RU95114847A - Heterocyclyl-benzoyl-guanidine, a method for their production, a pharmaceutical position, and a method for its production - Google Patents

Heterocyclyl-benzoyl-guanidine, a method for their production, a pharmaceutical position, and a method for its production

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Publication number
RU95114847A
RU95114847A RU95114847/04A RU95114847A RU95114847A RU 95114847 A RU95114847 A RU 95114847A RU 95114847/04 A RU95114847/04 A RU 95114847/04A RU 95114847 A RU95114847 A RU 95114847A RU 95114847 A RU95114847 A RU 95114847A
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Russia
Prior art keywords
formula
diaminomethylene
denotes
atoms
heterocyclyl
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RU95114847/04A
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Russian (ru)
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RU2152390C1 (en
Inventor
Герике Рольф
Дорш Дитер
Баумгарт Манфред
Минк Клаус-Отто
Байер Норберт
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Мерк Патент Гмбх
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Priority claimed from DE4430861A external-priority patent/DE4430861A1/en
Application filed by Мерк Патент Гмбх filed Critical Мерк Патент Гмбх
Publication of RU95114847A publication Critical patent/RU95114847A/en
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Publication of RU2152390C1 publication Critical patent/RU2152390C1/en

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Claims (6)

1. Гетероциклил-бензоил-гуанидины формулы I
Figure 00000001

где R1 обозначает A, CF3, CH2F, CHF2, C2F5, CN, NO2, Гал, C ≡ CH или -X-R4;
R2 и R3 каждый, независимо друг от друга, обозначают Н, Гал, А, -X-R4, CN, NO2, CF3, CH2F, CHF2, C2F5, CH2CF3, -SOn-R6, -SO2NR4R5, Ph или OPh;
R4 обозначает Н, А, циклоалкил с 5-7 С-атомами, циклоалкилметил с 6-8 С-атомами, CF3, CH2F, CHF2, CH2CF3, Ph или -CH2-Ph;
R5 обозначает Н или А или R4 и R5 вместе также обозначают алкилен с 4-5 С-атомами, причем одна CH2-группа может быть заменена также на O, S, NH, N-A или N-CH2-Ph;
R6 обозначает А или Ph;
Het обозначает одно- или двухъядерный, насыщенный, ненасыщенный или ароматический гетероцикл с 1-4 N-, O- и/или S-атомами, связанными через N или С, который незамещен или одно-, двух- или трехкратно может быть замещен с помощью Гал, CF3, A, -X-R4, CN, NO2 и/или кислорода карбонила;
А обозначает алкил с 1-6 С-атомами;
Х обозначает О, S или NR5;
Ph обозначает незамещенный или одно-, двух- или трехкратно замещенный с помощью А, ОА, NR4R5, F, Cl, Br, J или CF3 фенил;
n обозначает 1 или 2;
Гал обозначает фтор, хлор, бром или йод;
а также их физиологически приемлемые соли.1. Heterocyclyl-benzoyl-guanidines of the formula I
Figure 00000001

where R 1 denotes A, CF 3 , CH 2 F, CHF 2 , C 2 F 5 , CN, NO 2 , Gal, C ≡ CH or -XR 4 ;
R 2 and R 3 each, independently of one another, denote H, Gal, A, -XR 4 , CN, NO 2 , CF 3 , CH 2 F, CHF 2 , C 2 F 5 , CH 2 CF 3 , -SO n -R 6 , -SO 2 NR 4 R 5 , Ph or OPh;
R 4 is H, A, cycloalkyl with 5-7 C-atoms, cycloalkylmethyl with 6-8 C-atoms, CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , Ph or -CH 2 -Ph;
R 5 is H or A or R 4 and R 5 together also represent alkylene with 4-5 C-atoms, and one CH 2 -group can also be replaced with O, S, NH, NA or N-CH 2 -Ph;
R 6 is A or Ph;
Het denotes a single or dual-core, saturated, unsaturated or aromatic heterocycle with 1-4 N-, O- and / or S-atoms linked through N or C, which can be unsubstituted or substituted one-, two- or three-fold with Gal, CF 3 , A, -XR 4 , CN, NO 2 and / or carbonyl oxygen;
And denotes alkyl with 1-6 C-atoms;
X is O, S or NR 5 ;
Ph denotes unsubstituted or one-, two- or three-fold substituted with A, OA, NR 4 R 5 , F, Cl, Br, J, or CF 3 phenyl;
n is 1 or 2;
Gal refers to fluorine, chlorine, bromine or iodine;
and their physiologically acceptable salts. 2. Гетероциклил-бензоил-гуанидины по п.1, представляющие собой:
(а) N-диаминометилен-2-этил-4-(1-имидазолил)-5-метилсульфонилбензамид;
(б) N-диаминометилен-2-метил-4-(1-имидазолил)-5-метилсульфонил-бензамид;
(в) N-диаминометилен-2-метил-4-(3-гидрокси-пиперидино)-5-метилсульфонил-бензамид;
(г) N-диаминометилен-2-этил-4-(3-пиридил)-5-метилсульфонил-бензамид;
(д) N-диаминометилен-2-этил-4-(2-пиридил)-5-метилсульфонил-бензамид;
(е) N-диаминометилен-2-этил-4-(1,4-дигидро-4-оксо-1-пиридил)-5- метилсульфонил-бензамид;
(ж) N-диаминометилен-2-этил-3-метилсульфонил-4-(3-пиридил)-бензамид,
а также их физиологически приемлемые соли.2. Heterocyclyl-benzoyl-guanidines according to claim 1, representing:
(a) N-diaminomethylene-2-ethyl-4- (1-imidazolyl) -5-methylsulfonylbenzamide;
(b) N-diaminomethylene-2-methyl-4- (1-imidazolyl) -5-methylsulfonyl-benzamide;
(c) N-diaminomethylene-2-methyl-4- (3-hydroxy-piperidino) -5-methylsulfonyl-benzamide;
(d) N-diaminomethylene-2-ethyl-4- (3-pyridyl) -5-methylsulfonylbenzamide;
(e) N-diaminomethylene-2-ethyl-4- (2-pyridyl) -5-methylsulfonylbenzamide;
(e) N-diaminomethylene-2-ethyl-4- (1,4-dihydro-4-oxo-1-pyridyl) -5-methylsulfonyl-benzamide;
(g) N-diaminomethylene-2-ethyl-3-methylsulfonyl-4- (3-pyridyl) -benzamide,
and their physiologically acceptable salts. 3. Гетероциклил-бензоил-гуанидины по п.1 в качестве ингибитора целлюлярного Nа+/Н+ - антиносителя.3. Heterocyclyl-benzoyl-guanidines according to claim 1 as an inhibitor of cellular Na + / H + - anti-carrier. 4. Способ получения гетероциклил-бензоилгуанидинов формулы I по п.1, а также их солей, отличающийся тем, что соединение формулы II
Figure 00000002

где R1, R2, R3 и Неt имеют вышеуказанные значения;
Q обозначает Сl, Вr, ОА, О-СО-А, О-СО-Рh, ОН или другую, реакционноспособную, этерифицированную до сложноэфирной ОН-группу, соответственно, легко нуклеофильно замещаемую удаляемую группу,
вводят во взаимодействие с гуанидином; или бензоилгуанидин формулы III
Figure 00000003

где R1, R2 и R3 имеют вышеуказанные значения, R7 обозначает F, Сl, Вr или J, вводят во взаимодействие с гетероциклическим соединением формулы IV
Неt - D
где Неt имеет вышеуказанное значение,
D обозначает Н; В(ОН)2, триалкилсилил, катион щелочного металла или аммоний, или легко замещаемый металлоорганический остаток, или соответствующее формуле I соединение, которое вместо одного или нескольких атомов водорода содержит одну или несколько восстанавливаемых групп и/или одну или несколько дополнительных С-С- и/или С-N-связей, обрабатывают восстановителем, или соответствующее формуле I соединение, которое вместо одного или нескольких атомов водорода содержит одну или несколько сольволизируемых групп, обрабатывают сольволизирующим средством, и/или полученное основание формул I путем обработки кислотой превращают в одну из его солей.4. The method of obtaining heterocyclyl-benzoylguanidines of the formula I according to claim 1, as well as their salts, characterized in that the compound of formula II
Figure 00000002

where R 1 , R 2 , R 3 and t have the above values;
Q denotes Cl, Br, OA, O-CO-A, O-CO-Ph, OH, or another, reactive, esterified to ester OH group, respectively, easily nucleophilically replaceable leaving group,
enter into interaction with guanidine; or benzoylguanidine of formula III
Figure 00000003

where R 1 , R 2 and R 3 have the above values, R 7 denotes F, Cl, Br or J, is introduced into interaction with a heterocyclic compound of formula IV
No - d
where Not has the above meaning,
D is H; In (OH) 2 , a trialkylsilyl, an alkali metal cation or ammonium, or an easily replaceable organometallic residue, or a compound corresponding to formula I, which instead of one or more hydrogen atoms contains one or more reducing groups and / or one or more additional C-C- and / or CNN bonds, are treated with a reducing agent, or a compound corresponding to formula I, which instead of one or several hydrogen atoms contains one or more solvolizable groups, is treated with a solvolysis agent, and / or the obtained base of formulas I is converted into one of its salts by treatment with acid. 5. Способ получения фармацевтических композиций, отличающийся тем, что соединение формулы I по п. 1 и/или одну из его физиологически приемлемых солей вместе с по меньшей мере одним, твердым, жидким или полужидким носителем или вспомогательным веществом доводят до пригодной дозировочной формы. 5. A method of obtaining pharmaceutical compositions, characterized in that the compound of formula I under item 1 and / or one of its physiologically acceptable salts, together with at least one solid, liquid or semi-liquid carrier or auxiliary substance is brought to a suitable dosage form. 6. Фармацевтическая композиция, отличающаяся тем, что она содержит по меньшей мере одно соединение общей формулы I по п. 1 и/или одну из его физиологически приемлемых солей, в эффективном количестве. 6. Pharmaceutical composition, characterized in that it contains at least one compound of general formula I according to claim 1 and / or one of its physiologically acceptable salts, in an effective amount.
RU95114847/04A 1994-08-31 1995-08-30 Heterocyclyl-benzoylguanidines, method of their synthesis and pharmaceutical composition RU2152390C1 (en)

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DEP4430861.2 1994-08-31
DE4430861A DE4430861A1 (en) 1994-08-31 1994-08-31 Heterocyclyl-benzoylguanidines

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AT (1) ATE175406T1 (en)
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