RU2043991C1 - Dihydrobenzofuran carboxamides or its pharmaceutically acceptable salts and method of their synthesis - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: dihydrobenzofuran carboxamides of the formula

where m 0-1, m. p. is 290-300 C (at decomposition), or their salt. Reagent 1:

. Reagent 2:

Description

 The invention relates to new dihydrobenzfuran derivatives of carboxamide, a production method and pharmaceutical compositions based on them.

(I) где m равно 0 или 1, а символ

означает, что азабициклическое кольцо может быть либо в эндо- либо в экзо-ориентации.The invention provides compounds of formula I

(I) where m is 0 or 1, and the symbol

means that the azabicyclic ring can be either in the endo- or exo-orientation.

 The invention also includes pharmaceutically acceptable salts of the compounds of formula (I), as well as all isomers of the formula, both separate and in mixture. Preferably, in the above formula (I), the substituent is in the endo orientation. Pharmaceutically acceptable salts of the compounds of formula (I) are salts of suitable pharmaceutically acceptable acids, such as salts of inorganic acids, for example hydrochloric or sulfuric acids, or salts of organic acids, such as organic carboxylic acids, for example citric, tartaric, fumaric and the like. or organic sulfonic acids, for example methanesulfonic or ethanesulfonic acids. In particular, salts of hydrochloric (hydrochloric) acid hydrochloride are preferred.

 Specific examples of the compounds of formula (I) are the following compounds, either in the exo orientation or in the endo orientation, preferably in the endo orientation.

1) 4-amino-5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,3-dihydrobenzo [b] furan-7-carboxamide,
2) 4-amino-5-chloro-N- (9-methyl-9-azabicyclo [3.3.1] non-3-yl) -2,3-dihydrobenzo [b] furan-7-carboxamide, and pharmaceutically acceptable salts based on them, especially hydrochlorides.

2)

В настоящем описании в тех случаях, когда формула имеет заместитель с символом

эта формула может представлять соединение, имеющее азабициклическое кольцо только в эндо-ориентации или только в экзо-ориентации, или эта формула может представлять смесь обоих соединений, имеющих азабициклическое кольцо в эндо-ориентации и соединений с азабициклическим кольцом в экзо-ориентации.Structural formulas of the listed compounds:
1)

2)

In the present description, in cases where the formula has a substituent with the symbol

this formula may represent a compound having an azabicyclic ring only in an endo orientation or only in an exo orientation, or this formula may be a mixture of both compounds having an azabicyclic ring in an endo orientation and compounds with an azabicyclic ring in an exo orientation.

(II) или реакционноспособного производного этого соединения с соединением формулы (III):
H₂N A (III), в котором А представляет группу формулы

и если это необходимо, подкисление свободного соединения формулы (I) или получение свободного соединения формулы (I) из его соли и/или, если это необходимо, разделение смеси изомеров соединения формулы (I) на отдельные изомеры.Compounds of the invention are prepared by a process comprising: reacting a compound of formula (II)

(II) or a reactive derivative of this compound with a compound of formula (III):
H ₂ NA (III) in which A represents a group of the formula

and if necessary, acidifying the free compound of formula (I) or obtaining the free compound of formula (I) from its salt and / or, if necessary, separating the mixture of isomers of the compound of formula (I) into separate isomers.

The reactive compound of formula (II) may, for example, be the corresponding C ₁ -C ₄ alkyl ester, the corresponding halogen derivative, in particular chloride or mixed anhydride mixed with the corresponding carboxylic acid. A preferred mixed anhydride is an anhydride obtained by reacting a compound of formula (II) with ethyl chloroformate. The reaction between the compound of formula (II) or a reactive compound based on it and the compound of formula (III) can be carried out according to known methods. In particular, the reaction between the compound of formula (II) and the compound of formula (III) can, for example, be carried out in an inert, preferably anhydrous organic solvent such as, for example, dimethylformamide, in the presence of a condensing agent, for example N, N-carbonyldiimidazole, according to standard methods. A possible conversion to a salt of a free compound of formula (I), a possible preparation of a compound of formula (I) in free form from its salt can be carried out in a standard way using known and conventional procedures of organic chemistry.

 The compound of formula (II) is a known compound and can be obtained by known methods.

 Compounds of formula (III) are also well known compounds and can be prepared by known methods. For example, a compound of formula (III) in which group A is endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl, that is, it is an endo-8-methyl-8-azabicyclo [3.2 .1] octane-3-amine, can be obtained according to the known procedure. And the compound of formula (III), in which group A represents endo-9-methyl-9-azabicyclo [3.3.1] non-3-yl, that is, this compound is endo-9-methyl-9-azabicyclo [3.3. 1] nonan-3-amine, can be obtained according to a known procedure.

The compounds of formula (I) are 5HT ₃ receptor antagonists, which is confirmed, for example, by the fact that they have been found to be active in the fight against Bezold-Yarich chemoreflex provoked by 5-HT in anesthetized rats.

в отношении 5НТ₃, полученные в этом тесте для соединений изобретения 4-амино-5-хлоро-N-(9-метил-9-азабицикло[3.3.1] нон-3-ил)-2,3-дигид- робензо [b] фуран-7-карбоксамида (внутренний код FCE 27270) и 4-амино-5-хлоро-N-(8-метил-8-азабицикло[3.2.1]окт-3-ил)-2,3- дигидробензо [b] фуран-7-карбоксамида) (внутренний код FCE 27271) в сравнении с известными соединениями прототипа-соединением Ondansetron, а именно (±)-1.2.3.4-тетрагидро-9-метил-3-(2-метилимидазол-1- ил-метил)-карбазол-4-оном. Данные, приведенные в табл. 1, свидетельствует о том, что тестируемые соединения изобретения, как антагонисты 5НТ₃ рецептора обладают существенно большей активностью в сравнении с соединением прототипа.In the table. 1 shows data on antagonistic activity

in relation to 5HT ₃ obtained in this test for compounds of the invention 4-amino-5-chloro-N- (9-methyl-9-azabicyclo [3.3.1] non-3-yl) -2,3-dihydrobenzo [ b] furan-7-carboxamide (internal code FCE 27270) and 4-amino-5-chloro-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,3-dihydrobenzo [ b] furan-7-carboxamide) (internal code FCE 27271) in comparison with the known compounds of the prototype Ondansetron compound, namely (±) -1.2.3.4-tetrahydro-9-methyl-3- (2-methylimidazol-1-yl methyl) carbazole-4-one. The data given in table. 1, indicates that the tested compounds of the invention, as 5HT ₃ receptor antagonists, have significantly greater activity compared to the prototype compound.

 Inhibition of the Betzold-Yarich reflex caused by 5-HT (20 mg / kg intravenously) by intravenous administration of FCE 27270.FCE 2721 and Ondansetron to anesthetized rats. The data given in table. 1 correspond to an average value of ± S.E.M. in a group of 6 animals.

It was also found that the proposed compounds are active and are selective inhibitors of ³ H-GR 65630 binding (selective 5-HT ₃ receptor antagonist).

в этом тесте для соединений изобретения FCE 27270 и FCE 27271 в сравнении с известными соединениями прототипа ондасетроном, MDL 72222 и метоклопрамидом (Metoclopramide).In the table. 2 presents data obtained

in this test for compounds of the invention FCE 27270 and FCE 27271 in comparison with the known compounds of the prototype ondasetron, MDL 72222 and metoclopramide (Metoclopramide).

CP 65630 это соединение формулы

Тестируемые соединения способны взаимодействовать с 5-НТ₃-серотониновыми рецепторами, помеченными в энторинальной коре головного мозга крыс с помощью ³Н-GR 65630. Из перечисленных в таблице соединений FCE 27270, 27271 и Ондансетрон взаимодействуют в соответствии с двухсайтовой нелинейной моделью присоединения, в то время как MDL 72222 и метоклопрамид замещают ³Н-GR 65630 согласно односайтовому нелинейному присоединению, что является причиной того, почему для этих двух последних соединений в таблице приведено только одно значение Ki (а не два). Данные, приведенные в таблице, четко свидетельствуют о том, что активность соединений изобретения превосходит активность соединений прототипа.MDL 72222 is a compound of the formula

CP 65630 is a compound of the formula

The tested compounds are able to interact with 5-HT ₃ -serotonin receptors labeled in the entorhinal cortex of rats with ³ H-GR 65630. Of the compounds listed in the table, FCE 27270, 27271 and Ondansetron interact in accordance with the two-site non-linear model of attachment, while while MDL 72222 and metoclopramide replace ³ H-GR 65630 according to a single-site non-linear attachment, which is the reason why only the Ki value (rather than two) is shown in the table for the last two compounds. The data shown in the table clearly indicate that the activity of the compounds of the invention exceeds the activity of the compounds of the prototype.

 The compounds of the invention may be useful, for example, in the treatment of disorders of the central nervous system, for example in the treatment of psychosis and fear, and / or in the treatment of disorders of peristalsis of the small intestine, and / or vomiting. From the point of view of the activity shown by the proposed compounds, they can also be useful, for example, as a means against migraines or drug addiction, or against excessive addiction to drugs, or as activators of cognitive abilities. It was also found that the compounds can be used as painkillers (analgesics). The activity of the compounds as analgesics was demonstrated in a test such as the test described by Dubvisson and Dennis in "Formalin Test: A Quantitative Study of the Analgesic Effect of Morphine, Meperidine, and Brain Stimulation in Rats and Mice."

 Since the compounds of formula (I) have an analgesic effect, they can be used, for example, in the treatment of pain in mammals, for example in the treatment of certain forms of inflammatory pain in humans. The compounds can be administered over a wide range of dosage forms, for example, they can be administered orally in the form of tablets, pills, capsules, suspensions, drops or syrups; they can be prescribed for parenteral administration, for example, they can be administered intravenously, intramuscularly in the form of solutions or suspensions, or administered subcutaneously.

 Pharmaceutical compositions containing the compounds can be prepared by standard methods using conventional carriers or diluents. Traditional carriers or diluents are, for example, water, gelatin, lactose, starches, magnesium stearate, talc, vegetable oils, cellulose and the like. Tablets, pills or capsules may, for example, contain a binder, such as, for example, tragacanth gum, medicinal media, such as calcium hydrogen phosphate, disintegrants, such as corn starch, lubricants, such as magnesium stearate, sweeteners, such such as sucrose or perfumes, such as, for example, a cherry flavor.

 Suitable pharmaceutical forms for parenteral use are sterile aqueous solutions or dispersions and sterile powders for the preparation of "extempora". The dosage of the compounds for both prophylactic and therapeutic purposes will depend on the chosen form of administration, on the particular compound chosen, on the particular patient to be treated, and on the nature and severity of the disease. A suitable effective therapeutic dosage may be, for example, a dosage ranging from about 0.01 to 20 mg / kg body weight. Preferably, when the compounds can, for example, be administered once or in several doses so that the total daily dose is in the range from about 0.02 to about 10 mg / kg per day.

 The examples are illustrative only and do not limit the scope of the invention.

К перемешиваемому раствору 4-амино-5-хлоро-2,3-дигидробенз [b]фуран-7-карбоновой кислоты (2,13 г, 0,01 моль) в 30 мл безводного диметилформамида добавляют N, N-карбонилдиимидазол (1,96 г, 0,012 моль). В раствор продувают азот и перемешивают при комнатной температуре, продолжая перемешивать в течение ночи, вслед за тем по каплям добавляют раствор эндо-8-метил-8-азабицикло [3.2.1]октан-3-амина (1,40 г, 0,01 моль) в 5 мл безводного диметилформамида. Реакционную смесь нагревают при 70^оС в течение 18 ч, охлаждают, выливают в воду и экстрагируют метиленхлоридом. Органический слой промывают дважды раствором бикарбоната натрия и высушивают над безводным сульфатом натрия. Раствор отфильтровывают, выпаривают досуха и полученный продукт очищают методом флеш-хроматографии (SiO₂) (CH₂Cl₂-MeOH- NH₄OH 30% 80:20:1, в качестве элюента), вслед за тем обрабатывают раствором хлористоводородной кислоты в этаноле: полученный твердый остаток отфильтровывают и перекристаллизовывают из этанола, получив в результате 1,6 г названного продукта с т. пл. 290-300^оС (с разл.).Example 1. 4-amino-5-chloro-N- (endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,3-dihydrobenzo [b] furan- 7-carboxamide ^. Hcl

To a stirred solution of 4-amino-5-chloro-2,3-dihydrobenz [b] furan-7-carboxylic acid (2.13 g, 0.01 mol) in 30 ml of anhydrous dimethylformamide add N, N-carbonyldiimidazole (1, 96 g, 0.012 mol). Nitrogen was purged into the solution and stirred at room temperature, while stirring overnight, then a solution of endo-8-methyl-8-azabicyclo [3.2.1] octane-3-amine (1.40 g, 0, 01 mol) in 5 ml of anhydrous dimethylformamide. The reaction mixture was heated at ⁷⁰ ° C for 18 hours, cooled, poured into water and extracted with methylene chloride. The organic layer was washed twice with sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solution is filtered off, evaporated to dryness and the resulting product is purified by flash chromatography (SiO ₂ ) (CH ₂ Cl ₂ -MeOH-NH ₄ OH 30% 80: 20: 1, as eluent), and then it is treated with a solution of hydrochloric acid in ethanol : the resulting solid residue is filtered off and recrystallized from ethanol, resulting in 1.6 g of the title product with mp. 290-300 ^{° C} (dec.).

+

+

+

)
2,64 (с, 3Н, NCH₃)
3,04 (т, J 8,8 Гц, 2Н, ОСН₂С

)
3,79 (м, 2Н,

+

)
4,02 (9, J 6,2 Гц, 1Н,

)
4,73 (т, J 8,8 Гц, 2Н, ОС

СН₂)
5,95 (с, 2Н, ⌀ N

)
7,42 (c, 1H, ⌀

)
1,78 (д, J 7,2 Гц, 1Н, CONH)
10,2 (шир.с. 1Н, NH⁺)
П р и м е р 2. Следующие соединения могут быть также получены из соответствующей карбоновой кислоты и соответствующего амина в соответствии с процедурой, описанной в примере 1: 4-амино-5-хлоро-N-(эндо-9-метил-9-азабицикло[3.3.1] нон-3-ил)-2,3-дигидробенз о[b] фуран-7-карбоксамид x xHCl, т.пл. 260-280^оС (с разл.):

¹H-ЯМР (200 МГц, DMSO)
1,3-2,5 (м, 10Н, СН₂

+

+

+

+

)
2,80 (с, 3Н, NCH₃)
3,04 (т, J 8,8 Гц, 2Н, ОСН₂С

)
3,60 (м, 2Н,

+

)
4,52 (м, 1Н,

)
4,72 (т, J 8,8 Гц, 2Н, ОС

СН₂)
5,94 (с, 2Н, ⌀ N

)
7,39 (д, J 7,7 Гц, 1Н, CONH)
7,46 (c, 1H, ⌀

)
9,20 (шир.с. 1Н, NH⁺)
П р и м е р 3. Таблетки, каждая из которых содержит 60 мг активного ингредиента и весит 150 мг, могут быть получены путем смешения и последующего прессования следующих ингредиентов, мг:
4-Амино-5-хлоро-N-
(эндо-8-метил-8-азаби-
цикло [3.2.1]окт-3-ил)-2,3-
дигидробензо [b] фуран-7-
карбоксамида, хлористово- дородная соль 60 Крахмал 50
Микрокристаллическая целлюлоза 30 Поливинилпирролидон 5
Натриевая соль карбок-
симетилированного крахмала 4,5 Стеарат магния 0,5
П р и м е р 4. Капсулы, каждая из которых содержит 80 мг активной субстанции и дозирована по 200 мг, могут быть получены следующим образом. Состав, мг:
4-Амино-5-хлоро-N-
(эндо-8-метил-
8-азабицикло[3.2.1]
окт-3-ил)-2,3-дигид- робензо[b]
фуран-7-карбоксамид, хлористоводородная соль 80 Кукурузный крахмал 60
Микрокристаллическая целлюлоза 59 Стеарат магния 1
Этот состав может быть инкапсулирован по капсулам, состоящим из двух частей и выполненным из твердого желатина, в каждую капсулу загружают по 200 мг состава. ¹ H-NMR (200 MHz, DMSO)
1.8-2.5 (m. 8H, CH ₂

+

+

+

)
2.64 (s, 3H, NCH ₃ )
3.04 (t, J 8.8 Hz, 2H, OCH ₂ C

)
3.79 (m, 2H,

+

)
4.02 (9, J 6.2 Hz, 1H,

)
4.73 (t, J 8.8 Hz, 2H, OS

CH ₂ )
5.95 (s, 2H, ⌀ N

)
7.42 (s, 1H, ⌀

)
1.78 (d, J 7.2 Hz, 1H, CONH)
10.2 (br.s. 1H, NH ⁺ )
PRI me R 2. The following compounds can also be obtained from the corresponding carboxylic acid and the corresponding amine in accordance with the procedure described in example 1: 4-amino-5-chloro-N- (endo-9-methyl-9- azabicyclo [3.3.1] non-3-yl) -2,3-dihydrobenz o [b] furan-7-carboxamide x xHCl, m.p. 260-280 ^{° C} (dec.):

¹ H-NMR (200 MHz, DMSO)
1.3-2.5 (m, 10H, CH ₂

+

+

+

+

)
2.80 (s, 3H, NCH ₃ )
3.04 (t, J 8.8 Hz, 2H, OCH ₂ C

)
3.60 (m, 2H,

+

)
4.52 (m, 1H,

)
4.72 (t, J 8.8 Hz, 2H, OS

CH ₂ )
5.94 (s, 2H, ⌀ N

)
7.39 (d, J 7.7 Hz, 1H, CONH)
7.46 (s, 1H, ⌀

)
9.20 (br.s. 1H, NH ⁺ )
PRI me R 3. Tablets, each of which contains 60 mg of the active ingredient and weighs 150 mg, can be obtained by mixing and then pressing the following ingredients, mg:
4-amino-5-chloro-n-
(endo-8-methyl-8-azabi-
cyclo [3.2.1] oct-3-yl) -2.3-
dihydrobenzo [b] furan-7-
carboxamide, hydrochloride salt 60 Starch 50
Microcrystalline cellulose 30 Polyvinylpyrrolidone 5
Carbohydrate Salt
simmethyl starch 4.5 Magnesium stearate 0.5
PRI me R 4. Capsules, each of which contains 80 mg of active substance and dosed at 200 mg, can be obtained as follows. Composition, mg:
4-amino-5-chloro-n-
(endo-8-methyl-
8-azabicyclo [3.2.1]
oct-3-yl) -2,3-dihydrobenzo [b]
furan-7-carboxamide, hydrochloride salt 80 Corn starch 60
Microcrystalline Cellulose 59 Magnesium Stearate 1
This composition can be encapsulated in capsules, consisting of two parts and made of hard gelatin, 200 mg of the composition are loaded into each capsule.

Claims (4)

1. Dihydrobenzofuran carboxamides of the general formula I

where m 0 or 1;
symbol

means that the azabicyclic ring may be in endorientation or in exorientation, or its pharmaceutically acceptable salts. 2. Dihydrobenzofuran carboxamide or its salt according to claim 1, characterized in that it is a compound selected from the group consisting of 4-amino-5-chloro-N- (endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,3-dihydrobenzo [b] furan-7-carboxamide, 4-amino-5-chloro-N- (endo-9-methyl-9-azabicyclo [3.3.1] non-3- il) -2,3-dihydrobenzo [b] furan-7-carboxamide,
3. The dihydrobenzofuran carboxamide salt of general formula 1 according to claim 1, which is a hydrochloride salt. 4. The method of obtaining dihydrobenzofuran carboxamides of the formula 1, characterized in that the compound of the formula II

or its reactive derivative is reacted with a compound of formula III

where m and the symbol

have the indicated values
and, if necessary, carry out the salt formation reaction of the free compound of formula 1, or obtain a free compound from a salt of this compound, and / or, if necessary, separate the mixture of isomers of the compound of formula 1 into separate isomers. 5. Dihydrobenzofuran carboxamide according to claims. 1 3 or a pharmaceutically acceptable salt thereof having a 5 HT ₃ receptor antagonist activity.

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