which in itself was not toxic to AR 1.0 cells. After a four-day incubation with doxorubicin, proliferation was measured using a colorimetric test with sulforodamine B (Skehan et al., J. Natl. Cancer Inst. 82, pp. 1107-1112 (1990)). The results are shown in table. IN.

Результаты приведены в табл. С1 и С2.(b) Cells were grown for four days by titration of doxorubicin (0.263 nM - 17.24 μM) in the presence of a fixed concentration of each compound. Proliferation is calculated as described by Skehen et al., Ioc cit. Get IC ₅₀ (the concentration required to reduce proliferation to 50% of the untreated controls) for one doxorubicin and with each compound is used to calculate the potentiation index (PI):

The results are shown in table. C1 and C2.

3. Potentiation of toxicity of various cytotoxic agents
Measured by following the protocol described above for doxorubicin, potentiation indices of compound selection using a number of cell lines and a number of cytotoxic agents other than doxorubicin; the results are shown in table. D.

REFERENCE EXAMPLE 1A
Obtaining amines of General formula IX
Amines of the general formula IX are prepared as shown in Scheme 4 (see end of description) and table. 1.

 The reductive amination of 3,4-dimethoxybenzaldehyde is carried out as described in method 2b (IV) to give an intermediate secondary amine. Alternatively, this amine can be prepared by reacting veratrilamine with methyl chloroformate, followed by reduction of carbamate using lithium aluminum hydride. A mixture of amine (3.76 g), 4-nitroethoxyphenyl bromide (4.78 g) and sodium carbonate (3.3 g) in acetonitrile (25 ml) was heated to reflux for 3 hours. After cooling, treatment with water gives an orange oil (1.75 g). The nitro group is reduced in a hydrogen atmosphere over a catalyst of platinum (IV) dioxide in ethanol to give amine IX.b (1.3 g) (see Scheme 5 at the end of the description).

 A mixture of 4-nitrothiophenol (1.00 g, 6.44 mmol), 1,2-dibromoethane (1.39 ml, 2.5 equivalents) and potassium carbonate (2.22 g, 2.5 equivalents) in acetonitrile (15 ml) was stirred at room temperature for 30 minutes. Water treatment and fractional crystallization gave intermediate bromide (0.8 g, 47%).

 A mixture of bromide (336 mg, 1.28 mmol), 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (294 mg, 1.28 mmol) and potassium carbonate (372 mg, 2.1 equivalents) heated to boiling point under reflux in acetonitrile (10 ml) for 3 hours. Water treatment and flash chromatography (ethyl acetate / hexane) afforded the desired tertiary amine (236 mg, 49%).

Concentrated hydrochloric acid (0.3 ml) was added to a suspension of tertiary amine (236 mg, 0.63 mmol) in methanol (2 ml), iron (151 mg) was added, and the reaction mixture was heated to 80 ^{° C.} for 2 hours. Treatment with water gives amine IX.s in the form of a gum (195 mg, 90%).

Method IX.d
This compound is obtained analogously to method IX.c, using p-nitrophenol as the starting compound.

 The reduction of the nitro group in this case is performed in a hydrogen atmosphere over a catalyst of platinum (IV) dioxide in ethanol (see Scheme 6 at the end of the description).

Sodium carbonate (611 mg, 5.76 mmol) was added to a stirred solution of 1-methyl-6,7-dihydroxy-1,2,3,4-tetra-hydroisoquinoline hydrobromide (1.0 g, 3.84 mmol) in acetone-water mixtures (25 ml, 4: 1). The mixture was cooled to 0 ^{° C.} before adding benzyl chloroformate (0.63 ml, 4.19 mmol). The mixture was allowed to warm to room temperature and stirred for 2 days. The reaction mixture was filtered and separated, and the filtrate was concentrated in vacuo. The resulting aqueous solution was poured into EtOAc (80 ml), and the organic phase was washed with water (3 • 40 ml), then with brine (40 ml), dried (MgSO ₄ ), then concentrated in vacuo to give a brown oil. Purification by flash chromatography (SiO ₂ ; hexane: EtOAc, 1: 1) gives benzyl carbamate (817 mg) as a white foam.

Sodium hydride (60% dispersion; 2.10 g, 0.05 mol) and methyl iodide (27.25 ml, 0.44 mmol) are added to a solution of benzyl carbamate (2.74 g, 8.75 mmol) in THF ( 100 ml). DMSO (50 ml) was then added, and the reaction mixture was heated to reflux overnight. The reaction mixture was poured into EtOAc (200 ml) and water (100 ml). The organic phase is extracted, washed with water (3 x 100 ml) and brine (100 ml), then dried (MgSO ₄ ) to give a brown oil. Purification by flash chromatography (SiO ₂ ; hexane: EtOAc, 2: 1) gives the dimethoxy intermediate (2.7 g) as a yellow crystalline solid.

The benzyl carbamate group is cleaved by dissolving the intermediate (2.7 g, 8.63 mmol) in MeOH / CH ₂ Cl ₂ (1: 1, 270 ml) and reducing with Pd / activated C (700 mg) for 4 days at atmospheric pressure and at 40 psi for another 12 hours. Filtration and concentration in vacuo afforded the crude secondary amine (1.89 g) as an orange oil.

 Then the amine is reacted with 4-nitroethoxyphenyl bromide and reduced by method IX. b, obtaining amine IX.e as an orange solid (see Scheme 7 at the end of the description).

 A mixture of 4-nitroethoxyphenylamine hydrochloride (770 mg, 3.8 mmol), α, α′-dibromo-o-xylene (1.00 g, 3.8 mmol) and potassium carbonate (1.83 g, 13.3 mmol ) heated to boiling temperature under reflux in acetonitrile (20 ml) for 2 hours. Water treatment and flash chromatography (5% methanol in dichloromethane) give the desired tertiary amine (297 mg, 29%).

 The nitro group is reduced using atmospheric hydrogenation over a platinum (IV) dioxide catalyst in a methanol / dichloromethane mixture and purified using flash chromatography (ethyl acetate / hexane) to give amine IX.f (187 mg, 71%) (see Scheme 8 at the end of the description).

A mixture of 3-nitroethoxyphenyl alcohol (2.11 g), methane sulfonyl chloride (2.44 ml, 2.5 equivalents) and triethylamine (1.76 ml, 2 equivalents) in dichloromethane was stirred at 0 ^{° C.} for 4.5 hours . Treatment with water gives the desired mesylate as a yellow solid (2.27 g, 73%).

To a solution of mesylate (2.27 g) in N, N-dimethylformamide (20 ml) was added 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.13 g, 1 equivalent) and potassium carbonate (3.2 g, 2.5 equiv.) And the reaction mixture is heated to 100 ^{° C. for} 4 hours. Treatment with water gives a tertiary amine as a yellow oil (1.49 g, 47%).

 The reduction of the nitro group in this case is carried out in a hydrogen atmosphere over a platinum (IV) dioxide catalyst in ethanol and dichloromethane, which gives IX.g (1.11 g) (see Scheme 9 at the end of the description).

 A mixture of 4-nitrophenol (10 g, 72 mmol), epichlorohydrin (11.2 ml, 144 mmol) and potassium carbonate (10 g, 72 mmol) was stirred in N, N-dimethylformamide at room temperature for 18 hours. Water treatment gives the intermediate epoxide as an off-white crystalline solid (10.8 g, 77%).

 A mixture of epoxide (1.09 g, 5.6 mmol), 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.1 g, 9.3 mmol) and potassium carbonate (1.3 g , 9.3 mmol) in tetrahydrofuran (20 ml) and water (5 ml) was stirred at room temperature for 72 hours. Treatment with water and purification using flash chromatography (ethyl acetate) afforded the target alcohol as a white solid (390 mg, 50%). Hydrogenation of the nitro group is carried out as described in method IX.b, obtaining amine IX.h (see Scheme 10 at the end of the description).

 A solution of 3-methyl-4-nitrobenzoic acid (5.0 g, 0.03 mol) and thionyl chloride (10 ml) in toluene (100 ml) was heated to reflux for 3 hours, then allowed to cool overnight . The reaction mixture was concentrated, then subjected to azeotropic distillation with toluene and hexane to give acid chloride (quantitative yield) as an off-white, low melting solid.

To diazomethane (obtained from N-methyl-N-nitrosotoluene-p-sulfonamide, in excess, as described in Vogel's Practical Organic Chemistry, 4 th edition, p. 293), NEt ₃ (4 ml) was added. The reaction mixture was cooled (ice bath) before slowly adding the acid chloride in Et ₂ O. After 2 hours, acetic acid was added until the evolution of gaseous N ₂ ceased. The reaction mixture was filtered, concentrated in vacuo and the residue was dissolved in Et ₂ O, washed (sat. NH ₄ Cl, aq. K ₂ CO ₃ , brine), dried (Na ₂ SO ₄ ) and concentrated until crystallization started. Before filtering, it is allowed to crystallize in the refrigerator, which gives diazoketone (2.03 g) in the form of light brown crystals.

A solution of diazoketone (2.0 g, 10.0 mmol) in EtOH (13 mmol) is heated to boiling point and a brown solution is obtained, before slowly adding a solution of silver benzoate (125 mg, 0.54 mmol) in NEt ₃ (2 ml) . The mixture turns black and gaseous N _{2 is released} . Additional portions of silver benzoate are added until gas evolution ceases and heating to boiling point is obtained, and a brown solution is obtained before slowly adding a solution of silver benzoate (125 mg, 0.54 mmol) in NEt ₃ (2 ml). The mixture turns black and gaseous N _{2 is released} . Additional portions of silver benzoate are added until gas evolution ceases and heating to reflux is continued for 55 minutes. The reaction mixture was filtered through celite, then concentrated in vacuo to give a brown liquid. Purification by flash chromatography (SiO ₂ ; 5% hexane-EtOAc) afforded the desired ethyl ester (1.46 g) as a yellow liquid. Ethyl ether (1.35 g, 6.05 mmol) was dissolved in 1,4-dioxane (50 ml) and water (20 ml) was added until cloudy. LiOH • H ₂ O (762 mg, 0.017 mol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was acidified with hydrochloric acid, extracted with CH ₂ Cl ₂ (3 • 80 ml), dried (MgSO ₄ ) and concentrated in vacuo to give the desired acid (633 mg) as orange crystals.

A mixture of acid (630 mg, 8.23 mmol) and 1-hydroxybenzotriazole hydrate (546 mg, 4.04 mmol) in DMF (30 mm) was stirred at room temperature for 10 minutes. 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline (780 mg, 4.04 mmol) was added and then dicyclohexylcarbodiimide (667 mg, 3.23 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was filtered, and the filtrate was concentrated in vacuo, treated with dilute hydrochloric acid and then with a dilute sodium hydroxide solution, and extracted into CH ₂ Cl ₂ . The organic phase is washed (water, then brine), dried (Na ₂ SO ₄ ). The solvent was evaporated in vacuo to give a yellow residue. Purification by flash chromatography (SiO ₂ ; hexane-EtOAc, 1: 1) gives the desired amide (760 mg) as an off-white crystalline solid. The nitro group is reduced using the same conditions as described in method IX.b, with Pd / activated C (50 mg). Purification by flash chromatography (SiO ₂ ; hexane-EtOAc, 1: 1) afforded the intermediate amine (695 mg) as a white foam. Amide (730 mg, 2.15 mmol) is reduced by adding a solution in tetrahydrofuran (10 ml) to a stirred suspension of lithium aluminum hydride (244 mg, 6.43 mmol) in THF (5 ml) at room temperature. The reaction mixture was heated to reflux for 2 hours, then cooled before gently adding water (0.5 ml) to CH ₂ Cl ₂ (20 ml). MgSO _{4 was} added and the reaction mixture was stirred for 10 minutes, filtered and the filtrate was evaporated in vacuo to give the desired amine XI.i (661 mg) as an off-white crystalline solid.

Method IX.j
Using 3-methoxy-4-nitrobenzoic acid as the starting material and using a method similar to method IX.i, amine IX.j is obtained (see Scheme 11 at the end of the description).

 A mixture of amine (336 mg, 1.61 mmol), 4-nitrobenzyl bromide (289 mg, 1.34 mmol) and potassium carbonate (277 mg, 2.01 mmol) in acetonitrile (50 ml) was stirred at room temperature for 2.5 hours . Treatment with water gives the desired intermediate product, and the nitro group is then reduced as in method IX. b, obtaining IX.k as a yellow oil (380 mg) (see Scheme 12 at the end of the description).

A mixture of 2- (4-nitrophenyl) propionic acid (5.0 g, 26 mmol) and thionyl chloride (3.75 g, 52 mmol) is heated to reflux in toluene (30 ml) for 2 hours before cooling and removing the solvent in vacuo to give the acid chloride. The acid chloride (5.47 g, 26 mmol) is dissolved in dichloromethane (50 ml) at 0 ^{° C.} and 6.7-dimethoxy-1,2,3,4-tetrahydroisoxinoline (3.7 g, 24 mmol) is added to this solution. and triethylamine (5.4 ml, 39 mmol) and the reaction mixture was stirred for 7 hours. Acid / base treatment and flash chromatography (1% methanol in dichloromethane) give the desired amide (4.98 g, 56%).

 The nitro group is reduced using atmospheric hydrogenation over palladium on carbon, and the amide is reduced to the desired amine IX.1 using lithium aluminum hydride in tetrahydrofuran (see Scheme 13 at the end of the description).

 Isovaniline is alkylated with iodobutane and then reductive amination is carried out as described in method 2b (IV), which gives an intermediate secondary amine. The reaction of this amine with 4-nitroethoxyphenyl bromide in acetonitrile and then hydrogenation of the nitro group in atmospheric hydrogen over a platinum (IV) catalyst give the target amine IX.m (see Scheme 14 at the end of the description).

The mesylate is obtained from 3-nitroethoxyphenyl bromide as in method IX.g. A mixture of mesylate (1.0 g, 4.1 mmol) and sodium cyanide (400 mg, 8.2 mmol) was stirred in dimethyl sulfoxide (25 ml) at 90 ^{° C.} for 7 days. Treatment with water gives the target nitrile (651 mg, 91%).

 Nitrile (615 mg) was heated to reflux in a 1.5 M sodium hydroxide solution (25 ml) for 5 hours. Treatment with water gives an intermediate carboxylic acid (548 mg). This acid is converted to the acid chloride using thionyl chloride in toluene, and then reacted with 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline to give the amide. The amide and nitro group are then reduced in a manner analogous to method IX.i to give amine IX.n. (see diagram 15 at the end of the description).

 A mixture of 3,4-dimethoxybenzoyl chloride (3.9 g, 19.2 mmol) and 7-nitro-1,2,3,4-tetrahydroisoquinoline (2.81 g, 15.8 mmol) in dichloromethane (200 ml) is stirred in for 2 hours and then filtered. The filtrate was collected and, after treatment with water and flash chromatography (1-10% methanol in dichloromethane), the desired amide was obtained as a yellow oil (3.25 g, 46%). Then, the nitro group and amide are reduced analogously to method IX.i. Amine IX.o is obtained as a yellow oil (1.37 g) (see Scheme 16 at the end of the description).

 4-Nitroethoxyphenylamine hydrochloride and 3,4-dimethoxybenzaldehyde are stirred in methanol with triethylamine for 3 hours. Hexane is then added to precipitate the desired imine, which is collected by filtration. The imine is reduced to an intermediate secondary amine using sodium borohydride in methanol, and this amine is then alkylated by heating under reflux for 16 hours with 2-iodopropane and potassium carbonate in acetonitrile. Hydrogenation of the nitro group using palladium on carbon in a hydrogen atmosphere gives amine IX.p in the form of a yellow gum.

REFERENCE EXAMPLE 1B
Obtaining amines of General formula IX '
Amines of the general formula IX 'are prepared as shown in table. 2.

 Preparation of 3- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) propylamine (IX'd) (see Scheme 17 at the end of the description).

A mixture of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (5 g, 20 mmol), 3-chloropropionitrile (1.96 g, 20 mmol) and potassium carbonate (9 g, 60 mmol) in DMF (100 ml) is heated at 100 ^o C for 4 hours. Concentration in vacuo, followed by treatment and concentration, afforded the intermediate nitrile as a pale yellow solid (3.68 g).

To a solution of intermediate nitrile (600 mg, 2.44 mmol) in tetrahydrofuran (5 ml) was added a suspension of lithium aluminum hydride (280 mg, 7.32 mmol) in tetrahydrofuran (25 ml) at 0 ^{° C.} under a nitrogen atmosphere. The reaction mixture was stirred for 30 minutes and then left to warm to room temperature for 12 hours. The reaction was quenched by the slow addition of water (0.28 ml), NaOH (2H, 0.28 ml) and water (0.9 ml). The mixture was dried over magnesium sulfate and filtered. The organic layer was concentrated in vacuo to give the title compound IX'.d as a yellow oil (510 mg).

REFERENCE EXAMPLE 2A
Obtaining 2-nitrobenzamides of the General formula V (see scheme 18 at the end of the description).

 A mixture of 4,5-dimethoxy-2-nitrobenzoic acid (7.0 g, 0.031 mol) and thionyl chloride (4.5 ml, 2 equivalents) was heated to reflux in toluene (140 ml) for 2 hours. After cooling, the solvent was removed in vacuo to give the acid chloride as a yellow solid (quantitative yield).

 A mixture of acid chloride (851 mg), amine IX.m (1.09 g) and triethylamine (1 equivalent) in dichloromethane (18 ml) was stirred for 18 hours at room temperature. Treatment with water and flash chromatography (ethyl acetate) give the desired 2-nitrobenzamide V.13 as a white solid (737 mg).

 Using a similar synthesis method and using a suitably substituted nitrobenzoic acid or nitrobenzoyl chloride and amine IX, the following are obtained. 3 nitro compounds of formula V.

 In a variant of the above scheme, 2-nitro-5-halogenbenzamide, such as V.16 or V.26, can be converted to another compound of formula V by substituting the halide with a suitable nucleophile, such as an amine or thiol, in a suitable solvent, such as N, N-dimethylformamide or acetonitrile (see Scheme 19 at the end of the description).

 To a solution of V.16 (200 mg, 0.42 mmol) in N, N-dimethylformamide (2 ml) was added sodium thiomethylate (50 mg, 0.72 mmol), and the reaction mixture was stirred at room temperature for 72 hours. The mixture was then diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, and the solvent was removed in vacuo to give V.18 as a yellow solid (190 mg, 89%).

 Nitrobenzamide V.17 is obtained by heating to a boiling point under reflux a mixture of V.26 in acetonitrile with excess dimethylamine (40% aqueous solution) for 8 hours (see Scheme 20 at the end of the description).

REFERENCE EXAMPLE 2B
Obtaining 2-nitrobenzamides of General formula VI '
N- {4- [2- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} -2-nitro-4-trifluoromethylbenzamide (VI'.24) (see diagram 21 at the end of the description).

A mixture of 2-nitro-α, α, α-trifluoro-p-toluic acid (0.25 g, 1.06 mmol), thionyl chloride (0.5 ml) and toluene (5.0 ml) is heated to reflux refrigerator for 4 hours. The solution was concentrated in vacuo and azeotroped with toluene to give crude acid chloride. This acid chloride was added to a solution of amine IX'.b (0.28 g, 0.88 mmol) and triethylamine (0.18 ml, 1.33 mule) in anhydrous CH ₂ Cl ₂ (10 ml) and stirred at room temperature 24 hours. After appropriate treatment, trituration with diethyl ether, compound VI'.24 is obtained in the form of an off-white powder (0.44 g).

 Using a similar synthesis method and using the corresponding nitrobenzoic acid V 'and amine IX', the following are obtained. 4 nitro compounds of formula VI '.

REFERENCE EXAMPLE 3A
Obtaining 2-aminobenzamides of the general formula VI from the corresponding nitro compounds (see Scheme 22 at the end of the description).

A solution of V.12 (140 mg, 0.30 mmol) in ethanol (5 ml) and CH ₂ Cl ₂ (5 ml) was purged with nitrogen and a suspension of platinum (IV) oxide (30 mg) was added. The mixture was stirred in hydrogen at atmospheric pressure for 2 hours, filtered through celite ^™ and concentrated in vacuo to afford VI.12 as a white foam (126 mg, 96%).

 Using similar methods, receive aminobenzamide VI, listed in table. 5.

 Alternatively, for sulfur-containing compounds, the following method can be used (see Scheme 23 at the end of the description).

Concentrated hydrochloric acid (140 μl) was added to a solution of nitrobenzamide, V. 3 (147 mg, 0.30 mmol) in methanol (2 ml). Iron (72 mg) was added and the reaction mixture was heated to 80 ^{° C.} for 2 hours and then cooled. The reaction mixture was made basic (saturated sodium carbonate), extracted into ethyl acetate, dried over magnesium sulfate and the solvent removed in vacuo to give an off-white solid, which was purified using flash chromatography (ethyl acetate) to obtain the desired 2-aminobenzamide, VI. 3 (47 mg, 34%).

 Using a similar method, get 2-aminobenzamide (see scheme 24 at the end of the description).

REFERENCE EXAMPLE 3B
Obtaining 2-aminobenzamides of the general formula VIII 'from the corresponding nitro compounds
2-amino-N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide (VIII'.23) (see Scheme 25 in end of description).

A solution of VI'.23 (12 g, 0.026 mmol) in ethanol (200 ml) and CH ₂ Cl ₂ (160 ml) was purged with nitrogen and a suspension of platinum (IV) oxide was added. The mixture was stirred in hydrogen at atmospheric pressure for 4 hours, filtered through celite ^™ and concentrated in vacuo. Recrystallization from methanol gave white crystals VIII'.23 (9.6 g).

 Using similar methods, receive aminobenzamide VIII ', are listed in table. 6.

REFERENCE EXAMPLE 4A
Obtaining 2-aminobenzamides of the general formula VI from the corresponding anthranilic acids (see Scheme 26 at the end of the description).

A solution of 3-aminopyrazine-2-carboxylic acid (500 mg, 3.60 mmol), amine IX. a (1.12 g, 3.60 mmol), N-cyclohexyl-N- (2-morpholinoethyl) carbodiimide-methyl-p-toluene sulfonate (1.68 g, 3.96 mmol), 1-hydroxybenzotriazole (486 mg, 3.6 mmol) and triethylamine (501 μl, 3.60 mmol) in anhydrous CH ₂ Cl ₂ (30 ml) was stirred at room temperature for 5 days. Subsequent treatment with water and recrystallization from ethyl acetate gave the title compound VI.19 as a pale yellow solid (733 mg).

 Using methods similar to the above, get aminobenzamides listed in table. 7.

REFERENCE EXAMPLE 4B
Preparation of 2-aminobenzamides of general formula VIII ′ from the corresponding anthranilic acids
2-amino-N- {4- [2- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} -5-methylbenzamide (VIII'.12) ( see diagram 27 at the end of the description).

A solution of 2-amino-5-methyl-benzoic acid (190 mg, 0.96 mmol), amine IX '. b (300 mg, 0.96 mmol), N-cyclohexyl-N- (2-morpholinoethyl) carbodiimide-methyl-p-toluene sulfonate (449 mg, 1.06 mmol) and 1-hydroxybenzotriazole (143 mg, 1, 06 mmol) in anhydrous CH ₂ Cl ₂ (10 ml) was stirred at room temperature for 48 hours. Subsequent treatment and flash chromatography on silica gel in methanol: ethyl acetate (2:98) afforded the title compound VIII'.12 as a pale yellow solid (58 mg).

 2-amino-N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] -4-fluoro-benzamide (VIII'.07) (see Scheme 28 in end of description).

To a stirred solution of N-cyclohexyl-N- (2-morpholinoethyl) carbodiimide-methyl-p-toluene sulfonate (238 mg, 0.56 mmol) and 1-hydroxybenzotriazole (76 mg, 0.56 mmol) in anhydrous CH ₂ C1 ₂ (10 ml) add 2-amino-4-fluorobenzoic acid (80 mg, 0.52 mmol), followed by triethylamine (0.08 ml, 0.57 mmol) and amine IX'.a (200 mg, 0, 51 mmol). The mixture was stirred at room temperature for 48 hours. Treatment and flash chromatography on silica gel in methanol: dichloromethane (5:95) gave aminobenzamide VIII'.07 as a yellow solid (57 mg).

 Using methods similar to the two described above, get listed in table. 8 aminobenzamides.

REFERENCE EXAMPLE 5
Obtaining 2-aminoamides of General formula VI from the corresponding complex 2-amino ester VII (see scheme 29 at the end of the description).

 To a solution of methyl 3-amino-2-thiophene-carboxylate (7.56 g, 48.1 mmol) in dichloromethane (40 ml) was added a solution of di-tert-butyl dicarbonate (11.55 g, 52 mmol) in dichloromethane (10 ml) and then 4-dimethylaminopyridine (600 mg, 4.8 mmol). After stirring for 4 hours at room temperature, the reaction 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 using flash chromatography (10% ethyl acetate in hexane) to give the desired tert-butyl carbamate (4.40 g, 36%).

 To a solution of tert-butyl carbamate (1.01 g, 3.95 mmol) in tetrahydrofuran (4 ml) and methanol (8 ml) was added a solution of sodium hydroxide (316 mg, 7.9 mmol) in water (4 ml). After stirring for 18 hours at room temperature, the mixture was acidified to pH 4, extracted into ethyl acetate, dried over magnesium sulfate, and the solvent was removed in vacuo to give the desired acid as a white solid (800 mg, 83%).

 A mixture of a carboxylic acid intermediate (150 mg, 0.62 mmol), N-cyclohexyl-N- (2-morpholinoethyl) carbodiimide-methyl-p-toluene sulfonate (288 mg, 0.68 mmol), 1-hydroxybenzotriazole (92 mg, 0.68 mmol) and IX.a (175 mg, 0.56 mmol) in dry dichloromethane (8 ml) were stirred at room temperature for 3 days. The reaction mixture was then diluted with dichloromethane, washed with water and a saturated sodium carbonate solution, dried over magnesium sulfate and the solvent was removed in vacuo to give a yellow gum which was purified using flash chromatography (silica, ethyl acetate) to give the desired amide as a white foam (112 mg, 33%).

 Anhydrous gaseous hydrogen chloride was bubbled through a suspension of amide (202 mg, 0.38 mmol) in 1,4-dioxane for 10 seconds, and the reaction mixture was stirred for 1 hour. Then the reaction mixture was made basic (sodium carbonate) and extracted into ethyl acetate, dried over magnesium sulfate and the solvent was removed in vacuo to give aminoamide VI.20 as a white solid (151 mg, 91%).

 Using similar methods, aminoamides are obtained (see table. 9).

К горячему раствору 2-хлор-3-хинолинкарбоксальдегида (500 мг, 2,61 ммоль) в трет-бутаноле (7 мл) и воде (12 мл) добавляют по каплям в течение 15 минут горячий раствор перманганата калия (580 мг, 3,67 ммоль) в воде (15 мл). После перемешивания в течение 1 часа при температуре кипения с обратным холодильником, реакционной смеси дают охладиться и MnO₂-осадок отфильтровывают и промывают водой и трет-бутанолом. рН фильтрата доводят до рН 5, используя 2Н раствор соляной кислоты, и затем экстрагируют хлороформом, сушат над сульфатом магния, и растворитель удаляют в вакууме, получая кислоту в виде желтого твердого продукта (210 мг, 39%).REFERENCE EXAMPLE 6A
Obtaining commercially available acids of the General formula

A hot solution of potassium permanganate (580 mg, 3, 67 mmol) in water (15 ml). After stirring for 1 hour at the boiling temperature under reflux, the reaction mixture was allowed to cool and the MnO ₂ precipitate was filtered off and washed with water and tert-butanol. The filtrate was adjusted to pH 5 using a 2N hydrochloric acid solution, and then extracted with chloroform, dried over magnesium sulfate, and the solvent was removed in vacuo to give the acid as a yellow solid (210 mg, 39%).

 The target acid can alternatively be prepared by alkaline hydrolysis using sodium or lithium hydroxide from an appropriate ester such as 2-methyl-thiazole-4-carboxylic acid ethyl ester or 4-hydroxy-quinoline-3-carboxylic acid ethyl ester in a suitable solvent, such as 1,4-dioxane or methanol.

REFERENCE EXAMPLE 6B
Obtaining acids of the General formula R ⁵¹ -CO ₂ N
(I) 4-cyclohexyloxybenzoic acid (see Scheme 30 at the end of the description).

Potassium carbonate (2.26 g, 16.4 mmol) is added to a solution of methyl 4-hydroxybenzoate (1.0 g, 6.6 mmol) and cyclohexyl bromide (1.62 ml, 13.1 mmol) in dimethylformamide (20 ml). The mixture was heated at 100 ^{° C.} for 24 hours, cooled, filtered and concentrated in vacuo. Processing followed by chromatography on silica gel (hexane: ethyl acetate 5: 1) gives methyl 4-cyclohexyl benzoate (169 mg). This product was dissolved (162 mg, 0.69 mmol) in a mixture of 1,4-dioxane (10 ml) and water (5 ml) and lithium hydroxide monohydrate (32 mg, 0.76 mmol) was added. The mixture was stirred at room temperature for 18 hours. Additional lithium hydroxide (32 mg) was added and stirring was continued for 4 hours. The mixture was added to ethyl acetate, washed with brine and concentrated to give the title compound as a yellow solid (27 mg).

К раствору 6-метокси-3-пиридинкарбоксальдегида (50 мг, 0,36 ммоль), полученного по способу Comins and Killpack (J. Org. Chem., 1990, 55, 69-73), в трет-бутаноле (0,5 мл) добавляют раствор перманганата калия (81 мг) в воде (1,0 мл). Смесь перемешивают при комнатной температуре два часа и затем добавляют насыщенный раствор сульфита натрия до исчезновения пурпурового цвета. Реакционную смесь экстрагируют хлороформом несколько раз, когда она постепенно подкисляется разбавленной НСl (2 н.). Экстракты хлороформа концентрируют в вакууме, получая указанное в заглавии соединение (42 мг) в виде белого твердого вещества.(II) 6-methoxy-3-pyridinecarboxylic acid

To a solution of 6-methoxy-3-pyridinecarboxaldehyde (50 mg, 0.36 mmol) obtained by the method of Comins and Killpack (J. Org. Chem., 1990, 55, 69-73) in tert-butanol (0.5 ml) add a solution of potassium permanganate (81 mg) in water (1.0 ml). The mixture was stirred at room temperature for two hours, and then a saturated solution of sodium sulfite was added until the purple color disappeared. The reaction mixture was extracted with chloroform several times when it was gradually acidified with dilute HCl (2N). The chloroform extracts were concentrated in vacuo to give the title compound (42 mg) as a white solid.

Гидроперекись трет-бутила (70%, 1,0 мл, 7,25 ммоль) и раствор FeSO₄•7H₂O (3,02 г, 10,9 ммоль) в воде (8 мл) добавляют одновременно к раствору метил-2-пиразин-карбоксилата (250 мг, 1,81 ммоль) и пропиональдегида (0,78 мл, 0,9 ммоль) в H₂SO₄ (0,75 мл) при 0^oС. Реакционной смеси дают нагреться до комнатной температуры и перемешивают 2 часа. Добавляют твердый Na₂S₂O₅ (до отрицательного теста крахмал/йодид), и смесь экстрагируют дихлорметаном. Концентрация в вакууме и флэш-колоночная хроматография на силикагеле в этилацетате: гексане (15:85) дают метил-5-пропионил-2-пиразинкарбоксилат в виде бледно-желтого твердого вещества (106 мг). Метиловый эфир обрабатывают LiOH (25 мг, 0,6 ммоль) в тетрагидрофуране (15 мл) и воде (0,5 мл). Через 2 часа при комнатной температуре смесь подкисляют НСl (2 н.). Обработка с последующей концентрацией органической фазы в вакууме дают указанное в заглавии соединение (92 мг).(III) 5-Propionylpyrazinecarboxylic acid

Tert-butyl hydroperoxide (70%, 1.0 ml, 7.25 mmol) and a solution of FeSO ₄ • 7H ₂ O (3.02 g, 10.9 mmol) in water (8 ml) are added simultaneously to a solution of methyl-2 pyrazine carboxylate (250 mg, 1.81 mmol) and propionaldehyde (0.78 ml, 0.9 mmol) in H ₂ SO ₄ (0.75 ml) at 0 ^° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. Solid Na ₂ S ₂ O _{5 was} added (starch / iodide was negative) and the mixture was extracted with dichloromethane. Concentration in vacuo and flash column chromatography on silica gel in ethyl acetate: hexane (15:85) gave methyl 5-propionyl-2-pyrazinecarboxylate as a pale yellow solid (106 mg). Methyl ether is treated with LiOH (25 mg, 0.6 mmol) in tetrahydrofuran (15 ml) and water (0.5 ml). After 2 hours at room temperature, the mixture was acidified with HCl (2 N). Work-up followed by concentration of the organic phase in vacuo afforded the title compound (92 mg).

Смесь 3-хинолинкарбоновой кислоты (1,73 г, 10,0 ммоль) в трифторуксусной кислоте (20 мл) с двуокисью платины (200 мг) встряхивают в аппарате Парра при 10-15 фунт/кв. дюйм. Спустя 90 минут реакционную смесь фильтруют, и растворитель удаляют в вакууме, получая масло. Масло добавляют по каплям в диэтиловый эфир, получая белый твердый продукт, который собирают фильтрацией и затем перекристаллизовывают из этилацетат/гексана, получая указанное в заглавии соединение в виде белого твердого вещества (770 мг).(IV) 5,6,7,8-tetrahydroquinoline-3-carboxylic acid

A mixture of 3-quinoline carboxylic acid (1.73 g, 10.0 mmol) in trifluoroacetic acid (20 ml) with platinum dioxide (200 mg) was shaken in a Parr apparatus at 10-15 psi. inch. After 90 minutes, the reaction mixture was filtered, and the solvent was removed in vacuo to give an oil. The oil was added dropwise to diethyl ether to give a white solid, which was collected by filtration and then recrystallized from ethyl acetate / hexane to give the title compound as a white solid (770 mg).

EXAMPLE 2
Obtaining compounds of formula (I) according to a variant of the method (a)
Method A 9616 (see scheme 31 at the end of the description).

 A mixture of 3-quinoline carboxylic acid (500 mg, 2.89 mmol), thionyl chloride (0.42 ml, 5.8 mmol) and toluene (15 ml) was heated to reflux for two hours. The mixture was cooled and the solvent was removed in vacuo to give the acid chloride as a white solid.

 To a solution of amine VI.22 (67 mg, 0.15 mmol) in anhydrous dichloromethane (2 ml) was added acid chloride (41 mg, 1.4 equivalents) while cooling in an ice / water bath. The resulting solution was allowed to warm to room temperature and then stirred for 18 hours. The reaction mixture was diluted with dichloromethane (30 ml), washed with saturated sodium bicarbonate solution (2 • 20 ml), dried over magnesium sulfate and the solvent was removed in vacuo to give a solid product, which was purified using flash chromatography (silica gel, ethyl acetate) to obtain 9616 as a white solid (39 mg, 44%).

When the acid chloride, R ⁹ —COCl, is commercially available, it is directly purchased. Other compounds obtained in a similar manner are listed in table. eleven.

 Method B 9653 (see diagram 32 at the end of the description).

 A solution of amine VI.7 (165 mg), 5-methylpyrazine-carboxylic acid (63 mg, 1.2 equivalents), cyclohexyl-N- (2-morpholinoethyl) carbodiimide-methyl-p-toluene-sulfonate (162 mg, 1, 0 equivalent) and 1-hydroxybenzotriazole monohydrate (51 mg, 1.0 equivalent) in dry dichloromethane (15 ml) was stirred at room temperature for 18 hours. The reaction mixture was then diluted with dichloromethane, washed with water and a saturated solution of sodium carbonate, dried over magnesium sulfate and the solvent was removed in vacuo to give a solid product which was purified by flash chromatography (silica gel, ethyl acetate) to give 9653 as a white solid (31 mg )

 Other compounds obtained in a similar manner are listed in table. 10.

 Method C 9617 (see scheme 33 at the end of the description).

 To a solution of 6-methyl-nicotinic acid (21 mg, 0.15 mmol) and amine VI.22 (50 mg, 0.11 mmol) in anhydrous dichloromethane (2 ml) was added 2-chloro-1-methylpyridinium iodide (41 mg, 0.15 mmol). The mixture was stirred at room temperature for 7 days. A saturated solution of sodium carbonate (15 ml) was added and the mixture was extracted twice with dichloromethane (30 ml). The combined organic layers are dried over dry magnesium sulfate and concentrated in vacuo. Flash chromatography on silica gel (ethyl acetate) gives 9617 (11 mg, 18%) as a white solid.

 Other compounds obtained in a similar manner are listed in table. 10.

REFERENCE EXAMPLE 7
Synthesis of Intermediate Bromide of Formula XII
The bromide of formula XIIa is prepared according to Scheme 34 (see end of description).

To an ice cold solution of 7a, 4-nitrofeniletilovogo alcohol (5.0 g, 29.9 mol) and imidazole (2.25 g, 32.9 mmol) in CH ₂ Cl ₂ (200 mL) was added dimethylhexylsilyl chloride (6 5 ml, 33.2 mmol). The reaction mixture was stirred at room temperature for 16 hours, then diluted with Et ₂ O (200 ml). The ether solution is washed with water (200 ml), 2 N. HCl (200 ml) and brine (200 ml) were dried (MgSO ₄ ) and the solvent was removed under reduced pressure to give compound 7b (10 g) as a yellow liquid.

7c
To a solution of 7b (10 g, 32.6 mmol) in EtOH (250 ml) was added PtO ₂ (400 mg), after which gaseous H _{2 was} passed. The reaction mixture was vigorously stirred for 3 days, filtered through celite, and the solvent was removed under reduced pressure to give compound 7c (9.88 g) as a yellow liquid.

7d
To a cooled solution of 7c (8.78 g, 31.75 mmol) and 2-nitrobenzoyl chloride (7.1 g, 38.11 mmol) in CH ₂ Cl ₂ (40 ml), NEt ₃ (6.6 ml, 47, 64 mmol) and the reaction mixture was allowed to warm to room temperature. After 16 hours, the reaction mixture was washed with water (40 ml) and the washings were extracted again with CH ₂ Cl ₂ (2 • 40 ml). The combined organic phase was dried (MgSO ₄ ), and the solvent was removed under reduced pressure to obtain a brown gummy solid. This solid was stirred in hexane for 2 hours to give a white solid, which was filtered and then dissolved in CH ₂ Cl ₂ and filtered through a pad of flash silica gel. The solvent was removed under reduced pressure to give compound 7d (6 g) as a white solid.

7e
7d (5.0 g, 11.7 mmol) was reduced as described for 7c reduction using EtOH (100 ml) and PtO ₂ (200 mg). Compound 7e (4.42 g) was obtained as a peach colored solid.

7f
To a solution of 7e (4.75 g, 11.9 mmol) and 3-quinolinecarbonyl chloride (2.7 g, 14.3 mmol) in CH ₂ Cl ₂ (70 ml) was added NEt ₃ (2.5 ml, 17.9 mmol). The reaction mixture was stirred at room temperature for 16 hours, then poured into a dilute solution of sodium carbonate (70 ml). The layers were separated, the organic layer was washed with water and then dried (MgSO ₄ ). The solvent was removed under reduced pressure to give compound 7f (4.9 g) as an off-white solid.

7g
To a solution of 7f (4.78 g, 8.64 mmol) in THF (100 ml) was added tetrabutylammonium fluoride (1 M in THF; 19.2 ml, 17.28 mmol) at room temperature, and the solution was allowed to mix for 4 of the day. The solvent was removed under reduced pressure, and the residue was dissolved in EtOAc (100 ml), after which sufficient water was added to obtain a precipitate. The precipitate was filtered off and washed with water, then Et ₂ O. The residue was azeotroped with toluene and dried in vacuo to give compound 7g (3 g) as a cream-colored solid.

XIIa
To a solution of 7g (3.0 g, 7.29 mmol) and triphenylphosphine (3.8 g, 14.58 mmol) in DMF (25 ml) was added N-bromosuccinimide (2.6 g, 14.58 mmol). The reaction mixture was heated at 50 ^{° C.} for 16 hours, then cooled, after which MeOH (5 ml) was added. After 5 minutes, Et ₂ O was added until a precipitate appeared. The precipitate was filtered off and washed with Et ₂ O. The residue was dried in vacuo to give compound XIIa (2.13 g) as an off-white solid.

EXAMPLE 3
Obtaining compounds of formula (I) according to a variant of the method (b) (see scheme 35 at the end of the description).

 A mixture of 3a (I) (68 mg, 0.35 mmol), which is a compound of formula XX, and obtained as described below, XIIa (166 mg, 0.35 mmol), potassium carbonate (72 mg, 0.52 mmol) and tetrabutylammonium iodide (0.1 equivalent) in N, N-dimethylformamide (3 ml) was stirred at room temperature for 4 days. The reaction mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was removed in vacuo to give a brown gum. Flash chromatography (silica gel, ethyl acetate) and recrystallization (methanol / dichloromethane) give 9630 as a white solid (43 mg, 21%).

 Using similar methods, the following compounds of formula (I) are prepared (see Table 10A).

 Method 3a (I) (see scheme 36 at the end of the description).

A solution of triethylamine (7.2 ml, 0.052 mol) and homoveratrylamine (1.92 ml, 0.011 mol) in dichloromethane (10 ml) was added to a solution of methyl chloroformate (8 ml, 0.103 mol) in dichloromethane (50 ml) and cooled to -78 ^o C. The reaction mixture was warmed to room temperature and stirred for 18 hours. The mixture was then poured into a saturated sodium carbonate solution, extracted with dichloromethane, dried over magnesium sulfate and the solvent was removed in vacuo to give a yellow oil, which was purified using flash chromatography (1% methanol in ethyl acetate) to give methyl carbamate (2.06 g , 78%).

A solution of methyl carbamate (2.0 g, 8.37 mmol) in tetrahydrofuran (60 ml) was added dropwise to a suspension of lithium aluminum hydride (1.59 g, 41.9 mmol) in tetrahydrofuran (60 ml) and cooled to 0 ^° C. the mixture was allowed to warm to room temperature and stirred for 18 hours. Water (2.2 ml) was added to the reaction mixture, followed by 2N. sodium hydroxide solution, additional water (2.2 ml) and magnesium sulfate. After stirring for 15 minutes, the mixture was filtered and the filtrate was concentrated in vacuo to give 3a (I) as a yellow oil (1.61 g, 99%).

 Method 3a (II) (see scheme 37 at the end of the description).

 A mixture of 3,4-dimethylbenzoic acid (3.5 g, 23.33 mmol) and thionyl chloride (3.5 ml, 46.7 mmol) is heated to reflux in toluene for 2 hours, then cooled and removed solvent in vacuo to give the crude acid chloride as an oil. The acid chloride was dissolved in dichloromethane (50 ml) and 40% methylamine in water (18 ml, 10 equivalents) was added under ice-cooling. After stirring for 48 hours, treatment with water gives a yellow solid, which is purified using flash chromatography (silica; ethyl acetate / hexane) to give the desired amide as a white solid (1.84 g, 49%).

 To a solution of amide (1.00 g, 6.13 mmol) in dry tetrahydrofuran (20 ml) was added lithium aluminum hydride (698 mg, 2 equivalents), and the reaction mixture was heated to reflux for 3 hours. After cooling and water treatment, a pale oil is obtained, which is purified using flash chromatography (silica, ethyl acetate) to give 3a (II) as a colorless oil (175 mg, 19%).

 Method 3a (III) (see scheme 38 at the end of the description).

To concentrated sulfuric acid (80 ml), cooled to 0 ^° C., 1,2,3,4-tetrahydroisoquinoline (20.2 ml, 161 mmol) was added dropwise. Potassium nitrate (17.5 g, 173 mmol) is carefully added in portions. After stirring for 16 hours, the reaction mixture was made basic with a concentrated solution of ammonium hydroxide, extracted with chloroform, dried over magnesium sulfate and the solvent was removed in vacuo to give a brown oil. This oil was dissolved in ethanol (120 ml) and concentrated hydrochloric acid was added, and the resulting precipitate was collected by filtration and recrystallized from methanol to give 3a (III) hydrochloride salt (11.2 g, 33%).

Methods 3a (IV), 3a (VI), 3a (VII), 3a (IX), 3a (X), 3a (XII), 3a (XIII) and 3a (XIV)
All amines 3a (IV), 3a (VI), 3a (VII), 3a (IX), 3a (X), 3a (XII), 3a (XIII) and 3a (XIV) are obtained by reductive amination from the corresponding aromatic aldehyde. The method includes reacting the aldehyde with an amine, such as methylamine, ethylamine or butylamine, in a suitable solvent, such as methanol or toluene. The resulting imine is reduced to the desired amine using hydrogenation over a platinum (IV) dioxide catalyst in a suitable solvent such as ethanol, or using lithium aluminum hydride in tetrahydrofuran.

 Method 3a (V) (see scheme 39 at the end of the description).

 A mixture of 3-hydroxy-4-methoxybenzaldehyde (1.00 g, 6.57 mmol), 2-iodopropane (0.79 ml, 1.2 equivalents) and potassium carbonate (1.09 g, 1.2 equivalents) is heated to boiling temperature under reflux in acetonitrile for 5 hours. Treatment with water gives the desired intermediate aldehyde. Reductive amination, as described in method 3a (IV), gives the desired amine 3a (V). Amines 3a (VIII) and 3a (XI) are obtained in a similar manner using the appropriate commercially available aldehyde and reacting with an alkylating agent such as 1-iodobutane or 2-iodopropane, and then reductive amination to the target amine.

 Method 3a (XV) (see diagram 40 at the end of the description).

 A solution of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (5.0 g, 22 mmol) in an excess of a mixture of 48% hydrobromic acid (80 ml) and 50% hypophosphoric acid (0.4 ml ) heated to boiling temperature under reflux for 4 hours. The cooled reaction mixture was filtered and washed with methanol and diethyl ether to give the desired dihydroxylated compound as a white solid (4.75 g, 88%). To a solution of this substance (4.75 g) in a 4: 1 acetone: water mixture was added sodium carbonate (3.07 g), and the mixture was cooled in an ice bath. Then benzyl chloroformate (3.06 ml) was added and the reaction mixture was stirred for 18 hours, after which it was filtered. The filtrate was collected and treated with water, followed by flash chromatography (hexane / ethyl acetate) and trituration with diethyl ether to give benzyl carbamate (3.6 g, 62%).

To a solution of benzyl carbamate (1 g, 3.34 mmol) in N, N-dimethylformamide (50 ml) was added dibromomethane (0.28 ml, 3.99 mmol) and potassium carbonate (2.75 g, 19.7 mmol), and the mixture is heated to 100 ^{° C.} for 1.5 hours. After cooling and filtering, the filtrate was collected and treatment with water and flash chromatography (hexane 5: 1 ethyl acetate) gave the desired 1,3-dioxolane (669 mg, 64%).

 Atmospheric hydrogenation over palladium on carbon in a methanol / dichloromethane mixture cleaves benzyl carbamate to give the desired amine 3a (XV).

 Method 3a (XVI) (see scheme 41 at the end of the description).

 To a solution of benzyl carbamate intermediate (obtained above) (500 mg, 1.67 mmol) in tetrahydrofuran (10 ml), sodium hydride (60% dispersion in mineral oil, 385 mg, 10.03 mmol), iodoethane (6.6 ml, 83.6 mmol) and dimethyl sulfoxide (5 ml). The reaction mixture was heated to reflux for 18 hours. After treatment with water and double flash chromatography (hexane 5: 1 ethyl acetate), a yellow oil is obtained (549 mg, 92%). Benzyl carbamate is cleaved as described above to give amine 3a (XVI).

EXAMPLE 4
Obtaining compounds of formula Ia by combining an amine of formula VIII ′ with an activated acid of formula R ⁵¹ CO ₂ H (process variant (a ′))
Method A (see Scheme 42 at the end of the description).

(2- {4- [2- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) quinoline-3-carboxylic acid amide (9544)
A mixture of 3-quinoline carboxylic acid (4.0 g, 0.023 mol), thionyl chloride (3.4 ml, 0.046 mol) and toluene (100 ml) was heated to reflux for two hours. The mixture was cooled, concentrated in vacuo and triturated with hexane to give crude acid chloride (4.15 g) as a white solid. To a suspension of acid chloride (2.64 g, 14.0 mmol) in anhydrous dichloromethane (100 ml) amine VIII.23 (4.0 g, 9.3 mmol) was added while cooling in an ice / water bath. The resulting solution was allowed to warm to room temperature and then stirred for another hour. A diluted potassium carbonate solution (100 ml) was added and the mixture was extracted three times with chloroform. The combined organic layers are dried over dry magnesium sulfate and evaporated before crystallization begins. An equal volume of diethyl ether was added and the mixture was allowed to crystallize to give 9544 as a white solid (5.4 g).

Other compounds obtained in a similar manner are listed in table. 11. When the acid chloride, R ⁵¹ -COCl, is commercially available, it is directly purchased.

Method B
(2- {4- [2- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) furan-3-carboxylic acid amide (9526) (see chart 43 at the end of the description).

 Solution of 3-furancarboxylic acid (19 mg, 0.17 mmol), amine VIII'.23 (75 mg, 0.17 mmol), cyclohexyl-N- (2-morpholinoethyl) carbodiimide-methyl-p-toluene-sulfonate (79 mg, 0.19 mmol) and 1-hydroxybenzotriazole monohydrate (25 mg, 0.19 mmol) in dry dichloromethane (5.0 ml) was stirred at room temperature for 18 hours. Saturated brine was added and the mixture was extracted twice with dichloromethane (25 ml). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on silica gel (2% methanol, 98% ethyl acetate) followed by recrystallization from ethyl acetate gives the title compound 9526 (18 mg) as a yellow crystalline solid. Other compounds obtained in a similar manner are listed in table. eleven.

Method C
N- (2- {4- [2- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) -6-methyl-nicotinamyl (9557) (see diagram 44 at the end of the description).

 To a solution of 6-methylnicotinic acid (47 mg, 0.34 mmol) and amine VIII '. 23 (75 mg, 0.17 mmol) in anhydrous dichloromethane (5.0 ml) add triethylamine (0.05 ml, 0.34 mmol) and then 2-chloro-1-methylpyridinium-iodide (44 mg, 0.17 mmol). The mixture was stirred at room temperature for 5 days. A saturated solution of sodium carbonate (15 ml) was added and the mixture was extracted twice with dichloromethane (30 ml). The combined organic layers are dried over dry magnesium sulfate and concentrated in vacuo. Flash chromatography on silica gel (2% methanol, 98% ethyl acetate) followed by trituration with diethyl ether afforded the title compound (9557) (8 mg) as a white solid.

Method D
2- (4-Isopropyl-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] -3-methylbenzamide (9398) (see diagram 45 at the end of the description).

 Thionyl chloride (5 ml) is added to a suspension of 4-isopropylbenzoic acid (5.0 g, 0.03 mol) in toluene (50 ml) and then dimethylformamide (1 drop). The mixture was heated to reflux for 2 hours, cooled and concentrated in vacuo to give crude acid chloride (5.5 g) as a yellow oil. This acid chloride (68 mg, 0.37 mmol) was added to the amine VIII ′ mixture. 08 (110 mg, 0.3 mmol) and 2 M sodium hydroxide solution while cooling in an ice / water bath. The mixture was allowed to warm to room temperature and stirred vigorously for 5 hours. The mixture was extracted twice with ethyl acetate (15 ml), once with brine (15 ml), dried over magnesium sulfate and concentrated in vacuo. Flash chromatography (2% methanol / 98% dichloromethane) on silica gel followed by trituration with diethyl ether gave 9398 (16 mg) as a white solid. Recrystallization of sludge from mother liquors gives a second portion of the title compound (15 mg). Other compounds obtained in a similar manner are listed in table. eleven.

EXAMPLE 5
Interconversion of compounds of formula Ia:
Compounds of formula (I) prepared as described in Example 4 are converted to other compounds of formula (Ia) as described below.

 (I) 2- (2-Hydroxybenzoylamino) -N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl] benzamide (9535) (see diagram 46 at the end of the description).

 To a solution of 9534 (0.035 g, 0.06 mmol) in methanol (2 ml) was added sodium hydroxide (3 mg, 0.077 mmol) in water (0.5 ml). The mixture was stirred at room temperature for 2 hours and then, while heating to reflux for another 3 hours. An additional portion of sodium hydroxide (0.18 mmol) was added and heating was continued to reflux for three hours. The mixture was cooled, acidified (2 M HCl) and slightly alkalinized with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (2 x 25 ml), washed with brine (30 ml). The organic phases are dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography (silica gel, ethyl acetate) gives 9535 as a white solid (19 mg, 58%). Other compounds obtained in a similar manner are 9549 of 9540 and 9559 of 9548.

 (II) 2- (4-Isopropyl-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro -1H-isoquinolin-2-yl) ethyl] -5-phenylbenzamide (9432) (see diagram 47 at the end of the description).

 Phenylboronic acid (5 mg, 0.038 mmol) and tetrakis (triphenylphosphine) palladium (2 mg, 0.00173 mmol) in a mixture of ethylene glycol dimethyl ether (0.5 ml) and a solution are added to a solution of 9394 (20 mg, 0.035 mmol). sodium carbonate (2 M, 0.04 ml, 0.08 mmol). The mixture is heated under reflux for 3.5 hours. The mixture was cooled and water (10 ml) was added. The mixture was extracted with ethyl acetate (2 • 15 ml), washed with water (20 ml) and dried over magnesium sulfate. Filtration and concentration in vacuo followed by chromatography (silica gel, ethyl acetate) give 9432 (15 mg, 75%).

 (III) 2- (4-Isopropyl-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] -4-amino-benzamide (9435) (see diagram 48 at the end of the description).

 Platinum (IV) oxide (5 mg) was added to a solution of 9420 (47 mg, 0.086 mmol) in methanol (2 ml) and ethyl acetate (2 ml), and the mixture was stirred under hydrogen gas at atmospheric pressure for 18 hours. The mixture was filtered through silica gel (10% methanol, 90% ethyl acetate) and concentrated in vacuo to give 9435 (42 mg, 95%) as a yellow powder.

 (IV) (2- {4- [2- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} -5-hydroxyamino-phenyl) quinoxaline-2-carbonic amide acids (9542) (see Scheme 49 at the end of the description).

 Platinum (IV) oxide (4 mg) was added to a solution of 9541 (38 mg) in ethanol (25 ml) and dichloromethane (25 ml), and the mixture was stirred under hydrogen gas at atmospheric pressure for 18 hours. The mixture was filtered through silica gel and concentrated in vacuo. Triturated with ethyl acetate (x1) then diethyl ether (x3) to give 9542 (29 mg, 80%) as a yellow solid.

EXAMPLE 6
Obtaining compounds of formula (Ia) using protective groups
(a) 2- (4-Isopropyl-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] -3-hydroxybenzamide (9424) receive as shown in scheme 50 (see the end of the description).

Stage (I)
A solution of commercially available 3-hydroxyanthranilic acid (324 mg, 2.12 mmol), amine IX'a (500 mg, 2.12 mmol), N-cyclohexyl-N- (2-morpholinoethyl) carbodiimide-methyl-p-toluene -sulfonate (987 mg, 2.33 mmol), 1-hydroxybenzo-triazole monohydrate (315 mg, 2.33 mmol) and triethylamine (0.32 ml, 2.44 mmol) in anhydrous dichloromethane (20 ml) are stirred at room temperature for 3 days. Treatment with water followed by flash chromatography (2% methanol, 98% dichloromethane, silica gel) and trituration (diethyl ether) gave VIII'.29 (174 mg) as an orange solid.

Stage (II)
Solution VIII '. 29 (170 mg, 0.46 mmol), imidazole (34 mg, 0.50 mmol) and tert-butyldimethylsilyl chloride (76 mg, 0.50 mmol) in dimethylformamide (10 ml) were stirred at room temperature for 3 days . Additional tert-butyldimethylsilyl chloride (206 mg, 1.37 mmol) and imidazole (93 mg, 1.37 mmol) were added and the mixture was stirred for 4 hours. Treatment with water followed by flash chromatography (2% methanol, 98% ethyl acetate, silica gel) gave VIII'.30 (142 mg) as a yellow oil.

Stage (III)
Triethylamine (1.12 ml, 8.04 mmol) and amine VIII'.30 (1.57 g, 3.24 mmol) are added to the stirred solution of 4-isopropylbenzoyl chloride (preparation method as described for 9398, 738 mg, 4 , 04 mmol) in anhydrous dichloromethane (20 ml) while cooling in an ice / water bath. The mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was poured into a saturated solution of sodium carbonate (50 ml) and extracted twice with dichloromethane (75 ml). The combined organic extracts were dried over dry magnesium sulfate and concentrated in vacuo. Flash chromatography (2% methanol, 98% ethyl acetate, silica gel) gives 2- (4-isopropyl-benzoylamino) -3- (tert-butyl-dimethyl-silanyloxy) -N- [2- (6,7-dimethoxy-1 , 2,3,4-tetra-hydronaphthalen-2-yl) ethyl] benzamide (367 mg) as a cream-colored solid.

Stage (IV)
A solution of tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 0.63 ml, 0.63 mmol) is added to a solution of 2- (4-isopropyl-benzoylamino) -3- (tert-butyl-dimethyl-silanyloxy) -N- [2- (6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl) ethyl] benzamide (365 mg, 0.58 mmol) in tetrahydrofuran (20 ml) while cooling in an ice / water bath. After stirring for 30 minutes, the mixture was poured into a saturated solution of ammonium chloride (30 ml) and extracted twice with ethyl acetate (50 ml). The combined organic layers were washed with water (50 ml), brine (50 ml), dried over dry magnesium sulfate and concentrated in vacuo. Flash chromatography (2% methanol, 98% ethyl acetate, silica gel) affords 9424 (220 mg) as a pale yellow solid.

 (b) (2- {4- [2- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} -4-hydroxyphenyl) quinoxaline-2-carbonic amide acids (9554) are prepared as shown in Scheme 51 (see end of description).

Stage (I)
Imidazole (1.8 g, 26.1 mmol) and tert-butyldimethylsilyl chloride (3.95 g, 26.1 mmol) are added to a solution of commercially available 5-hydroxyanthranilic acid (1.0 g, 6.54 mmol) in dimethylformamide (40 ml) while cooling in an ice / water bath. The mixture was allowed to warm to room temperature and stirred for 18 hours. Treatment with water gives a crude sample of 2-amino-5- (tert-butyl-dimethyl-silanyloxy) benzoic acid (1.74 g), which is used in step (II) without further purification.

Stage (II)
2-amino-5- (tert-butyl-dimethyl-silanyloxy) benzoic acid from step (I) (1.6 g), amine IX'.b (1.87 g, 6.0 mmol), N-cyclohexyl- N- (2-morpholinoethyl) carbodiimide methyl p-toluene sulfonate (2.79 g, 6.6 mmol) and 1-hydroxybenzotriazole monohydrate (0.89 g, 6.6 mmol) are dissolved in anhydrous dichloromethane (50 ml) and stirred at room temperature for 3 days. Treatment with water followed by flash chromatography (silica gel) gave VIII'.31 (443 mg) as a yellow foam.

Stage (III)
2-Quinoxaloyl chloride (67 mg, 0.35 mmol) was added to the amine VIII ′ solution. 31 (20 mg, 0.28 mmol) and triethylamine (0.10 ml, 0.72 mmol) in anhydrous dichloromethane (10 ml) while cooling in an ice / water bath. The mixture was allowed to warm to room temperature and stirred for 18 hours. Treatment with water and flash chromatography (silica gel, 2% methanol, 98% ethyl acetate) gives (4- (tert-butyldimethylsilanyloxy) -2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H- isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) quinoxaline-2-carboxylic acid amide (183 mg) as a yellow foam.

Stage (IV)
A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 0.067 ml, 0.067 mmol) is added to a solution of (4- (tert-butyldimethylsilanyloxy) -2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H -isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) quinoxaline-2-carboxylic acid amide (150 mg, 0.21 mmol) in tetrahydrofuran (10 ml) under cooling in an ice / water bath. The mixture was stirred for 30 minutes, poured into a saturated solution of ammonium chloride (20 ml) and extracted twice with ethyl acetate (30 ml). The combined organic phases are washed with water (30 ml), brine (30 ml), dried over dry magnesium sulfate and concentrated in vacuo. Flash chromatography (silica gel, 2% methanol, 98% ethyl acetate) and trituration with diethyl ether gave 9554 (32 mg) as a yellow solid.

 (c) (5-amino-2- {4- [2- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) quinoline-3-carboxylic acid amide (9589) receive as shown in scheme 52 (see the end of the description).

Stage (I)
A solution of 4-amino-2-nitrobenzoic acid (0.96 g, 5.3 mmol), amine IX '. b (1.65 g, 5.3 mmol), hydroxybenzotriazole monohydrate (0.79 g, 5.8 mmol), N-cyclohexyl-N- (2-mor-folinoethyl) carbodiimide-methyl-p-toluene sulfonate (2.46 g, 5.8 mmol) in anhydrous dichloromethane (15 ml) was stirred at 20-25 ^{° C.} for 18 hours. Water (15 ml) was added and the mixture was extracted three times with dichloromethane (15 ml). The combined organic extracts were dried over dry magnesium sulfate and concentrated in vacuo. Trituration with diethyl ether and flash chromatography (10% methanol, 90% dichloromethane) give the intermediate nitroamine (0.42 g) as a solid orange.

Stage (II)
A solution of the product of stage (I) (0.42 g, 0.88 mmol), di-tert-butyl dicarbonate (0.24 g, 1.10 mmol) and N, N-dimethyl-aminopyridine (5 mg, 0, 04 mmol) in anhydrous dichloromethane (15 ml) was stirred in an ice / water bath for one hour, allowed to warm to room temperature and stirred for another three days. Potassium carbonate solution (15 ml) was added and the mixture was extracted three times with dichloromethane (15 ml). The combined organic layers are dried over magnesium sulfate and in vacuo. Chromatography (2.5% methanol, 97.5% dichloromethane, silica gel) gives the intermediate protected nitroamine (0.37 g).

Stage (III)
To a solution of this product (0.35 g, 0.61 mmol) in ethanol (5 ml) and dichloromethane (5 ml) was added 10% palladium on carbon (35 mg). The mixture was stirred under gaseous hydrogen at atmospheric pressure for eighteen hours. The mixture is filtered through celite ^™ and concentrated until crystallization begins. After cooling, the product, amine VIII'.32 (0.19 g), is isolated as a yellow crystalline solid.

Stage (IV)
Amin VIII '. 32 (192 mg, 0.35 mmol) was added to a suspension of quinoline-3-carboxylic acid chloride (82 mg, 0.43 mmol) in anhydrous dichloromethane (3 ml) while cooling in an ice / water bath. The resulting solution was stirred for one hour, allowed to warm to room temperature and stirred for an additional eighteen hours. A dilute potassium carbonate solution (30 ml) was added and the mixture was extracted with chloroform (30 ml). The organic phase is washed four times with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. Trituration with dry diethyl ether and recrystallization (methanol, dichloromethane) give the product Boc-protected 9589 as a cream-colored solid (0.19 g).

Stage (V)
A solution of the above compound (78 mg, 0.11 mmol) was stirred in a mixture of 5 N. hydrochloric acid (20 ml) and ethanol (25 ml) for three days. The mixture was made basic with saturated potassium carbonate solution and extracted three times with dichloromethane (50 ml). The combined organic phases are dried over dry magnesium sulfate and concentrated in vacuo. Flash chromatography (2.5% methanol, 97.5% dichloromethane) and recrystallization from methanol / dichloromethane afforded the title compound 9589 as a light brown solid (15 mg).

EXAMPLE 7
Obtaining compounds of formula Ia obtained from methyl anthranilate (process variant (b '))
A method for producing compounds of formula (Ia) through an intermediate of formula XII ′ is shown in Scheme 53 (see end of description).

The reaction of commercially available methyl anthranilate X 'with an acid chloride of formula R ⁵¹ -COCl in the presence of triethylamine using dichloromethane as solvent, at room temperature, for 1-14 hours, gives an intermediate product of general formula XI'. The hydrolysis of intermediate ester XI 'is carried out by treating it with sodium hydroxide in methanol / water while heating to reflux for 1-5 hours. Acidification of the HCl mixture followed by treatment gives intermediate acid XII ′.

 The final product of formula Ia is prepared by combining this acid with amine IX '. a. 1,1-carbonyldiimidazole (1.1 equivalents) was added to a solution of the intermediate acid in THF, and the mixture was stirred for one hour at room temperature. Amine IX'.a (1.0 equivalent) and pyridinium-p-toluene sulfonate (2.6 equivalents) were added to this mixture. The resulting mixture was heated under reflux for 56 hours and cooled. After removal of solvent and processing, the product was purified by flash chromatography on silica gel. Obtained by this General method of connection are summarized in table. 12.

EXAMPLE 8
Obtaining compounds of formula Ia through azalactones of general formula XIII ′ (process variant (c ′)) (see Scheme 54 at the end of the description).

The reaction of commercially available anthranilic acid with an acid chloride of the general formula R ⁵¹ —COCl in pyridine or in a pyridine / dichloromethane mixture at 0 ^{° C.} for 3-8 hours gives the possibility of preparing azalactone intermediates of the formula XIII ′. Treatment of this intermediate with amine IX ′. and when heated to reflux in toluene in the presence of p-toluenesulfonic acid or camphorsulfonic acid for 14-24 hours, it leads to compounds of the general formula Ia. The final products are purified by flash chromatography on silica gel. In this way, the following compounds of formula Ia are obtained (see Scheme 55 at the end of the description).

EXAMPLE 9
Salt production
Hydrochloride salts of the compounds of formula (I) are obtained by treating a solution of the compounds in THF with 2 molar hydrochloric acid, followed by sonication to obtain a clear solution. Then, the solvent was removed in vacuo, and the residual solution was freeze dried to give a hydrochloride salt.

 According to an alternative method, hydrogen chloride salts are obtained by bubbling gaseous HCl through a solution of the corresponding free base in THF, followed by evaporation to dryness.

EXAMPLE 10
Pharmaceutical composition
Tablets, each weighing 0.15 g and containing 25 mg of the compound of the invention, can be prepared as follows:
Composition for 10,000 tablets
The compound according to the invention - 250 g
Lactose - 800 g
Corn Starch - 415 g
Talc Powder - 30 g
Magnesium Stearate - 5 g
The compound of the invention, lactose and half of corn starch are mixed. The mixture is then passed through a sieve with an opening size of 0.5 mm. Corn starch (10 g) is suspended in warm water (90 ml). The resulting paste is used to granulate the powder. The granules are dried and crushed into small pieces on a sieve with a hole size of 1.4 mm. The remaining amount of starch, talc and magnesium stearate is added, gently mixed and formed into tablets.

EXAMPLE 11
Studies of compounds of formula (I)
The compounds obtained in examples 2-9 are investigated by mass spectroscopy, microanalysis, proton NMR and, in some cases, infrared spectroscopy. The results are shown in table. 13 and 14.

Claims (17)

1. Derivatives of anthranilic acid of the formula I

where each of R, R ¹ and R ² that are the same or different, is H, C ₁ -C ₆ -alkyl, OH, C ₁ -C ₆ -alkoxy, halogen, nitro or N (R ¹⁰ R ¹¹ ), where each of R ¹⁰ and R ¹¹ that are the same or different, denotes H or C ₁ -C ₆ -alkyl, or R ¹ and R ² , being attached to adjacent positions of the cycle

together form a methylenedioxy or ethylenedioxy group;
R ³ is H or C ₁ -C ₆ alkyl;
R ⁴ is C ₁ -C ₆ alkyl or R ⁴ is —CH ₂ - or —CH ₂ CH ₂ -, which is attached either (I) to position 2 of the ring

completing a saturated 5- or 6-membered nitrogen-containing ring fused ring

, or (II) to position in the cycle

adjacent to the one to which X is bonded, which is a single bond, thereby completing a saturated 5- or 6-membered nitrogen-containing ring fused to the ring

;
R ⁵ is H, OH or C ₁ -C ₆ alkyl;
X is a single bond, O, S, or —O— (CH ₂ ) _p -, where p is an integer from 1 to 6;
R ⁶ is H, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy;
q is 0 or 1;
Ar is a phenyl, naphthyl or heterocyclic group which represents a 5- or 6-membered heterocyclic ring containing S, or a 6-membered heterocyclic ring containing N;
each of R ⁷ and R ⁸ , which are the same or different, is H, unsubstituted or substituted C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxy, halogen, phenyl, -NHOH, nitro, the above-defined group N (R ¹⁰ R ¹¹ ) or an SR ¹² group, where R ¹² is H or C ₁ -C ₆ alkyl; or R ⁷ and R ⁸ , when located on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a benzene ring or methylenedioxy substituent;
R ⁹ is a phenyl or unsaturated heterocyclic group which represents a 5- or 6-membered heterocyclic ring containing 1 or 2 of O, N or S, each of which is unsubstituted or substituted with C ₁ -C ₆ alkyl, OH, C ₁ - With _6- alkoxy, halogen, C ₃ -C ₆ -cycloalkyl, phenyl, benzyl, trifluoromethyl, nitro, acetyl, benzoyl or N (R ¹⁰ R ¹¹ ) as defined above, or two substituents at adjacent positions of the ring of said phenyl or heterocyclic group together complete a saturated or unsaturated 6-membered cycle;
n is 0 or 1;
m is 0 or an integer from 1 to 3,
or their pharmaceutically acceptable salts. 2. The compound according to claim 1, having the following structure A:

where (a) each of R, R ¹ and R ² that are the same or different is H, OH, NO ₂ , N (R ¹⁰ R ¹¹ ), halogen or C ₂ -C ₆ alkoxy, or R is H and R ¹ and R ² form, together with the carbon atoms to which they are bonded, a methylenedioxy or ethylenedioxy group, provided that all R, R ¹ and R ² are not H and each of R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , Ar, X and m have the meanings defined in paragraph 1, or (b) each of R, R ¹ and R ² that are the same or different, denotes H or OMe and each of R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , Ar, X, and m are as defined in claim 1. 3. The compound according to claim 1, having the following structure B:

where R, R ¹ -R ³ , R ⁵ -R ⁹ , Ar and n have the meanings indicated in paragraph 1. 4. The compound according to claim 1, having the following structure C:

where R, R ¹ -R ³ , R ⁵ -R ⁹ , Ar, X and m are as defined in paragraph 1. 5. The compound according to claim 1, having the following structure D:

where R, R ¹ -R ⁹ , Ar, m and n are as defined above for formula I;
X in position 3 or 4 of the cycle

has the meanings indicated in paragraph 1. 6. The compound according to claim 1, having the formula Ia

where R ¹¹ and R ²¹ , which may be the same or different, each represents hydrogen or methoxy;
R ³¹ and R ⁴¹ , which may be the same or different, are each independently selected from H, CH ₃ , CF ₃ , F, Cl, Br, NH ₂ , NO ₂ , NHOH, methoxy, hydroxy and phenyl; or R ³¹ and R ⁴¹ , when located on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a benzene ring or methylenedioxy substituent;
R ⁵¹ is 2-furanyl, 3-furanyl, 2-thiophene, 3-thiophene, 2-indolyl or 2-benzofuranyl or a cycle of one of the following formulas II ′, III ′ or IV ′:

where R ⁶¹ and R ⁷¹ , which may be the same or different, are selected from hydrogen, linear or branched C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, phenyl, benzyl, trifluoromethyl, F, Cl, Br, OR ¹² , NO ₂ , dimethylamino, diethylamino, acetyl and benzoyl, or R ⁶¹ and R ⁷¹ , when located on adjacent carbon atoms, form, together with the carbon atoms to which they are attached, a benzene ring or methylenedioxy substituent;
R ⁸¹ and R ⁹¹ , which may be the same or different, each represents hydrogen, methyl or methoxy, or R ⁸¹ and R ⁹¹ , when located on adjacent carbon atoms, form, together with the pyridine to which they are attached, a quinoline or 5.6 , 7,8-tetrahydroquinoline ring system;
R ¹⁰¹ and R ¹¹¹ , which may be the same or different, each represents hydrogen, methyl or propionyl; or R ¹⁰¹ and R ¹¹¹ , when located on adjacent carbon atoms, form, together with the carbon atoms to which they are attached, a benzene ring;
R ¹²¹ is H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, phenyl, benzyl or acetyl;
r is 0 or 1;
s is 1, 2 or 3,
or a pharmaceutically acceptable salt thereof. 7. The compound according to claim 6, where in the formula Ia r is 1, s is 2, R ¹¹ and R ^{21 are} both methoxy and R ⁵¹ is a 2-quinoxalo group, 3-quinoline group, 2-pyrazine group or 3-pyridine group, all of these the groups are unsubstituted or substituted. 8. The compound according to claim 1, which represents:
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) 2-chloro-quinolin-3-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) 4-hydroxy-7-trifluoromethyl-quinoline-3-carboxylic amide acids
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} thiophen-3-yl) quinoline-3-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} -4-dimethylamino-phenyl) quinoline-3-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} -4-dimethylaminophenyl) quinoxaline-2-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} thiophen-3-yl) quinoxaline-2-carboxylic acid amide,
(3- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} pyridin-2-yl) quinoxaline-2-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) 4-hydroxy-quinolin-3-carboxylic acid amide,
(3- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} -4-methylthiophen-2-yl) quinoxaline-2- amide carboxylic acid
(3- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} -4-methylthiophen-2-yl) quinolin-3- amide carboxylic acid
[2- (4- {2 - [(3,4-dimethoxy-benzyl) methyl-amino] ethyl} phenylcarbamoyl) phenyl] quinoxaline-2-carboxylic acid amide,
[2- (4- {2 - [(3,4-dimethoxy-benzyl) methyl-amino] ethyl} phenylcarbamoyl) phenyl] quinoline-3-carboxylic acid amide,
{2- [2-3,4-dimethoxy-benzyl) -1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl] phenyl} quinoxaline-2-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} -4-methylsulfanyl-phenyl) quinoline-3-carboxylic acid amide,
(4- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} thiophen-3-yl) quinoline-3-carboxylic acid amide,
N- (4- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} thiophen-3-yl) -6-methyl-nicotinamide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl sulfanyl] phenylcarbamoyl} phenyl) quinoline-3-carboxylic acid amide,
(3- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} pyrazin-2-yl) quinoline-3-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethoxy] phenylcarbamoyl} phenyl) quinoline-3-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) quinoline-3-carboxylic acid amide,
(2- {4- [2- (1,3-dihydro-isoindol-2-yl) ethyl] phenylcarbamoyl} phenyl) quinoline-3-carboxylic acid amide,
(2- {4- [2- (6,7-dichloro-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) quinoline-3-carboxylic acid amide,
(2- {4- [2- (7,8-dichloro-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) quinoline-3-carboxylic acid amide,
{2- [4- (2- {[2- (3,4-dimethoxy-phenyl) ethyl] methylamino} ethyl) phenylcarbamoyl] phenyl} quinoline-3-carboxylic acid amide,
[2- (4- {2 - [(3,4-dimethyl-benzyl) methyl-amino] ethyl} phenylcarbamoyl) phenyl] quinoline-3-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethoxy] phenylcarbamoyl} phenyl) quinoxaline-2-carboxylic acid amide,
(2- {3- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) quinoline-3-carboxylic acid amide,
(2- {4- [2- (7-nitro-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) quinoline-3-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) amide 2-methylthiazole-4-carboxylic acid,
[2- (4- {2 - [(3,4-dimethoxy-benzyl) ethyl-amino] ethyl} phenylcarbamoyl} phenyl] quinoline-3-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) 2-methyl-oxazole-4-carboxylic acid amide,
[2- (4- {2 - [(3-isopropoxy-4-methoxybenzyl) methyl-amino] ethyl} phenylcarbamoyl) phenyl] quinoline-3-carboxylic acid amide,
[2- (4- {2- {methyl- (3,4,5-trimethoxybenzyl) amino] ethyl} phenylcarbamoyl) phenyl] quinoline-3-carboxylic acid amide,
[2- (4- {2- [Butyl- (3,4-dimethoxy-benzyl) amino] ethyl} phenylcarbamoyl) phenyl] quinoline-3-carboxylic acid amide,
[2- (4- {2 - [(4-butoxy-3-methoxy-benzyl) methyl-amino] ethyl} phenylcarbamoyl) phenyl] quinoline-3-carboxylic acid amide,
[2- (4- {2 - [(3,4-difluoro-benzyl) methyl-amino] ethyl} phenylcarbamoyl) phenyl] quinoline-3-carboxylic acid amide,
[2- (4- {2 - [(2,3-dihydro-benzo [1,4] dioxin-6-ylmethyl) methyl-amino] ethyl} phenylcarbamoyl) phenyl] quinoline-3-carboxylic acid amide,
[2- (4- {2 - [(4-isopropoxy-3-methoxy-benzyl) methyl-amino] ethyl} phenylcarbamoyl) phenyl] quinoline-3-carboxylic acid amide,
[2- (4- {2 - [(3-hydroxy-4-methoxy-benzyl) methyl-amino] ethyl} phenylcarbamoyl) phenyl] quinoline-3-carboxylic acid amide,
(2- {4- [3- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) -2-hydroxy-propoxy] phenylcarbamoyl} phenyl) amine quinoline-3-carboxylic acid,
(2- (4- {2 - [(4-hydroxy-3-methoxy-benzyl) methyl-amino] ethyl} phenylcarbamoyl) phenyl] quinoline-3-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] -2-methyl-phenylcarbamoyl} phenyl) quinoline-3-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] -2-methoxy-phenylcarbamoyl} phenyl) quinoline-3-carboxylic acid amide,
[2- (4- {[(3-isopropoxy-4-methoxybenzyl) methylamino] methyl} phenylcarbamoyl) phenyl] quinoline-3-carboxylic acid amide,
(2- {3- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) 5-methylpyrazine-2-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) -1-methyl-ethyl] phenylcarbamoyl} phenyl) quinoline-3-carboxylic acid amide,
[2- (4- {2 - [(4-dimethylamino-benzyl) methyl-amino] ethyl} phenylcarbamoyl) phenyl] quinoline-3-carboxylic acid amide,
[2- (4- {2 - [(3-butoxy-4-methoxy-benzyl) methyl-amino] ethyl} -phenylcarbamoyl) -4,5-dimethoxy-phenyl] quinoline-3-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] -2-methoxy-phenylcarbamoyl} phenyl) amide 5-methyl-pyrazin-2- carboxylic acid
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] -2-methyl-phenylcarbamiol} phenyl) pyrazine-2-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] -2-methoxy-phenylcarbamoyl} phenyl) pyrazine-2-carboxylic acid amide,
(2- {3- [3- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) propyl] phenylcarbamoyl} phenyl) quinoline-3-carboxylic acid amide,
N- [2- (4- {[(3-isopropoxy-4-methoxy-benzyl) methyl-amino] methyl} phenylcarbamoyl) phenyl] nicotinamide,
[5-chloro-2- (4- {2 - [(3,4-dimethoxy-benzyl) methyl-amino] ethyl} phenylcarbamoyl) phenyl] quinoline-3-carboxylic acid amide,
(2- {4- [2- (7,8-dihydro-5H- [1,3] dioxolo [4,5-q] isoquinolin-6-yl) ethyl] phenylcarbamoyl} phenyl) quinoline-3-carboxylic acid amide ,
(2- {4- [2- (6,7-diethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) quinoline-3-carboxylic acid amide,
(6- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} thieno [2,3-b] pyrazin-7-yl) amine quinoline -3-carboxylic acid,
[2- (4- {2 - [(3,4-dimethoxy-benzyl) methyl-amino] ethyl} phenylcarbamoyl) -4,5-difluoro-phenyl] quinoline-3-carboxylic acid amide,
[2- (4- {2 - [(3,4-dimethoxy-benzyl) methyl-amino] ethyl} phenylcarbamoyl) -5-methyl-phenyl] quinoline-3-carboxylic acid amide;
[2- (4- {2 - [(3,4-dimethoxy-benzyl) isopropyl-amino] ethyl} -phenylcarbamoyl) phenyl] quinoline-3-carboxylic acid amide,
[2- (4- {2 - [(3,4-dimethoxy-benzyl) methyl-amino] ethyl} phenylcarbamoyl) -5-nitro-phenyl] quinoline-3-carboxylic acid amide,
2- (4-isopropyl-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] benzamide,
2- (4-isopropyl-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] -6-chloro-benzamide,
2- (4-isopropyl-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] -5-chloro-benzamide,
2- (4-isopropyl-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] -4-chloro-benzamide,
2- (4-isopropyl-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] -3-chloro-benzamide,
2- (4-isopropyl-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] -5-bromo-benzamide,
2- (4-isopropyl-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] -4-fluoro-benzamide,
2- (4-isopropyl-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] -3-methylbenzamide,
2- (4-isopropyl-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] -3-methoxy-benzamide,
2- (4-isopropyl-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] -3-hydroxybenzamide,
2- (4-isopropyl-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] -4-nitro-benzamide,
2- (4-isopropyl-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] -4-amino-benzamide,
2- (4-isopropyl-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] -5-phenylbenzamide,
[2- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] amide 3- (4-isopropyl-benzoylamino) naphthalene-2-carboxylic acid,
2- (4-dimethylamino-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] benzamide,
2- (4-propyl-benzoylamino) -H- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] benzamide,
2- (4-pentyl-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] benzamide,
2- (4-cyclohexyl-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] benzamide,
{2- [2- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethylcarbamoyl] phenyl} diphenyl-4-carboxylic acid amide,
{2- [2- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethylcarbamoyl] phenyl} naphthalene-2-carboxylic acid amide,
{2- [2- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethylcarbamoyl] phenyl} benzo [1,3] dioxol-5-carboxylic acid amide,
2- (4-diethylamino-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] benzamide,
2- (4-tert-butyl-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] benzamide,
2-benzoylamino-N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] benzamide,
2- (4-bromo-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] benzamide,
2- (4-nitro-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] benzamide,
2- (4-phenoxy-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] benzamide,
2- (4-benzoyl-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] benzamide,
2- (4-benzyl-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] benzamide,
2- (4-cyclohexyloxybenzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] benzamide,
2- (4-benzyloxy-benzoylamino) -N- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] benzamide,
Pyridine-2-carboxylic acid {2- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethylcarbamoyl] phenyl} amide
N- {2- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethylcarbamoyl] phenyl} nicotinamide,
N- {2- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethylcarbamoyl] phenyl} isonicotinamide,
{2- [2- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethylcarbamoyl] phenyl} pyrazine-2-carboxylic acid amide,
{2- [2- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethylcarbamoyl] phenyl} quinoxaline-2-carboxylic acid amide,
{2- [2- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethylcarbamoyl] phenyl} isoquinoline-1-carboxylic acid amide,
{2- [2- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethylcarbamoyl] phenyl} quinoline-2-carboxylic acid amide,
{2- [2- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethylcarbamoyl] phenyl} isoquinoline-3-carboxylic acid amide,
{2- [2- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethylcarbamoyl] phenyl} quinoline-3-carboxylic acid amide,
{2- [2- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethylcarbamoyl] phenyl} thiophene-3-carboxylic acid amide,
{2- [2- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethylcarbamoyl] phenyl} 1H-indole-2-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl} quinoxaline-2-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} -5-hydroxyaminophenyl) quinoxaline-2-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} -4-methyl-phenyl) quinoxaline-2-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} -4-hydroxyphenyl) quinoxaline-2-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} -5-nitro-phenyl) quinoxaline-2-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} -5-trifluoromethyl-phenyl) quinoxaline-2-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} -5-fluoro-phenyl) quinoxaline-2-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} -3-fluoro-phenyl) quinoxaline-2-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} -4-fluoro-phenyl) quinoxaline-2-carboxylic acid amide;
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} -4,5-dimethoxy-phenyl) quinoxaline-2-carboxylic acid amide ,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) quinoline-3-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} -5-fluoro-phenyl) quinoline-3-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} -4-fluoro-phenyl) quinoline-3-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} -4,5-dimethoxy-phenyl) quinoline-3-carboxylic acid amide ;
(6- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} benzo [1,3] dioxol-5-yl) quinolin-3 amide -carboxylic acid
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} -5-nitro-phenyl) quinoline-3-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} -4-methyl-phenyl) quinoline-3-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} -5-methyl-phenyl) quinoline-3-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} -4-chloro-phenyl) quinoline-3-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} -5-chloro-phenyl) quinoline-3-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} -5-amino-phenyl) quinoline-3-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) quinoline-2-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) amide 5,6,7,8-tetrahydroquinoline-3-carbon acids
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) pyridine-2-carboxylic acid amide,
N- (2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) nicotinamide,
N- (2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) isonicotinamide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) pyrazine-2-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) 5-methyl-pyrazine-2-carboxylic acid amide,
N- (2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl phenylcarbamoyl} phenyl) -6-methyl-nicotinamide,
H- (2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) -6-methoxy-nicotinamide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) 5-propionyl-pyrazine-2-carboxylic acid amide,
2-benzoylamino-N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide,
2-benzoylamino-N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} -5-methylbenzamide,
2-benzoylamino-N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} -4-methylbenzamide,
2-benzoylamino-N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} -6-methylbenzamide,
2- (2-fluoro-benzoylamino) -N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide,
2- (3-fluoro-benzoylamino) -N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide,
2- (4-fluoro-benzoylamino) -N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide,
2- (2,4-difluoro-benzoylamino) -N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide,
2- (2,6-difluoro-benzoylamino) -N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide,
2- (2-chloro-benzoylamino) -N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide,
2- (3-chloro-benzoylamino) -N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide,
2- (4-chloro-benzoylamino) -N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide,
2- (2-methyl-benzoylamino) -N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide,
2- (3-methyl-benzoylamino) -N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide,
2- (4-methyl-benzoylamino) -N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide,
2- (2-methoxy-benzoylamino) -N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide,
2- (3-methoxy-benzoylamino) -N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide,
2- (4-methoxy-benzoylamino) -N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide,
2- (2-hydroxy-benzoylamino) -N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide,
2- (3-hydroxy-benzoylamino) -N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide,
2- (4-hydroxy-benzoylamino) -N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide,
2- (2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenylcarbamoyl) phenyl ester of acetic acid,
3- (2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenylcarbamoyl) phenyl ester of acetic acid,
4- (2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenylcarbamoyl) phenyl ester of acetic acid,
2- (2-trifluoromethyl-benzoylamino) -N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide,
2- (3-trifluoromethyl-benzoylamino) -N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide,
2- (3-dimethylamino-benzoylamino) -N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide,
2- (4-isopropyl-benzoylamino) -N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide,
2- (4-cyclohexyl-benzoylamino) -N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) naphthalene-1-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) naphthalene-2-carboxylic acid amide,
2- (3,4-dichloro-benzoylamino) -N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide,
2- (3,4-dimethyl-benzoylamino) -N- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenyl} benzamide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) thiophene-2-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) thiophene-3-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) furan-3-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) 1H-indole-2-carboxylic acid amide,
(2- {4- [2- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) benzofuran-2-carboxylic acid amide,
2- (4-cyclohexyl-benzoylamino) -N- [3- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) propyl] benzamide,
2- (4-cyclohexyl-benzoylamino) -N- [2- (3,4-dihydro-1H-isoquinolin-2-yl) ethyl] benzamide,
(2- {4- [3- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) propyl] phenylcarbamoyl} phenyl) quinoxaline-2-carboxylic acid amide,
(2- [4- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl] phenylcarbamoyl} phenyl) quinoxaline-2-carboxylic acid amide,
(2- {4- [2- (3,4-dihydro-1H-isoquinolin-2-yl) ethyl] phenylcarbamoyl} phenyl) quinoline-3-carboxylic acid amide,
{2- [4- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl] phenylcarbamoyl} phenyl) quinoline-3-carboxylic acid amide,
or a pharmaceutically acceptable salt thereof.  9. The compound of claim 1 or 6 for use as an inhibitor of P-glycoprotein.  10. The compound according to claim 9 for use to enhance the action of cytotoxicity of a chemotherapeutic agent.  11. A pharmaceutical or veterinary composition having activity as an inhibitor of P-glycoprotein, containing an active principle and a pharmaceutically or veterinarily acceptable carrier or diluent, characterized in that as an active principle it contains a compound according to claim 1 or 6. 12. A method of producing a compound according to claim 1, which includes the processing of aminobenzamide of the formula VI

where Ar, R ⁷ and R ⁸ have the meanings indicated in paragraph 1;
Z is a fragment

where m, n, q, R, R ¹ -R ⁶ and X have the meanings indicated in paragraph 1,
a carboxylic acid of the formula R ⁹ —COOH or an activated derivative thereof, wherein R ⁹ is as defined in claim 1; and, if necessary, removing any optional protecting groups present, and / or, if necessary, converting one compound of formula I to another compound of formula I, and / or, if necessary, converting one compound of formula I to its pharmaceutically acceptable salt, and / or, if necessary, converting the salt into a free compound of formula I. 13. A method of obtaining a compound according to claim 1, which includes processing a compound of formula XII

where Ar, R ⁵ , R ⁶ -R ⁹ , X, q and m have the meanings indicated in paragraph 1,
amine of the formula XX

where R, R ¹ -R ⁴ and n have the meanings indicated in paragraph 1;
and, if necessary, removing any optional protecting groups present, and / or, if necessary, converting one compound of formula I to another compound of formula I, and / or, if necessary, converting one compound of formula I to its pharmaceutically acceptable salt, and / or if necessary, converting the salt into a free compound of formula I. 14. A method of obtaining a compound according to claim 6, which includes processing aminobenzamide of the formula VIII '

where R ³¹ and R ⁴¹ are as defined in claim 6 and are optionally protected;
Z 'denotes a fragment

where r, s, R ¹¹ and R ²¹ have the meanings indicated in paragraph 6,
a carboxylic acid of the formula R ⁵¹ —COOH or an activated derivative thereof, wherein R ⁵¹ is as defined in claim 6, and, if necessary, removing any optional protecting groups present, and / or, if necessary, converting one compound of formula Ia to another compound formula Ia, and / or, if necessary, converting one compound of formula Ia to its pharmaceutically acceptable salt, and / or, if necessary, converting the salt into a free compound of formula Ia. 15. A method of obtaining a compound according to claim 6, which includes processing the compounds of formula XII '

where R ⁵¹ has the meanings indicated in paragraph 6,
amine of formula IX '

where r, s, R ¹¹ and R ²¹ have the meanings indicated in paragraph 6;
and, if necessary, removing any optional protective groups present, and / or, if necessary, converting one compound of formula Ia to another compound of formula Ia, and / or, if necessary, converting one compound of formula Ia into its pharmaceutically acceptable salt, and / or, if necessary, converting the salt into a free compound of formula Ia. 16. A method of obtaining a compound according to claim 6, which includes the treatment of azalactone of the formula XIII '

where R ⁵¹ has the meanings indicated in paragraph 6, by an amine of formula IX '

where r, s, R ¹¹ and R ²¹ have the above meanings,
and, if necessary, removing any optional protective groups present, and / or, if necessary, converting one compound of formula Ia to another compound of formula Ia, and / or, if necessary, converting one compound of formula Ia into its pharmaceutically acceptable salt, and / or, if necessary, converting the salt into a free compound of formula Ia.  17. The compound according to claim 1, used in the preparation of a medicament for use as an inhibitor of P-glycoprotein. Priorities for items:
08/19/1997 on pp. 1-5, 8;
10/18/1996 on pp. 6-11, 14-16.

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