RU2150470C1 - Bicyclic thiophene derivatives, method of their synthesis and composition based on thereof - Google Patents

Abstract

FIELD: organic chemistry, pharmacy. SUBSTANCE: invention describes the novel bicyclic derivatives of thiophene of the general formula (I)

where values R¹,R²,R³,R⁴,R⁵, n are given in p. 1 of the invention claim. Compounds show antagonistic effect with respect to gonadotropin-releasing hormone. Invention describes also method of their synthesis and composition based on said. EFFECT: new compounds indicated above, valuable pharmacological property. 18 cl, 98 ex

Description

 The invention relates to a pharmaceutical composition for inhibiting gonadotropin-releasing hormone, which contains a fused bicyclic compound consisting of a homo- or heterocyclic 5-7-membered ring group and a homo- or heterocyclic 5-7-membered ring group. The present invention also relates to new thiophene derivatives containing a fused ring and their salts. The present invention also relates to methods for producing new thiophene derivatives containing a fused ring and their salts.

BACKGROUND OF THE INVENTION
The secretion of the hormone of the anterior pituitary gland proceeds under the control of the peripheral hormones secreted by the target organs for the corresponding hormones, and accelerating the secretion or slowing down the secretion of the hormone from the hypothalamus, which is the highest central organ of the anterior pituitary gland (in the present description, these hormones are called by the general term " hypothalamic hormone "). Currently, nine types of hormones have been confirmed as hypothalamic hormones, including, for example, thyrotropin-releasing hormone (TRH) or gonadotropin-releasing hormone (GnRH) [gonadotropin-releasing hormone sometimes called the lutenizing hormone releasing hormone (LuRH.sup.2H.sup.2H). , authors M. Iriku and K. Toyama, published in Bunkohdo, p. 610-618, 1986)]. It is believed that these hypothalamic hormones exert their effect through the receptor, which is believed to exist in the anterior pituitary gland (see ibid.); studies have been conducted of genes specific for these hormones, including human hormones (Receptor Kiso To Rinsho, authors H. Imura et al., published in Asakura Shoten, p. 297-304, 1993). Thus, antagonists and agonist substances, having a specific and selective effect on these receptors, control the action of the hypothalamic hormone and the secretion of the hormone of the anterior pituitary gland. Therefore, it is believed that these substances are useful as prophylactic and therapeutic agents in the treatment of diseases that depend on the hormone of the anterior pituitary gland.

 Leuprorelin acetate (Fujino et al., Biological and Biophysical Research Communications, Vol. 60, pp. 406-413, (1974); RTD Oliver et al., British Journal of Cancers, Vol. 59, p. 823 (1989); and Toguchi et al., Journal of International Medical Research, Vol. 18, pp. 35-41), which is a highly reactive derivative of the gonadotropin-releasing hormone, one of the hypothalamic hormones (hereinafter referred to as GnRH) (AVSchally et al., Journal of Biological Chemistry, Vol. 246, pp. 246 (1971); R. Burgus et al., Proceedings of Natural Academic Science US, Vol. 69, pp. 278-282 (1972)), when administered in multiple doses, reduction in the production of the hormone gonadotropin in the pituitary gland, resulting in reduced the reactivity of the gonadotropin hormone in the testes and ovaries and the secretion of testosterone and estrogen is suppressed. In addition, leuprorelin acetate has an antitumor effect on hormone-dependent cancers such as prostate cancer, and is widely used for clinical purposes. Leuprorelin acetate also finds wide clinical use as a therapeutic agent, in particular for endometriosis and premature puberty. It is believed that the high antitumor activity of leuprorelin acetate is due to its high resistance compared to the natural (GnRH) gonadotropin-releasing hormone to the protease and high affinity for the GnRH receptor, which leads to a decrease in the sensitivity of gonadotropin-releasing hormone due to a decrease in the number of receptors. However, since leuprorelin acetate is an ultra-agonist of the gonadotropin-releasing hormone receptor, it is known that immediately after the first administration there is a temporary deterioration in the health status of patients, accompanied by an increase in the concentration of testosterone in the serum due to the action of the pituitary gonadotropin (acute effect). In the cases described above, medications that inhibit the gonadotropin-releasing hormone that have the same therapeutic effect as described above but do not cause the aforementioned temporary effect of the pituitary gonadotropin (acute effect) are desirable. As compounds having the indicated antagonistic activity with respect to gonadotropin releasing hormone, a number of compounds are described, including, for example, derivatives of gonadotropin releasing hormone, such as direct chain peptides (US Pat. Nos. 5,141,000, 5,171,835), derivatives of cyclic hexapeptides (Japanese Patent Application S61 1986 ( ) - 191698) or derivatives of bicyclic peptides (Journal of Medical Chemistry, Vol. 36, pp. 3265-3273 (1993)). However, all these compounds are peptides, which causes a number of problems associated, for example, with dosage forms, drug stability, duration of action and stability during the metabolism. To solve these problems, orally administered drugs are required, which are gonadotropin-releasing hormone antagonists, and especially non-peptide drugs. However, there are currently no reports of the development of non-peptide drugs that are gonadotropin-releasing hormone antagonists.

 The aim of the present invention are new compounds with excellent antagonistic activity against gonadotropin releasing hormone, as well as agents that are excellent antagonists with respect to gonadotropin releasing hormone.

Description of the invention
Thus, an object of the present invention is a pharmaceutical composition for inhibiting gonadotropin-releasing hormone, which contains a fused bicyclic compound consisting of a homo- or heterocyclic 5-7-membered ring and a homo- or heterocyclic 5-7-membered ring. The present invention also relates to new condensed ring thiophene derivatives and salts thereof. Further, the present invention relates to methods for producing new condensed ring thiophene derivatives and salts thereof.

где R¹ и R² каждый независимо обозначают атом водорода или группу, присоединенную через атом углерода, атом азота, атом кислорода или атом серы;
R³ является необязательно замещенной гомо- или гетероциклической группой;
R⁴ обозначает атом водорода, формильную группу, цианогруппу, низший алкил, замещенный группой, которая присоединяется через атом серы, или гидроксильную группу; карбонильную группу, замещенную углеводородным остатком, который необязательно имеет заместители, этерифицированную или амидированную карбоксильную группу;
R⁵ является атомом водорода или группой, присоединенной через атом углерода;
n обозначает число от 0 до 3 при условии, что гомо- или гетероциклическая группа, обозначенная R³, не содержит в качестве заместителя группу, которая приводится в Европейской патентной заявке EP-A-443568 и в Европейской патентной заявке ЕР-А-520423 и имеет следующую формулу:

где R⁶ обозначает необязательно замещенную 5-7-членную гетероциклическую группу, которая содержит в качестве группы, способной образовывать кольцо, карбонильную группу, тиокарбонильную группу и необязательно окисленный атом серы, или группу, которая может в них превращаться, группу, которая может образовывать анион, или группу, которая может быть превращена в анион;
Z является необязательно замещенным ароматическим углеводородным остатком, необязательно содержащим гетероатом или необязательно замещенную гетероциклическую группу;
V обозначает химическую связь или мостиковую группу, или его соль;
(2) соединение по пункту (1), где R³ обозначает группу формулы

где R⁷ обозначает атом водорода, атом галогена или группу, присоединенную через атом углерода, атом азота, атом кислорода или атом серы;
R⁸ является атомом водорода, атомом галогена, нитрогруппой, цианогруппой или углеводородным остатком, который может быть замещен группой, присоединенной через атом кислорода, атом азота или атом серы;
(3) соединение по пункту (1), где любой один из радикалов R¹ или R² обозначает группу формулы
R⁹-(CH₂)_m-,
где R⁹ обозначает группу, присоединенную через атом азота;
m обозначает число от 0 до 3, а другой радикал обозначает группу формулы
R¹⁰-A-
где R¹⁰ обозначает необязательно замещенный фенил, а A обозначает химическую связь или мостиковую группу;
(4) соединение формулы II

где R¹¹ обозначает атом водорода, низший алкил или группу формулы
Q-(CH₂)_p-
где Q обозначает арил, который может быть замещен a) атомом галогена, b) нитрогруппой, c) цианогруппой, d) аминогруппой, e) необязательно замещенной карбоксильной группой, f) низшей алкилендиоксигруппой или g) группой формулы: -A-R¹⁵, в которой A обозначает химическую связь или мостиковую группу, R¹⁵ обозначает алкил, необязательно замещенную циклоалкильную или необязательно замещенную гетероциклическую группу;
R¹² является атомом водорода, алкилом, необязательно замещенным арилом, необязательно замещенным аралкилом, необязательно замещенным циклоалкилом;
R¹³ обозначает необязательно замещенную аминогруппу;
R¹⁴ обозначает необязательно замещенный арил;
r обозначает число от 0 до 3,
или его соль;
(5) соединение по пункту (4), где R¹¹ обозначает группу формулы:
Q-(CH₂)_p-
где Q обозначает арил, который может быть замещен a) атомом галогена, b) нитрогруппой, c) цианогруппой, d) аминогруппой, e) необязательно замещенной карбоксильной группой, f) низшей алкилендиоксигруппой или g) группой формулы: -A-R¹⁵, в которой A обозначает химическую связь или мостиковую группу, R¹⁵ обозначает алкил;
(6) соединение по пункту (4), где Q обозначает арил, который может быть замещен атомом галогена;
(7) соединение по пункту (4), где R¹³ обозначает необязательно замещенную моноаралкиламиногруппу;
(8) соединение по пункту (4), где R¹³ обозначает необязательно замещенную бензиламиногруппу;
(9) соединение по пункту (4), где R¹⁴ обозначает необязательно замещенный фенил;
(10) соединение, которое представляет собой этиловый эфир 3- (N-бензил-N-метиламинометил)-4,7-дигидро-7-(2-метоксибензил)-2- (4-метоксифенил)-4-оксотиено[2,3-b]пиридин-5-карбоновой кислоты или его соль;
(11) соединение, которое представляет собой этиловый эфир 3- (N-бензил-N-метиламинометил)-4,7-дигидро-7-(2-фторбензил)-2- (4-метоксифенил)-4-оксотиено[2,3-b]пиридин-5-карбоновой кислоты или его соль;
(12) соединение, которое представляет собой этиловый эфир 2-(4-ацетиламинофенил)-3-(N-бензил-N-метиламинометил)-4,7-дигидро- 7-(2-фторбензил)-4-оксотиено[2,3-b]пиридин-5-карбоновой кислоты или его соль;
(13) соединение, которое представляет собой 5-бензиламино-метил- 1-(2-хлор-6-фторбензил)-2,4-(1H, 3H)-диоксо-6-(4-метоксифенил) -3-фенилтиено[2,3-d]пиримидин или его соль;
(14) соединение, которое представляет собой 5-бензоил-3- (N-бензил-N-метиламинометил)-7-(2,6-дифторбензил)-4,7-дигидро-4- оксо-2-(4-пропиониламинофенил)тиено[2, 3-b]пиридин или его соль;
(15) соединение, которое представляет собой 5-бензоил-3- (N-бензил-N-метиламинометил)-7-(2,6-дифторбензил)-4,7-дигидро-2- (4-N'-метилуреидофенил)-4-оксотиено[2,3-b]пиридин или его соль;
(16) соединение, которое представляет собой 3-(N-бензил-N- метиламинометил)-7-(2,6-дифторбензил)-4,7-дигидро-5-изобутирил-4- оксо-2-(4-пропиониламинофенил)тиено[2,3-b]пиридин или его соль;
(17) соединение, которое представляет собой 3-(N-бензил-N- метиламинометил)-7-(2,6-дифторбензил)-4,7-дигидро-5-изобутирил-2- (4-N'-метилуреидофенил)-4-оксотиено[2,3-b]пиридин или его соль;
(18) соединение, которое представляет собой 3-(N-бензил-N -метиламинометил)-7-(2,6-дифторбензил)-4,7-дигидро-2-(4-N'- метилуреидофенил)-4-оксотиено[2,3-b]пиридин-5-(N-изопропил)карбоксамид или его соль;
(19) соединение, которое представляет собой 3-(N-бензил-N- метиламинометил)-7-(2,6-дифторбензил)-4,7-дигидро-2-(4-N'- метилуреидофенил)-4-оксотиено[2,3-b]пиридин-5-(N-изопропил-N- метил)карбоксамид или его соль;
(20) соединение, которое представляет собой 3-(N-бензил-N- метиламинометил)-7-(2,6-дифторбензил)-4,7-дигидро-2- (4-N'- метилуреидофенил)-4-оксотиено[2,3-b]пиридин-5-(N-бензил-N-метил) карбоксамид или его соль;
(21) способ получения соединения по пункту (3), который включает взаимодействие соединения формулы III

где R⁴, R⁵ и n имеют те же значения, что и указанные по пункту (1);
R⁷ и R⁸ имеют те же значения, что и указанные по пункту (2);
R¹⁰ и m имеют те же значения, что и указанные по пункту (3);
X обозначает уходящую группу; или его соли с соединением формулы:
R⁹H,
где R⁹ имеет то же значение, что и указанное по пункту (3), или его солью;
(22) способ получения соединения по пункту (5), который включает взаимодействие соединения формулы IV

где R^11' обозначает группу формулы
Q-(CH₂)_p-
где Q обозначает арил, который может быть замещен a) атомом галогена, b) нитрогруппой, c) цианогруппой, d) аминогруппой, e) необязательно замещенной карбоксильной группой, f) низшей алкилендиоксигруппой или g) группой формулы: -A-R¹⁵, в которой А обозначает химическую связь или мостиковую группу, R¹⁵ обозначает алкил;
R^12' обозначает алкил, необязательно замещенный арил, необязательно замещенный аралкил или необязательно замещенный циклоалкил;
R¹⁴ и r имеют те же значения, что и указанные в пункте (4);
X обозначает уходящую группу; или его соли с соединением формулы
R¹³H
где R¹³ имеет то же значение, что и указанное в пункте (4), или его солью;
(23) композиция для ингибирования гонадотропинвысвобождающего гормона, которая содержит необязательно замещенное конденсированное бициклическое соединение, состоящее из гомо- или гетероциклического 5-7-членного кольца и гомо- или гетероциклического 5-7-членного кольца; носителя; наполнителя или разбавителя;
(24) композиция по пункту (23), где необязательно замещенное конденсированное бициклическое соединение представляет собой соединение формулы V

где кольцо W представляет собой необязательно замещенное гомо- или гетероциклическое 5-7-членное кольцо;
R¹⁶ является необязательно замещенным углеводородным остатком;
R¹⁷ обозначает атом водорода или группу, присоединенную посредством атома углерода, атома азота, атома кислорода или атома серы;
o обозначает 1 или 2;
(25) композиция по пункту (24), где кольцо W представляет собой кольцо формулы VI

где R¹ и R² каждый независимо обозначают атом водорода или группу, присоединенную через атом углерода, атом азота, атом кислорода или атом серы;
(26) композиция по пункту (23), где необязательно замещенное конденсированное бициклическое соединение является соединением формулы VII

где кольцо Y представляет собой необязательно замещенное гетероциклическое 5-7-членное кольцо;
R¹⁸ и R¹⁹ каждый независимо обозначают необязательно замещенный углеводородный остаток;
(27) композиция по пункту (26), где кольцо Y представляет собой кольцо формулы VIII

где R²⁰ и R²¹ каждый независимо обозначают атом водорода, необязательно замещенный углеводородный остаток;
(28) композиция по пункту (23), которая представляет собой композицию для предотвращения или лечения заболеваний, вызываемых половыми гормонами;
(29) композиция по пункту (23), которая представляет собой композицию для предотвращения или лечения рака, доброкачественной гипертрофии предстательной железы или миомы матки, зависимых от половых гормонов;
(30) композиция по пункту (29), в которой рак, зависимый от половых гормонов, включает рак предстательной железы, рак матки, рак молочной железы и аденому гипофиза;
(31) композиция по пункту (28), в которой заболевание, зависимое от половых гормонов, включает гипертрофию предстательной железы, эндометриоз, миому матки и преждевременное половое созревание;
(32) композиция для контроля за беременностью, которая содержит соединение или его соль, указанное в пункте (23), носитель, наполнитель или разбавитель;
(33) композиция для контролирования менструального цикла, которая содержит соединение или его соль, указанное по пункту (23), носитель, наполнитель или разбавитель; и
(34) композиция по пункту (32), которая представляет собой композицию для контрацепции;
(35) способ ингибирования гонадотропинвысвобождающего гормона у млекопитающего, нуждающегося в подобном лечении, который заключается во введении млекопитающему, страдающему от расстройства, вызываемого гонадотропинвысвобождающим гормоном, эффективного количества композиции по пункту (23);
(36) способ по пункту (35), где расстройством, вызываемым гонадотропинвысвобождающим гормоном, является заболевание, зависимое от половых гормонов;
(37) способ по пункту (35), где расстройством, вызываемым гонадотропинвысвобождающим гормоном, является рак, доброкачественная гипертрофия предстательной железы или миома матки, зависимые от половых гормонов;
(38) способ по пункту (37), где рак, зависимый от половых гормонов, включает рак предстательной железы, рак матки, рак молочной железы и аденому гипофиза;
(39) способ по пункту (36), где заболевание, зависимое от половых гормонов, выбирают из группы, включающей гипертрофию предстательной железы, эндометриоз, миому матки и преждевременное половое созревание;
(40) способ контроля за беременностью у млекопитающего, нуждающегося в подобном лечении, который заключается во введении эффективного количества композиции по пункту (23);
(41) способ контролирования менструального цикла у млекопитающего, нуждающегося в подобном лечении, который заключается во введении эффективного количества композиции по пункту (23);
(42) способ контрацепции у нуждающегося в этом млекопитающего, который заключается во введении эффективного количества композиции по пункту (23);
(43) использование необязательно замещенного конденсированного бициклического соединения, состоящего из гомо- или гетероциклического 5-7-членного кольца и гомо- или гетероциклического 5-7-членного кольца, для получения композиции, ингибирующей гонадотропинвысвобождающий гормон, с цельно ингибирования гонадотропинвысвобождающего гормона у млекопитающего, страдающего от расстройства, вызываемого гонадотропинвысвобождающим гормоном;
(44) использование по пункту (43), где расстройством, вызываемым гонадотропинвысвобождаюшим гормоном, является заболевание, зависимое от половых гормонов;
(45) использование по пункту (43), где расстройством, вызываемым гонадотропинвысвобождающим гормоном, является рак, доброкачественная гипертрофия предстательной железы или миома матки, зависимые от половых гормонов;
(46) использование по пункту (45), где рак, зависимый от половых гормонов, включает рак предстательной железы, рак матки, рак молочной железы и аденому гипофиза;
(47) использование по пункту (45), где заболевание, зависимое от половых гормонов, включает гипертрофию предстательной железы, эндометриоз, миому матки и преждевременное половое созревание;
(48) использование необязательно замещенного конденсированного бициклического соединения, состоящего из гомо- или гетероциклического 5-7-членного кольца и гомо- или гетероциклического 5-7-членного кольца, для получения композиции, ингибирующей гонадотропинвысвобождающий гормон, с целью контролирования беременности у нуждающегося в этом млекопитающего;
(49) использование необязательно замещенного конденсированного бициклического соединения, состоящего из гомо- или гетероциклического 5-7-членного кольца и гомо- или гетероциклического 5-7-членного кольца, для получения композиции, ингибирующей гонадотропинвысвобождающий гормон, с целью контролирования менструального цикла у нуждающегося в этом млекопитающего; и
(50) использование необязательно замещенного конденсированного бициклического соединения, состоящего из гомо- или гетероциклического 5-7-членного кольца и гомо- или гетероциклического 5-7-членного кольца, для получения композиции, ингибирующей гонадотропинвысвобождающий гормон, с целью контрацепции нуждающегося в этом млекопитающего.In particular, the present invention relates to (1) a compound of formula I

where R ¹ and R ² each independently represent a hydrogen atom or a group attached via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom;
R ³ is an optionally substituted homo- or heterocyclic group;
R ⁴ represents a hydrogen atom, a formyl group, a cyano group, lower alkyl substituted with a group that is attached via a sulfur atom, or a hydroxyl group; a carbonyl group substituted with a hydrocarbon residue, which optionally has substituents, an esterified or amidated carboxyl group;
R ⁵ is a hydrogen atom or a group attached via a carbon atom;
n denotes a number from 0 to 3, provided that the homo- or heterocyclic group designated R ³ does not contain, as a substituent, the group described in European Patent Application EP-A-443568 and European Patent Application EP-A-520423 and has the following formula:

where R ⁶ denotes an optionally substituted 5-7 membered heterocyclic group which contains, as a group capable of forming a ring, a carbonyl group, a thiocarbonyl group and an optionally oxidized sulfur atom, or a group that can be converted into them, a group that can form an anion or a group that can be converted into an anion;
Z is an optionally substituted aromatic hydrocarbon residue, optionally containing a heteroatom or an optionally substituted heterocyclic group;
V denotes a chemical bond or a bridging group, or a salt thereof;
(2) the compound according to paragraph (1), where R ³ denotes a group of the formula

where R ⁷ represents a hydrogen atom, a halogen atom or a group attached via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom;
R ⁸ is a hydrogen atom, a halogen atom, a nitro group, a cyano group or a hydrocarbon residue, which may be substituted by a group attached via an oxygen atom, a nitrogen atom or a sulfur atom;
(3) the compound according to paragraph (1), where any one of the radicals R ¹ or R ² denotes a group of the formula
R ⁹ - (CH ₂ ) _m -,
where R ⁹ denotes a group attached via a nitrogen atom;
m is a number from 0 to 3, and the other radical is a group of the formula
R ¹⁰ -A-
where R ¹⁰ denotes optionally substituted phenyl, and A denotes a chemical bond or a bridging group;
(4) a compound of formula II

where R ¹¹ denotes a hydrogen atom, lower alkyl or a group of the formula
Q- (CH ₂ ) _p -
where Q is aryl, which may be substituted by a) a halogen atom, b) a nitro group, c) a cyano group, d) an amino group, e) an optionally substituted carboxy group, f) a lower alkylenedioxy group or g) a group of the formula: -AR ¹⁵ in which A denotes a chemical bond or a bridging group, R ¹⁵ denotes an alkyl, optionally substituted cycloalkyl or optionally substituted heterocyclic group;
R ¹² is a hydrogen atom, alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl;
R ¹³ is an optionally substituted amino group;
R ¹⁴ is optionally substituted aryl;
r denotes a number from 0 to 3,
or its salt;
(5) the compound according to paragraph (4), wherein R ¹¹ is a group of the formula:
Q- (CH ₂ ) _p -
where Q is aryl, which may be substituted by a) a halogen atom, b) a nitro group, c) a cyano group, d) an amino group, e) an optionally substituted carboxy group, f) a lower alkylenedioxy group or g) a group of the formula: -AR ¹⁵ in which A denotes a chemical bond or a bridging group, R ¹⁵ denotes alkyl;
(6) the compound of (4), wherein Q is aryl which may be substituted by a halogen atom;
(7) the compound of (4), wherein R ¹³ is an optionally substituted monoaralkylamino group;
(8) the compound of (4), wherein R ¹³ is an optionally substituted benzylamino group;
(9) the compound of (4), wherein R ¹⁴ is optionally substituted phenyl;
(10) a compound which is 3- (N-benzyl-N-methylaminomethyl) -4,7-dihydro-7- (2-methoxybenzyl) -2- (4-methoxyphenyl) -4-oxotieno ethyl ester [2, 3-b] pyridine-5-carboxylic acid or a salt thereof;
(11) a compound which is 3- (N-benzyl-N-methylaminomethyl) -4,7-dihydro-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -4-oxothieno ethyl ester [2, 3-b] pyridine-5-carboxylic acid or a salt thereof;
(12) a compound which is ethyl 2- (4-acetylaminophenyl) -3- (N-benzyl-N-methylaminomethyl) -4,7-dihydro-7- (2-fluorobenzyl) -4-oxo-thieno [2, 3-b] pyridine-5-carboxylic acid or a salt thereof;
(13) a compound which is 5-benzylamino-methyl- 1- (2-chloro-6-fluorobenzyl) -2,4- (1H, 3H) dioxo-6- (4-methoxyphenyl) -3-phenylthieno [ 2,3-d] pyrimidine or a salt thereof;
(14) a compound which is 5-benzoyl-3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-4-oxo-2- (4-propionylaminophenyl ) thieno [2, 3-b] pyridine or its salt;
(15) a compound that is 5-benzoyl-3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-2- (4-N'-methylureidophenyl) -4-oxo-thieno [2,3-b] pyridine or a salt thereof;
(16) a compound that is 3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-5-isobutyryl-4-oxo-2- (4-propionylaminophenyl ) thieno [2,3-b] pyridine or a salt thereof;
(17) a compound that is 3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-5-isobutyryl-2- (4-N'-methylureidophenyl) -4-oxo-thieno [2,3-b] pyridine or a salt thereof;
(18) a compound which is 3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-2- (4-N'-methylureidophenyl) -4-oxothieno [2,3-b] pyridin-5- (N-isopropyl) carboxamide or a salt thereof;
(19) a compound which is 3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-2- (4-N'-methylureidophenyl) -4-oxo-thieno [2,3-b] pyridin-5- (N-isopropyl-N-methyl) carboxamide or a salt thereof;
(20) a compound which is 3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-2- (4-N'-methylureidophenyl) -4-oxo-thieno [2,3-b] pyridin-5- (N-benzyl-N-methyl) carboxamide or a salt thereof;
(21) a method for producing a compound according to paragraph (3), which comprises reacting a compound of formula III

where R ⁴ , R ⁵ and n have the same meanings as specified in paragraph (1);
R ⁷ and R ⁸ have the same meanings as specified in paragraph (2);
R ¹⁰ and m have the same meanings as indicated in paragraph (3);
X is a leaving group; or its salt with a compound of the formula:
R ⁹ H
where R ⁹ has the same meaning as specified in paragraph (3), or its salt;
(22) a method for producing a compound according to (5), which comprises reacting a compound of formula IV

where R ^{11 '} denotes a group of the formula
Q- (CH ₂ ) _p -
where Q is aryl, which may be substituted by a) a halogen atom, b) a nitro group, c) a cyano group, d) an amino group, e) an optionally substituted carboxy group, f) a lower alkylene dioxo group, or g) a group of the formula: -AR ¹⁵ in which A denotes a chemical bond or a bridging group, R ¹⁵ denotes alkyl;
R ^{12 ′} is alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted cycloalkyl;
R ¹⁴ and r have the same meanings as specified in paragraph (4);
X is a leaving group; or its salt with a compound of the formula
R ¹³ H
where R ¹³ has the same meaning as specified in paragraph (4), or its salt;
(23) a composition for inhibiting gonadotropin releasing hormone, which comprises an optionally substituted fused bicyclic compound consisting of a homo- or heterocyclic 5-7 membered ring and a homo- or heterocyclic 5-7 membered ring; carrier; filler or diluent;
(24) the composition of (23), wherein the optionally substituted fused bicyclic compound is a compound of formula V

where the ring W is an optionally substituted homo- or heterocyclic 5-7 membered ring;
R ¹⁶ is an optionally substituted hydrocarbon residue;
R ¹⁷ represents a hydrogen atom or a group attached via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom;
o is 1 or 2;
(25) the composition according to paragraph (24), where the ring W is a ring of formula VI

where R ¹ and R ² each independently represent a hydrogen atom or a group attached via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom;
(26) the composition of (23), wherein the optionally substituted fused bicyclic compound is a compound of formula VII

where ring Y is an optionally substituted heterocyclic 5-7 membered ring;
R ¹⁸ and R ¹⁹ each independently represent an optionally substituted hydrocarbon residue;
(27) the composition according to paragraph (26), where the ring Y is a ring of formula VIII

where R ²⁰ and R ²¹ each independently represent a hydrogen atom, an optionally substituted hydrocarbon residue;
(28) the composition of (23), which is a composition for preventing or treating diseases caused by sex hormones;
(29) the composition of (23), which is a composition for preventing or treating cancer, benign prostatic hypertrophy, or uterine fibroids dependent on sex hormones;
(30) the composition of (29), wherein the sex hormone dependent cancer includes prostate cancer, uterine cancer, breast cancer, and pituitary adenoma;
(31) the composition of (28), wherein the sex hormone-dependent disease comprises prostate hypertrophy, endometriosis, uterine fibroids, and premature puberty;
(32) a pregnancy control composition that contains a compound or its salt as set forth in paragraph (23), a carrier, excipient or diluent;
(33) a composition for controlling the menstrual cycle, which contains the compound or its salt according to (23), a carrier, excipient or diluent; and
(34) the composition according to (32), which is a composition for contraception;
(35) a method for inhibiting gonadotropin-releasing hormone in a mammal in need of a similar treatment, which is to administer to a mammal suffering from a disorder caused by gonadotropin-releasing hormone an effective amount of a composition according to paragraph (23);
(36) the method of (35), wherein the disorder caused by gonadotropin releasing hormone is a sex hormone dependent disease;
(37) the method of (35), wherein the disorder caused by gonadotropin releasing hormone is cancer, benign prostatic hypertrophy or uterine fibroids, dependent on sex hormones;
(38) the method of (37), wherein the sex hormone dependent cancer comprises prostate cancer, uterine cancer, breast cancer, and pituitary adenoma;
(39) the method of paragraph (36), wherein the sex hormone-dependent disease is selected from the group consisting of prostatic hypertrophy, endometriosis, uterine fibroids and premature puberty;
(40) a method for controlling pregnancy in a mammal in need of a similar treatment, which comprises administering an effective amount of a composition according to (23);
(41) a method for controlling the menstrual cycle in a mammal in need of a similar treatment, which comprises administering an effective amount of a composition according to (23);
(42) a method of contraception in a mammal in need thereof, which comprises administering an effective amount of a composition according to paragraph (23);
(43) using an optionally substituted fused bicyclic compound consisting of a homo- or heterocyclic 5-7-membered ring and a homo- or heterocyclic 5-7-membered ring to obtain a gonadotropin-releasing hormone inhibiting composition to completely inhibit gonadotropin-releasing hormone in a mammal, suffering from a disorder caused by gonadotropin releasing hormone;
(44) the use of (43), wherein the disorder caused by gonadotropin-releasing hormone is a sex hormone dependent disease;
(45) the use of (43), wherein the disorder caused by gonadotropin-releasing hormone is cancer, benign prostatic hypertrophy or uterine fibroids dependent on sex hormones;
(46) the use of (45), wherein sex hormone dependent cancer includes prostate cancer, uterine cancer, breast cancer, and pituitary adenoma;
(47) the use of (45), wherein the sex hormone dependent disease includes prostate hypertrophy, endometriosis, uterine fibroids and premature puberty;
(48) using an optionally substituted fused bicyclic compound consisting of a homo- or heterocyclic 5-7-membered ring and a homo- or heterocyclic 5-7-membered ring to obtain a gonadotropin-releasing hormone inhibiting composition in order to control pregnancy in a person in need thereof a mammal;
(49) using an optionally substituted fused bicyclic compound consisting of a homo- or heterocyclic 5-7-membered ring and a homo- or heterocyclic 5-7-membered ring to obtain a gonadotropin-releasing hormone inhibiting composition in order to control the menstrual cycle of the needy this mammal; and
(50) using an optionally substituted fused bicyclic compound consisting of a homo- or heterocyclic 5-7 membered ring and a homo- or heterocyclic 5-7 membered ring to produce a gonadotropin-releasing hormone inhibiting composition for contraception of a mammal in need thereof.

Examples of groups attached through a carbon atom designated R ¹ , R ² , R ⁵ and R ⁷ include those groups, each of which optionally contains substituents, such as alkyl (in particular, (C ₁ -C ₆ ) alkyl, such as methyl , ethyl, propyl, iso-propyl, butyl, tert-butyl, pentyl and hexyl), cycloalkyl (in particular (C ₃ -C ₆ ) cycloalkyl such as cyclopropyl, cyclopentyl and cyclohexyl), alkoxyalkyl (in particular (C ₁ -C ₃ ) alkoxy (C ₁ -C ₆ ) alkyl, such as methoxymethyl, ethoxymethyl, ethoxybutyl and propoxyhexyl), hydroxyalkyl (in particular hydroxy (C ₁ -C ₆ ) alkyl, such as hydroxymethyl, hydroxyethyl, hydroxybutyl and hydroxypropyl), alkenyl (in particular (C ₂ -C ₆ ) alkenyl such as vinyl, butadienyl and hexatrienyl), formyl group, carboxyl group, alkoxycarbonyl group (in particular (C ₁ -C ₆ ) an alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group and a tert-butoxycarbonyl group), a cyano group, an amido group, a mono-dialkylcarbamoyl group (in particular a mono-, di (C ₁ -C ₆ ) alkylcarbamoyl group, such as a methylcarbamoyl group, ethylcarbamoyl group, hex ilkarbamoilnaya group, methylethylcarbamoyl group and a dimethylcarbamoyl group), an amidino group, an aryl (in particular, (C ₆ -C ₁₄₎ aryl such as phenyl, naphthyl and anthracenyl), aralkyl (particularly, (C ₇ -C ₂₀₎ aralkyl such such as benzyl, benzhydryl and trityl) and heterocyclic groups bonded to a carbon atom (in particular, 5-membered cyclic groups containing, in addition to carbon atoms, from 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, as 2- or 3-thienyl group, 2- or 3-furyl group, 2- or 3-pyrrolyl group pa, 2-, 3- or 4-pyridyl group, 2-, 4- or 5-oxazolyl group, 2-, 4- or 5-thiazolyl group, 3-, 4- or 5-pyrazolyl group, 2, 4- or 5-imidazolyl group, 3-, 4- or 5-isoxazolyl group, 3-, 4- or 5-isothiazolyl group, 3- or 5- (1,2,4-oxadiazolyl group), 1,3,4- oxadiazolyl group, 3- or 5- (1,2,4-thiadiazolyl group), 1,3,4-thiadiazolyl group, 4- or 5- (1,2,3-thiadiazolyl group), 1,2,5- a thiadiazolyl group, a 1,2,3-triazolyl group, a 1,2,4-triazolyl group and a 1H- or 2H-tetrazolyl group; 6-membered cyclic groups containing, in addition to carbon atoms, from 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, such as an N-oxide-2-, 3- or 4-pyridyl group, 2-, 4 - or a 5-pyrimidinyl group, an N-oxide-2-, 4- or 5-pyrimidinyl group, a 2- or 3-thiomorpholinyl group, a 2- or 3-morpholinyl group, an oxoimidazinyl group, a dioxotriazinyl group, a pyrrolidinyl group, a piperidinyl group, pyranyl group, thiopyranyl group, 1,4-oxadinyl group, 1,4-thiazinyl group, 1,3-thiazinyl group na, 2- or 3-piperazinyl group, triazinyl group, oksotriazinilnaya group, 3- or 4-pyridazinyl group, a pyrazinyl group or N-oxido-3- or 4-pyridazinyl group; and 5-8 membered cyclic groups or their condensed rings containing, in addition to carbon atoms, from 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, for example bicyclic or tricyclic condensed cyclic groups containing, in addition to carbon atoms, from 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, such as a benzofuranyl group, a benzothiazolyl group, a benzoxazolyl group, a tetrazolo [1,5-b] pyridazinyl group, a triazolo [4,5-b] pyridazinyl group, benzoimide azolyl group, quinolinyl group, isoquinolinyl group, cinnolinyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, indolysinyl group, quinolysinyl group, 1,8-naphthylisinyl group, purinyl group, pteridinyl group, dibenzofuranyl group, phenridiene, carbide group, chromanyl group, benzoxazinyl group, phenazinyl group, phenothiazinyl group and phenoxazinyl group).

Examples of substituents which may have the above groups attached via a carbon atom include (C ₆ -C ₁₄ ) aryl (in particular phenyl or naphthyl) optionally substituted with 1-4 substituents selected, for example, from (a) hydroxyl group, (b) amino groups, (c) mono- or di- (C ₁ -C ₆ ) alkylamino groups (in particular methylamino groups, ethylamino groups) and (d) (C ₁ -C ₆ ) alkoxy groups (in particular, methoxy groups, ethoxy groups, propoxy groups and hexyloxy groups) and (e) a halogen atom (fluorine, chlorine, bromine, iodine); a mono- or di- (C ₁ -C ₆ ) alkylamino group (in particular a methylamino group, an ethylamino group, a propylamino group, a dimethylamino group and a diethylamino group); A (C ₁ -C ₄ ) acylamino group (in particular, a formylamino group and an acetylamino group); hydroxyl group; carboxyl group; nitro group; A (C ₁ -C ₆ ) alkoxy group (in particular, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group and a butoxy group); (C ₁ -C ₆ ) alkylcarbonyloxy group (in particular, acetoxy group and ethylcarbonyloxy group), a halogen atom (in particular fluorine, chlorine, bromine and iodine), and such optionally substituted groups attached via a nitrogen atom, such as the groups below. The number of substituents is from 1 to 6, preferably from 1 to 3.

Examples of groups attached through a nitrogen atom and designated R ¹ , R ² , R ⁷ , R ⁹ or R ¹⁷ include groups, each of which optionally contains substituents, which have the formula
-NR ²² R ²³
where R ²² represents a hydrogen atom, alkyl, cycloalkyl, aryl, heterocyclic groups and —SO _p - (p is 1 or 2), and R ¹⁴ represents a hydrogen atom or alkyl, and heterocyclic groups attached via a nitrogen atom (in particular, 1H -1-pyrrolyl group, 1-imidazolyl group, pyrazolyl group, indolyl group, 1H-1-indazolyl group, 7-purinyl group, 1-pyrrolidinyl group, 1-pyrrolinyl group, 1-imidazolidinyl group, pyrazolidinyl group, piperazinyl group, pyrazolidinyl group, 4-morpholinyl group 4-thiomorpholinyl group). These alkyl, cycloalkyl, aryl or heterocyclic groups have the same meanings as previously indicated.

Examples of substituents which may have groups attached via a nitrogen atom include (C ₁ -C ₆ ) alkyl (in particular methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl and tert-butyl) , (C ₂ -C ₆ ) alkenyl (in particular vinyl, 1-methyl vinyl, 1-propenyl and allyl), (C ₂ -C ₆ ) alkynyl (in particular ethinyl, 1-propynyl and propargyl), (C ₃ -C ₆ ) cycloalkyl (in particular cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), (C ₅ -C ₇ ) cycloalkenyl (in particular cyclopentyl and cyclohexenyl), (C ₇ -C ₁₁ ) aralkyl (in particular benzyl, alpha -methylbenzyl and phenethyl), (C ₆ -C ₁₄ ) aryl (in particular osti, phenyl and naphthyl), (C ₁ -C ₆ ) alkoxy group (in particular, methoxy group, ethoxy group, propoxy group, iso-propoxy group, n-butoxy group, iso-butoxy group, sec-butoxy group and tert-butoxy group), (C ₆ - C ₁₄ ) an aryloxy group (in particular a phenoxy group), (C ₁ -C ₆ ) an alkanoyl group (in particular a formyl group, an acetyl group, a propionyl group, an n-butyryl group and an isobutyl group), (C ₆ -C ₁₄ ) an arylcarbonyl group (in particular, a benzoyl group), (C ₁ -C ₆ ) alkanoyloxy group (in particular, formyloxy group, acetyloxy group, propi onyloxy group, n-butyryloxy group and isobutyryloxy group), (C ₆ - C ₁₄ ) arylcarbonyloxy group (in particular, benzoyloxy group), carboxy group, (C ₁ -C ₆ ) alkoxycarbonyl group (in particular, methoxycarbonyl group, ethoxycarbonyl group propoxycarbonyl group, iso-propoxycarbonyl group, n-butoxycarbonyl group, iso-butoxycarbonyl group and tert-butoxycarbonyl group), carbamoyl group, N-mono (C ₁ -C ₄ ) alkylcarbamoyl group (in particular, N-methylcarbamoyl group, N- ethyl carbamoyl gro pu, N-propylcarbamoyl group, N-iso-propylcarbamoyl group, N-butylcarbamoyl group), N, N-di- (C ₁ -C ₄₎ alkylcarbamoyl group (in particular, N, N-dimethylcarbamoyl group, N, N- diethylcarbamoyl group, N, N-dipropylcarbamoyl group and N, N-dibutylcarbamoyl group), a cyclic aminocarbonyl group, in particular a 1-aziridinylcarbonyl group, 1-azetidinylcarbonylphenyl group, 1-pyrrolidinylcarbonylphenylphenylphenylphenylphenylphenyl group, 1-pyrrolidinylcarbonylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylmethyl group, 1-pyrrolidinylcarbonylphenyl group morpholinkarbonyl group), atom g logena (fluorine, chlorine, bromine and iodine), mono-, di- or trihalo (C ₁ -C ₄₎ alkyl (especially, chloromethyl, dichloromethyl, trifluoromethyl and trifluoroethyl), oxo, amidino, imino, amino, mono- or di- (C ₁ -C ₄ ) alkylamino group (in particular methylamino group, ethylamino group, propylamino group, iso-propylamino group, butylamino group, diethylamino group, di-iso-propylamino group and dibutylamino-6-amino-3-cycloamino , in addition to the carbon atom and one nitrogen atom, from up to three heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom (in particular, an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a pyrrolinyl group, a pyrrolyl group, a pyrazolyl group, an imidazolidinyl group, a piperidino group, a morpholino group, a dihydro diphenopyropyrino dihydroperipirin group group and N-ethylpiperazinyl group), (C ₁ - C ₆ ) alkanoylamino group (in particular, the formamide group, acetamide group, trifluoroacetamide group, propionylimido group, butyrylamido group and iso-butyrylamido group), benzamido group, carbamoylamino group, N- (C ₁ -C ₄ ) alkylcarbamoylamino group (in particular, N-methylcarbamoylamino group, N-ethylcarbamoylamino group, N-propylcarbamoylaminoamino-butylamino-amino-butylamino-amino-butylamino-amino-butylamino-amino-butylamino-amino-amino-butylamino-amino-butylamino-amino-butylamino-amino-butylamino-amino di- (C ₁ -C ₄₎ alkilkapbamoilaminogruppu (in particular, N, N-dimetilkarbamoilaminogruppu, N, N-dietilkarbamoilaminogruppu, N, N-dipropilkarbamoilaminogruppu and N, N-dibutilkarbamoilaminogruppu), (C ₁ -C ₃₎ alkylenedioxy (particularly , methylenedioxy group and ethylenedioxy group), -B (OH) ₂ , hydro a strong group, an epoxy (-O-) group, a nitro group, a cyano group, a mercapto group, a sulfo group, a sulfino group, a phosphono group, a dihydroxyboryl group, a sulfamoyl group, a (C ₁ -C ₆ ) alkylsulfamoyl group, in particular an N-methylsulfamoyl group, group, N-propylsulfamoyl group, N-isopropylsulfamoyl group and N-butylsulfamoyl group), di- (C ₁ -C ₆ ) alkylsulfamoyl group (in particular, N, N-dimethylsulfamoyl group, N, N-diethylsulfamoyl group, N , N-dipropylsulfamoyl group and N, N-dibutylsulfon moilnuyu group), (C ₁ -C ₆₎ alkylthio (in particular methylthio, ethylthio, propylthio, iso-propylthio, n-butylthio, sec-butylthio and tert-butylthio), phenylthio, (C ₁ -C ₆₎ alkylsulfinyl group (in particular, methylsulfinyl group, ethylsulfinyl group, propylsulfinyl group and butylsulfinyl group), phenylsulfinyl group, (C ₁ -C ₆ ) alkylsulfonyl group (in particular, methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group and butylsulfonyl group y) a phenylsulfonyl group. The number of substituents varies from 1 to 6, preferably from 1 to 3.

Examples of groups attached through an oxygen atom and designated R ¹ , R ² and R ⁷ include a hydroxyl group and groups each of which optionally contain substituents, such as alkoxy, cycloalkoxy, aryloxy, aralkyloxy and heterocyclic hydroxyl groups. Alkyl, cycloalkyl, aryl, aralkyl and heterocyclic groups in the indicated alkoxy group, cycloalkoxy group, aryloxy group, aralkyloxy group and heterocyclic hydroxyl groups have the same meanings as above.

 The substituents which may have the indicated oxygen atom have the same meanings as the above groups attached via the nitrogen atom.

Examples of groups attached through a sulfur atom and designated R ¹ , R ² , R ⁷ and R ¹² include a mercapto group, an alkylthio group, a cycloalkylthio group, an arylthio group, an aralkylthio group and heterocyclic thio groups. Alkyl, cycloalkyl, aryl, aralkyl and heterocyclic groups in the indicated alkylthio group, cycloalkylthio group, arylthio group, aralkylthio group and heterocyclic thio groups have the same meanings as above.

 The substituents which may have the indicated sulfur atom have the same meanings as the above groups attached via a nitrogen atom.

Examples of homocyclic groups in the optionally substituted homocyclic groups designated R ³ include 3-7 membered cyclic hydrocarbon groups consisting only of carbon atoms, for example, (C ₃ -C ₇ ) cycloalkane (in particular cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane) and (C ₃ -C ₇ ) cycloalkene (in particular cyclopropene, cyclobutene, cyclopentene, cyclohexene and cycloheptene).

Examples of substituents that may have these homocyclic groups include (C ₁ -C ₁₅ ) alkyl (in particular methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl , heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and pentadecyl), (C ₃ - C ₁₀ ) cycloalkyl (in particular cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), (C ₂ -C ₁₀ ) alkenyl ( in particular, vinyl, allyl, 2-methylallyl, 2-butenyl, 3-butenyl and 3-octenyl), (C ₂ -C ₁₀ ) alkynyl (in particular ethynyl, 2-propynyl and 3-hexynyl), (C ₃ -C ₁₀₎ cycloalkenyl (especially, the cycle propenyl, cyclopentenyl and cyclohexenyl), (C ₆ - C ₁₀₎ aryl (especially phenyl and naphthyl), (C ₇ -C ₁₉₎ aralkyl (especially benzyl, phenylethyl and trityl), a nitro group, a hydroxyl group, a mercapto group, oxo group, thioxo group, cyano group, carbamoyl group, carboxyl group, (C ₁ -C ₅ ) alkoxycarbonyl group (in particular, methoxycarbonyl group and ethoxycarbonyl group), sulfo group, halogen atom (in particular, fluorine, chlorine, bromine and iodine), ( C ₁ -C ₆ ) alkoxy group (in particular, methoxy group, ethoxy group, propoxy group, iso-propoxy group pu, butoxy group, iso-butoxy group, sec-butoxy group and tert-butoxy group), (C ₆ -C ₁₀ ) aryloxy group (in particular, phenoxy group), (C ₁ -C ₆ ) alkylthio group (in particular methylthio group, ethylthio group, n- propylthio group, iso-propylthio group, n-butylthio group and tert-butylthio group), (C ₆ -C ₁₀ ) arylthio group (in particular phenylthio group), (C ₁ -C ₆ ) alkylsulfinyl group (in particular methylsulfinyl group and ethylsulfinyl group), (C ₆ -C ₁₀₎ arylsulfinyl group (particularly fenilsulfinilnuyu group), (C ₁ -C ₆₎ alkylsulfonyl group (in ca tnosti, methylsulfonyl group and ethylsulfonyl group), (C ₆ -C ₁₀₎ arylsulfonyl group (particularly phenylsulfonyl group), amino, (C ₁ -C ₆₎ acylamino (especially acetylamino and propylamino group), a mono- or di- (C ₁ -C ₄ ) alkylamino group (in particular methylamino group, ethylamino group, n-propylamino group, iso-propylamino group, n-butylamino group, dimethylamino group and diethylamino group), (C ₃ -C ₈ ) cycloalkylamino group, in particular cyclopropylamino-cycloamino and cyclo eksilaminogruppu), (C ₆ -C ₁₀₎ arylamino group (in particular, anilino), (C ₁ -C ₆₎ alkanoyl group (especially, a formyl group, an acetyl group and a hexanoyl group), (C ₆ -C ₁₀₎ arylcarbonyl ( in particular benzoyl) and 5- or 6-membered heterocyclic groups containing, in addition to carbon atoms, from 1 to 4 heteroatoms selected from an oxygen, sulfur or nitrogen atom (in particular, a 2- or 3-thienyl group, 2- or 3-furyl group, 3-, 4- or 5-pyrazolyl group, 2-, 4- or 5-thiazolyl group, 3-, 4- or 5-isothiazolyl group, 2-, 4- or 5-oxazolyl group uppu, 3-, 4- or 5-isoxazolyl group, 2-, 4- or 5-imidazolyl group, 1,2,3- or 1,2,4-triazolyl group, 1H or 2H-tetrazolyl group, 2-, 3- or 4-pyridyl group, 2-, 4- or 5-pyrimidyl group, 3- or 4-pyridazinyl group, quinolinyl group, isoquinolinyl group and indolyl group). The number of substituents varies from 1 to 6, preferably from 1 to 3.

Examples of the above optionally substituted heterocyclic groups designated R ³ include 5-8 membered cyclic groups or a fused ring thereof containing, in addition to carbon atoms, from 1 to 4 heteroatoms such as an oxygen atom, a sulfur atom and a nitrogen atom, for example 5- cyclic membered groups containing, in addition to carbon atoms, from 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, such as a 2- or 3-thienyl group, a 2- or 3-furyl group, 2- or 3- pyrrolyl group, 2-, 3- or 4-pyridyl group, 2-, 4- or 5-oxazolyl group, 2-, 4- or 5-thiazolyl group, 3-, 4- or 5-pyrazolyl group, 2, 4- or 5-imidazolyl group, 3-, 4- or 5-isoxazolyl group, 3- A 4- or 5-isothiazolyl group, a 3- or 5- (1,2,4-oxadiazolyl group), a 1,3,4-oxazolyl group, a 3- or 5- (1,2,4-thiadiazolyl group), 1,3,4-thiadiazolyl group, 4- or 5- (1,2,3-thiadiazolyl group), 1,2,5-thiadiazolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl a group and a 1H- or 2H-tetrazolyl group; 6-membered cyclic groups containing, in addition to carbon atoms, from 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, such as an N-oxide-2-, 3- or 4-pyridyl group, 2-, 4 - or 5-pyrimidinyl group, N-oxide-2-, 4- or 5-pyrimidinyl group, thiomorpholinyl group, morpholinyl group, oxoimidazinyl group, dioxotriazinyl group, pyrrolidinyl group, piperazinyl group, pyraninyl group, thiopyranyl group, 1,4- oxazinyl group, 1,4-thiazinyl group, 1,3-thiazinyl group, piperazi a nyl group, a triazinyl group, an oxotriazinyl group, a 3- or 4-pyridazinyl group, a pyrazinyl group or an N-oxide-3- or 4-pyridazinyl group; bicyclic or tricyclic fused cyclic groups containing, in addition to carbon atoms, from 1 to 4 heteroatoms selected from a sulfur atom and a nitrogen atom, for example, a benzofuranyl group, a benzothiazolyl group, a benzoxazolyl group, a tetrazolo [1,4-b] pyridazinyl group, a triazolo [4,5-b] pyridazinyl group, benzoimidazolyl group, quinolinyl group, isoquinolinyl group, cinnolinyl group, phthaladinyl group, quinazolinyl group, quinoxalinyl group, indolidinyl group, quinolidinyl ith group, 1,8-naphthylidinyl group, purinyl group, pteridinyl group, dibenzofuranyl group, carbazolyl group, acridinyl group, phenanthridinyl group, chromanyl group, benzoxadinyl group, phenazinyl group, phenothiazinyl group and phenoxazinyl group.

Examples of substituents which may have these heterocyclic groups include (C ₁ -C ₆ ) alkyl (in particular methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl and tert-butyl), (C ₂ -C ₆ ) alkenyl (in particular vinyl, 1-methylvinyl, 1-propenyl and allyl), (C ₂ -C ₆ ) alkynyl (in particular ethynyl, 1-propynyl and propargyl), (C ₃ -C ₆ ) cycloalkyl (in particular cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), (C ₅ - C ₇ ) cycloalkenyl (in particular cyclopentenyl and cyclohexenyl), (C ₇ -C ₁₁ ) aralkyl (in particular benzyl, alpha-methylbenzyl and phenethyl), (C ₆ -C ₁₄₎ aryl (in particular ti, phenyl and naphthyl), (C ₁ -C ₆₎ alkoxy (in particular methoxy, ethoxy, propoksirgruppu, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy group), (C ₆ - C ₁₄ ) aryloxy group
(in particular, phenoxy), (C ₁ -C ₆ ) alkanoyl group (in particular, formyl group, acetyl group, propionyl group, n-butyryl group and isobutyl group), (C ₆ -C ₁₄ ) arylcarbonyl group ( in particular, a benzoyl group), (C ₁ -C ₆ ) alkanoyloxy group (in particular, formyloxy group, acetyloxy group, propionyloxy group, n-butyryloxy group and iso-butyryloxy group), (C ₆ -C ₁₄ ) arylcarbonyloxy group (in particular, benzoyloxy group, (C ₁ -C ₆ ) alkoxycarbonyl group (in particular methoxycarbonyl group ppu, ethoxycarbonyl group, n-propoxycarbonyl group, iso-propoxycarbonyl group, n-butoxycarbonyl group, iso-butoxycarbonyl group and tert-butoxycarbonyl group), carbamoyl group, N-mono (C ₁ -C ₄ ) alkylcarbamoyl group (in particular N-methylcarbamoyl group, N-ethylcarbamoyl group, N-propylcarbamoyl group, N-iso-propylcarbamoyl group and N-butylcarbamoyl group), N, N-di- (C ₁ -C ₄ ) alkylcarbamoyl group (in particular, N, N -dimethylcarbamoyl group, N, N-diethylcarbamoyl group, N, N-dtpropi a carbamoyl group and an N, N-dibutylcarbamoyl group), a cyclic aminocarbonyl group (in particular, a 1-aziridinylcarbonyl group, a 1-azetidinylcarbonyl group, a 1-pyrrolidinylcarbonyl group, a 1-piperidinylcarbonyl group, an N-methylpipenoylcarbonyl group and an N-methylpipinoylcarbinyl group) fluorine, chlorine, bromine and iodine), mono-, di- or trihalo (C ₁ -C ₄ ) alkyl (in particular chloromethyl, dichloromethyl, trifluoromethyl and trifluoroethyl), oxo group, amidino group, imino group, amino group, mono- or di- (C ₁ -C ₄ ) alkylamino a group (in particular, a methylamino group, an ethylamino group, a propylamino group, an iso-propylamino group, a butylamino group, a dimethylamino group, a diethylamino group, a dipropylamino group, a di-iso-propylamino group and a dibutylamino group) from one to three heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom (in particular, an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a pyrrolinyl group, pyrrolyl g uppu, imidazolyl group, pyrazolyl group, imidazolidinyl group, piperidino group, morpholino group, digidropropiridilnuyu group, a pyridyl group, a N-methylpiperazinyl group, N-etilpiperazinilnuyu group), (C ₁ -C ₆₎ alkanoylamino (especially formamidogruppu, acetamido, triftoratsetamidogruppu, propionylamido group, butyrylamido group and iso-butyrylamido group), benzamide group, carbamoylamino group, N- (C ₁ -C ₄ ) alkylcarbamoylamino group (in particular, N-methylcarbamoylamino group, N-ethylcarbamoylamino N-propylcarbamoylamino group, N-iso-propylcarbamoylamino group and N-butylcarbamoylamino group), N, N-di- (C ₁ -C ₄ ) alkylcarbamoylamino group (in particular, N, N-dimethylcarbamoylamino group, N, N-amino-diamylamino and N, N-dibutylcarbamoylamino group), (C ₁ -C ₃ ) alkylenedioxy group (in particular, methylenedioxy group and ethylenedioxy group), -B (OH) ₂ , hydroxyl group, epoxy (-O-) group, nitro group, cyano group, mercapt , sulfino group, phosphono group, dihydroxyboryl group, sulfamoyl group PUF, (C ₁ -C ₆₎ alkilsulfamoilnuyu group (in particular, N-metilsulfamoilnuyu group, N-ethylsulfamoyl group, N-propilsulfamoilnuyu group, N-iso-propilsulfamoilnuyu group and N-butilsulfamoilnuyu group), di- (C ₁ -C ₆ ) an alkyl sulfamoyl group (in particular, an N, N-dimethyl sulfamoyl group, an N, N-diethyl sulfamoyl group, an N, N-dipropyl sulfamoyl group and an N, N-dibutyl sulfamoyl group), a (C ₁ -C ₆ ) alkylthio group (particularly methyl , ethylthio group, propylthio group, iso-propylthio group, n-butylthio group, sec-butylthio group and t-b utylthio group), phenylthio group, (C ₁ -C ₆ ) alkylsulfinyl group (in particular, methylsulfinyl group, ethylsulfinyl group, propylsulfinyl group and butylsulfinyl group), phenylsulfinyl group, (C ₁ -C ₆ ) alkylsulfonyl group (in particular methylsulfonyl group ethylsulfonyl group, propylsulfonyl group and butylsulfonyl group), phenylsulfonyl group. The number of substituents varies from 1 to 6, preferably from 1 to 3.

As the ester group in the optionally esterified carboxyl group designated R ⁴ , for example, alkyl, cycloalkyl, aryl and heterocyclic groups can be indicated, and they have the same meanings as mentioned above.

Examples of amidated carboxyl groups designated R ⁴ include groups of the formula — CONR ²² R ²³ (wherein R ²² and R ²³ have the same meanings as previously defined).

As lower alkyl in lower alkyl substituted with a group which is attached via a sulfur atom and is designated R ⁴ , for example, mention should be made of, for example, (C ₁ -C ₆ ) alkyl, such as methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, pentyl, hexyl and the like. A group attached via a sulfur atom has the same meaning as previously defined.

Lower alkyl in lower alkyl substituted with an optionally substituted hydroxyl group, which is designated R ⁴ , has the same meaning as previously defined.

As substituents on the lower alkyl group containing an optionally substituted hydroxyl, previously designated R ⁴ , for example, (C ₁ -C ₆ ) alkyl (in particular methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl), optionally containing from 1 to 4 substituents selected from a halogen atom (in particular chlorine, bromine and fluorine), (C ₆ - C ₁₀ ) aryl (in particular phenyl and naphthyl), (C ₇ -C ₁₂ ) aralkyl (in particular benzyl and phenylethyl) and nitro groups; (C ₆ -C ₁₀ ) aryl (in particular phenyl and naphthyl), optionally containing from 1 to 4 substituents selected from a halogen atom (in particular chlorine, bromine and fluorine), (C ₁ -C ₆ ) alkyl (in in particular methyl, ethyl and n-propyl), (C ₆ - C ₁₀ ) aryl (in particular phenyl and naphthyl); (C ₇ -C ₁₂ ) aralkyl (in particular benzyl, phenylethyl and naphthylmethyl) optionally containing from 1 to 4 substituents selected from a halogen atom (in particular chlorine, bromine and fluorine), (C ₁ -C ₆ ) alkyl (in particular methyl, ethyl and n-propyl), (C ₆ -C ₁₀ ) aryl (in particular phenyl and naphthyl), (C ₇ -C ₁₂ ) aralkyl (in particular benzyl and phenethyl) and nitro groups; (C ₁ -C ₆ ) alkylcarbonyl group (in particular, acetyl group and propionyl group), optionally containing from 1 to 3 substituents selected from formyl group, halogen atom (in particular, chlorine, bromine and fluorine), (C ₁ - C ₆ ) alkyl (in particular methyl, ethyl and n-propyl), (C ₆ -C ₁₀ ) aryl (in particular phenyl and naphthyl), (C ₇ -C ₁₂ ) aralkyl (in particular benzyl and phenylethyl) and nitro groups; A (C ₆ -C ₁₀ ) aryloxycarbonyl group (in particular a phenyloxycarbonyl group and a naphthyloxycarbonyl group) optionally containing from 1 to 4 substituents selected from a halogen atom (in particular chlorine, bromine and fluorine), (C ₁ -C ₆ ) alkyl (in particular methyl, ethyl and n-propyl), (C ₆ -C ₁₀ ) aryl (in particular phenyl and naphthyl), (C ₇ -C ₁₂ ) aralkyl (in particular benzyl and phenylethyl) and a nitro group; (C ₆ -C ₁₀ ) arylcarbonyl group (in particular, benzoyl group and naphthylcarbonyl group) optionally containing from 1 to 4 substituents selected from a halogen atom (in particular chlorine, bromine and fluorine), (C ₁ -C ₆ ) alkyl (in particular methyl, ethyl and n-propyl), (C ₆ -C ₁₀ ) aryl (in particular phenyl and naphthyl), (C ₇ -C ₁₂ ) aralkyl (in particular benzyl and phenylethyl) and a nitro group; (C ₇ -C ₁₂ ) an aralkylcarbonyl group (in particular a benzylcarbonyl group and a phenethylcarbonyl group) optionally containing from 1 to 4 substituents selected from a halogen atom (in particular chlorine, bromine and fluorine), (C ₁ -C ₆ ) alkyl (in particular methyl, ethyl and n-propyl), (C ₆ -C ₁₀ ) aryl (in particular phenyl and naphthyl), (C ₇ -C ₁₂ ) aralkyl (in particular benzyl and phenylethyl) and a nitro group; and a pyranyl or furanyl group, a tri (C ₁ -C ₄ ) alkylsilyl group (in particular a trimethylsilyl and triethylsilyl group), optionally containing from 1 to 4 substituents selected from a halogen atom (in particular chlorine, bromine and fluorine), ( C ₁ -C ₆ ) alkyl (in particular methyl, ethyl and n-propyl), (C ₆ -C ₁₀ ) aryl (in particular phenyl and naphthyl), (C ₇ -C ₁₂ ) aralkyl (in particular benzyl and phenethyl) and nitro groups.

As a hydrocarbon residue in a carbonyl group optionally substituted with a hydrocarbon residue, which is denoted by R ⁴ , mention may be made, for example, of saturated or unsaturated hydrocarbon residues containing up to 25 carbon atoms. Examples thereof include alkyl (in particular (C ₁ -C ₈ ) alkyl, such as methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl, pentyl and hexyl), cycloalkyl (in particular (C ₃ -C ₆ ) cycloalkyl, such as cyclopropyl, cyclobutyl and cyclohexyl), alkoxyalkyl (in particular, (C ₁ -C ₃ ) alkoxy (C ₁ -C ₆ ) alkyl, such as methoxymethyl, ethoxymethyl, ethoxybutyl and propoxyhexyl), alkenyl (in particular , (C ₂ -C ₆ ) alkenyl such as vinyl, butenyl, butadienyl and hexatrienyl), aryl (in particular (C ₆ -C ₁₄ ) aryl such as phenyl, naphthyl and anthracenyl) and aralkyl (in particular ( C ₇ -C ₂₀ ) aralkyl, such as to benzyl, benzhydryl and trityl).

An optionally substituted 5-7 membered heterocyclic group containing, as a group capable of replacing a ring, a carbonyl group, a thiocarbonyl group, an optionally oxidized sulfur atom or a group which can be converted and designated by R ⁶ therein, has the same meaning, as indicated, starting on page 5 on line 45 and ending on page 9 on line 35 of European Patent Application EP-A-0520423.

Examples of anion-forming groups or groups capable of converting to the amino group, designated as R ⁶ above, include a carboxyl group, a (C ₁ -C ₄ ) alkoxycarbonyl group, a cyano group, a tetrazolyl group, an amide trifluoromethanesulfonic acid group, a phosphoric acid group and a sulfonic acid group. As a bridge group denoted by V, for example, mention may be made of the groups - (C = O) -, -O-, -S-, -NH-, - (C = O) - NH-, -O-CH ₂ -, -S-CH ₂ - and -CH = CH-.

 The optionally substituted aromatic hydrocarbon residue, optionally containing a heteroatom and optionally substituted heterocyclic group, designated as ring Z, has the same meaning as that indicated on page 5 in lines 38 to 44 of European Patent Application EP-A-0520423.

As the aryl designated by R ¹¹ , or as an optionally substituted aryl designated as R ¹² or R ¹⁴ , for example, monocyclic or fused polycyclic aromatic hydrocarbon residues can be mentioned. Preferred examples thereof include (C ₆ -C ₁₄ ) aryl such as phenyl, naphthyl, antryl, phenanthryl, acenaphthenyl, and the like. Most preferred of these are phenyl, 1-naphthyl and 2-naphthyl.

The number of substituents is one or more, preferably from one to three. Examples of substituents include (C ₁ -C ₃ ) alkyl (in particular methyl, ethyl, propyl), (C ₂ -C ₄ ) alkenyl (in particular vinyl, allyl, 2-butenyl), (C ₃ -C ₄ ) alkynyl (in particular propargyl, 2-butynyl), (C ₃ -C ₇ ) cycloalkyl (in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), aryl (in particular phenyl, naphthyl), 5-9 membered aromatic heterocyclic a group containing from 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (in particular, a furyl group, a thienyl group, a pyrrolyl group, a thiazolyl group, an imidazolyl group , pyrazolyl group, pyridyl group), a 5-9 membered non-aromatic heterocyclic group containing from 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (in particular, an oxiranyl group, an azetidinyl group, an oxetanyl group, a thietanyl group, pirrodinilnuyu group tetrahydrofuryl group, tioranilnuyu group, a piperidinyl group, tetrahydropyranyl group, morpholinyl group, thiomorpholinyl group, a piperazinyl group), (C ₇ -C ₁₀₎ aralkyl (particularly, benzyl, phenethyl), aminogr PUF, N-monosubstituted amino group (in particular, N- (C ₁ -C ₆₎ alkylamino such as methylamino, ethylamino, propylamino), N, N-disubstituted amino group (in particular, N, N- (C ₁ -C ₆ ) an alkylamino group such as a dimethylamino group, a diethylamino group), an amidino group, an acyl group (in particular a (C ₁ -C ₈ ) alkylcarbonyl group such as an acetyl group, a propionyl group, a butyryl group; A (C ₁ -C ₁₄ ) arylcarbonyl group, such as a benzoyl group; (C ₇ -C ₁₂ ) an aralkyloxycarbonyl group such as a benzoyloxycarbonyl group), a carbamoyl group, an N-substituted carbamoyl group (in particular, an N- (C ₁ -C ₆ ) alkylcarbamoyl group such as a methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group ), N, N-disubstituted carbamoyl group (in particular, N, N-di (C ₁ - C ₆ ) alkylcarbamoyl group such as dimethylcarbamoyl group, diethylcarbamoyl group), sulfamoyl group, N-monosubstituted sulfamoyl group (in particular N - (C ₁ -C ₆ ) alkylsulfamoyl a group such as a methyl sulfamoyl group, an ethyl sulfamoyl group, a propyl sulfamoyl group), an N, N-disubstituted sulfamoyl group (in particular an N, N-di (C ₁ -C ₆ ) alkyl sulfamoyl group such as a dimethyl sulfamoyl group, a diethyl sulfamoyl group), carboxylic acid a group, (C ₁ -C ₃ ) alkoxycarboxyl group (in particular, a methoxycarboxyl group, ethoxycarboxyl group), a hydroxyl group, (C ₁ -C ₃ ) alkoxy group (in particular, a methoxy group, ethoxy group, propoxy group), which may have a substituent (in particular , (C ₁ -C ₃ ) alkyl, halogen atom, (C ₁ -C ₃ ) alkylthio group, hydroxyl group), (C ₂ -C ₄ ) alkenyloxy group (in particular, vinyloxy group, allyloxy group), cycloalkyloxy group (in particular, (C ₃ -C ₇₎ cycloalkyloxy group such as cyclopropyloxy group, tsiklobutiloksigruppa), aralkyloxy group (especially, (C ₇ -C ₁₀₎ aralkyloxy group such as benzyloxy), aryloxy (especially phenyloxy, naphthyloxy), a mercapto group, (C ₁ -C ₃₎ alkylthio (in particular methylthio, ethylthio, propylthio group), aralkylthio group (in ca tnosti, (C ₇ - C ₁₀₎ aralkylthio group such as benzylthio), an arylthio group (specifically, phenylthio, naphthylthio), (C ₁ -C ₃₎ alkylenedioxy (in particular methylenedioxy, ethylenedioxy, propylenedioxy), sulfo, cyano, azido , nitro group, nitroso group, halogen atom (fluorine, chlorine, bromine and iodine), etc.

As the aralkyl in the optionally substituted aralkyl designated by R ¹² , mention should be made, for example, of arylalkyl. Aryl has the same meaning as previously indicated. Examples of alkyl include (C ₁ -C ₆ ) alkyl, such as methyl, ethyl, propyl, butyl, pentyl, hexyl. The substituents have the same meanings as indicated for the substituents aryl may have, indicated by R ¹² .

As cycloalkyl in the optionally substituted cycloalkyl designated as R ¹¹ and R ¹² , mention should be made, for example, of (C ₃ -C ₁₀ ) cycloalkyl and (C ₃ -C ₁₀ ) bicycloalkyl. Preferred examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3, 2,1] nonyl, bicyclo [4,2,1] nonyl, bicyclo [4,3,1] decyl. Most preferred among them are cyclopentyl and cyclohexyl. The substituents have the same meaning as indicated for the substituents that aryl designated as R ¹² may have.

As a heterocyclic group in an optionally substituted heterocyclic group designated by R ¹¹ , mention should be made, for example, of a 5-13 membered aromatic heterocyclic group containing from one to four heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom; or a saturated or unsaturated non-aromatic heterocyclic group.

 Examples of aromatic heterocyclic groups include an aromatic monocyclic heterocyclic group (in particular, furyl group, thienyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isotisolyl group, imidazolyl group, pyrazolyl group, 1,2,4-oxadiazolyl group , 3,4-oxadiazolyl group, furazanyl group, 1,2,3-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, tetrazolyl group, pyridyl th group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group), aromatic heterocyclic group with a fused ring (in particular, benzofuranyl group, isobenzofuranyl group, benzo [b] thienyl group, indoryl group, isoindoryl group, 1H-indazolyl group, benzoimidazolyl group, benzoxazolyl group, 1,2-benzoisoxazolyl group, benzothiazolyl group, 1,2-benzoisothiazolyl group, 1H-benzotriazolyl group, quinolinyl group, isoquinolinyl th group, cinnolinyl group, quinazolinyl group, quinoxalinyl group, phthalazinyl group, naphthylidinyl group, purinyl group, pteridinyl group, carbazolyl group, alpha-carbolinyl group, beta-carbolinyl group, gamma-carbolinyl group, acridinyl group, phenoxyl group, phenoxyl group, phenoxyl group, phenoxy group, phenoxy group, phenoxy group, phenoxyl group, phenoxyl group, phenoxyl group, phenoxyl group, phenoxy group , phenazinyl group, phenoxathiinyl group, thianthrenyl group, phenanthridinyl group, phenanthroline group, indolysinyl group, pyrrolo [1,2-b] pyridazinyl group ppu, pyrazolo [1,5-a] pyridyl group, imidazo [1,2-a] pyridyl group, imidazo [1,5-a] pyridyl group, imidazo [1, 2-b] pyridazinyl group, imidazo [1, 2-a] pyridazinyl group, 1,2,4-triazolo [4,3-a] pyridyl group, 1,2,4-triazolo [4,3-b] pyridazinyl group}.

 Examples of non-aromatic heterocyclic groups include an oxylanyl group, azetisinyl group, oxetanyl group, thietanyl group, pyrrolidinyl group, tetrahydrofuranyl group, thiolanyl group, piperidyl group, tetrahydropyranyl group, morpholinyl group, thiomorpholinyl group, piperazinyl group.

A heterocyclic group may have one or more substituents, preferably one to three substituents. The substituents have the same meaning as indicated for the optionally substituted aryl designated by R ¹² .

 As substituents in the optionally substituted carboxyl group designated as Q, mention may be made, for example, of an alkyl, cycloalkyl, aryl, aralkyl, heterocyclic group. They have the same meaning as previously indicated.

As the lower alkylenedioxy group designated as Q, mention may be made, for example, of a (C ₁ -C ₆ ) alkylenedioxy group (in particular, a methylenedioxy group, an ethylenedioxy group, a propylenedioxy group, 2,2-dimethylmethylenedioxy group).

As lower alkyl designated as R ¹¹ , mention should be made, for example, of (C ₁ -C ₆ ) alkyl (in particular methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl, pentyl, hexyl).

As the optionally substituted amino group designated as R ¹³ , mention should be made, for example, of a group of the formula —NR ²² R ²³ , where R ²² is an optionally substituted aryl, an optionally substituted heterocyclic group; R ²³ represents a hydrogen atom, optionally substituted alkyl.

 Optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heterocyclic group have the same meanings as previously defined.

As the separation group, denoted by the symbol "A", it is necessary to indicate, for example, (C ₁ -C ₄ ) alkylene (in particular methylene, ethylene), (C ₂ -C ₆ ) alkenyl (in particular, vinylene, butadiene) ; a group of the formula: - (CH ₂ ) _c NR ²⁴ -, where c is a number from 0 to 3, R ²⁴ is a hydrogen atom, (C ₁ -C ₆ ) alkyl (in particular methyl, ethyl, butyl); a group of the formula: —CO—; a group of the formula: —CONR ²² -, wherein R ^{22 is} as previously defined; -O-; -S-; a group of the formula: —NR ²² S (O) _e -, where e is a number from 0 to 2, R ²² has the same meaning as previously indicated.

Среди этих циклических групп предпочтительны группы формулы

Далее, циклическая группа формулы

является особенно предпочтительной.A preferred example of a 5-7 membered homo or heterocyclic group (W ′ ring) in an optionally substituted fused bicyclic compound consisting of a 5-7 membered homo or heterocyclic ring group (W ′ ring) and a 5-7 membered homo or a heterocyclic ring group (Y ′ ring) includes a 5- or 6-membered homo- or heterocyclic group, more preferably a 5- or 6-membered heterocyclic group. Specific examples of the ring W 'include ring groups of the formula

Among these cyclic groups, groups of the formula are preferred.

Next, a cyclic group of the formula

is particularly preferred.

где R¹ и R² имеют то же самое значение, что и указанное ранее.The most preferred example of said ring W is a group of the formula

where R ¹ and R ² have the same meaning as above.

Среди этих циклических групп предпочтительны группы формулы:

Далее циклическая группа формулы

является особенно предпочтительной.A preferred example of a 5-7 membered homo or heterocyclic group (Y ′ ring) in an optionally substituted fused bicyclic compound consisting of a 5-7 membered homo or heterocyclic ring group (W ′ ring) and a 5-7 membered homo or a heterocyclic ring group (Y ′ ring) includes a six-membered homo- or heterocyclic group, more preferably a six-membered heterocyclic group. Specific examples of the ring W 'include ring groups of the formula

Among these cyclic groups, groups of the formula are preferred:

Further, the cyclic group of the formula

is particularly preferred.

где R¹⁶ обозначает необязательно замещенный углеводородный остаток, R¹⁷ обозначает атом водорода или группу, присоединенную через атом углерода, атом азота, атом кислорода или атом серы, о равно 1 или 2;
или кольцевую группу формулы

где R²⁰ и R²¹ каждый независимо обозначают атом водорода, необязательно замещенный углеводородный остаток.The most preferred example of said Y 'ring is a ring group of the formula

where R ¹⁶ denotes an optionally substituted hydrocarbon residue, R ¹⁷ denotes a hydrogen atom or a group attached via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom, o is 1 or 2;
or a ring group of the formula

where R ²⁰ and R ²¹ each independently represent a hydrogen atom, an optionally substituted hydrocarbon residue.

Examples of hydrocarbon residues in optionally substituted hydrocarbon residues designated R ¹⁶ , R ²⁰ and R ²¹ include alkyl, cycloalkyl, aryl and aralkyl, as previously described.

Examples of substituents that may have these optionally substituted hydrocarbon residues include those that optionally contain from one to five substituents selected, for example, from a nitro group, a hydroxyl group, an oxo group, a thioxo group, a cyano group, a carbamoyl group, a carboxyl group, (C ₁ - C ₄ ) alkoxycarbonyl group (in particular, methoxycarbonyl group and ethoxycarbonyl group), sulfo group, halogen atom (fluorine, chlorine, bromine and iodine), (C ₁ -C ₆ ) alkoxy group (in particular, methoxy group, ethoxy group py, propoxy groups, iso-propoxy groups, butoxy groups, iso-butoxy groups, 2-butoxy groups and tert-butoxy groups), (C ₆ -C ₁₂ ) aryloxy groups (in particular phenoxy groups), halogen (C ₆ -C ₁₆ ) aryl (in particular , o-, m- or p-chlorophenoxy groups and o-, m- or p-bromophenoxy groups), (C ₁ -C ₆ ) alkylthio groups (in particular methylthio groups, ethylthio groups, n-propylthio groups, iso-propylthio groups, n-butylthio groups and tert-butylthio groups), (C ₆ -C ₁₂₎ arylthio (especially phenylthio), (C ₁ -C ₆₎ alkylsulfinyl group (particularly a methylsulfinyl group and etilsulfi yl group), (C ₁ -C ₆₎ alkylsulfonyl group (particularly, a methylsulfonyl group and ethylsulfonyl group), amino, (C ₁ -C ₆₎ acylamino (especially formylamino, acetylamino and propylamino), mono- or di- (C ₁ -C ₄ ) alkylamino groups (in particular methylamino groups, ethylamino groups, n-propylamino groups, isopropylamino groups, n-butylamino groups, dimethylamino groups and diethylamino groups), (C ₁ -C ₆ ) acyl groups (in particular, formyl groups, acetyl groups and hexanoyl groups), (C ₆ -C ₁₂₎ arylcarbonyl c pp (in particular, a benzoyl group) and 5- or 6-membered heterocyclic groups containing, in addition to carbon atoms, from 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom or a nitrogen atom, for example a 2- or 3-thienyl group, 2- or 3-furyl group, 3-, 4- or 5-pyrazolyl group, 2-, 4- or 5-thiazolyl group, 3-, 4- or 5-isothiazolyl group, 2-, 4- or 5-oxazolyl groups of 3-, 4- or 5-isoxazolyl group, 2-, 4- or 5-imidazolyl group, 1,2,3- or 1,2,4-triazolyl group, 1H- or 2H-tetrazolyl group, 2- , 3- or 4-pyridyl group, 2-, 4-yl 5-pyrimidyl group, 3- or 4-pyridazinyl group, a quinolinyl group, isoquinolinyl group, and an indolyl group, and (C ₁ -C ₁₀₎ haloalkyl (in particular, difluoromethyl, trifluoromethyl, trifluoroethyl and trichloroethyl), and in that case a hydrocarbon group is a cycloalkyl, cycloalkenyl, aryl or aralkyl group, from (C ₁ -C ₆ ) alkyl (in particular methyl, ethyl, propyl, isopropyl and butyl). The number of substituents varies from 1 to 6, preferably from 1 to 3.

A group attached via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom designated R ¹⁷ has the same meaning as previously indicated.

R ¹ and R ^{2 are} preferably such that either one of them is a group of the formula
R ⁹ - (CH ₂ ) _m -
where R ⁹ denotes a group attached via a nitrogen atom, am denotes an integer from 0 to 3, and the other is a group designated by the General formula
R ¹⁰ -A-
where R ¹⁰ denotes an optionally substituted phenyl group, and A denotes a bridging group.

An optionally substituted group attached through a nitrogen atom denoted by R ⁹ has the same meaning as previously defined.

Examples of substituents in the optionally substituted phenyl group designated above R ¹⁰ include a halogen atom (fluorine, chlorine, bromine or iodine), (C ₁ -C ₈ ) alkyl (in particular methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, iso-pentyl and neopentyl) optionally substituted with one to three halogen atoms (fluorine, chlorine, bromine or iodine), a (C ₁ -C ₈ ) alkoxy group (in particular , methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group and iso-butoxy group), optionally containing as substituents one to three halogen atoms (fluorine, chlorine, bromine or iodine), (C ₁ -C ₈ ) alkylthio group (in particular methylthio group, ethylthio group, propylthio group, iso-propylthio group, butylthio group, sec-butylthio group, tert-butylthio group pentylthio group, iso-pentylthio group and neopentylthio group), optionally containing from one to three halogen atoms (fluorine, chlorine, bromine or iodine) as substituents, (C ₁ -C ₆ ) alkanoyloxy group (in particular, formyloxy group, acetoxy group and propionyloxy group) group, carboxyl group, A (C ₁ -C ₆ ) alkoxycarbonyl group (in particular a methoxycarbonyl group, an ethoxycarbonyl group and a tert-butoxycarbonyl group), a cyano group, a nitro group, an amido group and a mono- or di (C ₁ -C ₆ ) alkylcarbamoyl group (in particular a methylcarbamoyl group , ethylcarbamoyl group and dimethylcarbamoyl group). The number of substituents varies from 1 to 5, preferably from 1 to 3.

 The bridge group denoted by A has the same meaning as previously indicated.

где R⁷ обозначает атом водорода или группу, присоединенную через атом углерода, атом азота, атом кислорода или атом серы, a R⁸ обозначает атом галогена, нитрогруппу, цианогруппу или необязательно замещенный алифатический углеводородный остаток, присоединенный через атом кислорода, атом азота или атом серы.R ^{3 is} preferably a group of the formula

where R ⁷ denotes a hydrogen atom or a group attached via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom, and R ⁸ denotes a halogen atom, a nitro group, a cyano group or an optionally substituted aliphatic hydrocarbon residue attached through an oxygen atom, a nitrogen atom or a sulfur atom .

The above optionally substituted groups attached via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom, designated R ⁷ , have the same meanings as above.

Examples of an optionally substituted aliphatic hydrocarbon residue in an optionally substituted hydrocarbon residue attached via an oxygen atom, a nitrogen atom or a sulfur atom and previously designated R ⁸ include (C ₁ -C ₁₅ ) alkyl (in particular methyl, ethyl, propyl, iso-propyl , butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and pentadecyl), (C ₃ -C ₈ ) cycloalkyl (in particular cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), (C ₂ -C ₁₀ ) alkenyl (in particular vinyl, allyl, 2-me tilallyl, 2-butenyl, 3-butenyl and 3-octenyl), (C ₂ -C ₁₀ ) alkynyl (in particular ethynyl, 2-propynyl and 3-hexynyl) and (C ₁ -C ₆ ) alkoxy (in particular methoxy group, ethoxy group, propoxy group and butoxy group). Examples of substituents which may have these hydrocarbon groups include a nitro group, a hydroxyl group, an oxo group, a thioxo group, a cyano group, a carbamoyl group, a carboxyl group, a (C ₁ -C ₄ ) alkoxycarbonyl group (in particular a methoxycarbonyl group and an ethoxycarbonyl group), a sulfo group, a halogen atom (in particular fluorine, chlorine, bromine and iodine), a (C ₁ -C ₄ ) alkoxy group (in particular a methoxy group, ethoxy group, propoxy group, iso-propoxy group, butoxy group, isobutoxy group, sec-butoxy group and tert-butoxy and a group), (C ₁ -C ₄ ) alkylthio group (in particular methylthio group, ethylthio group, n-propylthio group, iso-propylthio group, n-butylthio group and tert-butylthio group), amino group, (C ₁ -C ₆ ) alkanoylamino group, in particular acetylamino group and propionylamino group), mono- or di- (C ₁ -C ₄ ) alkylamino group (in particular, methylamino group, ethylamino group, n-propylamino group, iso-propylamino group, n-butylamino group, dimethylamino group and diethylamino group), ₄ ) (C ₁ alkanoyl group (in particular, formyl group, acetyl group and propionyl group pu), and 5- or 6-membered heterocyclic groups containing, in addition to carbon atoms, from 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom or a nitrogen atom, which optionally may contain from 1 to 4 substituents selected from (a ) a halogen atom (in particular fluorine, chlorine, bromine and iodine); and (b) (C ₁ -C ₄ ) alkyl (in particular methyl, ethyl, propyl, iso-propyl), for example, a 2- or 3-thienyl group, a 2- or 3-furyl group, 3-, 4- or a 5-pyrazolyl group, a 2-, 4- or 5-thiazolyl group, a 3-, 4- or 5-isothiazolyl group, a 2-, 4- or 5-oxazolyl group, a 3-, 4- or 5-isoxazolyl group, 2-, 4- or 5-imidazolyl group, 1,2,3- or 1,2,4-triazolyl group, 1H- or 2H-tetrazolyl group, 2-, 3- or 4-pyridyl group, 2-, 4 or a 5-pyrimidyl group, a 3- or 4-pyridazinyl group, a quinolinyl group, an isoquinolinyl group and an indolyl group, and (C ₁ -C ₆ ) haloalkyl (in particular difluoromethyl, trifluoromethyl, trifluoroethyl and trichloroethyl). The number of substituents varies from 1 to 4, preferably from 1 to 3.

R ^{11 is} preferably a group of the formula
- (CH) _p Q '
where p is an integer from 1 to 3;
Q ′ is aryl which may be substituted by a halogen atom, a nitro group, a cyano group, an amino group, an optionally substituted carboxy group, a lower alkylenedioxy group of the formula: —AR ¹⁶ , where R ¹⁶ is a lower alkyl group and A has the same meaning as indicated earlier.

Aryl, which may be substituted by a halogen atom, a nitro group, a cyano group, an amino group, an optionally substituted carboxyl group, a lower alkylene dioxyl group of the formula: —AR ¹⁶ denoted by Q ′, has the same meaning as previously defined. The lower alkyl group has the same meaning as previously indicated.

 Q 'is preferably an aryl which may be substituted by a halogen atom (fluorine, chlorine, bromine and iodine).

R ^{13 is} preferably an optionally substituted monoaralkylamino group. The optionally substituted aralkyl in the optionally substituted monoaralkylamino group has the same meaning as previously defined. Aralkyl is preferably benzyl.

R ^{14 is} preferably an optionally substituted phenyl which has the same meaning as previously defined.

где кольцо W, R¹⁶, R¹⁷ и о имеют те же самые значения, что и указанные ранее; или соединением формулы VII

где R¹⁸ и R¹⁹ каждый независимо обозначают необязательно замещенный углеводородный остаток, а кольцо Y имеет то же самое значение, что и указанное ранее.An optionally substituted fused bicyclic compound consisting of a 5-7 membered homo or heterocyclic group and a 5-7 membered homo or heterocyclic group is preferably a compound of formula V

where the ring W, R ¹⁶ , R ¹⁷ and o have the same meanings as previously indicated; or a compound of formula VII

where R ¹⁸ and R ¹⁹ each independently represent an optionally substituted hydrocarbon residue, and ring Y has the same meaning as previously indicated.

Optionally substituted hydrocarbon residues designated R ¹⁸ and R ¹⁹ have the same meanings as previously defined.

где R²⁰ и R²¹ имеют те же самые значения, что и указанные ранее.Ring Y is preferably an optionally substituted 5-7 membered heterocyclic ring group, with the exception of 4-pyridone. More preferably, ring Y is a ring group of formula VIII

where R ²⁰ and R ²¹ have the same meanings as previously indicated.

где R¹ и R² имеют те же самые значения, что и указанные ранее.Ring W is preferably a ring group of formula VI

where R ¹ and R ² have the same meanings as previously indicated.

 Compounds (I), (II), (VII) and their salts can be easily obtained by methods known in the art, which are exemplified by the following Production Methods 1-16.

 The previously indicated optionally substituted fused bicyclic compound consisting of a 5-7 membered homo or heterocyclic group and a 5-7 membered homo or heterocyclic group can be prepared according to Preparation Methods 1-16 or similar methods.

[Production Method 1]
In accordance with the method given by K. Gewald, E. Schinke and H. Boettcher, Chem. Ber., Bd. 99, 94-100 (1966), the corresponding ketone or aldehyde having an active methylene group (i) is reacted with a cyanoacetic acid ester derivative and sulfur to produce a 2-aminothiophene derivative (ii). In particular, in the case of a ketone (R ^{1 ′} ≠ H), it is refluxed together with a cyanoacetic ester derivative in the presence of acetic acid and ammonium acetate in a suitable solvent, such as toluene, to obtain an alkylidene cyanoacetic acid ester derivative, which is then heated in a suitable a solvent, for example ethanol, in the presence of sulfur and a base to give a 2-aminothiophene derivative (ii). And in the case of an aldehyde (R ^{1 ′} = H), it is refluxed in a suitable solvent, such as dimethylformamide, with a derivative of cyanacetic ester, sulfur and a base to obtain a 2-aminothiophene derivative (ii). The compound (ii) obtained by this method is heated in accordance with the method described by Kuwata et al. (German patent 2435025), together with ethoxymethylene malonic acid diethyl ether to give the adduct (iii). The adduct is mixed in a solvent that does not adversely affect the reaction (in particular, alcohols, such as ethanol or methanol), in the presence of a base (in particular, an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide) in the temperature range from about 10 to 70 ^o C and get carboxylic acid (iv). The resulting carboxylic acid (iv) is cyclized by heating in polyphosphoric acid ester to obtain the thieno [2,3-b] pyridine derivative (v). Compound (v) is mixed in a solvent that does not adversely affect the reaction (in particular, amides, such as dimethylformamide or dimethylacetamide), in the presence of a halogen-containing aralkyl derivative and a base (in particular, an organic base, such as pyridine and triethylamine) in the temperature range from about 10 to 100 ^o C to obtain the derivative of 4,7-dihydro-4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid, indicated by formula Ia. The compound (Ia) is then mixed with N-bromosuccinimide (NBS) in a solvent that does not adversely affect the reaction (in particular, halogenated hydrocarbons such as carbon tetrachloride and chloroform) in the presence of α, α′-azobisisobutyronitrile in the temperature range from about 30 to 100 ^o C to obtain the compound (Ib). Compound (Ib) is mixed with various amines in a solvent which does not adversely affect the reaction (in particular, amides, such as dimethylformamide or dimethylacetamide, nitrile, such as acetonitrile, and alcohols, such as ethanol), in the presence of a base in the range temperatures from about 10 to 100 ^o C to obtain compound (I). The Production Method 1 described above is shown in Scheme 1 (see the end of the description), where R ^{1 ′} is a hydrogen atom or an alkyl group, R ′ is an alkyl group, X is a leaving group, Xa is a halogen atom, and R ² , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ⁹ , m and n have the same meanings as above.

Alkyl groups R ^{1 ′} and R ′ have the same meanings as previously indicated.

 As the leaving group denoted by X, for example, a group that can be substituted with a nucleophilic agent, such as a hydrocarbon residue containing a heteroatom (in particular an oxygen atom, a sulfur atom, a nitrogen atom), which has a negative charge, can be mentioned. Preferred examples of leaving groups include a halogen atom (in particular iodine, bromine, chlorine), an alkanoyloxy group (in particular an acetoxy group), an alkylsulfonyloxy group (in particular a methanesulfonyloxy group), an alkyl-arylsulfonyloxy group (in particular p-toluenesulfonyloxy.

 The halogen atom designated Xa is fluorine, bromine, chlorine, iodine. Most preferred of these is bromine.

[Production Method 2]
In almost the same way as in Production Method 1, a 2-aminothiophene derivative not containing a substituent at position 5 (vi), which can be obtained by the method described in Karl Gewald (K. Gewald, Chem. Ber., Bd. 98 , 3571-3577 (1965); K. Gewald, E. Schinke, Chem. Ber., Bd. 99, 2712-2715 (1966)) are reacted with ethoxymethylene malonic acid when heated with diethyl ether in accordance with the method described in Kuwata et al. (German patent 2435025) to obtain adduct (vii). The adduct is mixed at a temperature in the range of about 10 to 60 ^° C. in a solvent which does not adversely affect the reaction (in particular alcohols, such as ethanol or methanol), in the presence of a suitable base (in particular an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide) and get carboxylic acid (viii). Compound (viii) is subjected to various cationic substitution reactions and, as the case may be, appropriate functional group substitution in order to introduce the substituent R ² , which is then subjected to a cyclization reaction by heating with a polyphosphoric acid ester to obtain a thieno derivative [2,3- b] pyridine (ix). Compound (ix) is mixed with a halogen-containing aralkyl derivative in a solvent that does not adversely affect the progress of the reaction (in particular, amides, such as dimethylformamide or dimethylacetamide), in the presence of a base in the temperature range of from about 10 to 100 ^o C to obtain the ester derivative 4,7-dihydro-4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid, formula Ia. As a cationic substitution reaction, mention should be made, for example, of nitration (fuming nitric acid - concentrated sulfuric acid, sodium nitrate - concentrated sulfuric acid), acylation (acid chloride - aluminum chloride), formylation (phosphorus oxychloride - dimethylformamide or N-methylformanilide) and bromination (N-bromosuccinimide, bromine - pyridine). Further, compound (Ia) is subjected to almost the same treatments as in Production Method 1 to obtain compounds (Ib) and (I). The method of obtaining 2 is shown in Scheme 2 (see the end of the description),
where each character has the same meaning as previously indicated.

[Production Method 3]
Derived alantoic (alantoic) acid (x) is stirred in the temperature range from about 30 to 110 ^o C in an equivalent or excessive amount relative to compound (x), triphosgene in a solvent that does not adversely affect the reaction (in particular, ethers such as tetrahydrofuran and 1,4-dioxane) to give the isatoic isatoic acid derivative (xi). Then, the halogenated derivative (xii) is stirred at a temperature in the range of about 40 to 130 ^° C. in a solvent which does not adversely affect the reaction (in ethers such as tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbons such as benzene and toluene, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, alkyl sulfoxides, such as dimethyl sulfoxide), in the presence of a base (in particular an alkali metal carbonate such as potassium carbonate, an alkali metal hydride such as hyd d sodium hydride and potassium hydride, alkali metal alkoxide such as potassium butoxide) to give a substituted derivative (xiii). The derivative (xiii) is reacted with an equivalent or a slight excess with respect to compound (xiii) (in particular from about 1.1 to 1.5 equivalents) of the beta-keto ester derivative (xiv) in a temperature range of from about 40 to 110 ^o C in a solvent which does not adversely affect the reaction (in ethers such as tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbons such as benzene and toluene, amides such as N, N-dimethylformamide and N, N dimethylacetamide, alkyl sulfoxides such as dimethyls ulphoxide), in the presence of a base (in particular an alkali metal carbonate such as potassium carbonate, an alkali metal hydride such as sodium hydride and potassium hydride, an alkali metal alkoxide such as potassium butoxide) to obtain compound (Va). The Production Method 3 described above is shown in Scheme 3 (see the end of the description), where each symbol has the same meaning as previously indicated.

[Production Method 4]
The pyridine derivative (xv) is mixed together with an equivalent or excess, with respect to compound (xv), of triphosgene in a solvent which does not adversely affect the reaction (in particular, in ethers such as tetrahydrofuran and 1,4-dioxane) in the temperature range from about 30 to 110 ^o C to obtain the derivative of the acid anhydride (xvi). Then, the halogenated derivative (xii) is mixed in a solvent that does not adversely affect the reaction (in ethers such as tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbons such as benzene and toluene, amides such as N, N- dimethylformamide and N, N- dimethylacetamide, alkilsulfoksidah such as dimethyl sulfoxide) at temperatures ranging from about 40 to 130 ^o C in the presence of a base (such as an alkali metal carbonate such as potassium carbonate, alkali metal hydride such as sodium hydride atria and potassium hydride, alkali metal alkoxide such as potassium butoxide) to give a substituted derivative (xvii). The derivative (xvii) is reacted with an equivalent or a slight excess (in particular, from about 1.1 to 1.5 equivalents) of the beta-keto-acid ester derivative (xiv) in a solvent that does not adversely affect the reaction (in ethers) such as tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbons such as benzene and toluene, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, alkyl sulfoxides such as dimethyl sulfoxide) in the presence of a base (in particular alkali metal carbonate such as potassium carbonate, an alkali metal hydride such as sodium hydride and potassium hydride, an alkali metal alkoxide such as potassium butoxide) in the temperature range of from about 40 to 110 ^° C. to give compound (Vb). The Production Method 4 described above is shown in Scheme 4 (see the end of the description), where each symbol has the same meaning as previously indicated.

[Production Method 5]
In a suitable solvent that does not adversely affect the progress of the reaction (in particular, in ethers such as tetrahydrofuran, ethyl ether and 1,4-dioxane), an ether derivative of 4,7-dihydro-4-oxo-thieno [2,3- b] pyridine-5-carboxylic acid (Va) is mixed together with a suitable reducing agent (in particular lithium aluminum hydride) in the temperature range from about 0 to 80 ^o C to obtain the derivative of 4,7-dihydro-thieno [2,3-b ] pyridin-4-one of the formula Ic. The specified derivative is mixed with a suitable oxidizing agent (in particular, manganese dioxide) in a suitable solvent (in particular dichloromethane or chloroform) in the temperature range from about 10 to 80 ^o C to obtain a 5-formyl derivative. The derivative (Id) obtained in this way is mixed together with the Grignard reagent in a temperature range of from about 0 to 80 ^o C in a solvent that does not adversely affect the reaction (in particular, in ethers such as tetrahydrofuran and ethyl ether), obtaining the corresponding derivative of the secondary alcohol (Ie). Compound (Ie) is mixed with a suitable oxidizing agent (in particular metal oxide such as manganese dioxide) in a suitable solvent (in particular a halogenated hydrocarbon such as dichloromethane and chloroform) in the temperature range of from about 10 to 80 ^° C. obtaining a 5-carbonyl derivative (If). The Production Method 5 described above is shown in Scheme 5 (see the end of the description), where R ²⁵ denotes a hydrocarbon residue, and the remaining symbols have the same meanings as above.

The hydrocarbon residue R ²⁵ has the same meaning as the hydrocarbon residue in a carbonyl group optionally substituted with a hydrocarbon residue R ⁴ .

[Production Method 6]
The 4,7-dihydro-4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid ester derivative (Ia ') is stirred at a temperature in the range of from about 10 ^° C. to about 100 ^° C. in a solvent with an aluminum amide derivative, which is prepared in advance from the corresponding aluminum reagent (in particular trimethylaluminum and diisobutylaluminum hydride (DIBAL)) and an amine in a suitable solvent that does not adversely affect the reaction (in particular, halogenated hydrocarbons such as dichloromethane and chloroform, and ethers such as tetrahydro uranium, ethyl ether and dioxane), to give an amide derivative of 4,7-dihydro-4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid (Ia ''). The specified derivative (Ia ″) is mixed with a Grignard reagent in a suitable solvent that does not adversely affect the course of the reaction (in particular tetrahydrofuran and ethyl ether), in the temperature range from about minus 78 to 80 ^o C to obtain the corresponding ketone derivative ( If). The Production Method 6 described above is shown in Scheme 6 (see end of description), where R ²⁶ is alkyl or aryl; R ²⁷ and R ²⁸ each represent a hydrogen atom or a hydrocarbon residue; the remaining characters have the same meanings as previously indicated.

Alkyl or aryl, designated as R ²⁶ above, have the same meanings as previously defined.

The hydrocarbon residue R ²⁷ and R ²⁸ have the same meaning as the hydrocarbon residue in a carbonyl group optionally substituted with a hydrocarbon residue R ⁴ .

[Production Method 7]
In a suitable solvent that does not adversely affect the reaction (in particular, halogenated hydrocarbons such as dichloromethane; ethers such as tetrahydrofuran, ethyl ether and dioxane; and pyridine), the 4,7-dihydro-5-hydroxymethylthieno derivative is mixed [2,3-b] pyridin-4-one (Ia ″) together with a suitable halogenating agent (in particular thionyl chloride and methanesulfonyl chloride) in the temperature range of from about 0 to 100 ^o C to obtain the derivative of 4,7-dihydrothieno [2,3-b] pyridin-4-one (Ig). The specified derivative (Ig) is mixed together with a suitable nucleophilic reagent in a suitable solvent that does not adversely affect the course of the reaction (in particular in ethers such as tetrahydrofuran and ethyl ether; and amides such as dimethylformamide) to obtain the corresponding 5 -substituted derivative (Ih). The Production Method 7 described above is shown in Scheme 7 (see the end of the description), where X 'is a leaving group, z is an oxygen atom, a sulfur atom or a nitrogen atom, optionally having a hydrocarbon residue as a substituent, and the remaining symbols have the same values as specified above.

As the leaving group denoted by X ′, mention should be made, for example, of groups that readily undergo substitution reactions with a nucleophilic reagent [in particular, a hydrocarbon residue containing a heteroatom with a negative charge (in particular, an oxygen atom, a sulfur atom and a nitrogen atom) , designated as ^- YR ¹⁶ ]. In particular, an aralkyloxy group (e.g., an acetoxy group), an alkylsulfonyloxy group (e.g., a methanesulfonyloxy group) and an alkylarylsulfonyloxy group (e.g., p-toluenesulfonyloxy group) should be mentioned.

The hydrocarbon residue in a nitrogen atom, optionally substituted with a hydrocarbon residue, discussed above, has the same meaning as the hydrocarbon residue in a carbonyl group, optionally substituted with a hydrocarbon residue, previously designated R ⁴ .

[Production Method 8]
In a suitable solvent that does not adversely affect the reaction (in particular ethers such as tetrahydrofuran, ethyl ether and dioxane; and pyridine), the 4,7-dihydro-5-formylthieno derivative [2,3-b] is mixed pyridin-4-one (Ih) with a suitable Wittig reagent in the temperature range of from about 0 to 100 ^o C to obtain the derivative of 4,7-dihydrothieno [2,3-b] pyridin-4-one (Ij). The specified derivative (Ij) is stirred in the temperature range from about 10 to 100 ^o C with a suitable reducing agent [in particular, hydrogenated in a stream of hydrogen in the presence of a catalyst (eg palladium on carbon)] in a suitable solvent, which does not adversely affect the flow reactions (in particular alcohols such as ethyl alcohol; esters such as ethyl acetate; ethers such as tetrahydrofuran, ethyl ether and dimethylformamide) to give the corresponding 5-substituted about derivative (Ik). The Production Method 8 described above is shown in Scheme 8 (see end of description), where R ²⁹ and R ³⁰ each represent a hydrogen atom or a hydrocarbon residue; and the remaining characters have the same meanings as previously indicated.

The hydrocarbon residue indicated above as R ²⁹ and R ³⁰ has the same meaning as the hydrocarbon residue in the carbonyl group optionally substituted with a hydrocarbon residue, previously designated as R ⁴ .

[Production Method 9]
In a suitable solvent that does not adversely affect the reaction (in particular, ethers such as tetrahydrofuran and dioxane; and alcohols such as ethyl alcohol), the ether derivative 4,7-dihydro-4-oxo-thieno [2,3- b] pyridine-5-carboxylic acid (Ia ') is subjected to hydrolysis with stirring in the temperature range of from about 10 to 100 ^o C, adding acid (in particular an inorganic acid such as hydrochloric acid) or an aqueous solution of alkali (in particular 1 -4 N alkali metal hydroxide solution such as hydroxy d sodium, potassium hydroxide or lithium hydroxide). The resulting 5-carboxylic acid derivative is heated at a temperature in the range of from about 50 ^° C. to about 200 ^° C. in a suitable solvent that does not adversely affect the reaction to give the corresponding decarboxylated derivative (In). The Production Method 9 described above is shown in Scheme 9 (see the end of the description), where each symbol has the same meaning as previously indicated.

[Production Method 10]
Starting from the 2-aminothiophene derivative (ii), a urea (II) derivative is obtained, for example, according to the following methods A or B.

1. Method A. The 2-aminothiophene derivative (ii) obtained according to the procedure described in Production Method 1, or a salt thereof is reacted with an isocyanate derivative. An example of an isocyanate derivative are derivatives represented by the formula R ¹² —NCO (wherein R ¹² has the same meaning as previously defined). The reaction of compound (ii) or its salt with an isocyanate derivative is carried out in a solvent which does not adversely affect the reaction (in particular, tetrahydrofuran, pyridine, dioxane, benzene, dichloromethane, 1,2-dichloroethane, toluene, xylene), in the range temperatures from about 15 to about 130 ^° C. The isocyanate derivative is taken in an amount of from about 1 to 5 equivalents, preferably from about 1.1 to 2.5 equivalents, with respect to 1 equivalent of compound (ii). The reaction time is from several hours to several days, preferably from about 15 minutes to about two days.

2. Method B. An amine [in particular, a compound represented by the general formula R ¹² —NH ₂ (where R ¹² has the same meaning as previously defined)] is introduced into the addition reaction with an isocyanate derivative, which is obtained by reacting a 2- derivative aminothiophene (ii) or a salt thereof with phosgene or an equivalent compound (in particular diphosgene such as bis (trichloromethyl) carbonate, triphosgene such as trichloromethyl chloroformate). The reaction of the 2-aminothiophene derivative (ii) or its salt with phosgene or an equivalent compound is carried out in a solvent that does not adversely affect the reaction (in particular, dioxane, tetrahydrofuran, benzene, toluene, xylene, 1,2-dichloroethane, chloroform ), in the temperature range from about 40 to 120 ^o C. Phosgene or an equivalent compound is used in an amount of from about 0.5 to 2 equivalents, preferably from about 0.9 to 1.1 equivalents. The reaction time is from several minutes to several days, preferably from about 15 minutes to about two days. The amine addition reaction is carried out in a solvent that does not adversely affect the course of the reaction (in particular, pyridine, tetrahydrofuran, dioxane, dichloromethane, 1,2-dichloroethane, toluene, xylene), in the temperature range from about 15 to 130 ^o C. Amine take in an amount of from about 1 to 5 equivalents, preferably from about 1.1 to 3 equivalents. The reaction time is from several minutes to several days, preferably from about 15 minutes to about two days.

 The compound (XV) or its salt obtained in this way is reacted with a base to carry out a cyclization reaction to obtain a thieno [2,3-d] pyrimidine derivative (XVI). The cyclization reaction is carried out in a solvent, which does not have a harmful effect on its course. Examples of the solvent are alcohols, such as methanol, ethanol and propanol, and ethers, such as dioxane and tetrahydrofuran.

 As the base, for example, an alkali metal alkoxide such as methylate, sodium ethylate or sodium isopropoxide and an alkali metal hydride such as sodium hydride are used.

The amount of base used with respect to 1 equivalent of compound (XV) is from 1 to 5 equivalents, preferably from about 1.5 to 3 equivalents. The reaction temperature range is from about 10 ^° C. to the boiling point of the solvent used, preferably from about 25 ^° C. to the boiling point of the solvent used.

 The reaction time is from several minutes to several days, preferably from about 10 minutes to about two days.

Compound (XVI) and a halogen-containing aralkyl derivative are mixed in the presence of a base (in particular an organic base, such as pyridine or triethylamine) in a solvent that does not adversely affect the reaction (in particular, amides, such as dimethylformamide or dimethylacetamide), a temperature of from about 10 to 100 ^o C to obtain a derivative of 2,4-dioxotieno [2,3-d] pyrimidine (IIa). Further, the indicated compound (IIa) is mixed together with N-bromosuccinimide in a solvent which does not adversely affect the course of the reaction (in particular, halogenated hydrocarbons, such as carbon tetrachloride or chloroform), in the presence of α, α′-azobisisobutyronitrile and obtain the compound ( IIb). Further, this compound is mixed together with various amines in the presence of a base in a solvent which does not adversely affect the reaction (in particular, amides, such as dimethylformamide or dimethylacetamide, nitriles, such as acetonitrile, alcohols, such as ethanol), in the temperature range from about 10 to 100 ^o C to obtain compound (II). If necessary, said compound is converted to the corresponding salt using a suitable acid (in particular hydrochloric acid or oxalic acid).

 The Production Method 10 described above is shown in Scheme 10 (see the end of the description), where each symbol has the same meaning as previously indicated.

[Production Method 11]
The amino group of the 2-aminothiophene derivative (xvii) is protected (for example, using BOC) and mixed according to the method of T. Hirohashi et al. (German patent 2155403 (1972), among others) or by the method of N. Nakanishi et al. (Japanese Patent 73, 01664 (1973), among others) with a halogen-containing acyl derivative in the presence of a base in a solvent that does not adversely affect the reaction (in particular, amides, such as dimethylformamide or dimethylacetamide), in the temperature range from about 0 to 100 ^o C to give derivative (xviii), which was stirred together with a suitable salt (for example, lithium iodide) in a suitable solvent (such as acetone or methyl ethyl ketone) to give derivative (xix), which is reacted deputy reaction with the corresponding amine (in particular ammonia) to obtain a derivative (xx) which is stirred in a solvent which does not adversely affect the reaction (in particular, toluene, dimethylformamide, dimethylacetamide, methanol or ethanol), if necessary, in the presence of a suitable catalyst (in particular sodium ethoxide or toluenesulfonic acid) in the temperature range from about 30 to 120 ^o C, which leads to dehydrocyclization, and thus receive the derivative (VIIa). The specified compound is mixed together with a halogen-containing derivative of aralkyl in the presence of bases (in particular organic bases, including potassium carbonate, pyridine and triethylamine) in a solvent that does not adversely affect the reaction (in particular, amides, such as dimethylformamide or dimethylacetamide ), in the temperature range from about 10 to 100 ^o C to obtain a derivative of 2-oxotieno [2,3-e] azepine (VIIb). Further, the indicated compound (VIIb) is mixed together with N-bromosuccinimide (NBS) in a solvent (in particular, halogenated hydrocarbons, including carbon tetrachloride and chloroform) in the presence of α, α′-azobisisobutyronitrile in the temperature range from about 30 to 100 ^o C to give compound (VIIe). The specified compound is mixed with various amines in the presence of a base in a solvent which does not adversely affect the reaction (in particular, amides, such as dimethylformamide or dimethylacetamide, nitriles, such as acetonitrile, alcohols, such as ethanol), in the temperature range from about 10 to 100 ^o C to obtain the compound (VIId). If necessary, the specified compound is converted into the corresponding salt using a suitable acid (in particular hydrochloric acid or oxalic acid).

 The Production Method 11 described above is shown in Scheme 11 (see the end of the description), where each symbol has the same meaning as previously indicated.

[Production Method 12]
The amino group of the 2-aminothiophene derivative, which can be obtained by the procedure described in Production Method 1, is protected (for example, using BOC) and mixed together with the halogen-containing aralkyl derivative in the presence of bases (in particular organic bases, including potassium carbonate, pyridine and triethylamine) in a solvent which does not adversely affect the reaction (in particular, amides, such as dimethylformamide or dimethylacetamide), in the temperature range from about 0 to 100 ^o C to obtain a derivative (xxi), which is subjected to alkaline hydrolysis using a suitable alkali (in particular sodium hydroxide) and a suitable solvent (in particular methanol, tetrahydrofuran) and the derivative obtained in this way are mixed with DPPA in a solvent which does not adversely affect the reaction (such as toluene, tetrahydrofuran, dimethylformamide, dimethylacetamide, ethanol) at temperatures ranging from about 0 to 100 ^o C and the resulting compound is converted into the ester derivative karbaminov minutes acids (xxii) using a suitable alcohol (particularly ethanol). The specified derivative is mixed in the presence of a base (in particular sodium ethoxide) in a solvent that does not adversely affect the reaction (in particular, dimethylformamide or dimethylacetamide), in the temperature range from about 0 to 100 ^o C to obtain the thieno derivative [2, 3-d] imidazol-2-one (VIIe). The specified compound is mixed together with a halogen-containing alkyl derivative in the presence of a base in a solvent that does not adversely affect the course of the reaction (in particular, amides, such as dimethylformamide or dimethylacetamide), in the temperature range from about 10 to 100 ^o C to obtain a derivative of the compound ( VIIf). Further, the indicated compound (VIIf) is mixed together with N-bromosuccinimide (NBS) in a solvent (in particular, halogenated hydrocarbons, including carbon tetrachloride and chloroform) in the presence of α, α′-azobisisobutyronitrile in the temperature range from about 30 to 100 ^o C to give compound (VIIg). This compound is then mixed with various amines in the presence of a base in a solvent which does not adversely affect the reaction (in particular, amides, such as dimethylformamide or dimethylacetamide, nitriles, such as acetonitrile, alcohols, such as ethanol), in the temperature range of approximately from 10 to 100 ^o C to obtain the compound (VIIh). If necessary, the specified compound is converted into the corresponding salt using a suitable acid (in particular hydrochloric acid or oxalic acid). The Production Method 12 described above is shown in Scheme 12 (see the end of the description), where each symbol has the same meaning as previously indicated.

[Production Method 13]
Based on the derivative of 2-aminothiophene (ii), which can be obtained according to the procedure described in Production Method 1, or its salts, an ethyl derivative of 4,5-dihydro-7-hydroxy-5-oxo-thieno [3, 2-b] pyridine is obtained -6-carboxylic acid (VIIj) according to the methodology of JMBarker et al. (J. Chem. Res. (N). 1980, 113; J. Chem. Res. (S), 6 (1980)). In particular, a 2-aminothiophene derivative (ii) or a salt thereof is reacted with a malonic acid ester to give compound (xxii), which is stirred in the presence of a suitable base (in particular sodium hydride) in a solvent that does not adversely affect the flow reaction (in particular, amides, including dimethylformamide or dimethylacetamide), in the temperature range from about 0 to 100 ^o C to obtain the derivative (VIIj). The specified derivative (VIIj) is mixed together with a halogen-containing derivative of aralkyl in the presence of bases (in particular organic bases, including potassium carbonate, pyridine and triethylamine) in a solvent that does not adversely affect the reaction (in particular, amides, such as dimethylformamide or dimethylacetamide), in the temperature range from about 10 to 100 ^o C and get the derivative (VIIk); the specified derivative is mixed together with N-bromosuccinimide (NBS) in a solvent (in particular, halogenated hydrocarbons, including carbon tetrachloride and chloroform) in the presence of α, α′-azobisisobutyronitrile in the temperature range from about 30 to 100 ^o C to obtain the compound ( VIIm). Further, this compound is mixed with various amines in the presence of a base in a solvent that does not adversely affect the reaction (in particular, amides, such as dimethylformamide or dimethylacetamide, nitriles, such as acetonitrile, alcohols, such as ethanol), in the temperature range from about 10 to 100 ^o C to obtain the compound (VIIn). If necessary, the specified compound is converted into the corresponding salt using a suitable acid (in particular hydrochloric acid or oxalic acid). The Production Method 13 described above is shown in Scheme 13 (see the end of the description), where each symbol has the same meaning as previously indicated.

[Production Method 14]
In a suitable solvent that does not adversely affect the reaction (in particular, halogenated hydrocarbons, including dichloromethane and chloroform, and ethers, including tetrahydrofuran, ethyl ether and dioxane), the 1,4-dihydro ether derivative is mixed oxoquinoline-3-carboxylic acid (Va ') together with an amide derivative of aluminum, which is previously synthesized from the corresponding aluminum reagent [in particular, trimethylaluminum, triethylaluminum or diisobutylaluminum hydride (DIBAL)] and amines, in int tore at temperatures from about 10 to about 100 ^o C to give an amide derivative of 1,4-dihydro-4-oxo-quinoline-3- carboxylic acid (Va ''). The specified derivative is mixed with the Grignard reagent in a suitable solvent, which does not adversely affect the reaction (in particular tetrahydrofuran and ethyl ether), in the temperature range from about 0 to 80 ^o C to obtain the corresponding derivative of the ketone (Vc). The above Production Method 14 is shown in Scheme 14 (see the end of the description),
where R ²⁶ is alkyl or aryl; R ²⁷ and R ²⁸ each represent a hydrogen atom or a hydrocarbon residue; the remaining characters have the same meanings as previously indicated.

Alkyl or aryl, designated as R ²⁶ above, have the same meanings as previously defined.

The hydrocarbon residue referred to above as R ²⁷ and R ²⁸ has the same meaning as the hydrocarbon residue in the carbonyl group optionally substituted with the hydrocarbon residue previously designated R '.

[Production Method 15]
In a suitable solvent that does not adversely affect the reaction (in particular, halogenated hydrocarbons, including dichloromethane and chloroform, and ethers, including tetrahydrofuran, ethyl ether and dioxane), the 1,4-dihydro-oxo-pyrido ether derivative is mixed [2,3-b] pyridine-3-carboxylic acid (Vd) together with an amide derivative of aluminum, which is synthesized from the corresponding aluminum reagent [in particular, trimethylaluminum, triethylaluminum and diisobutylaluminum hydride (DIBAL)] and amines, in in the range of temperatures from about 10 to 100 ^° C. to obtain the 1,4-dihydro-oxo-pyrido [2,3-b] pyridine-3-carboxylic acid amide derivative (Vd '). The specified derivative is mixed together with the Grignard reagent in a suitable solvent, which does not adversely affect the course of the reaction (in particular tetrahydrofuran and ethyl ether), in the temperature range from about 0 to 80 ^o C and receive the corresponding derivative of the ketone (Ve). The Production Method 15 described above is shown in Scheme 15 (see end of description), where R ²⁶ is alkyl or aryl; R ²⁷ and R ²⁸ each represent a hydrogen atom or a hydrocarbon residue; the remaining characters have the same meanings as previously indicated.

Alkyl or aryl, designated as R ²⁶ above, have the same meanings as previously defined.

The hydrocarbon residue referred to above as R ²⁷ and R ²⁸ has the same meaning as the hydrocarbon residue in the carbonyl group optionally substituted with the hydrocarbon residue previously designated R '.

[Production Method 16]
The 4,7-dihydro-4-oxo-thieno [2,3-b] pyridine derivative (Ip) is dissolved in a suitable solvent which does not adversely affect the course of the reaction (in particular ethers, including 1,2-dimethoxyethane, tetrahydrofuran and dioxane, and alcohols, including ethyl alcohol). To the solution is added in the presence of an equimolar amount or excess (2 to 10 equivalents) of a suitable base (in particular sodium carbonate) a suitable derivative of arylboric acid (in particular phenylboronic acid, 3-methoxyphenylboronic acid and 4-ethoxycarbonylphenylboronic acid). A suitable catalyst, in particular palladium, including tetrakis (triphenylphosphine) palladium, is added to the resulting mixture in an inert gas stream (in particular argon gas). The mixture is stirred for several minutes to several hours in a temperature range of from about 10 to 100 ^o C. Insoluble substances are filtered off and obtain the target derivative (Ig). The Production Method 16 described above is shown in Scheme 16 (see the end of the description), where R ³⁰ is an optionally substituted aryl group and the remaining symbols have the same meanings as above.

 As salts of the obtained compounds of the present invention, physiologically acceptable acid addition salts are preferred. Examples of such salts include salts with inorganic acids (in particular hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid) or with organic acids (in particular, formic acid, acetic acid, trifluoroacetic acid, fumaric acid , oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid). Further, if compound (I) of the present invention contains an acid group such as —COOH, then compound (I) can form a salt with an inorganic base (in particular, an alkali metal or alkaline earth metal, such as sodium, potassium, calcium, and magnesium; ammonium) or an organic base (in particular trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine and N, N'-dibenzylethylenediamine).

 Most preferred examples of the compounds or salts thereof of the present invention include: 3- (N-benzyl-N-methylaminomethyl) -4,7-dihydro-7- (2-methoxybenzyl) -2- (4-methoxyphenyl) -4- ethyl ester oxytieno [2,3-b] pyridine-5-carboxylic acid; 3- (N-benzyl-N-methylaminomethyl) -4,7-dihydro-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -4-oxo-thieno [2,3-b] pyridin-5- ethyl ester carboxylic acid; 2- (4-acetylaminophenyl) -3- (N-benzyl-N-methylaminomethyl) -4,7-dihydro-7- (2-fluorobenzyl) -4-oxo-thieno [2,3-b] pyridin-5- ethyl ester carboxylic acid; 5-benzylaminomethyl-1- (2-chloro-6-fluorobenzyl) -2,4- (1H, 3H) dioxo-6- (4-methoxyphenyl) -3-phenylthieno [2,3-d] pyrimidine; 5-benzoyl-3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-4-oxo-2- (4-propionylaminophenyl) thieno [2,3-b ] pyridine; 5-benzoyl-3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-2- (4-N'-methylureidophenyl) -4-oxothieno [2,3 -b] pyridine; 3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-5-isobutyryl-4-oxo-2- (4-propionylaminophenyl) thieno [2,3-b ] pyridine; 3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4, 7-dihydro-5-isobutyryl-2- (4-N'-methylureidophenyl) -4-oxothieno [2,3 -b] pyridine; 3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-2- (4-N'-methylureidophenyl) -4-oxothieno [2,3-b] pyridine -5- (N-isopropyl) carboxamide; 3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-2- (4-N'-methylureidophenyl) -4-oxothieno [2,3-b] pyridine -5- (N-isopropyl-N-methyl) carboxamide; 3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-2- (4-N'-methylureidophenyl) -4-oxothieno [2,3-b] pyridine -5- (N-benzyl-N-methyl) carboxamide or salts thereof.

 The resulting compounds or their salts of the present invention can be isolated and purified by known purification methods such as recrystallization, distillation and chromatography. In those cases when the compound (I) is obtained in free form, it can be converted into the corresponding salt using known methods or their analogues. On the contrary, if the compound is obtained in the form of a salt, then it can be converted into the free form or into another salt.

 In the case where the compound or its salt of the present invention is an optically active compound, it can be separated into a d-compound and an l-compound using conventional methods for resolving optical isomers.

 Since the compounds of the present invention have inhibitory activity against gonadotropin-releasing hormone and low toxicity, they can be safely used to treat diseases dependent on male hormones or female hormones, as well as for treating diseases caused by excessive secretion of these hormones in warm-blooded animals (in in particular in humans, monkeys, cows, horses, dogs, cats, rabbits, rats and mice), inhibiting the secretion of gonadotropin due to the inhibitory effect on the rutting receptor otropinvysvobozhdayuschego hormone. In particular, the compounds of the present invention are effective as a prophylactic and therapeutic agent for preventing or treating several hormone-dependent diseases, for example, sex hormone cancer (in particular, prostate cancer, cervical cancer, breast cancer, pituitary adenoma), benign prostatic hypertrophy, uterine fibroids, endometriosis, precocious puberty, amenorrhea, premenstrual syndrome, sclerocystic ovarian disease and it's common. The compounds of the present invention are also effective as a means of controlling fertility in both sexes (in particular, a means of controlling pregnancy and a means of controlling the menstrual cycle). The compounds of the present invention can also be used as agents for inducing ovulation in females. The compounds of the present invention can be used in the treatment of infertility due to the effect of the reverse action caused by the cessation of administration of the compounds of the present invention. Further, the compounds of the present invention are useful for modulating estrous cycles in animals in animal husbandry and as a means of improving the quality of meat used in food or accelerating the growth of animals. In addition, the compounds of the present invention are useful as a means of promoting spawning in fish. Although the compounds of the present invention can be used individually, they can also be effectively administered by administering in combination with steroidal and non-steroidal antiandrogenic agents. The compounds of the present invention can be used to suppress a temporary increase in plasma testosterone concentrations; this increase is observed with the administration of the gonadotropin-releasing hormone superantagonist, such as leuprorelin acetate. The compound of the present invention can be effectively used when administered in combination with chemotherapeutic agents for the treatment of cancer. In the treatment of prostate cancer, examples of chemotherapeutic agents include ifosfamide, UFT, adriamycin, peplomycin, cisplatin and the like. In the treatment of breast cancer, examples of chemotherapeutic agents include cyclofochamide, 5-FU-, UFT, methotrexate, adriamycin, metomycin C, mitoxantrone, and the like.

 If the compound of the present invention is used in the field of animal husbandry or in fisheries as a prophylactic or therapeutic agent in the treatment of the above diseases, it can be administered orally or non-orally in accordance with known methods. The compound is mixed with a pharmaceutically acceptable carrier and is usually administered orally in the form of a solid preparation, such as a tablet, capsule, granule or powder, or non-oral, as an intravenous, subcutaneous or intramuscular injection, or as a suppository or tablet for sublingual administration. Further, if the compound is administered sublingually, subcutaneously or intramuscularly in the form of formulations adapted for prolonged release of the drug, it may be a tablet for sublingual administration or a microcapsule. The daily dose varies depending on the degree of damage; age, gender, body weight and differences in sensitivity of the patient to whom the drug is administered; time and intervals between administrations, properties, dosage forms and types of medication; as well as the types of effective components, and usually amounts, although not specifically limited, from about 0.01 to 10 mg, preferably from about 0.02 to 2 mg, more preferably from about 0.01 to 1 mg per 1 kg of warm-blooded body weight animals, which is usually administered once a day or in the form of 2-4 separate doses. The daily dose when using the compound of the present invention in livestock or fisheries varies similarly to the conditions discussed above and is from about 0.001 to 5 mg, preferably from about 0.002 to 2 mg per 1 kg of animal body weight and is administered once a day or in 2-3 separate doses.

 As the above pharmaceutically acceptable carriers, various conventional organic and inorganic carriers are used, which are included in the solid compositions in the form of fillers, lubricants, binders and disintegrants; and in the form of solvents, solubilizers, dispersants, isotonizing agents, buffering agents and pain relievers in the composition of the liquid compositions. If necessary, other additives may also be used, such as preservatives, antioxidants, coloring agents and sweetening agents.

 Preferred examples of the above excipients are lactose, sugar, D-mannitol, starch, crystalline cellulose or light silica. Preferred examples of the above lubricants are magnesium stearate, calcium stearate, talc or colloidal silicon oxide. Preferred examples of the above binding agents are crystalline cellulose, sugar, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxymethyl cellulose and polyvinylpyrrolidone. Preferred examples of the above disintegrating agents are starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium crosscarmelose and sodium carboxymethyl starch. Preferred examples of the above solvents are water for injection, alcohol, propylene glycol, macrogol, sesame oil and corn oil. Preferred examples of the above solubilizers are polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, tris-aminomethane, cholesterol, triethanolamine, sodium carbonate and sodium citrate. Preferred examples of the above dispersants are surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride and glycerol monostearate; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose sodium, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose. Preferred examples of the above isotonic agents are sodium chloride, glycerin and D-mannitol. Preferred examples of the above buffering agents are phosphate, acetate, carbonate and citrate buffers. Preferred examples of the above painkillers include benzyl alcohol. Preferred examples of the above preservatives are p-hydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid. Preferred examples of the above antioxidants are sulfites and ascorbic acid.

 For example, a dispersant, a solubilizer, a stabilizing agent, an isotonic agent and a preservative are added to the compound of the present invention, mixed using known methods, and an intravenous, subcutaneous or intramuscular injection composition is obtained. Using known methods, lyophilized preparations can be obtained from these injections, if necessary.

 Examples of the above pharmaceutical compositions are oral agents (in particular powders, granules, capsules and tablets), injections, injections for droppers, topical agents (in particular, nasal preparations, transdermal preparations, etc.), ointments (in particular, rectal ointments, vaginal ointments, etc.), etc.

 These pharmaceutical compositions can be prepared by conventional methods that are commonly used in the manufacture of pharmaceutical compositions.

 The compound of the present invention or its salt can be administered by injection or in the form of an aqueous injection containing dispersing agents [in particular, Tween 80 (Atlas Powder, USA), HCO 80 (Nikko Chemicals, Japan), polyethylene glycol, carboxymethyl cellulose , sodium alginate, etc.], preservatives (in particular methyl paraben, propyl paraben, benzyl alcohol, etc.), isotonic agents (in particular sodium chloride, mannitol, sorbitol, glucose, etc.), etc. .d. or in the form of an oil injection by dissolving, suspending or emulsifying in vegetable oil (in particular olive oil, sesame oil, cottonseed oil, corn oil, etc.), propylene glycol, etc.

 In preparing a pharmaceutical composition for oral use, a compound of the present invention or a salt thereof is compressed, for example, together with fillers (in particular lactose, sucrose, starch, etc.), disintegrants (in particular starch, calcium carbonate, etc. .), binders (in particular, starch, gum arabic, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, etc.) or lubricants (in particular, talc, magnesium stearate, propylene glycol 6000, etc.), etc. , the composition is coated using known methods in order to mask taste, enteric coating or coating providing slow release of the drug. Examples of coating agents are hydroxypropyl methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Pluronic F 68, cellulose acetate phthalate, hydroxymethyl cellulose acetate succinate, methacrylic acid and Germany, methacrylic acid; red iron oxide and the like. An intermediate layer may be located between the core and the enteric coating according to known methods.

 In preparing compositions for external use, the compound of the present invention or its salt is subjected to treatments known in the art to obtain a solid, semi-solid and liquid composition for external use. For example, solid compositions are made as follows. From the compound of the present invention in its pure form or after the addition of fillers (in particular glycol, mannitol, starch, microcrystalline cellulose, etc.), thickeners (in particular, natural resins, cellulose derivatives, acrylic acid-based polymers, etc. n.) and similar substances and mixing with them prepare a powder composition. As for the liquid composition, a suspension in oil or water is prepared in much the same way as an injection. In the case of a semi-solid composition, preference is given to a gel in water or oil or ointment. Each of them may include a means for adjusting the pH (in particular, carboxylic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), antiseptic agents (in particular, p-hydroxybenzoate, chlorobutanol, benzalkonium chloride and etc.) etc.

 In the manufacture of, for example, an ointment, the compound of the present invention or its salt may be included in a solid, semi-solid or liquid ointment based on oil or water. Examples of substances that can be used in the above oil-based compositions are higher fatty acid glycerides [in particular cocoa butter, Witepsols (manufactured by Dynamite-Nobel), etc.], medium fatty acids [in particular, Miglyols (manufactured by Dynamite-Nobel), etc.] and vegetable oil (in particular sesame oil, soybean oil, cottonseed oil, etc.), etc. Examples of substances that can be used in aqueous compositions are polyethylene glycols and polypropylene glycol, and examples of substances that can be used in aqueous gels include natural resins, cellulose derivatives, vinyl polymers, acrylic acid polymers, and the like.

BEST MODE FOR CARRYING OUT THE INVENTION
The present invention is further explained in more detail by the following reference examples, Working examples and Test examples, however, they in no way limit the present invention.

 Proton magnetic resonance spectra (PMR) were obtained on a Varian GEMINI 200 (200 MHz) spectrometer, a JEOL LAMBADA 300 (300 MHz) spectrometer, or a Brucker AM 500 (500 MHz) spectrometer using tetramethylsilane as the internal standard. All delta chemical shifts are given in ppm.

Symbols that are used in the present description have the following meanings:
s: singlet; d: doublet; t: triplet; dt: doublet of triplets; m: multiplet; w: broadened signal.

Reference example 1
2-amino-5-phenylthiophene-3-carboxylic acid ethyl ester
To a mixture of ethyl cyanoacetic acid (6.1 g, 50 mmol), sulfur (1.61 g, 50 mmol), triethylamine (3.5 ml, 25 mmol) and dimethylformamide (10 ml) was added dropwise over 20 minutes at a temperature of 45 ^o C phenylacetaldehyde (50% solution in diethylphthalate; 12.05 g, 50 mmol). Then the reaction mixture was stirred for 9 hours at a temperature of 45 ^o C and evaporated. The resulting residue was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, which was then dried (over magnesium sulfate) and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel, and then recrystallized from ether-hexane to give yellowish plates (5.55 g, 45%), so pl. 124.5-125.5 ^o C (according to published data: 123-124 ^o C).

Elementary analysis for C ₁₃ H ₁₃ NO ₂ S (%):
calculated: C, 63.13; H 5.30; N, 5.66;
Found: C, 62.99; H 5.05; N, 5.63.

 1 H-NMR spectrum (200 MHz, chloroform-d): 1.37 (3H, t, J = 7.1 Hz), 4.30 (2H, d, J = 7.1 Hz), 5.97 (2H, w ), 7.17-7.46 (6H, m).

IR spectrum (KBr): 3448, 3320, 1667, 1590, 1549 cm ^-1 .

Reference example 2
2-amino-4-methyl-5- (4-methoxyphenyl) thiophen-3-carboxylic acid ethyl ester
A mixture of 4-methoxyphenylacetone (16.5 g, 0.10 mol), ethyl cyanoacetic acid (12.2 g, 0.10 mol), ammonium acetate (1.55 g, 20 mmol), acetic acid (4.6 ml, 80 mmol) and benzene (20 ml) are refluxed for 24 hours, removing the water formed during the reaction using a Dean-Stark nozzle. After cooling, the reaction mixture was evaporated under reduced pressure. The residue was poured into a mixture of dichloromethane and aqueous sodium bicarbonate. The organic layer was separated, washed with an aqueous solution of sodium chloride, dried (over magnesium sulfate) and the solvent was distilled off under reduced pressure. The residue was dissolved in ethanol and sulfur (3.21 g, 0.10 mol) and diethylamine (10.4 ml, 0.10 mol) were added to it. The mixture is stirred at a temperature of 50-60 ^o C for 2 hours and evaporated. The concentrate was extracted with ethyl acetate, the extract was washed with an aqueous solution of sodium chloride, dried (over magnesium sulfate) and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel, and then recrystallized from ether-hexane to give pale yellowish plates (11.5 g, 40%), so pl. 79-80 ^o C.

Elemental analysis for C ₁₅ H ₁₇ NO ₃ S (%):
calculated: C, 61.83; H 5.88; N, 4.81; S 11.01;
Found: C, 61.81; H 5.75; N 4.74; S 10.82.

 1 H-NMR spectrum (200 MHz, chloroform-d): 1.37 (3H, t, J = 7.1 Hz), 2.28 (3H, s), 3.83 (3H, s), 4.31 (2H quartet, J = 7.1 Hz), 6.05 (2H, w), 6.91 (2H, d, J = 8.8 Hz), 7.27 (2H, d, J = 8.8 Hz )

IR Spectrum (KBr): 3426, 3328, 1651, 1586, 1550, 1505, 1485 cm ^-1 .

 Mass spectrum (FAB-MS): m / z 291 (M +).

Reference example 3
Using instead of 4-methoxyphenylacetone various derivatives of acetone, according to a procedure similar to that described in Reference example 2, receive the compounds shown in Table 1.

Reference example 4
{3-Ethoxycarbonyl-5- (4-methoxyphenyl) -4-methylthiophen-2-yl} aminomethylene malonic acid diethyl ester
Ethoxymethylene malonic acid diethyl ether (7.45 g, 34.5 mmol) was added to the compound obtained in Reference Example 2 (10 g, 34.3 mmol). The mixture was stirred for 2 hours at a temperature of 120 ^° C. After cooling, ether was added to the reaction mixture to precipitate crystals. The crystals were separated by filtration and washed again, dried over phosphorus pentoxide under reduced pressure to obtain yellow crystals (14.2 g, 90%) with mp 122-123 ^o C.

 1H-NMR spectrum (200 MHz, chloroform-d): 1.32 (3H, t, J = 7.1 Hz), 1.38 (3H, t, J = 7.2 Hz), 1.41 (3H, t , J = 7.2 Hz), 2.34 (3H, s), 3.85 (3H, s), 4.25 (2H, quartet, J = 7.1 Hz), 4.38 (2H, quartet , J = 7.2 Hz), 4.45 (2H, quartet, J = 7.2 Hz), 6.95 (2H, d, J = 8.8 Hz), 7.31 (2H, d, J = 8.8 Hz), 8.22 (1H, d, J = 13.4 Hz), 12.74 (1H, d, J = 13.4 Hz).

IR Spectrum (KBr): 2984, 1720, 1707, 1688, 1653, 1559, 1518, 1499 cm ^-1 .

Reference example 5
Using the compounds obtained in Reference Example 3 or various thiophene derivatives commercially available as starting materials, by the procedure similar to that described in Reference Example 4, the compounds shown in Table 2 are obtained.

Reference Example 6
{3-Carboxy-5- (4-methoxyphenyl) -4-methylthiophen-2-yl} aminomethylene malonic acid diethyl ester
To a solution of the compound obtained in Reference Example 4 (7.0 g, 15.2 mmol) in dioxane (20 ml) at a temperature of 60-70 ^° C., a solution of potassium hydroxide (5.0 g, 75.7 mmol) is added with stirring ) in ethanol (30 ml). The mixture was stirred for one hour at the same temperature and left at room temperature for one hour. A 2 N hydrochloric acid solution (40 ml, 80 mmol) was added to the reaction mixture under ice cooling. The reaction mixture was evaporated under reduced pressure. The resulting yellow precipitate was separated by filtration, washed with a mixture of cold water and ethanol, and then dried over phosphorus pentoxide under reduced pressure to obtain a yellow powder (6.1 g, 93%) with mp. 184-187 ^o C.

1 H-NMR spectrum (200 MHz, DMSO-d ₆ ): 1.24 (3H, t, J = 7.1 Hz), 1.28 (3H, t, J = 7.2 Hz), 2.30 (3H, s), 4.15 (2H, quartet, J = 7.1 Hz), 4.24 (2H, quartet, J = 7.2 Hz), 7.03 (2H, d, J = 8.7 Hz) 7.37 (2H, d, J = 8.7 Hz), 8.08 (1H, d, J = 13.6 Hz), 12.41 (1H, d, J = 13.6 Hz).

IR Spectrum (KBr): 2422, 2980, 1719, 1653, 1607, 1551, 1512 cm ^-1 .

Reference example 7
Using the compounds obtained in Reference Example 5 as starting materials, by the procedure similar to that described in Reference Example 6, the compounds shown in Table 3 are obtained.

Reference example 8
4-hydroxy-2- (4-methoxyphenyl) -3-methylthieno [2,3-b] pyridine-5-carboxylic acid diethyl ester
To the polyphosphoric acid ester (90 ml) in small portions at a temperature of 190 ^° C., the compound obtained in Reference Example 6 (6.0 g, 13.8 mmol) is added with stirring. The mixture is stirred at the indicated temperature for 30 minutes. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel to give a yellow powder (3.65 g, 77%). To obtain a sample for analysis, the powder is recrystallized from ethanol and yellow crystals are obtained with mp. 162-163 ^o C.

Elemental analysis for C ₁₈ H ₁₇ NO ₄ S (%):
calculated: C, 62.96; H 4.99; N, 4.08; S 9.34;
Found: C, 62.89; H 5.04; N, 4.01; S 9.34.

 1 H-NMR spectrum (200 MHz, chloroform-d): 1.47 (3H, t, J = 7.1 Hz), 2.63 (3H, s), 4.87 (3H, s), 4.49 (2H quartet, J = 7.1 Hz), 6.99 (2H, d, J = 8.8 Hz), 7.44 (2H, d, J = 8.8 Hz), 8.84 (1H, s ), 12.11 (1H, s).

IR Spectrum (KBr): 3434, 2992, 1692, 1501, 1582, 1535, 1504 cm ^-1 .

 Mass spectrum (FAB-MS): m / z 344 (MH +).

Reference example 9
Using the compounds obtained in Reference Example 7 as starting materials, by the procedure similar to that in Reference Example 8, the compounds shown in Table 4 are obtained.

Reference Example 10
4-hydroxy-2- (4-nitrophenyl) -3-methylthieno [2,3-b] pyridine-5-carboxylic acid diethyl ester
To a solution of compound 1 obtained in Reference Example 9 (3.76 g, 12 mmol) in concentrated sulfuric acid (10 ml), while cooling with ice, a solution of sodium nitrate (1.27 g, 15.0 mmol) in concentrated sulfuric acid (5 ml). The mixture is stirred under the indicated conditions for 30 minutes. The reaction mixture is poured into ice water and extracted with chloroform. The extract was washed with an aqueous solution of sodium chloride, dried (over magnesium sulfate) and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel to give a yellow powder, which was recrystallized from ethanol to give yellow crystals (1.75 g, 41%) with mp. 260-261 ^o C.

Elemental analysis for C ₁₇ H ₁₄ N ₂ O ₅ S (%):
calculated: C 56.98; H 3.94; N, 7.82;
Found: C, 56.66; H 3.91; N, 7.86.

 1 H-NMR spectrum (200 MHz, chloroform-d): 1.49 (3H, t, J = 7.1 Hz), 2.70 (3H, s), 4.51 (2H, quartet, J = 7.1 Hz ), 7.70 (2H, d, J = 8.8 Hz), 8.34 (2H, d, J = 8.8 Hz), 8.89 (1H, s), 12.27 (1H, s )

IR Spectrum (KBr): 3002, 1692, 1605, 1514, 1350, 1290 cm ^-1 .

 Mass spectrum (FAB-MS): m / z 358 (MH +).

Reference example 11
4-hydroxy-5-hydroxymethyl-2- (4-methoxyphenyl) -3-methylthieno [2,3-b] pyridine
To a suspension (6 ml) of lithium aluminum hydride (0.0326 g, 0.87 mmol) in anhydrous tetrahydrofuran at room temperature (15-35 ^° C, the same range is intended hereinafter), a solution of the compound obtained in Reference Example 8 is added dropwise (0.20 g, 0.58 mmol) in anhydrous tetrahydrofuran (3 ml). The mixture was stirred at room temperature for 30 minutes, and then the Rochelle salt was added to the mixture. The precipitate formed is filtered off. If necessary, the reaction mixture is heated to boiling to complete the reaction. The precipitate was washed with ethyl alcohol and chloroform, the washing solutions were combined with the filtrate and evaporated. The residue was poured into a mixture of ethyl acetate and an aqueous solution of sodium chloride. The organic layer was dried (over magnesium sulfate), the solvent was distilled off under reduced pressure, and white crystals (0.13 g, 74%) were obtained, so pl. > 300 ^o C.

PMR spectrum (200 MHz, DMSO-d ₆ ): 2.55 (3H, s) 3.81 (3H, s), 4.41 (2H, s), 7.03 (2H, d, J-8, 8 Hz), 7.40 (2H, d, J = 8.8 Hz), 7.75 (1H, s).

IR (KBr): 3210, 2930, 1613, 1506, 1255 cm ^-1 .

 Mass spectrum (FAB-MS): m / z 302 (MH +).

Reference example 12
2-benzoyl-4-hydroxy-3-methylthieno [2,3-b] pyridine-5-carboxylic acid ethyl ester
To a mixture of compound 3 obtained in Reference Example 7 (5.0 g, 15.3 mmol) and anhydrous aluminum chloride (8.6 g, 64.5 mmol) in nitromethane (100 ml) slowly dropwise under a nitrogen atmosphere and while cooling in an ice bath, benzoyl chloride (3.6 ml, 31.0 mmol) is added. The mixture was stirred at room temperature for one hour, and then 14 hours at a temperature of 50 ^° C. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, dried (over magnesium sulfate), the solvent was distilled off under reduced pressure to obtain a brownish powder (7.58 g). Powder at a temperature of 120 ^o C with stirring, is added in small portions to a polyphosphoric acid ester. The mixture was stirred at the indicated temperature for 90 minutes, and then poured into ice water and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, dried (over magnesium sulfate) and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel to give a yellow powder (0.82 g, 16%). To obtain a sample for analysis, the powdery product is recrystallized from a mixture of chloroform-methanol and yellow crystals are obtained with so pl. 241-243 ^o C.

Elemental analysis for C ₁₈ H ₁₅ NO ₄ S • 0.25H ₂ O (%):
calculated: C, 62.51; H 4.52; N, 4.05;
Found: C, 62.77; H 4.22; N, 4.30.

1 H-NMR spectrum (200 MHz, CDCl ₃ -CD ₃ OD): 1.49 (3H, t, J = 7.1 Hz), 2.71 (3H, s), 4.53 (2H, quartet, J = 7 , 1 Hz), 7.49-7.70 (3H, br), 8.96 (1H, s).

IR Spectrum (KBr): 3004, 1692, 1638, 1603, 1582, 1537, 1431 cm ^-1 .

Reference Example 13
2-Phenylacetyl-4-hydroxy-3-methylthieno [2,3-b] pyridine-5-carboxylic acid ethyl ester
The target compound (1.47 g, 14%) with so pl. 208-214 ^o C receive, using as the starting compound obtained in Reference example 7, according to the method similar to that described in Reference example 12, replacing benzoyl chloride with phenylacetyl chloride.

Elemental analysis for C ₁₉ H ₁₇ NO ₄ S • 0.1 EtOAc (%):
calculated: C, 63.98; H 4.93; N, 3.85;
Found: C, 64.25; H 4.66; N, 3.52.

1 H-NMR spectrum (200 MHz, CDCl ₃ -CD ₃ OD): 1.47 (3H, t, J = 7.1 Hz), 2.99 (3H, s), 4.20 (2H, s), 4, 49 (2H, quartet, J = 7.1 Hz), 7.26-7.41 (5H, m), 8.96 (1H, s), 12.50 (1H, s).

IR Spectrum (KBr): 3424, 2986, 1694, 1601, 1580, 1535, 1495, 1439 cm ^-1 .

Reference Example 14
2-Bromo-4-hydroxy-3-methylthieno [2,3-b] pyridine-5-carboxylic acid ethyl ester
To a solution of compound 3 obtained in Reference Example 7 (17.8 g, 54.4 mmol) and pyridine (22 ml, 0.272 mmol) in chloroform (120 ml), a bromine solution (3.4 ml, 66 mmol) in chloroform (30 ml). The mixture was stirred for 30 minutes at room temperature, and then the reaction mixture was evaporated under reduced pressure. Diluted hydrochloric acid is added to the concentrate. The precipitated crystalline precipitate is filtered off, washed with water and a small amount of cold ether, dried in vacuum over phosphorus pentoxide and a brown powder is obtained. This powder is added in small portions to a polyphosphoric acid ester (100 ml) at a temperature of 120 ^° C. with stirring. The mixture was stirred at the indicated temperature for 90 minutes, and then poured into ice water and extracted with ethyl acetate. The extract was washed with an aqueous salt solution, dried (over magnesium sulfate) and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel to give a pale yellow powder (9.93 g, 58%). To obtain a sample for analysis, the powder was recrystallized from a mixture of chloroform-methanol to obtain colorless needles with mp 214-216 ^o C.

Elemental analysis for C ₁₁ H ₁₀ NO ₃ SBr (%):
calculated: C, 41.79; H 3.19; N, 4.43;
Found: C, 41.55; H 3.14; N, 4.53.

1 H-NMR spectrum (200 MHz, COCl ₃ -CD ₃ OD): 1.47 (3H, t, J = 7.1 Hz), 2.60 (3H, s), 4.50 (2H, quartet, J = 7 , 1 Hz), 8.82 (1H, s).

IR spectrum (KBr): 2990, 1605, 1578, 1533 cm ^-1 .

Reference Example 15
2-Bromo-4-hydroxy-3-methylthieno [2,3-b] pyridine-5-carboxylic acid ethyl ester (alternative method for the synthesis of the compound obtained in Reference example 14)
A mixture of the compound obtained in Reference Example 9 (0.24 g, 1.01 mmol), N-bromosuccinimide (10.198 g, 1.11 mmol) and chloroform (10 ml) was refluxed for 3 hours. After cooling, the reaction mixture was poured into an aqueous solution of sodium chloride and extracted with chloroform. The extract was washed with an aqueous solution of salt, dried (over magnesium sulfate), the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel to give a yellow powder, which was recrystallized from chloroform-methanol to give colorless needles (0.29 g, 91%) with mp. 214-216 ^o C.

Reference example 16
7-benzoyl-4,7-dihydro-2- (4-methoxyphenyl) -3-methyl-4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid ethyl ester
Benzoyl chloride (1.78 ml, 15.3 mmol) was added to a solution of the compound obtained in Reference Example 8 (5 g, 14.6 mmol) in pyridine (100 ml) while cooling in an ice bath. Stir at room temperature for 150 minutes and add ethanol (1 ml). The reaction mixture was evaporated under reduced pressure. The residue was poured into a mixture of dichloromethane and saturated aqueous sodium chloride. The organic layer was separated, the aqueous phase was extracted with dichloromethane. The organic extracts are combined, washed with water and dried (over magnesium sulfate). The solvent is distilled off, the residue is chromatographed on silica gel and recrystallized from ethanol to give white crystals (6.41 g, 98%) with mp. 110-112 ^o C.

Elemental analysis for C ₂₅ H ₂₁ NO ₅ S (%):
calculated: C, 67.10; H 4.73; N, 3.13;
Found: C, 66.95; H 4.68; N, 2.93.

 1 H-NMR spectrum (200 MHz, chloroform-d): 1.14 (3H, t, J = 7.7 Hz), 2.42 (3H, s), 3.85 (3H, s), 4.26 (2H quartet, J = 7.2 Hz), 6.98 (2H, d, J = 6.7 Hz), 7.40 (2H, d, J = 8.9 Hz), 7.57 (2H, t , J = 7.6 Hz), 7.70 (1H, t, J = 5.9 Hz), 8.27 (2H, d, J = 7.0 Hz), 9.14 (1H, s).

IR Spectrum (KBr): 2972, 1717, 1607, 1580, 1522, 1502 cm ^-1 .

Reference example 17
7-benzoyl-3-bromomethyl-4,7-dihydro-2- (4-methoxyphenyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid ethyl ester
A mixture of the compound obtained in Reference Example 16 (6.39 g, 14.3 mmol), N-bromosuccinimide (2.67 g, 15 mmol), α, α′-azobisisobutyronitrile (0.47 g, 2.86 mmol) and carbon tetrachloride (100 ml) is refluxed for one hour. Cool and insoluble matter separated by filtration. The filtrate was diluted with chloroform. The organic phase is washed with water and dried (over magnesium sulfate), the solvent is evaporated off under reduced pressure, and the residue is recrystallized from ethyl acetate to obtain colorless needles (7.02 g, 93%) with so pl. 124-126 ^o C.

Elemental analysis for C ₂₅ H ₂₀ NO ₅ SBr (%):
calculated: C 57.04; H 3.83; N 2.66;
Found: C, 57.16; H 3.85; N, 2.70.

 1 H-NMR spectrum (200 MHz, chloroform-d): 1.14 (3H, t, J = 7.2 Hz), 2.88 (3H, s), 4.26 (2H, quartet, J = 7.2 Hz ), 4.68 (2H, s), 7.04 (2H, d, J = 8.8 Hz), 7.53-7.75 (5H, m), 8.35 (2H, d, J = 7.0 Hz), 9.20 (1H, s).

IR spectrum (KBr): 2984, 1717, 1605, 1502 cm ^-1 .

Reference Example 18
3- (N-benzyl-N-methylaminomethyl) -4-hydroxy-2- (4-methoxyphenyl) thieno [2,3-b] pyridine-5-carboxylic acid ethyl ester
A mixture of the compound obtained in Reference Example 17 (6.73 g, 12.8 mmol), N-ethyldiisopropylamine (2.30 ml, 13.4 ml), N-benzylmethylamine (1.73 ml; 13.4 mmol) and dimethylformamide (100 ml) was stirred at room temperature for 40 minutes. The solvent was evaporated under reduced pressure and the residue was poured into a mixture of dichloromethane and saturated aqueous sodium chloride. The organic layer was separated, washed with water and dried (over magnesium sulfate). The solvent was distilled off under reduced pressure, and the residue was dissolved in a mixture of dichloromethane (100 ml) and ethanol (50 ml). To the resulting solution, while cooling in an ice bath, a solution of sodium ethoxide (0.88 g, 13 mmol) in ethanol (50 ml) was added and the mixture was stirred at room temperature for 4 hours. The mixture was neutralized with acetic acid, the solvent was distilled off under reduced pressure, and the residue was poured into a mixture of dichloromethane and a saturated aqueous solution of sodium chloride. The organic layer was separated, washed with water and dried (over magnesium sulfate). The solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel and recrystallized from ethanol to give colorless crystals (4.32 g, 73%) with mp. 175-177 ^o C.

Elemental analysis for C ₂₆ H ₂₆ N ₂ O ₄ S (%):
calculated: C, 67.51; H 5.67; N, 6.06;
Found: C, 67.43; H 5.72; N, 6.06.

 1 H-NMR spectrum (200 MHz, chloroform-d): 1.45 (3H, t, J = 7.2 Hz), 2.35 (3H, s), 3.75 (2H, w), 3.89 (3H , s), 3.92 (2H, s), 4.44 (2H, quartet, J = 7.2 Hz), 7.01 (2H, d, J = 6.7 Hz), 7.21-7 37 (7H, m), 8.87 (1H, s).

IR (KBr): 3424, 3000, 1686, 1607, 1504 cm ^-1 .

Reference example 19
2-amino-4-methyl-5- (4-nitrophenyl) thiophen-3-carboxylic acid ethyl ester
Using a procedure similar to that in Reference Example 1, taking 4-nitrophenylacetone (35.0 g, 195 mmol) instead of 4-methoxyacetone, ethyl cyanoacetic acid (23 g, 19.5 mmol), ammonium acetate (3.1 g, 40 mmol), acetic acid (9.1 ml, 159 mmol), sulfur (5.0 g, 160 mmol) and diethylamine (16.9 ml, 160 mmol), give the target compound as colorless crystals (22.2 g , 52%) with mp 168-170 ^o C (recrystallized from ether-hexane).

Elemental analysis for C ₁₄ H ₁₄ N ₂ O ₄ S (%):
calculated: C 54.89; H 4.61; N, 9.14;
Found: C, 54.83; H 4.90; N, 9.09.

 1 H-NMR spectrum (200 MHz, chloroform-d): 1.39 (3H, t, J = 7.1 Hz), 2.40 (3H, s), 4.34 (2H, quartet, J = 7.1 Hz ), 6.27 (2H, d), 7.48 (2H, d, J = 8.7 Hz), 8.23 (2H, d, J = 8.7 Hz).

IR Spectrum (KBr): 3446, 3324, 1667, 1580, 1545, 1506, 1491, 1475, 1410, 1332 cm ^-1 .

Reference Example 20
2,4 (1H, 3H) -Dioxo-5-methyl-6- (4-methoxyphenyl) thieno [2,3-d] pyrimidin-3-acetic acid ethyl ester
To the solution of the compound obtained in Reference Example 1 (5.00 g, 17.20 mmol) iso-cyanoacetic acid ethyl ester (2.90 ml, 25.80 mmol) is added. The mixture was stirred at 45 ^° C. for 6 hours and evaporated under reduced pressure. The concentrate was dissolved in ethanol (6 ml) and sodium ethoxide was added to the resulting solution [prepared from ethanol (30 ml) and sodium (0.79 g, 34.0 mmol)]. The mixture was stirred at room temperature for 24 hours and a 2 N hydrochloric acid solution (18 ml, 36 mmol) was added. Ethanol is distilled off under reduced pressure, the residue is filtered off, washed with a mixture of water and ethanol and dried under reduced pressure; Recrystallized from ethanol to give white needles (5.70 g, 89%) with mp. 164-165 ^o C.

Elemental analysis for C ₁₈ H ₁₈ N ₂ O ₅ S (%):
calculated: C 57.74; H 4.85; N, 7.48;
Found: C, 57.78; H 5.03; N, 7.45.

 1 H-NMR spectrum (200 MHz, chloroform-d): 1.30 (3H, t, J = 7.1 Hz), 2.45 (3H, s), 3.85 (3H, s), 4.26 (2H quartet, J = 7.2 Hz), 4.78 (2H, s), 6.95 (2H, d, J = 8.8 Hz), 7.31 (2H, d, J = 8.8 Hz ), 10.58 (1H, s).

IR Spectrum (KBr): 2914, 1742, 1713, 6550, 1605, 1568, 1528, 1499 cm ^-1 .

Reference example 21
Using, as starting materials, the compounds obtained in Reference Examples 2, 3 and 19, according to a procedure similar to that described in Reference Example 20, the compounds shown in Table 5 are obtained.

Reference Example 22
2,4 (1H, 3H) -Dioxo-6- (4-nitrophenyl) -5-methylthieno [2,3-d] pyrimidine-3-acetic acid ethyl ester
Concentrated sulfuric acid (12 ml) was added to compound 1 obtained in Reference Example 21 (2.20 g, 6.39 mmol). To the resulting mixture, while cooling in an ice bath, a solution of sodium nitrate (550 mg, 6.47 mmol) in concentrated sulfuric acid was added dropwise and stirred under the same conditions for one hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, dried (over magnesium sulfate) and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel to give a yellowish solid (1.30 g, 52%), which was recrystallized from ethyl acetate-hexane to give yellow crystals with mp. 277-280 ^o C.

Elemental analysis for C ₁₇ H ₁₅ N ₃ O ₆ S • 0.4H ₂ O (%):
calculated: C, 51.48; H 4.01; N, 10.59;
Found: C, 51.64; H 3.79; N, 10.61.

 1 H-NMR spectrum (200 MHz, chloroform-d): 1.33 (3H, t, J = 7.2 Hz), 2.56 (3H, s), 4.28 (2H, quartet, J = 7.2 Hz ), 4.79 (2H, s), 7.57 (2H, d, J = 8.8 Hz), 8.30 (2H, d, J = 8.8 Hz), 10.30 (1H, s )

IR Spectrum (KBr): 1748, 1719, 1663, 1522, 1460 cm ^-1 .

Reference example 23
2,4 (1H, 3H) -Dioxo-1- (2-fluorobenzyl) -6- (4-nitrophenyl) -5-methylthieno [2,3-d] pyrimidine-3-acetic acid ethyl ester
To a solution of the compound obtained in Reference Example 22 (700 mg, 1.90 mmol) in dimethylformamide (10 ml) was added potassium carbonate (372 mg, 2.70 mmol), potassium iodide (299 mg, 1.80 mmol) and 2-fluorobenzyl chloride (0.43 ml, 3.60 mmol). The mixture was stirred for 2 hours at room temperature, evaporated and the residue was poured into a mixture of ethyl acetate and an aqueous solution of sodium chloride. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic extracts are combined, washed with an aqueous solution of sodium chloride, dried (over magnesium sulfate) and the solvent is distilled off under reduced pressure. The residue was chromatographed on silica gel to give a white powder (500 mg, 56%) with mp. 155-158 ^o C.

Elemental analysis for C ₂₄ H ₂₀ N ₃ O ₆ SF • 0.5H ₂ O (%):
calculated: C 56.91; H 4.18; N, 8.30;
Found: C, 56.74; H 3.84; N, 8.25.

 1 H-NMR spectrum (200 MHz, chloroform-d): 1.32 (3H, t, J = 7.2 Hz), 3.84 (3H, s), 4.27 (2H, quartet, J = 7.2 Hz ), 4.84 (2H, s), 5.30 (2H, s), 7.06-7.33 (4H, m), 7.54 (2H, d, J = 8.9 Hz), 7 27 (2H, d, J = 8.9 Hz).

IR Spectrum (KBr): 1748, 1711, 1673, 1520, 1491 cm ^-1 .

Reference Example 24
Using the compounds obtained in Reference Example 21 as starting materials, by the procedure similar to that described in Reference Example 23, the compounds shown in Table 6 are obtained.

Reference example 25
5-Bromomethyl-2,4 (1H, 3H) -dioxo-1- (2-fluorobenzyl) - 6- (4-nitrophenyl) thieno [2,3-d] pyrimidine-3-acetic acid ethyl ester
A mixture of the compound obtained in Reference Example 23 (0.300 g, 0.603 mmol), N-bromosuccinimide (0.107 g, 0.603 mmol), α, α′-azobisisobutyronitrile (10 mg, 0.60 mmol) and carbon tetrachloride (15 ml) is boiled under reflux for two hours. Cool and insoluble matter separated by filtration. The filtrate was diluted with chloroform. The organic phase is washed with water and dried (over magnesium sulfate), the solvent is evaporated off under reduced pressure, and the residue is recrystallized from ethyl acetate to give colorless needles (0.284 g, 82%), so pl. 165-167 ^o C.

Elemental analysis for C ₂₄ H ₁₉ N ₃ O ₆ SBrF (%):
calculated: C, 50.01; H 3.32; N, 7.29;
Found: C, 49.87; H 3.27; N, 7.23.

 1 H-NMR spectrum (200 MHz, chloroform-d): 1.31 (3H, t, J = 7.1 Hz), 4.26 (2H, quartet, J = 7.1 Hz), 4.78 (2H, s ), 4.86 (2H, s), 5.30 (2H, s), 7.07-7.37 (4H, m), 7.75 (2H, d, J = 8.8 Hz), 8 33 (2H, d, J = 8.8 Hz).

IR Spectrum (KBr): 1713, 1673, 1524, 1477 cm ^-1 .

Reference example 26
Using the compounds obtained in Reference Example 24 as starting materials, by the procedure similar to that in Reference Example 25, the compounds shown in Table 7 are obtained.

Reference example 27
5-Benzylmethylaminomethyl-2,4- (1H, 3H) -dioxo-1- (2-fluorobenzyl) -6- (4-nitrophenyl) thieno [2,3-d] pyrimidine-3-acetic acid ethyl ester hydrochloride
To a solution of the compound obtained in Reference Example 25 (0.270 g, 0.47 mmol) in dimethylformamide (10 ml), while cooling in an ice bath, ethyldiisopropylamine (0.12 ml, 0.710 mmol) and benzylmethylamine (0.07 ml, 0.56 mmol). The mixture was stirred at room temperature for 20 hours. The reaction mixture was evaporated and the residue was poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic layer was separated and the aqueous phase was extracted with ethyl acetate. The organic extracts are combined, washed with an aqueous solution of sodium chloride, dried (over magnesium sulfate) and the solvent is distilled off under reduced pressure. The residue was chromatographed on silica gel to give a colorless oil (0.297 g, 100%). To a solution of this substance in ethyl acetate, a 1 N solution of hydrogen chloride in ether was added while cooling in an ice bath. The mixture was stirred for 10 minutes at the same temperature and evaporated under reduced pressure, and the concentrate was recrystallized from ethyl acetate-ether to give the corresponding hydrochloride (0.084 g) as white crystals; so pl. (hydrochloride) 120-128 ^o C.

Elemental analysis for C ₃₂ H ₂₉ N ₄ O ₆ SF • HCl • H ₂ O (%):
calculated: C 57.27; H 4.81; N, 8.35;
Found: C, 57.23; H 4.55; N, 8.42.

 1 H-NMR spectrum (200 MHz, chloroform-d) [free amine]: 1.31 (3H, t, J = 7.1 Hz), 2.16 (3H, s), 3.61 (2H, s), 3 97 (2H, s), 4.27 (2H, quartet, J = 7.1 Hz), 4.87 (2H, s), 5.31 (2H, s), 7.10-7.35 ( 9H, m), 7.97 (2H, d, J = 8.8 Hz), 8.23 (2H, d, J = 8.8 Hz).

IR Spectrum (KBr) [hydrochloride]: 1711, 1665, 1522, 1493 cm ^-1 .

Working example 1
4,7-Dihydro-7- (2-methoxybenzyl) -2- (4-methoxyphenyl) -3-methyl-4-oxo-thieno [2, 3-b] pyridine-5-carboxylic acid ethyl ester
To a suspension of sodium hydride (60% in oil; 123 mg, 3.08 mmol) in dimethylformamide (3 ml) in a nitrogen atmosphere and while cooling in an ice bath was added dropwise a solution of the compound obtained in Reference example 8 (1.0 g 2.91 mmol) in dimethylformamide (20 ml). The mixture was stirred for 30 minutes while cooling in an ice bath and a solution of 2-methoxybenzyl chloride (0.92 g, 5.87 mmol) in dimethylformamide (3 ml) was added dropwise to it. The reaction mixture was stirred at room temperature for 23 hours and then 2 hours at 70 ^° C. The reaction mixture was evaporated and the residue was poured into a mixture of ethyl acetate and an aqueous solution of sodium chloride. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic extracts are combined, washed with an aqueous solution of sodium chloride, dried (over magnesium sulfate) and the solvent is distilled off under reduced pressure. The residue was chromatographed on silica gel to give a pale yellow amorphous (0.95 g, 70%). To obtain a sample for analysis, the amorphous product is recrystallized from a mixture of dichloromethane - ether and get yellow prisms with so pl. 165-167 ^o C.

Elemental analysis for C ₂₆ H ₂₅ NO ₅ S • 0.5H ₂ O (%):
calculated: C, 66.08; H 5.55; N, 2.96;
Found: C, 66.33; H 5.44; N 2.74.

 1 H-NMR spectrum (200 MHz, chloroform-d): 1.41 (3H, t, J = 7.1 Hz), 2.65 (3H, s), 3.65 (3H, s), 3.86 (3H , s), 4.39 (2H, quartet, J = 7.1 Hz), 5.16 (2H, s), 6.92-7.00 (4H, m), 7.21-7.41 ( 4H, m), 8.41 (1H, s).

IR Spectrum (KBr): 2980, 1727, 1684, 1609, 1590, 1497, 1464 cm ^-1 .

Working example 2
Using as the initial compound obtained in Reference example 8, by the method similar to that described in Working example 1, receive the compounds shown in Table 8.

Working example 3
Using, as starting materials, the compounds obtained in Reference Examples 9 and 10, according to a procedure similar to that described in Working Example 1, the compounds shown in Table 9 are obtained.

Working example 4
4,7-dihydro-5-hydroxymethyl-7- (2-methoxybenzyl) -2- (4-methoxyphenyl) -3-methyl-4-oxo-thieno [2,3-b] pyridine
To a solution of the compound obtained in Reference Example 11 (0.12 g, 0.40 mmol) in dimethylformamide (10 ml) was added potassium carbonate (0.083 g, 0.60 mmol), 2-methoxybenzyl chloride (0.094 g) at room temperature 0.60 mmol) and potassium iodide (0.033 g, 0.29 mmol). The reaction mixture was stirred for 90 minutes at room temperature, and then for 2 hours at a temperature of 50 ^° C. The reaction mixture was evaporated and the residue was poured into a mixture of dichloromethane and water. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic extracts are combined, washed with an aqueous solution of sodium chloride, dried (over magnesium sulfate) and the solvent is distilled off under reduced pressure. The residue was chromatographed on silica gel to give a pale yellow amorphous substance, which was recrystallized from ethyl acetate to give colorless crystals with a melting point. 153-156 ^o C.

Elemental analysis for C ₂₄ H ₂₃ NO ₄ S (%):
calculated: C, 68.39; H 5.50; N, 3.32;
Found: C, 68.11; H 5.58; N, 3.24.

 1 H-NMR spectrum (200 MHz, chloroform-d): 2.67 (3H, s), 3.85 (3H, s), 3.86 (3H, s), 4.59 (2H, s), 5.12 (2H, s), 6.90-7.00 (4H, m), 7.15 (1H, d), 7.3-7.4 (3H, m), 7.45 (1H, s).

IR Spectrum (KBr): 3400, 2936, 2838, 1618, 1547, 1504, 1249 cm ^-1 .

Working example 5
5-Acetoxymethyl-4,7-dihydro-7- (2-methoxybenzyl) -2- (4-methoxyphenyl) - 3-methyl-4-oxo-thieno [2,3-b] pyridine
Anhydrous acetic acid (1.78 g, 19.0 mmol) was added at room temperature to a solution of the compound obtained in Working Example 4 (0.400 g, 0.96 mmol) in pyridine. The mixture was stirred for one hour at room temperature, evaporated and poured into a mixture of ethyl acetate and dilute hydrochloric acid. The aqueous layer was extracted with ethyl acetate. The extract was chromatographed on silica gel to give a colorless amorphous substance, which was recrystallized from ethyl ether to give colorless crystals (0.46 g, 100%), mp. 158-159 ^o C.

Elemental analysis for C ₂₆ H ₂₅ NO ₅ S (%):
calculated: C, 67.37; H 5.44; N, 3.02;
Found: C, 67.09; H 5.09; N, 3.06.

 1 H-NMR spectrum (200 MHz, chloroform-d): 2.07 (3H, s), 2.67 (3H, s), 3.84 (3H, s), 3.86 (3H, s), 5.11 (2H, s), 6.90-7.00 (4H, m), 7.18 (1H, d, J = 7.7 Hz), 7.3-7.4 (3H, m), 7, 69 (1H, s).

IR Spectrum (KBr): 1752, 1626, 1578, 1508, 1506, 1255 cm ^-1 .

Working example 6
3-Bromomethyl-4,7-dihydro-7- (2-methoxybenzyl) -2- (4-methoxyphenyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid ethyl ester
A mixture of the compound obtained in Working Example 1 (0.35 g, 0.755 mmol), N-bromosuccinimide (0.135 g, 0.758 mmol), α, α′-azobisisobutyronitrile (13 mg, 0.079 mmol) and carbon tetrachloride (5 ml) is boiled under reflux for two hours. It is cooled, insoluble matters are filtered off and the filtrate is diluted with chloroform. The organic phase is washed with an aqueous solution of sodium chloride and dried (over magnesium sulfate). The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain colorless needles (0.272 g, 66%) with mp. 200 - 201 ^o C.

Elemental analysis for C ₂₆ H ₂₄ NO ₅ SBr (%):
calculated: C 57.57; H 4.46; N, 2.58;
Found: C, 57.75; H 4.31; N, 2.31.

 1 H-NMR spectrum (200 MHz, chloroform-d): 1.40 (3H, t, J = 7.1 Hz), 3.86 (6H, s), 4.40 (2H, quartet, J = 7.1 Hz ), 5.05 (2H, s), 5.16 (2H, s), 6.92-7.04 (4H, m), 7.23-7.28 (1H, m), 7.34- 7.43 (1H, m), 7.57 (2H, d, J = 8.9 Hz), 8.46 (1H, s).

IR (KBr): 2980, 1725, 1607, 1588, 1497 cm ^-1 .

Working example 7
Using, as starting materials, the compounds obtained in Working Examples 3, 4, 19, 65, 66 and 73, by a procedure similar to that described in Working Example 6, the compounds shown in Table 10 are obtained.

Working example 8
3-Benzylaminomethyl-4,7-dihydro-7- (2-methoxybenzyl) -3- (4-methoxyphenyl) -4-oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester hydrochloride
To a solution of the compound obtained in Working Example 6 (0.245 g, 0.452 mmol) in dimethylformamide (5 ml), while cooling in an ice bath, triethylamine (0.10 ml, 0.717 mmol) and benzylamine (80 μl, 0.732 mmol) were added. The reaction mixture was stirred for 90 minutes at room temperature, evaporated and the residue was poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic extracts are combined, dried (over magnesium sulfate) and the solvent is distilled off under reduced pressure. The residue was chromatographed on silica gel to give a colorless oil (0.135 g, 53%). The oil was dissolved in ethanol (4 ml) and, while cooling in an ice bath, a 1 N solution of hydrogen chloride in ethanol (0.2 ml) was added. The mixture was stirred while cooling in an ice bath for 10 minutes. The reaction mixture was evaporated under reduced pressure and the residue was recrystallized from ethyl acetate and ether to give the corresponding hydrochloride (0.113 g) as white crystals, mp. 118-119 ^o C.

Elemental analysis for C ₃₃ H ₃₂ N ₂ O ₅ S • HCl • 0.9H ₂ O (%):
calculated: C, 63.79; H 5.64; N, 4.51;
Found: C, 64.03; H 5.44; N, 4.51.

 PMR spectrum (200 MHz, chloroform-d) free amine: 1.40 (3H, t, J = 7.1 Hz), 2.05 (1H, br), 3.81 (3H, s), 3.86 (3H, s), 3.87 (2H, s), 3.94 (2H, s), 4.40 (2H, quartet, J = 7.1 Hz), 5.18. (2H, s), 6.80 (2H, d, J = 8.8 Hz), 6.91-6.99 (2H, m), 7.20-7.42 (9H, m), 8, 45 (1H, s).

IR Spectrum (KBr) [hydrochloride]: 3422, 2938, 1719, 1605, 1560, 1545, 1502, 1460 cm ^-1 .

Working example 9
Using the compound obtained in Working Example 6 as the starting material, according to a procedure similar to that described in Working Example 8, the compounds shown in Table 11 are obtained.

Working example 10
Using the compounds obtained in Working Example 7 as starting materials, by the procedure similar to that described in Working Example 8, the compounds shown in Table 12 are obtained.

Working example 11
4,7-dihydro-7- (2-methoxybenzyl) -2- (4-methoxyphenyl) -3-methyl-4-oxo-thieno [2,3-b] pyridin-N-benzylpiperazinyl-5-carboxamide
While cooling in an ice bath, 1-benzylpiperazine (0.77 g, 4.37 mmol) was added dropwise a solution of diisobutylaluminum hydride in toluene (1.5 N, 2.9 ml, 4.37 mmol). Allow the mixture to warm to room temperature and mix for 30 minutes. To the solution at room temperature was added a solution of the compound obtained in Working Example 1 (0.50 g, 1.08 mmol) in toluene (5 ml). The mixture was stirred at room temperature for 15 hours and methylene chloride (30 ml) was added. The mixture was washed with water and dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain a solid (1.03 g), which was recrystallized from a mixture of methylene chloride - n-hexane and the target compound (0.48 g, 78%) was obtained, mp. 233-235 ^o C.

Elemental analysis for C ₃₅ H ₃₅ N ₃ O ₄ S • 0.5H ₂ O (%):
calculated: C, 69.75; H 6.02; N, 6.97; S 5.32;
Found: C, 69.88; H 6.06; N, 6.98; S 5.39.

 PMR spectrum (200 MHz, chloroform-d) 2.45-2.55 (4H, m), 2.63 (3H, s), 3.43-3.49 (2H, m), 3.55 (2H , s), 3.73-3.82 (2H, m), 3.84 (6H, s), 5.11 (2H, s), 6.89-6.98 (4H, m), 7, 21-7.40 (9H, m), 7.79 (2H, s).

Working example 12
Using the compound obtained in Working Example 1 as the starting material, according to a procedure similar to that described in Working Example 11, the compounds shown in Table 13 are obtained.

Working example 13
4,7-Dihydro-7- (2-methoxybenzyl) -2- (4-methoxyphenyl) -3- [N-methyl-N- (2-methoxybenzyl) aminomethyl] -4-oxo-thieno [2,3- b] pyridine-5-carboxylic acid
To a solution of compound 12 obtained in Working Example 9 (0.30 g, 0.52 mmol) in ethyl alcohol (5 ml) was added triethylamine (0.21 g, 2.1 mmol) and 2-methoxybenzyl chloride at room temperature (0.16 g, 1.0 mmol). The mixture was stirred at room temperature for 60 hours, evaporated and the residue was poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic extracts are combined, dried (over sodium sulfate) and the solvent is distilled off under reduced pressure. The residue was chromatographed on silica gel to give a yellow oil (0.23 g, 72%). The oil (0.07 g, 0.10 mmol) was dissolved in ethyl acetate (5 ml) and, while cooling in an ice bath, a 1 N solution of hydrogen chloride in ethanol (0.2 ml, 0.20 mmol) was added over 5 minutes. The reaction mixture was evaporated under reduced pressure and the residue was recrystallized from ethyl acetate-ether to give the corresponding hydrochloride (0.07 g, 100%) as white crystals, mp. 107-109 ^o C.

Elemental analysis for C ₃₅ H ₃₆ N ₂ O ₆ S • HCl • H ₂ O (%):
calculated: C, 63.01; H 5.89; N, 4.20;
Found: C, 63.57; H 6.05; N, 3.88.

 1 H-NMR spectrum (200 MHz, chloroform-d) [free amine]: 1.39 (3H, t, J = 7.2 Hz), 2.38 (3H, s), 3.71 (3H, s), 3 85 (3H, s), 3.87 (3H, s), 3.88 (2H, s), 4.30 (2H, s), 4.39 (2H, quartet, J = 7.2 Hz) 5.21 (2H, s); 6.77-7.70 (12H, m); 8.44 (1H, s).

IR Spectrum (KBr) [hydrochloride]: 3422, 2944, 1721, 1605, 1499, 1464, 1383, 1294, 1253 cm ^-1 .

 Mass spectrum (FAB): m / z 613 (MH +).

Working example 14
Using the compound obtained in Working Example 9 as the starting material, according to a procedure similar to that described in Working Example 13, the compounds shown in Table 14 are obtained.

Working example 15
2- (4-aminophenyl) -4,7-dihydro-7- (2-methoxybenzyl) - 3- (N-methyl-N-benzylaminomethyl) -4-oxo thieno [2,3-b] pyridin-5- ethyl ester carboxylic acid
To a solution of compound 1 obtained in Working Example 10 (0.60 g, 1.00 mmol) in methyl alcohol (10 ml) was added iron powder (0.22 g, 4.0 mmol). The mixture was vigorously stirred in an ice bath, and then the reaction mixture was poured into ice water and neutralized with sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with sodium chloride solution, dried (over sodium sulfate) and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel, and then recrystallized from chloroform-ether to give yellow needles (0.40 g, 71%), so pl. 120-122 ^o C.

Elemental analysis for C ₃₃ H ₃₃ N ₃ O ₄ S • 3 / 2H ₂ O (%):
calculated: C, 66.65; H 6.10; N, 7.07;
Found: C, 66.16; H 5.76; N, 7.13.

 1 H-NMR spectrum (200 MHz, chloroform-d) [free amine]: 1.38 (3H, t, J = 7.2 Hz), 2.14 (3H, s), 3.68 (3H, s), 3 87 (3H, s), 4.17 (2H, s), 4.39 (2H, quartet, J = 7.2 Hz), 5.21 (2H, s), 6.72 (2H, d) 6.69 (2H, t), 7.20 (4H, m), 7.35 (1H, t), 7.64 (2H, d), 8.37 (1H, s).

IR Spectrum (KBr) [hydrochloride]: 3454, 1690, 1603, 1499, 1386, 1317 cm ^-1 .

 Mass spectrum (FAB): m / z 568 (MH) +.

Working example 16
4,7-dihydro-5-hydroxymethyl-3- (N-methyl-N-benzylaminomethyl) -7- (2-methoxybenzyl) -2- (4-methoxyphenyl) -4-oxo-thieno [2,3-b] pyridine hydrochloride
To a solution of compound 2 obtained in Working Example 10 (0.390 g, 0.67 mmol) in methyl alcohol (40 ml) was added an aqueous solution of potassium carbonate [obtained from potassium carbonate (0.185 g, 1.34 mmol) and water (8 ml)]. The mixture was stirred at room temperature for 30 minutes, evaporated and the residue was poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic extracts were combined, dried (over magnesium sulfate) and the solvent was distilled off under reduced pressure to obtain a pale yellow oil (0.36 g, 100%). The oil (0.10 g) was dissolved in tetrahydrofuran (5 ml) and, while cooling in an ice bath, a 1 N solution of hydrogen chloride in ether (0.37 ml, 0.37 mmol) was added; the mixture is stirred while cooling in an ice bath for 10 minutes. The reaction mixture was evaporated under reduced pressure and the residue was recrystallized from ether to give the corresponding hydrochloride (0.10 g, 100%) as white crystals with mp. 135-140 ^o C.

Elemental analysis for C ₃₂ H ₃₃ N ₂ O ₄ SCl (%):
calculated: C, 66.60; H 5.76; N, 4.85;
Found: C, 66.57; H 5.90; N, 4.54.

 1 H-NMR spectrum (200 MHz, chloroform-d) [free amine]: 2.76 (3H, s), 3.86 (3H, s), 3.89 (3H, s), 4.37 (2H, s) 4.45 (1H, broad s), 4.55 (1H, broad s), 4.77 (2H, s), 5.53 (2H, s), 6.94 (2H, d, J = 8 , 2 Hz), 6.98 (1H, t, J = 7.4 Hz), 7.06 (2H, broad d), 7.3-7.45 (7H, m), 7.50 (1H, m), 8.27 (1H, s).

IR Spectrum (KBr) [hydrochloride]: 3388, 1607, 1499, 1460, 1253 cm ^-1 .

 Mass spectrum (FAB): m / z 541 (MH) +.

Working example 17
4,7-dihydro-7- (2-methoxybenzyl) -2- (4-methoxyphenyl) - 3- (N-methyl-N-benzylaminomethyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxamide hydrochloride
Anhydrous ammonia (22 ml) was dissolved in toluene (5 ml) at a temperature of minus 78 ^° C. and a solution of diisobutylaluminium hydride in toluene was added to the resulting solution at the same temperature. The mixture was allowed to warm to room temperature and was further stirred for 30 minutes. To the resulting solution at room temperature was added a solution of compound 15 obtained in Reference Example 9 (0.25 g, 0.425 mmol) in toluene (4 ml). The mixture was stirred at room temperature for one hour and poured into a mixture of dichloromethane and water. The organic layer was separated and the aqueous phase was extracted with dichloromethane. The organic extracts are combined, dried (over magnesium sulfate) and the solvent is distilled off under reduced pressure. The residue was chromatographed on silica gel to give colorless crystals. Crystals (0.130 g, 23 mmol) were dissolved in tetrahydrofuran (5 ml), while cooling in an ice bath, a 1 N solution of hydrogen chloride in ether (0.46 ml, 0.46 mmol) was added, and the mixture was stirred while cooling in an ice bath for 10 minutes. The reaction mixture was evaporated under reduced pressure and the residue was recrystallized from ether to give the corresponding hydrochloride (0.143 g, 100%) as white crystals, mp. 152-157 ^o C.

Elemental analysis for C ₃₂ H ₃₂ N ₃ O ₄ SCl (%):
calculated: C, 66.71; H 5.60; N, 4.86;
Found: C, 66.28; H 5.80; N, 4.51.

 1 H-NMR spectrum (200 MHz, chloroform-d) [free amine]: 2.84 (3H, s), 3.87 (3H, s), 3.88 (3H, s), 4.35 (1H, quartet, J = 4.8 Hz), 4.6-4.8 (3H, m), 5.31 (2H, s), 6.09 (1H, s), 6.95 (1H, t, J = 7 6 Hz), 6.99 (1H, t, J = 7.6 Hz), 7.03 (2H, d, J = 8.0 Hz), 7.30-7.36 (4H, m), 7.40-7.50 (5H, m), 8.94 (1H, s), 9.70 (1H, s), 11.61 (1H, s).

IR Spectrum (KBr) [hydrochloride]: 1663, 1605, 1578, 1502, 1255 cm ^-1 .

 Mass spectrum (FAB): m / z 554 (MH) +.

Working example 18
Compound 15 obtained in Working Example 9 was reacted with various amine derivatives according to a procedure similar to that described in Working Example 17, and the compounds shown in Table 15 were obtained.

Working example 19
4,7-Dihydro-7- (2-methoxybenzyl) -2- (3-methoxyphenyl) -3-methyloxythieno [2,3-b] pyridine-5-carboxylic acid ethyl ester
To a mixture of compound 7 obtained in Working Example 3 (0.615 g, 1.41 mmol), 3-methoxyphenylboronic acid (9.321 g, 2.11 mmol), 2 M sodium carbonate solution (3.53 ml, 7.06 mmol) and 1,2-dichloromethane (30 ml) was added under argon atmosphere tetrakis (triphenylphosphine) palladium (O) (0.163 g, 0.141 mmol) and refluxed for 24 hours. It is cooled, ethyl acetate is added, insoluble materials are filtered off through celite and the filtrate is poured into a mixture of ethyl acetate and an aqueous solution of sodium chloride. The organic layer was separated and the aqueous phase was extracted with ethyl acetate. The organic extracts are combined, washed with an aqueous solution of sodium chloride and dried (over magnesium sulfate). The solvent was distilled off under reduced pressure, and the residue was chromatographed on silica gel to give a white amorphous substance (0.446 g, 68%).

Elemental analysis for C ₂₆ H ₂₅ NO ₅ S • 0.5H ₂ O (%):
calculated: C, 66.08; H 5.55; N, 2.96;
Found: C, 66.33; H 5.40; N, 2.91.

 1 H-NMR spectrum (200 MHz, chloroform-d): 1.41 (3H, t, J = 7.1 Hz), 2.69 (3H, s), 3.84 (3H, s), 3.87 (3H , s), 4.39 (2H, quartet, J = 7.1 Hz), 5.16 (2H, s), 6.87-7.02 (5H, m), 7.20-7.42 ( 3H, m), 8.42 (1H, s).

IR Spectrum (KBr): 3440, 2638, 1727, 1688, 1607, 1493, 1465 cm ^-1 .

Working example 20
4,7-dihydro-2- (4-methoxyphenyl) -3- (N-methyl-N-benzylaminomethyl) -7- (2-methylthiobenzyl) -4- oxo-thieno [2,3-b] pyridin-5 ethyl ester hydrochloride carboxylic acid
A mixture of the compound obtained in Reference Example 18 (0.12 g, 0.26 mmol), potassium carbonate (54 mg, 0.39 mmol), 2-methylthiobenzyl chloride (54 mg, 0.31 mmol), potassium iodide (18 mg , 0.1 mmol) and dimethylformamide (3 ml) was stirred at a temperature of 50 ^o C for 2 hours. It is cooled and the solvent is distilled off under reduced pressure. The residue was chromatographed on silica gel and dissolved in ethyl acetate (20 ml). To the resulting solution was added a 1 N solution of hydrogen chloride in ether (0.33 ml) and the mixture was evaporated under reduced pressure. The concentrate was recrystallized from ether to give the corresponding hydrochloride (0.1 g, 64%) as pale yellow crystals, mp. 118-120 ^o C.

Elemental analysis for C ₃₄ H ₃₄ N ₂ O ₄ S ₂ • HCl • 0.4H ₂ O (%):
calculated: C, 63.57; H 5.62; N, 4.36;
Found: C, 63.81; H 5.82; N, 4.49.

 1 H-NMR spectrum (200 MHz, chloroform-d): 2.52 (3H, s), 2.94 (3H, s), 3.88 (3H, s), 4.38 (3H, quartet-like, J = 7, 1 Hz), 4.60 (1H, broad s), 4.75 (1H, broad s), 5.39 (2H, s), 7.04 (2H, d, J = 8.7 Hz), 7 23-7.53 (11H, m), 8.39 (1H, s), 11.82 (1H, broad s).

IR spectrum (KBr): 3406, 2980, 1719, 1605, 1502 cm ^-1 .

Working example 21
Using the compound obtained in Reference Example 18 as the starting material, reactions with various halogen derivatives are carried out according to a procedure similar to that described in Working Example 20, and the compounds shown in Table 16 are obtained.

Working example 22
4,7-dihydro-5-formyl-7- (2-methoxybenzyl) -2- (4-methoxyphenyl) - 3- (N-methyl-N-benzylaminomethyl) -4-oxo-thieno [2,3-b] pyridine
To a solution of the compound obtained in Working Example 16 (0.54 g, 0.10 mmol) in chloroform (10 ml) was added active manganese dioxide (0.27 g) and the mixture was stirred at room temperature for one hour. The reaction mixture was filtered through celite and the filter was washed with chloroform. The filtrate was combined and evaporated. The concentrate is chromatographed on silica gel to give a yellow solid, which is recrystallized from ethyl acetate-ether to give white crystals (0.014 g, 25%), mp 181-185 ^o C.

Elemental analysis for C ₃₂ H ₃₀ N ₂ O ₄ S • 0.8SiO ₂ (%):
calculated: C, 65.51; H 5.15; N 4.77;
Found: C, 63.25; H 5.30; N, 5.25.

 1 H-NMR spectrum (500 MHz, chloroform-d): 3.85 (3H, s), 3.87 (3H, s), 3.8-4.0 (2H, s), 4.33 (2H, s) 5.23 (2H, s), 6.9-7.1 (5H, m), 7.2-7.4 (7H, m), 7.64 (1H, d, J = 7.9 Hz ), 8.31 (1H, s), 10.45 (1H, s).

IR Spectrum (KBr): 2934, 1688, 1603, 1502, 1386, 1255 cm ^-1 .

 Mass spectrum (FAB): m / z 539 (MH) +.

Working example 23
2- (4-Acetylaminophenyl) -4,7-dihydro-7- (2-methoxybenzyl) - 3- (N-methyl-N-benzylaminomethyl) -4-oxo-thieno [2,3-b] pyridin-5- ethyl ester carboxylic acid
To the solution of the compound obtained in Working Example 15 (0.11 g, 0.20 mmol), acetic anhydride (1 ml) and pyridine (0.29 g, 10.0 mmol) were added while cooling in an ice bath. The mixture was stirred at room temperature for 8 hours, poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic extracts were washed with an aqueous solution of sodium chloride, dried (over magnesium sulfate) and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel and recrystallized from ether to give a white crystalline powder (0.17 g, 58%) so pl. 161-163 ^o C.

1 H-NMR spectrum (500 MHz, DMSO-d ₆ ): 1.35 (3H, t, J = 7.2 Hz), 2.10 (3H, s), 2.58 (3H, s), 3.82 ( 3H, s), 4.2-4.4 (4H, m), 4.42 (1H, d), 4.58 (1H, d), 5.51 (2H, s), 6.70 (1H , t), 7.05 (1H, d), 7.1-7.3 (1H, m), 7.3-7.5 (7H, m), 7.68 (1H, s), 7, 78 (2H, d), 8.88 (1H, s), 10.33 (1H, s).

IR Spectrum (KBr): 3258, 1717, 1686, 1605, 1495, 1317, 1253 cm ^-1 .

 Mass spectrum (FAB): m / z 610 (MH) +.

Working example 24
4,7-Dihydro-2- (4-formylaminophenyl) -7- (2-methoxybenzyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxo-thieno [2,3-b] pyridine-5- ethyl ester carboxylic acid
To a solution of the compound obtained in Working Example 15 (0.23 g, 4.00 mmol) in dichloromethane (5 ml), a mixture of acetic anhydride and formic acid was added while cooling in an ice bath [obtained by adding while cooling in an ice bath formic acid (99%, 6.00 mmol) to acetic anhydride (0.41 g, 4.00 mmol) and stirring at a temperature of 60 ^o C for 2 hours]. The mixture was stirred at room temperature for 8 hours, poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane. The extract was washed with an aqueous solution of sodium chloride, dried (over magnesium sulfate) and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel and recrystallized from chloroform-ether to give white needles (0.17 g, 72%) so pl. 185-187 ^o C.

Elemental analysis for C ₃₄ H ₃₃ N ₃ O ₅ S • 0.5H ₂ O (%)
calculated: C, 67.53; H 5.67; N, 6.95;
Found: C, 67.04; H 5.28; N, 6.97.

 1 H-NMR spectrum (200 MHz, chloroform-d): 1.38 (3H, t, J = 7.2 Hz), 2.13 (3H, s), 3.65 (2H, s), 3.87 (3H , s), 4.17 (2H, s), 4.38 (2H, quartet), 5.18 (2H, s), 6.97 (2H, t), 7.1-7.3 (8H, m), 7.38 (1H, t), 7.5-7.7 (2H, m), 7.8-7.9 (2H, m), 8.40 (1H, s), 8.44 (1H, s).

IR Spectrum (KBr): 3336, 2978, 1723, 1605, 1495, 1439, 1305 cm ^-1 .

 Mass spectrum (FAB): m / z 596 (MH) +.

Working example 25
Using, as starting materials, the compound obtained in Reference Example 11 and a derivative of the compound synthesized in Reference Example 18 by reduction using the procedure described in Reference Example 11, using the procedure similar to that described in Working Example 4, the compounds shown in Table 17.

Working example 26
Using the compound obtained in Working Example 7 as the starting material, according to a procedure similar to that described in Working Example 8, the compounds shown in Table 18 are obtained.

Working example 27
Using as the starting compound the compound obtained in Working Example 26, by a reaction similar to that described in Working Example 15, the compounds shown in Table 19 are obtained.

Working example 28
4,7-dihydro-7- (2-fluorobenzyl) -5-formyl-2- (4-methoxyphenyl) -3-methyl-4-oxo-thieno [2,3-b] pyridine
The compound obtained in Working Example 25 (4.10 g) was stirred for one hour at room temperature with manganese dioxide (20.5 g) in chloroform (120 ml). The reaction mixture was filtered through celite and the filtrate was evaporated to dryness, the residue was chromatographed on silica gel, then methylene chloride-ethyl acetate was recrystallized from the mixture to give colorless crystals (3.72 g, 83% yield).

 1 H-NMR spectrum (200 MHz, chloroform-d): 2.66 (3H, s), 3.85 (3H, s), 5.26 (2H, s), 6.96 (2H, d), 7.1 -7.4 (6H, m), 8.17 (1H, s), 10.44 (1H, s).

Working example 29
4,7-dihydro-7- (2-fluorobenzyl) -5- (1-hydroxyethyl) -2- (4-methoxyphenyl) -3-methyl-4-oxo-thieno [2,3-b] pyridine
The compound obtained in Working Example 28 (1.0 g) was dissolved in anhydrous tetrahydrofuran (50 ml). Methyl magnesium bromide (0.35 g) was added to the resulting solution while cooling in an ice bath, the mixture was allowed to warm to room temperature and stirred for three hours. The reaction mixture was filtered through celite and the filtrate was evaporated to dryness. A saturated aqueous solution of ammonium chloride (20 ml) and ethyl acetate (20 ml) were added to the residue, and the resulting mixture was stirred. The organic layer was separated, the aqueous phase was extracted with ethyl acetate (20 ml). The organic extracts are combined and dried. The solvent was distilled off under reduced pressure, the residue was chromatographed on silica gel to give a yellow amorphous substance (1.10 g, 100% yield).

 1 H-NMR spectrum (200 MHz, chloroform-d): 1.55 (3H, d), 2.66 (3H, s), 3.48 (3H, s), 4.94 (1H, quartet), 5.20 (2H, s), 6.95 (2H, d), 7.1-7.2 (3H, m), 7.3-7.4 (3H, m), 7.44 (1H, s).

Working example 30
The compound obtained in Working Example 28 is introduced into the reaction using, instead of methylmagnesium bromide, various Grignard reagents, in accordance with a procedure similar to that described in Working Example 29, and obtain the compounds shown in Table 20.

Working example 31
5-Acetyl-4,7-dihydro-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -3-methyl-4-oxo-thieno [2,3-b] pyridine
The compound obtained in Working Example 29 (0.50 g) was stirred for three hours in chloroform (50 ml) together with manganese dioxide at a temperature of 40 ^° C. The reaction mixture was filtered through celite and the filtrate was evaporated to dryness, the residue was recrystallized from hexane. ethyl acetate and get colorless crystals (0.35 g, yield 70%) with so pl. 215-216 ^o C.

Elemental analysis for C ₂₄ H ₂₀ NO ₃ S (%):
calculated: C, 68.44; H 4.78; N, 3.33;
Found: C, 68.35; H 4.70; N, 3.41.

 1 H-NMR spectrum (200 MHz, chloroform-d): 2.66 (3H, s), 2.78 (3H, s), 3.85 (3H, s), 5.25 (2H, s), 6.96 (2H, d), 7.1-7.5 (6H, m), 8.37 (1H, s).

 Mass spectrum (FAB): m / z 422 (MH) +.

Working example 32
Using the compound obtained in Working Example 30 as the starting material, according to a procedure similar to that described in Working Example 31, the compounds shown in Table 21 are obtained.

Working example 33
5-Acetyl-3-bromomethyl-4,7-dihydro-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -4-oxo-thieno [2,3-b] pyridine
The compound obtained in Working Example 31 (0.32 g) was dissolved in carbon tetrachloride (60 ml). The resulting solution was refluxed for two hours with N-bromosuccinimide (0.144 g) and α, α′-azobisisobutyronitrile (0.013 g). Cool and dilute with chloroform. The mixture was washed with saturated aqueous sodium bicarbonate (20 ml), dried and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel to give a yellow amorphous substance, which was recrystallized from a mixture of chloroform — isopropyl ether — ethyl acetate, and colorless needles were obtained (0.29 g, 75% yield), m.p. 226-228 ^o C.

 1 H-NMR spectrum (200 MHz, chloroform-d): 2.81 (3H, s), 3.86 (3H, s), 5.03 (2H, s), 5.26 (2H, s), 7.03 (2H, d), 7.1-7.5 (4H, m), 7.55 (2H, d), 8.38 (1H, s).

Working example 34
Using the compounds obtained in Working Example 32 as starting materials, by the procedure similar to that described in Working Example 33, the compounds shown in Table 22 are obtained.

Working example 35
5-Acetyl-4,7-dihydro-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxo-thieno [2,3-b] pyridine
The compound obtained in Working Example 33 (0.25 g) was dissolved in dimethylformamide (20 ml). To the resulting solution, diisopropylethylamine (0.079 g) and N-benzylmethylamine (0.074 g) were added at room temperature. The mixture was stirred for 90 minutes at room temperature and evaporated to dryness under reduced pressure. The residue was poured into a mixture of ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate (50 ml). The aqueous phase is extracted with ethyl acetate. The organic extracts are combined and dried. The solvent was distilled off under reduced pressure, and the residue was chromatographed on silica gel to give a yellow amorphous substance (0.27 g). It is dissolved in methylene chloride (5 ml) and a 1 N solution of hydrogen chloride in ether (1 ml) is added to the resulting solution while cooling in an ice bath. The precipitated crystalline precipitate was separated by filtration to obtain the target compound (0.22 g, yield 77%) with mp. 185-193 ^o C.

Elemental analysis for C ₃₂ H ₃₀ N ₂ O ₃ SClF • 2H ₂ O (%):
calculated: C, 62.68; H 5.59; N, 4.57;
Found: C, 63.16; H 5.62; N, 4.56.

 1 H-NMR spectrum (200 MHz, chloroform-d): 2.80 (3H, s), 2.87 (3H, s), 3.88 (3H, s), 4.3-4.4 (1H, m) 4.6-4.8 (3H, m), 5.35 (2H, s), 7.03 (2H, d), 7.2-7.5 (11H, m), 8.48 (1H c), 11.8 (1H, broad s).

 Mass spectrum (FAB): m / z 542 (MH) +.

Working example 36
Using, as starting materials, the compounds obtained in Working Example 34, by reactions similar to those described in Working Example 35, the compounds shown in Table 23 are obtained.

Working example 37
4,7-Dihydro-7- (2-fluorobenzyl) -3- (N-methyl-N-benzylaminomethyl) -2- (4-N'-methylureidophenyl) -4-oxo-thieno [2,3-b] pyridine ethyl ester - 5-carboxylic acid
Pyridine (0.5 ml) was added to a solution of the compound obtained in Working Example 26 (0.11, 0.20 mmol) in tetrahydrofuran (5 ml), and methyl isocyanate (0.064) was added dropwise and while cooling in an ice bath. ml). The mixture was stirred at room temperature for 4 hours and then evaporated under reduced pressure. The concentrate is dissolved in chloroform, washed with an aqueous solution of sodium chloride and dried (over sodium sulfate). The solvent was evaporated under reduced pressure, and the residue was chromatographed on silica gel, and then recrystallized from ethanol-ethyl acetate to give white needles (0.09 g, 73%), so pl. 216-220 ^o C.

Elemental analysis for C ₃₄ H ₃₃ NOSF • 2H ₂ O (%):
calculated: C, 62.95; H 5.75; N, 8.64;
Found: C, 63.22; H 5.60; N, 8.39.

1 H-NMR spectrum (500 MHz, DMSO-d ₆ ): 1.44 (3H, t), 2.25 (3H, s), 2.84 (3H, s), 4.35 (3H, s), 4.43 (2H, quartet), 4.90 (2H, broad s), 5.62 (2H, s), 7.20-7.32 (7H, m), 7.45-7.60 (6H , m), 8.85 (1H, s).

IR Spectrum (KBr): 3308, 1698, 1605, 1499, 1319, 1236, 1183 s ^-1 .

 Mass spectrum (FAB): m / z 613 (MH) +.

Working example 38
Using the compounds obtained in Working Example 27 as starting materials, according to reactions similar to those described in Working Examples 23, 24 and 37, the compounds are obtained in the form of their hydrochlorides shown in Table 24.

Working example 39
5-benzylmethylaminomethyl-2,4 (1H, 3H) -dioxo-1- (2-fluorobenzyl) -6- (4-methoxyphenyl) -3-phenylthieno [2,3-d] pyrimidine hydrochloride
Ethyl diisopropylamine (0.08 ml, 0.460 mmol) and methylbenzylamine (0.05 ml, 0.370) are added to a solution of compound 15 obtained in Reference Example 29 (0.150 g, 0.310 mmol) in dimethylformamide (10 ml) while cooling in an ice bath. mmol). It is stirred for 2 hours at room temperature, the reaction mixture is evaporated and the residue is poured into a mixture of ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous phase is extracted with ethyl acetate, the organic extracts are combined and dried (over magnesium sulfate). The solvent was distilled off under reduced pressure, and the residue was chromatographed on silica gel to give a colorless oil (0.159 g, 97%). The oil was dissolved in ethyl acetate (4 ml), and a 1 N solution of hydrogen chloride in ether (0.3 ml) was added to the resulting solution while cooling in an ice bath. It is stirred for 10 minutes while cooling in an ice bath, evaporated under reduced pressure, and the residue is recrystallized from ethyl acetate-ether to obtain the desired hydrochloride salt (0.144 g) with mp. 140-143 ^o C (hydrochloride).

Elemental analysis for C ₃₅ H ₃₀ N ₃ O ₃ SF • HCl • H ₂ O (%):
calculated: C, 65.05; H 5.14; N, 6.50;
Found: C, 65.14; H 5.03; N, 6.37.

 1 H-NMR spectrum (200 MHz, chloroform-d) [free amine]: 2.07 (3H, s), 3.57 (2H, s), 3.86 (3H, s), 3.90 (3H, s) , 5.30 (2H, s), 6.94 (2H, d, J = 8.8 Hz), 7.05-7.60 (14H, m), 7.66 (2H, d, J = 8 , 8 Hz).

IR Spectrum (KBr) [hydrochloride]: 1711, 1665, 1543, 1477 cm ^-1 .

Working example 40
Using the compounds obtained in Reference Example 28 as starting materials, by the procedure similar to that described in Working Example 39, the compounds shown in Table 25 are obtained.

Working example 41
3-Cyanomethyl-4,7-dihydro-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid ethyl ester
To a suspension of the compound obtained in Working Example 7 (Compound No. 10) (0.80 g, 1.51 mmol) in dimethyl sulfoxide, sodium cyanide (0.084 g, 1.66 mmol) was added at room temperature. The reaction mixture is heated to 60 ^° C. and stirred for 4 hours. Cool to room temperature and pour the mixture into water. It is extracted with ethyl acetate (50 ml x 2), the extract is washed with water and dried. The resulting solution was evaporated to dryness and a pale yellow oil (0.77 g) was obtained. The resulting product is used in Working Example 42 without further purification.

Working example 42
4,7-Dihydro-3-ethoxycarbonylmethyl-7- (2-fluorobenzyl) - 2- (4-methoxyphenyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid ethyl ester
To a solution of the compound obtained in Working Example 41 (0.77 g) in anhydrous ethanol (250 ml), concentrated sulfuric acid (50 drops) was added dropwise with stirring at room temperature. The resulting mixture was refluxed for 15 hours. The mixture was neutralized while cooling in an ice bath with excess aqueous sodium bicarbonate and extracted with ethyl acetate (500 ml x 3). The extract was washed with water, dried and evaporated under reduced pressure to give a brownish solid (0.72 g). It is chromatographed on silica gel to give crystals, which are recrystallized from ethyl acetate-hexane to give colorless crystals (0.28 g, through yield 35%), m.p. 199-201 ^o C.

Elemental analysis for C ₂₈ H ₂₆ NO ₆ SF • 0.7H ₂ O (%):
calculated: C, 62.72; H 5.02; N 2.61;
Found: C, 62.57; H 4.84; N, 2.53.

 1 H-NMR spectrum (300 MHz, chloroform-d) [free amine]: 1.38 (3H, t, J = 7.2 Hz), 2.68 (3H, t, J = 7.2 Hz), 3.84 (3H, s), 4.04 (2H, s), 4.16 (2H, quartet, J = 7.2 Hz), 4.37 (2H, quartet, J = 7.2 Hz), 5.23 (2H, s), 6.92-7.42 (8H, m), 8.36 (1H, s).

IR Spectrum (KBr): 3430, 1727, 1611, 1502, 1255, 1183, 1033, 762, 520 cm ^-1 .

Working example 43
4,7-Dihydro-7- (2-fluorobenzyl) -3-hydroxyethyl-2- (4-methoxyphenyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid ethyl ester
To a solution of the compound (0.21 g) obtained in Working Example 42 in anhydrous tetrahydrofuran was added lithium aluminum hydride while cooling in an ice bath. The reaction mixture was allowed to warm to room temperature and stirred for another hour, poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate (100 ml x 3). The extract was washed with an aqueous solution of ammonium chloride, dried and filtered. The filtrate was evaporated under reduced pressure to give a solid, which was chromatographed on silica gel to give a pale yellow amorphous (0.16 g, 66%).

 1 H-NMR spectrum (300 MHz, chloroform-d): 0.90 (3H, t, J = 7.2 Hz), 1.70 (1H, broad s), 3.29 (2H, t, J = 6.0 Hz), 3.84 (3H, s), 4.20-4.23 (2H, m), 4.37 (2H, quartet, J = 7.2 Hz), 5.29 (2H, s), 6.93-7.34 (8H, m), 8.45 (1H, s).

 Mass spectrum (FAB): m / z 482 (MH) +.

Working example 44
4,7-Dihydro-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -3- (N-methyl-N-benzylaminoethyl) -4-oxo-thieno [2,3-b] pyridin-5- ethyl ester carboxylic acid
To a solution of the compound obtained in Working Example 43 (0.08 g, 0.67 mmol) in methylene chloride (5 ml), an excess of phosphorus tribromide was added while cooling in an ice bath. The reaction mixture was allowed to warm to room temperature, stirred for another hour and ethyl acetate (20 ml) was added. Wash the mixture with water and dry. The filtrate was evaporated under reduced pressure to give a solid. It was dissolved in dimethylformamide (5 ml) and an excess of diisopropylethylamine (110 mg) and N-benzylmethylamine (100 mg) were added. The reaction mixture was stirred for another hour, ethyl acetate (20 ml) was added, washed with saturated aqueous sodium bicarbonate and saturated aqueous brine, and dried. The dried solution was evaporated under reduced pressure to give a solid, which was chromatographed on silica gel to give a pale yellow amorphous substance (0.005 g, 4%).

 1 H-NMR spectrum (300 MHz, chloroform-d): 1.40 (3H, t, J = 7.2 Hz), 2.70 (3H, s), 3.30-3.60 (4H, m), 3 , 83 (3H, s), 4.06 (2H, s), 4.40 (2H, quartet, J = 7.2 Hz), 5.28 (2H, s), 6.56-7.51 ( 13H, m), 8.45 (1H, s).

 Mass spectrum (FAB): m / z 585 (MH) +.

Working example 45
5- (1-Acetoxyethyl) -4,7-dihydro-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -3-methyl-4-oxo-thieno [2,3-b] pyridine
Anhydrous acetic acid (2.69 g, 26.3 mmol) was added to a solution of the compound obtained in Working Example 29 (0.55 g, 1.32 mmol) in pyridine (25 ml) while cooling in an ice bath. Allow the reaction mixture to warm to room temperature and stir for another 24 hours. The reaction mixture was evaporated under reduced pressure and the residue was poured into a mixture of ethyl acetate (50 ml) and 1 N hydrochloric acid solution (10 ml). The aqueous phase is extracted with ethyl acetate, the organic extracts are combined, washed with a saturated aqueous solution of sodium chloride and dried. The dried solution was evaporated under reduced pressure to give a solid, which was chromatographed on silica gel to give a pale yellow solid (0.67 g). It was recrystallized from ethyl acetate-hexane to give colorless crystals (0.492 g, 81%) with mp. 145-146 ^o C.

 1 H-NMR spectrum (200 MHz, chloroform-d): 1.56 (3H, d, J = 6.5 Hz), 2.07 (3H, s), 2.66 (3H, s), 3.04 (3H , s), 5.19 (2H, s), 6.13 (1H, quartet, J = 6.5 Hz), 6.94 (2H, d, J = 8.8 Hz), 7.10-7 50 (6H, m); 7.53 (1H, s).

Working example 46
5- (1-Acetoxyethyl) -4,7-dihydro-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxo-thieno [2,3- b] pyridine
To a solution of compound 13 obtained in Working Example 7 (0.15 g, 0.28 mmol) in dimethylformamide (15 ml), diisopropylamine (0.094 g, 0.34 mmol) and N-benzylmethylamine (0.041 g, 0.34 mmol). Stirred for one hour and the reaction mixture was evaporated under reduced pressure. The residue was poured into a mixture of ethyl acetate (50 ml) and saturated aqueous sodium bicarbonate (10 ml). The aqueous phase is extracted with ethyl acetate, the organic extracts are combined, washed with a saturated aqueous solution of sodium chloride and dried. The dried solution was evaporated under reduced pressure to give a solid, which was chromatographed on silica gel to give a pale yellow solid (0.05 g). It is recrystallized from ethyl acetate-diethyl ether to give colorless crystals (0.05 g, 29%), mp. 183-187 ^o C.

Elemental analysis for C ₃₄ H ₃₃ N ₂ O ₄ SF • 2H ₂ O (%):
calculated: C, 65.79; H 6.00; N, 4.51;
Found: C, 63.69; H 5.55; N, 5.02.

 1 H-NMR spectrum (500 MHz, chloroform-d): 1.59 (3H, d, J = 6.9 Hz), 2.09 (3H, s), 2.88 (3H, d, J = 4.7 Hz ), 3.88 (3H, s), 4.40 (1H, m), 4.5-4.7 (1H, m), 5.46 (2H, s), 6.16 (1H, m) 7.08 (2H, d, J = 7.2 Hz), 7.16 (1H, t, J = 9.5 Hz), 7.22 (1H, t, J = 7.6 Hz), 7 3-7.4 (3H, m); 7.4-7.5 (6H, m); 7.97 (1H, s).

 Mass spectrum (FAB): m / z 585 (MH) +.

Working example 47
Using the compound obtained in Working Example 7 as the starting material, according to a procedure similar to that described in Working Example 46, the compounds shown in Table 26 are obtained.

Working example 48
4,7-dihydro-7- (2-fluorobenzyl) -5- (1-hydroxyethyl) -2- (4-methoxyphenyl) - 3- (N-methyl-N-benzylaminomethyl) -4-oxo-thieno [2,3- b] pyridine
To a solution of the compound obtained in Working Example 46 (0.15 g, 0.28 mmol) in methanol (5 ml) was added an aqueous solution of potassium carbonate (obtained by dissolving 0.012 g of potassium carbonate in 1 ml of water), the resulting mixture was stirred in for 3 hours and evaporated under reduced pressure. The residue was poured into a mixture of ethyl acetate (20 ml) and saturated aqueous sodium bicarbonate (10 ml). The aqueous phase is extracted with ethyl acetate, the organic extracts are combined, washed with a saturated aqueous solution of sodium chloride and dried. The dried solution was evaporated under reduced pressure to give a solid (0.018 g, 77%) with mp. 183-187 ^o C.

Elemental analysis for C ₃₂ H ₃₁ N ₂ O ₃ SF • H ₂ O (%):
calculated: C, 68.55; H 5.93; N, 5.00;
Found: C, 68.69; H 5.79; N, 4.92.

 1 H-NMR spectrum (500 MHz, chloroform-d): 1.56 (3H, d, J = 6.4 Hz), 2.16 (3H, s), 3.68 (2H, broad s), 3.86 ( 3H, s), 4.17 (2H, s), 4.7-4.9 (1H, broad s), 4.97 (1H, quartet, J = 6.4 Hz), 5.22 (2H, s), 6.95 (2H, d, J = 6.9 Hz), 7.1-7.3 (5H, m), 7.13-7.18 (3H, m), 7.37 (1H , m), 7.46 (1H, s), 7.74 (2H, d, J = 8.6 Hz).

 Mass spectrum (FAB): m / z 543 (MH) +.

Working example 49
Using the compound obtained in Working Example 27 as the starting material, by the methods similar to those described in Working Examples 23, 24 and 37, the compounds are prepared as shown in Table 27.

Working example 50
4, 7-Dihydro-7- (2,6-difluorobenzyl) -3- (N-methyl-N-benzylaminomethyl) - 2- (4-nitrophenyl) -4-oxo-thieno [2,3-b] pyridin-5- (N-Isopropyl) Carboxamide
To a solution of isopropylamine (0.296 g, 5 mmol) in anhydrous methylene chloride (5 ml) at a temperature of 0 ^° C., a solution of trimethylaluminum in hexane (15%, 2.41 ml, 5.0 mmol) was added dropwise. Allow the mixture to warm to room temperature and stir for another hour. To the resulting solution, a solution of compound 2 obtained in Working Example 26 (0.12 g, 0.25 mmol) in anhydrous methylene chloride (3 ml) was added over 30 minutes while cooling in an ice bath. The mixture was stirred at room temperature for another hour, chloroform (50 ml) was added and the mixture was washed with water. The organic layer was separated, dried over sodium sulfate and evaporated to give a solid. It is recrystallized from a mixture of chloroform - ethyl acetate - ethyl ether, obtaining colorless crystals (0.096 g, 70%) with so pl. 200-202 ^o C.

 1 H-NMR spectrum (500 MHz, chloroform-d) [free amine]: 1.30 (6H, d, J = 6.7 Hz), 2.15 (3H, s), 3.66 (2H, s), 4 , 18 (2H, s), 4.18-4.31 (1H, m), 5.32 (2H, s), 7.00 (2H, d, J = 7.26 Hz), 7.13- 7.25 (5H, m), 7.42 (1H, t, J = 7.3 Hz), 8.02 (2H, d, J = 8.9 Hz), 8.26 (2H, d, J = 8.9 Hz), 8.73 (1H, s), 10.02 (1H, d, J = 9.1 Hz).

IR Spectrum (KBr): 2974, 1661, 1597, 1547, 1497, 1346, 1212, 1035 cm ^-1 .

 Mass spectrum (FAB): m / z 617 (MH) +.

Working example 51
Using, as starting materials, the compounds obtained in Reference Examples 26, 27, 37, 38 and 49, according to a procedure similar to that described in Working Example 50, the compounds shown in Table 28 and Table 29 are obtained.

Working example 52
5-Benzoyl- (2,6-difluorobenzyl) -4,7-dihydro-7-3-methyl-2- (4-nitrophenyl) -4-oxothieno [2,3-b] pyridine
Compound 4 obtained in Working Example 12 (3.93 g, 7.87 mmol) was dissolved by gentle heating in anhydrous tetrahydrofuran. To the resulting solution, dropwise, maintaining the temperature at 0 ^° C., a solution of phenyl magnesium bromide in tetrahydrofuran (1 M, 15.7 ml, 15.7 mmol) was added over 10 minutes and the mixture was stirred for another hour. The reaction mixture was poured into a mixture of ethyl acetate (300 ml) and water (50 ml). The aqueous phase is extracted with ethyl acetate, the organic extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure. The concentrate is chromatographed on silica gel to give yellow crystals (3.00 g, 74%), which are recrystallized from ethyl acetate-hexane; so pl. 114-116 ^o C.

Elemental analysis for C ₂₈ H ₁₈ N ₂ O ₄ SF ₂ • 0.77H ₂ O (%):
calculated: C, 63.56; H 3.70; N, 5.29;
Found: C, 63.83; H 3.95; N, 5.08.

 1 H-NMR spectrum (500 MHz, chloroform-d): 2.68 (3H, s), 5.30 (3H, s), 7.02 (2H, t, J = 8.1 Hz), 7.43 (3H , t, J = 7.2 Hz), 7.52-7.63 (3H, m), 7.86 (2H, d, J = 7.5 Hz), 7.99 (1H, s), 8 30 (2H, d, J = 8.7 Hz).

IR Spectrum (KBr): 3422, 3068, 1665, 1615, 1491, 1473, 1346, 853 cm ^-1 .

 Mass spectrum (FAB): m / z 517 (MH) +.

Working example 53
Using, as starting materials, the compounds obtained in Reference Example 51, by a procedure similar to that described in Working Example 52, the compounds shown in Table 30 are obtained.

Working example 54
2- (4-aminophenyl) -5-benzoyl-7- (2,6-difluorobenzyl) -4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -4-oxo thieno [2,3-b] pyridine
To a mixture of compound 1 obtained in Working Example 47 (0.30 g, 0.47 mmol) in ethyl alcohol (6 ml) was added one drop of concentrated hydrochloric acid, and the mixture turned into a homogeneous solution. To the solution, iron powder (0.105 g, 2.0 mmol) and concentrated hydrochloric acid (0.39 ml, 4.7 mmol) are added in portions. Stirred for 5 hours at room temperature and the reaction mixture was filtered through celite. A small amount of aqueous ammonia was added to the filtrate, and then evaporated under reduced pressure. The concentrate was poured into ice water, neutralized with sodium bicarbonate and extracted with ethyl acetate. The organic extracts are combined, washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel, and then recrystallized from isopropyl ether to give yellow needles (0.24 g, 84%), so pl. 126-128 ^o C.

Elemental analysis for C ₃₆ H ₂₉ N ₃ O ₂ SF ₂ • 1 / 2H ₂ O (%):
calculated: C, 68.93; H 5.04; N, 6.70;
Found: C, 68.71; H 5.18; N, 6.62.

 1 H-NMR spectrum (300 MHz, chloroform-d): 2.13 (3H, s), 3.65 (2H, s), 3.87 (2H, broad s), 4.14 (2H, s), 5, 28 (2H, s), 6.74 (2H, d, J = 8.7 Hz), 7.00 (2H, t, J = 7.8 Hz), 7.16-7.24 (5H, m ), 7.36-7.46 (3H, m), 7.53 (1H, t, J = 7.2 Hz), 7.62 (2H, d, J = 8.4 Hz), 7.89 (2H, d, J = 7.2 Hz); 7.94 (1H, s).

IR Spectrum (KBr): 3358, 1607, 1495, 1473, 1035 cm ^-1 .

 Mass spectrum (FAB): m / z 606 (MH) +.

Working example 55
2- (4-aminophenyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-5-isobutyryl-3- (N-methyl-N-benzylaminomethyl) -4-oxotieno [2,3-b] pyridine
To a mixture of compound 2 obtained in Working Example 47 (0.25 g, 0.415 mmol) in methanol (5 ml), iron powder (0.093 g, 1.66 mmol) and concentrated hydrochloric acid were added portionwise while cooling in an ice bath. 0.8 ml). Stirred for 1 hour at room temperature and the reaction mixture was filtered through celite. Saturated aqueous sodium bicarbonate solution (10 ml) was added to the filtrate and extracted with methylene chloride (30 ml x 3). The organic extracts were combined and washed with water, dried (over magnesium sulfate) and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel to give a yellow amorphous substance (0.203 g, 86%).

 1 H-NMR spectrum (300 MHz, chloroform-d): 1.18 (6H, d), 2.11 (3H, s), 3.65 (2H, s), 3.85 (2H, broad s), 4, 17 (2H, s), 4.18 (1H, m), 5.25 (2H, s), 6.73 (2H, d), 6.95 (2H, t), 7.10-7.26 (5H, m), 7.42 (1H, m), 7.58 (2H, d), 8.27 (1H, s).

Working example 56
5-Benzoyl-7- (2,6-difluorobenzyl) -4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -2- (4-propionylamidophenyl) -4-oxotieno [2,3-b] pyridine
The compound obtained in Working Example 54 (0.14 g, 0.23 mmol) was dissolved in anhydrous methylene chloride (2 ml). To the resulting solution, while cooling in an ice bath (0 ^° C.), triethylamine (0.038 ml) was added. It is stirred for some time and propionyl chloride (0.021 ml, 0.243 mmol) is added to the mixture. The mixture, while cooling in an ice bath, was stirred for another 40 minutes and poured into a mixture of methylene chloride (25 ml) and a strongly diluted aqueous solution of sodium bicarbonate (1 ml). The aqueous layer was again extracted with methylene chloride. The organic extracts were combined, washed with an aqueous solution of sodium chloride, dried (over magnesium sulfate) and the solvent was evaporated under reduced pressure to give a solid. It was recrystallized from ethyl acetate-isopropyl ether to give yellow needles (0.10 g, 65%) with mp. 226-228 ^o C.

Elemental analysis for C ₃₉ H ₃₃ N ₃ O ₃ SF ₂ • 0.7H ₂ O (%):
calculated: C, 69.46; H 5.14; N, 6.23;
Found: C, 69.60; H 5.18; N, 6.04.

This compound is dissolved in ethyl acetate and a saturated solution of hydrogen chloride in ether (equimolar amount or a slight excess) is added and crystals are obtained. They are recrystallized from isopropyl ether to give pale yellow needles (0.095 g, 61%) with mp 218-220 ^o C.

Elemental analysis for C ₃₉ H ₃₃ N ₃ O ₃ SF ₂ • HCl • 3.5H ₂ O (%):
calculated: C, 61.53; H 5.43; N 5.52;
Found: C, 61.83; H 5.33; N, 5.30.

1 H-NMR spectrum (300 MHz, DMSO-d ₆ ): 1.11 (3H, t, J = 7.2 Hz), 1.93 (3H, s), 2.35 (2H, quartet, J = 7.5 Hz), 3.44 (2H, s), 4.00 (2H, s), 5.62 (2H, s), 7.11-7.25 (6H, m), 7.43-7.72 (10H, m), 7.79 (2H, d, J = 7.5 Hz), 8.40 (1H, s), 10.03 (1H, s).

IR Spectrum (KBr): 3422, 3068, 1603, 1502, 1473, 1035 cm ^-1 .

 Mass spectrum (FAB): m / z 662 (MH) +.

Working example 57
Using, as starting materials, the compounds obtained in Reference Examples 54 and 55, by methods similar to those described in Working Examples 56 and 23, 24, 27 and 38, the compounds shown in Table 31 are obtained.

Working example 58
5-Benzoyl-7- (2,6-difluorobenzyl) -4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -2- (4-nitrophenyl) -4-oxothieno [2,3-b] pyridine
Compound 9 obtained in Working Example 51 (1.91 g, 3.09 mmol) was dissolved by heating in anhydrous tetrahydrofuran (30 ml). To the resulting solution, while cooling in an ice bath (0 ^° C.), a solution of phenyl magnesium bromide in tetrahydrofuran (1 M, 6.18 ml, 6.2 mmol) was added dropwise over 10 minutes. Stirred for one hour while cooling in an ice bath and poured into a mixture of ethyl acetate (100 ml) and dilute hydrochloric acid solution (0.5 N, 100 ml). The organic layer was separated, washed once again with an aqueous solution of sodium chloride, dried (over magnesium sulfate) and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel to give yellow crystals (1.00 g, 51%), which were then recrystallized from isopropyl ether to give yellow needles with mp. 197-199 ^o C.

Elemental analysis for C ₃₆ H ₂₇ N ₃ O ₄ SF ₂ • 0.7H ₂ O (%):
calculated: C, 66.70; H 4.42; N, 6.48;
Found: C, 66.59; H 4.48; N, 6.42.

1 H-NMR spectrum (300 MHz, CDCl ₃ ): 2.17 (3H, s), 3.61 (2H, s), 4.16 (2H, s), 5.30 (2H, s), 7.03 ( 2H, t, J = 8.1 Hz), 7.19-7.25 (5H, m), 7.40-7.47 (3H, m), 7.56 (2H, t, J = 7, 5 Hz), 7.88 (2H, d, J = 6.9 Hz), 7.96 (1H, s), 8.10 (2H, d, J = 8.7 Hz), 8.28 (2H , d, J = 8.7 Hz).

IR Spectrum (KBr): 3430, 1663, 1611, 1518, 1473, 1348, 853 cm ^-1 .

 Mass spectrum (FAB): m / z 636 (MH) +.

Working example 59
Using as starting materials compounds 2, 9 and 16 obtained in Reference Example 51, by the procedure similar to that described in Working Example 58, the compounds shown in Table 32 are obtained. This procedure is an alternative way to obtain the compounds described in Working Examples 56 and 57.

Working example 60
6- (4-aminophenyl) -2,4 (1H, 3H) -dioxo-1- (2-fluorobenzyl) -3-phenyl-5- (N-methyl-N-benzylaminomethyl) thieno [2,3-d] pyrimidine
Compound 4 obtained in Working Example 40 (0.15 g, 0.247 mmol) was dissolved in ethanol (15 ml) and 10% carbon palladium (15 mg) was added. Hydrogenate in an atmosphere of hydrogen for 8 hours at room temperature under pressure, one atmosphere. The reaction mixture was filtered through celite and the filtrate was evaporated under reduced pressure. The concentrate is chromatographed on silica gel to give a yellow amorphous substance (0.046 g, 32%).

1 H-NMR spectrum (300 MHz, CDCl ₃ ): 2.05 (3H, s), 3.57 (2H, s), 3.81 (2H, broad s), 3.89 (2H, s), 5.29 (2H, s), 6.69 (2H, d, J = 8.7 Hz), 7.05-7.56 (16H, m).

 Mass spectrum (FAB): m / z 577 (MH) +.

Working example 61
6- (4-Acetylaminophenyl) -2,4 (1H, 3H) dioxo-1- (2-fluorobenzyl) -3-phenyl-5- (N-methyl-N-benzylaminomethyl) -3-phenylthieno [2,3 -d] pyrimidine
The compound obtained in Working Example 60 (0.63 g, 0.11 mmol) was dissolved in anhydrous pyridine (5 ml) and acetic anhydride (0.01 ml, 0.11 mmol) was added. The mixture was stirred for two hours at room temperature and evaporated under reduced pressure. The concentrate was poured into a mixture of methylene chloride (30 ml) and saturated aqueous sodium chloride (10 ml). The organic layer was separated, the aqueous phase was further extracted with methylene chloride (30 ml). The organic extracts were dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel to give a colorless solid (0.01 g, 15%).

 1 H-NMR spectrum (300 MHz, chloroform-d): 2.06 (3H, s), 2.19 (3H, s), 3.57 (2H, s), 3.90 (2H, s), 5.30 (2H, s), 7.04-7.57 (16H, m), 7.70 (2H, d, J = 8.4 Hz).

Working example 62
4,7-Dihydro-7- (2-fluorobenzyl) -3-2- (4-hydroxyphenyl) -3-methyl-4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid ethyl ester
To a solution of compound 3 obtained in Working Example 65 (1.30 g, 2.70 mmol) in tetrahydrofuran (80 ml), a 1 M solution of hydrogen chloride in ether (81 ml, 81 mmol) was added while cooling in an ice bath. Stirred at room temperature for 60 hours and evaporated under reduced pressure. The concentrate was poured into a mixture of ethyl acetate (100 ml) and saturated aqueous sodium chloride (50 ml). The organic layer was separated, the aqueous phase was further extracted with ethyl acetate (50 ml). The organic extracts were dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-ethanol to give yellow needles (0.81 g, 69%) with mp. 225-227 ^o C.

Elemental analysis for C ₂₄ H ₂₀ NO ₄ SF • 0.1H ₂ O (%):
calculated: C, 65.62; H 4.63; N, 3.19;
Found: C, 65.46; H 4.65; N, 3.33.

 1 H-NMR spectrum (300 MHz, chloroform-d): 1.30 (3H, t, J = 7.0 Hz), 4.24 (2H, quartet, J = 7.0 Hz), 5.52 (2H, s ), 6.84 (2H, d, J = 8.4 Hz), 7.20-7.46 (6H, m), 8.65 (1H, s), 9.75 (1H, s).

IR Spectrum (KBr): 3856, 1711, 1611, 1589, 1510, 1493, 1448 cm ^-1 .

 Mass spectrum (FAB): m / z 438 (MH) +.

Working example 63
4,7-Dihydro-7- (2-fluorobenzyl) -2- (4-hydroxyphenyl) - 3- (N-methyl-N-benzylaminomethyl) -4-oxo-thieno [2,3-b] pyridin-5- ethyl ester carboxylic acid
Using starting compound No. 26 obtained in Working Example 7 (0.26 g, 0.46 mmol), N-methylbenzylamine (0.072 ml, 0.56 mmol) and N-ethyldiisopropylamine (0.12 ml, 0.69 mmol), obtained by a method similar to that described in Working example 8, an amorphous substance of yellow color (0.24 g). It was dissolved in ethanol (6 ml), 1 N hydrochloric acid solution (4 ml, 4 mmol) was added and stirred at room temperature for two hours. An additional amount of 1 N hydrochloric acid solution (8 ml, 8 mmol) was added and stirred at room temperature for 19 hours. Water containing sodium bicarbonate (1.01 g, 12.0 mmol) was added to the reaction mixture and extracted with 30 ml of ethyl acetate three times. The organic extracts were combined, dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel to give a colorless oil (0.15 g, 58%). It is dissolved in ethanol (3 ml) and a 1 M solution of hydrogen chloride in ether (0.35 ml, 0.35 mmol) is added while cooling in an ice bath. Stir at room temperature for 10 minutes and evaporate under reduced pressure. The residue was recrystallized from ether to give a white powder (0.116 g, 41% overall yield) as a hydrochloride salt, mp. 231-235 ^o C.

Elemental analysis for C ₃₂ H ₂₉ N ₂ O ₄ SF • HCl • 1.5H ₂ O (%):
calculated: C, 61.98; H 5.36; N, 4.52;
Found: C, 61.99; H 5.23; N, 4.55.

 1 H-NMR spectrum (300 MHz, chloroform-d): 1.39 (3H, t, J = 7.1 Hz), 2.53 (3H, broad s), 4.09 (2H, broad s), 4.38 (2H, quartet, J = 7.1 Hz), 4.39 (2H, broad s), 5.46 (2H, s), 7.05 (2H, d, J = 8.5 Hz), 7, 13-7.51 (11H, m), 8.57 (1H, s).

IR Spectrum (KBr): 3422, 2988, 1719, 1695, 1605, 1543, 1504, 1458 cm ^-1 .

Working example 64
2- (4-n-Butoxyphenyl) -4,7-dihydro-7- (2-fluorobenzyl) -3-methyl-4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid ethyl ester
To a solution of the compound obtained in Working Example 62 (0.30 g, 0.686 mmol) in dimethylformamide (10 ml), sodium hydride (30 mg, 0.75 mmol) was added while cooling in an ice bath and stirred at room temperature for hours. To the resulting solution was added n-butyl iodide (0.19 g, 1.03 mmol) and stirred at room temperature for 15 hours. The reaction mixture was evaporated under reduced pressure. The concentrate was poured into a mixture of ethyl acetate (100 ml) and saturated aqueous sodium chloride (50 ml). The organic layer was separated, the aqueous phase was further extracted with ethyl acetate (50 ml). The organic extracts were dried over sodium sulfate and the solvent was evaporated under reduced pressure. The solid residue was recrystallized from ethyl acetate-n-hexane to give colorless crystals (0.33 g, 97%) with mp. 119-121 ^o C.

Elemental analysis for C ₂₈ H ₂₈ NO ₄ SF • 0.2H ₂ O (%):
calculated: C, 67.64; H 5.76; N 2.82;
Found: C, 67.36; H 5.69; N, 2.68.

 Mass spectrum (FAB): m / z 494 (MH) +.

Working example 65
Using, as starting materials, compound 7 obtained in Reference Example 3 and compound 3 obtained in Reference Example 53, using a procedure similar to that described in Working Example 19, the compounds shown in Table 33 are obtained.

Working example 66
5-Benzoyl-7- (2,6-difluorobenzyl) -4,7-dihydro-2- (4-N-ethylaminocarboxyphenyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxo-thieno [2,3- b] pyridine
A solution of compound 3 obtained in Working Example 47 (0.15 g, 0.226 mmol) in ethanol (3 ml) and tetrahydrofuran (3 ml) is treated with a 1 N aqueous solution of sodium hydroxide (1.2 ml, 1.2 mmol) and get a derivative of a carboxylic acid. To a solution of this obtained carboxylic acid derivative in tetrahydrofuran (5 ml) in a nitrogen atmosphere and while cooling in an ice bath, triethylamine (0.084 ml, 0.60 mmol) was added and the mixture was stirred under the same conditions for one hour and then half an hour at room temperature temperature. To the resulting solution, a 70% aqueous solution of ethylamine (0.16 ml, 2.48 mol) was added dropwise while cooling in an ice bath, and then the mixture was stirred while cooling in an ice bath for 30 minutes and 2 hours at room temperature. temperature. The reaction mixture was poured into a mixture of ethyl acetate (50 ml) and saturated aqueous sodium chloride (50 ml). The organic layer was separated, the aqueous phase was further extracted with ethyl acetate (50 ml). The organic extracts were dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel to give a pale yellow amorphous substance (0.095 g, 63%). It is dissolved in methylene chloride (4 ml) and a 1 M solution of hydrogen chloride in ether (0.29 ml, 0.29 mmol) is added while cooling in an ice bath. Stir at room temperature for 10 minutes and evaporate under reduced pressure. The residue was recrystallized from a mixture of methylene chloride - ethyl acetate - ether and a pale yellow powder (0.088 g, total yield 56%) was obtained as a hydrochloride salt with a mp of 156-160 ^o C.

Elemental analysis for C ₃₉ H ₃₃ N ₃ O ₃ SF ₂ • HCl • 1.8H ₂ O (%):
calculated: C, 64.11; H 5.19; N, 5.75;
Found: C, 63.88; H 4.90; N, 5.59.

 1 H-NMR spectrum (300 MHz, chloroform-d) [free amine]: 1.28 (3H, t, J = 7.2 Hz), 2.13 (3H, broad s), 3.49-3.58 (2H , m), 3.62 (2H, broad s), 4.16 (2H, broad s), 5.30 (2H, s), 6.23 (3H, broad s), 6.99-7.05 (2H, m), 7.17-7.26 (5H, m), 7.39-7.58 (4H, m), 7.83-7.97 (7H, m).

IR Spectrum (KBr) [hydrochloride]: 3386, 3064, 1655, 1630, 1605, 1543, 1508, 1497, 1473 cm ^-1 .

 Mass spectrum (FAB): m / z 662 (MH) +.

Working example 67
Using as starting materials compounds 3 and 4, obtained in Reference example 47, by a method similar to that described in Working example 66, the compounds shown in Table 34 are obtained.

Working example 68
4,7-Dihydro-5-ethoxymethyl-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxo-thieno [2, 3-b] pyridine hydrochloride
Sodium hydride (19 mg, 0.475 mmol) was added to a solution of compound 2 obtained in Working Example 25 (0.23 g, 0.435 mmol) in anhydrous tetrahydrofuran (5 ml) under a nitrogen atmosphere while cooling in an ice bath, and stirred at 0 ^o C for 30 minutes. Ethyl iodide (0.038 ml, 0.475 mmol) was added to the resulting mixture and allowed to warm to room temperature. It is stirred at room temperature for 2 hours, ethyl iodide (0.038 ml, 0.475 mmol) is added and stirred for 19 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and poured into a mixture of ethyl acetate (30 ml) and a saturated aqueous solution of sodium bicarbonate (30 ml). The organic layer was separated, the aqueous phase was further extracted with ethyl acetate. The organic extracts are dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel to give a white solid (0.09 g, 37%). It is dissolved in methylene chloride (4 ml) and a 1 M solution of hydrogen chloride in ether (0.2 ml, 0.2 mmol) is added while cooling in an ice bath. Stir at room temperature for 10 minutes and evaporate under reduced pressure. The residue was recrystallized from a mixture of methylene chloride - ethyl acetate - ether and a white powder (0.058 g) was obtained in the form of a hydrochloride with a melting point of 200-204 ^o C.

Elemental analysis for C ₃₃ H ₃₃ N ₂ O ₃ SF • HCl • 0.5H ₂ O (%):
calculated: C, 65.82; H 5.86; N 4.65;
Found: C, 66.01; H 5.67; N 4.62.

 1 H-NMR spectrum (300 MHz, chloroform-d): 1.28 (3H, t, J = 7.0 Hz), 2.15 (3H, broad s), 2.86 (2H, broad s), 3.68 (2H, quartet, J = 7.0 Hz), 3.86 (3H, s), 4.21 (2H, s), 4.57 (2H, s), 5.31 (2H, s) 7.00-7.69 (14H, m).

 Mass spectrum (FAB): m / z 557 (MH) +.

Working example 69
5-benzyloxymethyl-4,7-dihydro-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxo-thieno [2,3-b] pyridine hydrochloride
Taking as starting material the compound 3 obtained in Working Example 25, and taking benzyl chloride instead of methyl iodide, according to a procedure similar to that described in Working Example 68, the desired compound is obtained in the form of a pale yellow crystalline powder (0.10 g, 79 %) with mp 77-83 ^o C.

Working example 70
4,7-dihydro-5-ethylthiomethyl-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxo-thieno [2,3-b] pyridine hydrochloride
To a solution of compound 2 obtained in Working Example 25 (0.15 g, 0.284 mmol) in anhydrous tetrahydrofuran (5 ml) was added tributylphosphine (0.36 mg, 1.44 mmol) and diethyl disulfide (0.18 ml, 1, 46 mmol) and the resulting mixture was refluxed for five hours. Tributylphosphine (0.72 ml, 2.88 mmol) and diethyl disulfide (0.36 ml, 2.92 mmol) were added to the mixture and refluxed for three days. Cooled to room temperature and poured into a mixture of ethyl acetate (50 ml) and saturated aqueous sodium chloride (50 ml). The organic layer was separated, the aqueous phase was further extracted with ethyl acetate (50 ml). The organic extracts are dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel to give a white solid (0.124 g, 76%). It is dissolved in methylene chloride (3 ml) and a 1 M solution of hydrogen chloride in ether (0.45 ml, 0.45 mmol) is added while cooling in an ice bath. Stir under cooling in an ice bath for 10 minutes and evaporate under reduced pressure. The residue was recrystallized from a mixture of methylene chloride - ethyl acetate - ether and a white powder (0.09 g) was obtained in the form of a hydrochloride salt with mp. 213-217 ^o C.

Elemental analysis for C ₃₃ H ₃₃ N ₂ O ₂ S ₂ F • HCl • H ₂ O (%):
calculated: C, 63.19; H 5.78; N, 4.47;
Found: C, 63.21; H 5.69; N, 4.59.

 1 H-NMR spectrum (300 MHz, chloroform-d): 1.27 (3H, t, J = 7.4 Hz), 2.23 (3H, broad s), 2.56 (2H, quartet, J = 7.4 Hz), 3.76 (2H, s), 3.79 (2H, s), 3.86 (3H, s), 4.25 (2H, broad s), 5.25 (2H, broad s), 6.97 (2H, d, J = 8.6 Hz), 7.12-7.39 (10H, m), 7.71 (2H, broad s).

IR Spectrum (KBr): 3480, 2966, 1609, 1520, 1458 cm ^-1 .

 Mass spectrum (FAB): m / z 573 (MH) +.

Working example 71
Ethyl ester 7- (2,6-difluorobenzyl) -4,7-dihydro-6-isobutyl-3- (N-methyl-N-benzylaminomethyl) -4-oxo-2- (4-propionylaminophenyl) thieno [2,3 -b] pyridine-5-carboxylic acid
To the mixture of compound 5 obtained in Working Example 49 (0.10 g, 0.159 mmol) and copper iodide (0.095 g, 0.5 mmol) isobutylmagnesium bromide (0.5 ml, 1 mmol) was added while cooling in a bath ice. Anhydrous tetrahydrofuran (20 ml) was added to the resulting mixture while cooling in an ice bath, and stirred for one hour. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate (50 ml x 3). The organic extracts are combined, dried over sodium sulfate and evaporated under reduced pressure. The resulting oil (0.124 g) was dissolved in methylene chloride (5 ml), dichlorodicyanoquinone (0.0207 g, 0.091 mmol) was added to the resulting solution, and the mixture was stirred under cooling in an ice bath for two hours. The reaction mixture was poured into a mixture of chloroform (50 ml) and water (30 ml). The organic layer was separated, the aqueous phase was further extracted with chloroform (50 ml). The organic extracts are combined, dried over sodium sulfate and evaporated under reduced pressure to obtain a brown oil (0.02 g, 32%). The oil was recrystallized from ethyl acetate-n-hexane to give dark brown crystals with a melting point of 135-137 ^o C.

Elemental analysis for C ₃₉ H ₄₁ N ₃ O ₄ SF ₂ • C ₈ H ₂ Cl ₂ N ₂ O ₂ • 1.4 NaCl (%): calculated: C 58.49; H 4.91; N, 6.35;
Found: C, 58.34; H 5.01; N, 6.75.

 1 H-NMR spectrum (300 MHz, chloroform-d): 1.07 (6H, broad s), 1.23 (3H, broad s), 1.46 (3H, t, J = 6.3 Hz), 2.10 (1H, broad s), 2.30-2.96 (7H, m), 4.30-4.53 (6H, m), 5.55 (2H, broad s), 6.94-7.90 (12H, m).

IR Spectrum (KBr): 3428, 2970, 2214, 1725, 1688, 1628, 1589, 1504, 1470, 1386, 1152, 1025, 789, 748, 700 cm ^-1 .

 Mass spectrum (FAB): m / z 686 (MH) +.

Working example 72
5-cyano-4,7-dihydro-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) - 3-methyl-4-oxo-thieno [2,3-b] pyridine
A mixture of compound 6 obtained in Working Example 12 (0.435 g, 1.03 mmol) and phosphorus oxychloride (0.145 ml, 1.56 mmol) was refluxed for one hour. It is cooled, poured into a mixture of chloroform and an aqueous solution of sodium bicarbonate. The organic layer was separated, the aqueous phase was further extracted with chloroform. The organic extracts are combined, washed with sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel, and then recrystallized from ethyl acetate-isopropyl ether to give pale yellow crystals (0.225 g, 70%), so pl. 215-216 ^o C.

Working example 73
5-Ethylsulfinylmethyl-4,7-dihydro-7- (2-fluorobenzyl) - 2- (4-methoxyphenyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxo-thieno [2,3-b] pyridine hydrochloride
To a solution of the compound obtained in Working Example 71 (0.15 g, 0.26 mmol) in methylene chloride (4 ml), while cooling in an ice bath, a 1 M solution of hydrogen chloride in ether (0.29 ml, 0, 29 mmol) and stirred under the indicated conditions for five minutes. The mixture was evaporated under reduced pressure to give a yellow amorphous substance. It was dissolved in methylene chloride (5 ml) and, while cooling in an ice bath, a solution of m-chloroperbenzoic acid (45 mg, 0.26 mmol) in methylene chloride (5 ml) was added dropwise over 10 minutes. Stirred at a temperature of 0 ^o C for 1.5 hours and 1.5 hours at room temperature, and then the reaction mixture was poured into a mixture of chloroform and an aqueous solution of sodium bicarbonate. The organic layer was separated, the aqueous phase was further extracted with chloroform. The organic extracts are combined, washed with sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel to give a pale yellow syrup (60 mg, 38.9%). The resulting syrup (50 mg, 0.085 mmol) was dissolved in methylene chloride (4 ml) and, while cooling in an ice bath, a 1 M solution of hydrogen chloride in ether (0.13 ml, 0.13 mmol) was added, and then stirred under the indicated conditions for five minutes. The mixture was evaporated under reduced pressure, the residue was recrystallized from ether to give a yellow powder (37 mg, 53%) as a hydrochloride salt, mp 216-219 ^o C.

Working example 74
6- (Aminophenyl) -2,4 (1H, 3H) -dioxo-1- (2,6-difluorobenzyl) -5- (N-methyl-N-benzylaminomethyl) -3-phenylthieno [2,3-d] pyrimidine
Using compound 17 obtained in Working Example 40 as the starting material, by the method similar to that described in Working Example 68, the target compound is obtained as an amorphous substance (yield 65%).

 1 H-NMR spectrum (300 MHz, chloroform-d): 2.05 (3H, s), 3.56 (2H, s), 3.81 (2H, broad s), 3.88 (2H, s), 5, 36 (2H, s), 6.71 (2H, d, J = 8.7 Hz), 6.91 (2H, t, J = 8.7 Hz), 7.21-7.53 (13H, m )

Working example 75
Using as the starting material the compound obtained in Working Example 60, by the procedure similar to that described in Working Example 61, the following compounds are obtained:
N 1: 2,4 (2H, 3H) -dioxo-1- (2-fluorobenzyl) -5- (N-methyl-N-benzylaminomethyl) -3-phenyl-6- (4-propionylaminophenyl) thieno hydrochloride [2, 3-d] pyrimidine (yield: 86%, mp 172-175 ^° C),
N 2: 2,4 (2H, 3H) -dioxo-1- (2-fluorobenzyl) -6- (4-isobutyrylaminophenyl) -5- (N-methyl-N-benzylaminomethyl) -3-phenylthieno hydrochloride [2,3 -d] pyrimidine (yield: 77%, mp 185-188 ^° C),
N 3: 2,4 (2H, 3H) -dioxo-1- (2-fluorobenzyl) -6- (4-methoxyacetylaminophenyl) -5- (N-methyl-N-benzylaminomethyl) -3-phenylthieno hydrochloride [2,3 -d] pyrimidine (yield: 88%, mp 157-162 ^° C).

Working example 76
Using the compound obtained in Working Example 8 (100 mg), lactose (165 mg), corn starch (5 mg), polyvinyl alcohol (4 mg) and magnesium stearate (1 mg), a tablet was prepared in the usual manner.

Working example 77
The compound obtained in Working Example 8 (5 g) was dissolved in distilled water for injection and the total volume was adjusted to 100 ml. The solution is sterilized by filtration through a 0.22 μm membrane filter (manufactured by Sumitomo Electric Industries, Ltd or Zartolius, Inc.) and placed in 2 ml sterile ampoules, and then lyophilized in the usual manner to obtain a lyophilized solution injection solution containing 100 mg of the drug per ampoule.

Working example 78
Using the compound 15 obtained in Working Example 9 (100 mg), lactose (165 mg), corn starch (25 mg), polyvinyl alcohol (4 mg) and magnesium stearate (1 mg), a tablet was prepared in the usual manner.

Working example 79
Compound 15 obtained in Working Example 9 (5 g) was dissolved in distilled water for injection and the total volume was adjusted to 100 ml. The solution is sterilized by filtration through a 0.22 μm membrane filter (manufactured by Sumitomo Electric Industries, Ltd or Zartolius, Inc.) and placed in 2 ml sterile ampoules, and then lyophilized in the usual manner to obtain a lyophilized solution injection solution containing 100 mg of the drug per ampoule.

Working example 80
Using the compound 3 obtained in Working Example 21 (100 mg), lactose (165 mg), corn starch (25 mg), polyvinyl alcohol (4 mg) and magnesium stearate (1 mg), a tablet was prepared in the usual manner.

Working example 81
Compound 3 obtained in Working Example 21 (5 g) was dissolved in distilled water for injection and the total volume was adjusted to 100 ml. The solution is sterilized by filtration through a 0.22 μm membrane filter (manufactured by Sumitomo Electric Industries, Ltd or Zartolius, Inc.) and placed in 2 ml sterile ampoules, and then lyophilized in the usual manner to obtain a lyophilized solution injection solution containing 100 mg of the drug per ampoule.

Working example 82
Using the compound obtained in Working Example 23 (100 mg), lactose (165 mg), corn starch (25 mg), polyvinyl alcohol (4 mg) and magnesium stearate (1 mg), a tablet was prepared in the usual manner.

Working example 83
The compound obtained in Working Example 23 (5 g) was dissolved in distilled water for injection and the total volume was adjusted to 100 ml. The solution is sterilized by filtration through a 0.22 μm membrane filter (manufactured by Sumitomo Electric Industries, Ltd or Zartolius, Inc.) and placed in 2 ml sterile ampoules, and then lyophilized in the usual manner to obtain a lyophilized solution injection solution containing 100 mg of the drug per ampoule.

Working example 84
Using the compound obtained in Working Example 56 (100 mg), lactose (165 mg), corn starch (25 mg), polyvinyl alcohol (4 mg) and magnesium stearate (1 mg), a tablet was prepared in the usual manner.

Working example 85
The compound obtained in Working Example 56 (5 g) was dissolved in distilled water for injection and the total volume was adjusted to 100 ml. The solution is sterilized by filtration through a 0.22 μm membrane filter (manufactured by Sumitomo Electric Industries, Ltd or Zartolius, Inc.) and placed in 2 ml sterile ampoules, and then lyophilized in the usual manner to obtain a lyophilized solution injection solution containing 100 mg of the drug per ampoule.

Working example 86
Using the compound 2 obtained in Working Example 57 (100 mg), lactose (165 mg), corn starch (25 mg), polyvinyl alcohol (4 mg) and magnesium stearate (1 mg), a tablet was prepared in the usual manner.

Working example 87
Compound 2 obtained in Working Example 57 (5 g) was dissolved in distilled water for injection and the total volume was adjusted to 100 ml. The solution is sterilized by filtration through a 0.22 μm membrane filter (manufactured by Sumitomo Electric Industries, Ltd or Zartolius, Inc.) and placed in 2 ml sterile ampoules, and then lyophilized in the usual manner to obtain a lyophilized solution injection solution containing 100 mg of the drug per ampoule.

Working example 88
Using the compound 3 obtained in Working Example 57 (100 mg), lactose (165 mg), corn starch (25 mg), polyvinyl alcohol (4 mg) and magnesium stearate (1 mg), a tablet was prepared in the usual manner.

Working example 89
Compound 3 obtained in Working Example 57 (5 g) was dissolved in distilled water for injection and the total volume was adjusted to 100 ml. The solution is sterilized by filtration through a 0.22 μm membrane filter (manufactured by Sumitomo Electric Industries, Ltd or Zartolius, Inc.) and placed in 2 ml sterile ampoules, and then lyophilized in the usual manner to obtain a lyophilized solution injection solution containing 100 mg of the drug per ampoule.

Working example 90
Compound 7 obtained in Working Example 51 (5 g) was dissolved in distilled water for injection and the total volume was adjusted to 100 ml. The solution is sterilized by filtration through a 0.22 μm membrane filter (manufactured by Sumitomo Electric Industries, Ltd or Zartolius, Inc.) and placed in 2 ml sterile ampoules, and then lyophilized in the usual manner to obtain a lyophilized solution injection solution containing 100 mg of the drug per ampoule.

Working example 91
Compound 8 obtained in Working Example 51 (5 g) was dissolved in distilled water for injection and the total volume was adjusted to 100 ml. The solution is sterilized by filtration through a 0.22 μm membrane filter (manufactured by Sumitomo Electric Industries, Ltd or Zartolius, Inc.) and placed in 2 ml sterile ampoules, and then lyophilized in the usual manner to obtain a lyophilized solution injection solution containing 100 mg of the drug per ampoule.

Working example 92
(1) The compound obtained in Working Example 56 to 5 g
(2) Lactose, crystalline cellulose (granules) - 330 g
(3) D-mannitol - 29 g
(4) Unsubstituted hydroxypropyl cellulose - 20 g
(5) Talc - 25 g
(6) Hydroxypropyl cellulose - 50 g
(7) Aspartame - 3 g
(8) Dipotassium salt of glycerogen - 3 g
(9) Hydroxypropyl methyl cellulose 2910 - 30 g
(10) Titanium oxide - 3.5 g
(11) Yellow Iron Sesquioxide - 0.5 g
(12) Light silicic anhydride - 1 g
In purified water, (1), (3), (4), (5), (7) and (8) are suspended or dissolved. The granules of the core (2) are coated with a suspension or solution, and unprocessed fine granules are obtained, which are coated with (9) - (11), and small coated granules are obtained, which are mixed with (12), to obtain 500 g of small granules that contain 1 % of the compound obtained in Working Example 56. 500 mg of granules obtained by the indicated method are packaged.

Test Example 1
Obtaining ¹²⁵ I-leuprorelin
10 μl of a 3 • 10 ^-4 M aqueous solution of leuprorelin and 10 μl of a solution of 0.01 mg / ml lactoperoxidase in 0.1 M HEPES buffer solution (pH 7.4) are placed in a test tube to which 10 μl [37 MBq in 0 , 1 M HEPES buffer solution (pH = 7.4)] of Na ¹²⁵ I solution. The mixture was stirred and 10 μl of a 0.001% hydrogen peroxide solution was added thereto and left at room temperature for 20 minutes. To stop the reaction, 700 μl of a 0.05% trifluoroacetic acid solution was added to the mixture. The product is purified by reverse phase high pressure liquid chromatography. When conducting high pressure liquid chromatography, the following conditions apply.

¹²⁵ I-Leiprorelin elutes with a retention time of 26 to 27 minutes.

Column: TSK gel ODS-80 ^TM CTR (4.6 mm x 10 cm).

 Eluent: Solvent A (0.05% trifluoroacetic acid).

 Solvent B (40% acetonitrile - 0.05% trifluoroacetic acid).

 0 minutes (100% Solvent A) - 3 minutes (100% Solvent A) - 7 minutes (50% Solvent A + 50% Solvent B) - 40 minutes (100% Solvent B).

 Elution temperature: room temperature.

 The flow rate of the eluent: 1 ml / min.

Test Example 2
Obtaining membrane fraction of the anterior pituitary gland of rats containing gonadotropin-releasing hormone receptors
Forty Wister rats (males 8 weeks old) are sacrificed, the anterior pituitary glands are separated and washed with ice-cold homogenization buffer solution (25 mM Tris [Tris (hydroxymethyl) aminomethane] - HCl, 0.3 M sucrose, 1 mM diamine tetraacetic acid glycol ether 0.25 mM phenylmethyl sulfochloride, 10 u / ml aprotinin, 1 μg / ml pepstatin, 20 μg / ml leupeptin, 100 μg / ml phosphoramidone, 0.03% sodium azide solution, pH = 7.5). The pituitary gland is suspended in 2 ml of homogenization buffer and homogenized in a Polytron homogenizer. Centrifuge separation is carried out for 15 minutes with an acceleration of 700g. The liquid above the precipitate is separated, placed in a centrifuge beaker and centrifuged for an hour with an acceleration of 100000g, obtaining a membrane fraction in the form of a precipitate. The resulting precipitate was suspended in 2 ml of assay buffer (25 mM Tris-HCl, 1 mM ethylenediaminetetraacetic acid, 0.1% bovine serum albumin, 0.25 mM phenylmethyl sulfochloride, 1 μg / ml pepstatin, 20 μg / ml leipeptin, 100 μg / ml of phosphoramidone, 0.03% sodium azide solution, pH 7.5) and centrifuged for one hour with an acceleration of 100000g. The membrane preparation is isolated in the form of a precipitate, which is again suspended in 10 ml of analysis buffer, poured into ampoules and stored until use at a temperature of minus 80 ^o C.

Test Example 3
Obtaining a membrane fraction of Chinese hamster ovary cells containing human gonadotropin releasing hormone receptors
Chinese hamster ovary cells (10 ⁹ ) expressing human gonadotropin releasing hormone receptors are suspended in phosphate buffered saline to which 5 mM ethylenediaminetetraacetic acid (PBS-EDTA) is added. The suspension is centrifuged for 5 minutes with an acceleration of 100g. 10 ml of cell homogenization buffer (10 mM sodium bicarbonate, 5 mM ethylenediaminetetraacetic acid, pH 7.5) was added to the pellet cake obtained from the cells and homogenized in a Polytron homogenizer. Centrifuge separation is carried out for 25 minutes with an acceleration of 400g. The liquid above the precipitate was transferred to an ultracentrifuge beaker and centrifuged for one hour with an acceleration of 100000g to obtain a membrane fraction in the form of a precipitate. The resulting precipitate was suspended in 2 ml of assay buffer and centrifuged again for one hour with an acceleration of 100000g. The membrane preparation is isolated in the form of a precipitate, which is again suspended in 20 ml of analysis buffer, poured into ampoules and stored until use at a temperature of minus 80 ^o C.

Test Example 4
Determination of the degree of inhibition of binding of ¹²⁵ I-leuprorelin
Membrane fractions of the pituitary gland of rats and Chinese hamster ovary cells expressing human gonadotropin releasing hormone receptors obtained in Test Examples 2 and 3 were diluted with assay buffer to a concentration of 200 μg / ml and 188 μg / ml, respectively, and placed in test tubes. In cases where membrane fractions of the anterior pituitary of the rat are used, 2 μl of a 0.1 mM solution of the compound dissolved in 60% dimethyl sulfoxide and 10 μl of a 38 nM solution of ¹²⁵ I-leuprorelin are simultaneously added. In cases where membrane fractions of Chinese hamster ovary cells expressing human gonadotropin-releasing hormone receptors are used, 2 μl of a 2 mM solution of the compound dissolved
in 60% dimethyl sulfoxide, and 10 μl of a 38 nM solution of ¹²⁵ I-leuprorelin. To determine the maximum binding value, a solution is prepared for the reaction, to which 2 μl of a 100 μM solution of leuprorelin in 60% dimethyl sulfoxide and 10 μl of a 38 nM solution of ¹²⁵ I-leuprorelin are simultaneously added.

When using membrane fractions of the anterior pituitary of rats, the reaction is carried out for 90 minutes at a temperature of 4 ^o C, and in the case when using membrane fractions of Chinese hamster ovary cells expressing human gonadotropin releasing hormone receptors, the reaction is carried out for 60 minutes at a temperature of 25 ^o C. the Reaction mixture is filtered through funnels with a glass filter company "Whatman" (GF-F), treated with polyethyleneimine. At the end of the filtering, the amount of radioactivity ¹²⁵ I-leuprorelin remaining on the filter is determined using a gamma radiation counter.

When calculating the ratio (TB-SB) / (TB-NSB) • 100 (SB: radioactivity obtained by adding the compound; TB: maximum binding radioactivity; NSB: non-specific binding radioactivity), determine the degree of inhibition of binding (in percent) for each test compound . In addition, the degree of inhibition is determined by changing the concentration of the test compound, and the concentration of the test compound inhibiting the amount of (TB-NSB) by 50% (IC ₅₀ value) is determined using a Hill graph. The results obtained are presented in Table 35.

Test Example 5
Inhibition of the secretion of lutenizing hormone / follicle-stimulating hormone by the grown primary cells of the anterior pituitary of rats
The glands of the anterior pituitary gland of 40 Wistar rats (males aged 8 weeks) are placed in Petri dishes containing buffer A (0.7 mM sodium dihydrogen phosphate, 137 mM sodium chloride, 5 mM potassium chloride, 25 mM HEPES, 50 μg / ml gentamicin sulfate ), washed once with buffer A, divided into four parts and washed twice more. A portion of the rat anterior pituitary gland washed in this manner is placed in a conical flask with a stopper that contains an enzyme I solution (buffer A containing 0.4% collagenase, 0.4% bovine serum albumin, 10 μg / ml deoxyribonuclease and 0.2% glucose ) The mixture is kept, shaking, in an incubator for an hour at a temperature of 37 ^o C. Tissue fragments are taken with a pipette and dispersed. The resulting dispersion was transferred to a centrifugation tube and centrifuged for 6 minutes to separate the supernatant. An enzyme II solution (enzyme I solution containing 10% pancreatin) was added to the residue and the mixture was kept in an incubator for 8 minutes at a temperature of 37 ^° C and 2 ml of cow fetal serum was added. The mixture is again centrifuged for 6 minutes with an acceleration of 480g and the supernatant is removed. The residue is suspended in 10 ml of culture medium I (Eagle-modified Dulbecco medium, which contains 10% fetal bovine serum, 20 ml HEPES, 20 units / ml penicillin G, 50 μg / ml streptomycin and 3.7 g / l sodium bicarbonate) and filtered through a sieve of nylon. The material obtained by filtration is washed twice in 10 ml portions of culture medium I, and then the cells are suspended in medium I for culture growth with a density of 5 • 10 ⁵ cells per milliliter. One milliliter of each suspension of cells is placed in each cell of a tablet having 24 cells, which is kept in an incubator in an atmosphere of 5% carbon dioxide - 95% air for 3 days at a temperature of 37 ^o C, 2 ml of culture medium II is added to each cell (medium I for growing a culture without 10% serum of the fetal cow), and then incubated for one hour. The culture medium is separated. 800 μl of fresh culture medium II is added to each well of a 24-mesh tablet, and then compound 15, obtained in Working Example 9, dissolved in 0.2% (v / v) dimethyl sulfoxide and 100 μl of 5 nM gonadotropin-releasing solution is added at the same time. hormones. A culture to which no compound was added was used as a control solution. After standing in the incubator for 3 hours at a temperature of 37 ^° C., 500 μl of culture supernatant is isolated and centrifuged for 10 minutes with an acceleration of 1000 g to separate the supernatant. The concentrations of lutenizing hormone and follicle-stimulating hormone in the supernatant are determined using a radioimmunoassay kit (from Amersham Inc.).

 When calculating the ratio according to the formula 100 - (concentration of luteinizing hormone or follicle-stimulating hormone in the presence of a compound) / (concentration of luteinizing hormone or follicle-stimulating hormone in control solution) • 100, the degree of inhibition (in%) of secretion of luteinizing hormone by each compound or follicle-stimulating hormone is determined. Compound 15 inhibits the secretion of luteinizing hormone by 28 + 9.0% (p <0.01, n = 3) and inhibits the secretion of follicle-stimulating hormone by 20 + 10% (p <0.01, n = 3).

 Based on the results, it was shown that compound 15 synthesized in Working Example 9 has antagonistic activity for GnRH.

Test Example 6
Inhibition of Testosterone Concentration in Rat Plasma Compound 15 obtained in Working Example 9 was dissolved in vehicle I (20% propylene glycol — 80% physiological saline). The solution was administered subcutaneously once to male SD rats (age 8 weeks, n = 5). The dose is 30 mg per kilogram of body weight. As controls use animals that were introduced only the media. 24 hours after administration under ether anesthesia, blood samples were taken from the cervical vein. Ethylenediaminetetraacetic acid is immediately added to the blood to a final concentration of 3 mg / ml and aprotinin to a final concentration of 300 thousand IU per milliliter. The mixture is centrifuged for 15 minutes with an acceleration of 3000g and the concentration of testosterone in the plasma is determined by radioimmunoassay.

 The amount of testosterone suppression (in percent) in the test compounds is determined by the formula: 100 - (concentration of testosterone in the plasma of the test group) / (concentration of testosterone in the plasma of the control group) • 100.

 Compound 15 synthesized in Working Example 9 shows an inhibition value of 38 + 9.7% (p <0.05).

Test Example 7
Inhibition of plasma testosterone concentration in mice
The compound obtained in Working Example 56 is dissolved in vehicle II (0.5% cellulose dissolved in distilled water). The solution was administered orally once a day for three consecutive days to male ICR mice (age 12 weeks, n = 12). The dose is 30 mg per kilogram of body weight. As control, ICR mice (n = 15) were used, to which only the vehicle was administered. 24 hours after administration under ether anesthesia, blood samples were taken from the cervical vein. Ethylenediaminetetraacetic acid is immediately added to the blood to a final concentration of 3 mg / ml and aprotinin to a final concentration of 300 thousand IU per milliliter. The mixture is centrifuged for 15 minutes with an acceleration of 3000g and the concentration of testosterone in the plasma is determined by radioimmunoassay.

 The amount of testosterone suppression (in percent) in the test compounds is determined by the formula: 100 - (concentration of testosterone in the plasma of the test group) / (concentration of testosterone in the plasma of the control group) • 100.

 The compound synthesized in Working Example 56 shows an inhibition value of 85 + 9.7% (p <0.05).

 The gonadotropin releasing hormone antagonist of the present invention is effective as a prophylactic or therapeutic agent for preventing or treating several hormone dependent diseases, for example, sex hormone cancer (in particular prostate cancer, pituitary adenoma, cervical cancer, breast cancer), benign hypertrophy of the prostate gland, uterine fibroids, endometriosis, premature puberty, amenorrhea, premenstrual syndrome, sclerocyst ovarian disease of ovaries and acne vulgaris, or as a means of controlling fertility (in particular, a contraceptive), a means of treating infertility and a means of controlling the menstrual cycle. Further, in animal husbandry, the gonadotropin releasing hormone antagonist of the present invention is effective as a means of modulating estrous cycles in animals, improving the quality of meat used in food or accelerating the growth of animals, and also in fisheries as a means of accelerating spawning in fish.

Industrial use
A composition having gonadotropin-releasing hormone antagonistic activity of the present invention is effective as a prophylactic or therapeutic agent for preventing or treating several hormone-dependent diseases, for example, sex hormone-related cancer (in particular, prostate cancer, cervical cancer, breast cancer, pituitary adenomas), benign prostatic hypertrophy, uterine fibroids, endometriosis, premature puberty, amenor ei, premenstrual syndrome, sclerocystic disease of the ovaries and acne vulgaris; it is effective as a means of controlling pregnancy and a means of controlling the menstrual cycle); can be used as a contraceptive for males and females and as a means of inducing ovulation in females; can be used in the treatment of infertility due to the effect of the reverse effect caused by the cessation of administration of the compounds of the present invention; useful in animal husbandry as a means of modulating estrous cycles in animals and a means of improving the quality of meat used in food or accelerating the growth of animals; it is useful as a means of accelerating spawning in fish.

Claims (18)

1. Bicyclic derivatives of thiophene of the General formula

where R ¹ and R ² each independently represents (i) hydrogen, (ii) a group bonded via a carbon atom selected from optionally substituted alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, formyl, phenylacetyl, benzoyl, carboxyl, alkoxycarbonyl, cyano, amido, mono- or dialkylcarbamoyl, amidino, optionally substituted phenyl, benzyl, or (iii) halogen;
R ³ represents (i) optionally substituted phenyl, naphthyl, phenyl-vinyl or pyridyl;
R ⁴ represents (i) hydrogen, (ii) formyl, (iii) cyano, (iv) lower alkyl substituted with (1) an alkylthio or alkylsulfinyl group or (2) an optionally substituted hydroxyl group, (v) a carbonyl group which can be substituted with an optionally substituted hydrocarbon residue, or (vi) an esterified or amidated carboxyl group;
R ⁵ represents (i) hydrogen or alkyl;
n is 0, 1, 2 or 3;
with the proviso that R ³ representing optionally substituted phenyl, naphthyl, phenyl-vinyl or pyridyl is not substituted with a group of the formula

in which R ⁶ represents an optionally substituted 5 to 7-membered heterocyclic group having, as a group capable of forming a ring, carbonyl, thiocarbonyl, optionally oxidized sulfur atom or a group capable of converting into them, a group capable of forming an anion, or a group, capable of turning into an anion;
Z represents an optionally substituted aromatic hydrocarbon residue, optionally containing a heteroatom, optionally substituted 5-membered cyclic groups containing in addition to a carbon atom from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted 6-membered cyclic groups containing in addition to an atom carbon from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or optionally substituted 5 to 8-membered cyclic groups or fused rings containing in addition to the carbon atom from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen;
V represents a chemical bond or a linking group;
or its salt. 2. The compound according to claim 1, where R ³ means a group of the formula

where R ⁷ represents a hydrogen atom, a halogen atom or a group attached via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom;
R ⁸ is a hydrogen atom, a halogen atom, a nitro group, a cyano group or a hydrocarbon residue, which may be substituted by a group attached via an oxygen atom, a nitrogen atom or a sulfur atom. 3. The compound according to claim 1, where either R ¹ or R ² denotes a group of the formula
R ⁹ - (CH ₂ ) _m -,
where R ⁹ denotes a group attached via a nitrogen atom; m denotes a number from 0 to 3,
and another radical denotes a group of the formula
R ¹⁰ -A-,
where R ¹⁰ is optionally substituted phenyl;
A denotes a chemical bond or a bridging group.  4. The compound according to claim 1, which is ethyl 3- (N-benzyl-N-methylaminomethyl) -4,7-dihydro-7- (2-methoxybenzyl) -2- (4-methoxyphenyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid or a salt thereof.  5. The compound according to claim 1, which is ethyl 3- (N-benzyl-N-methylaminomethyl) -4,7-dihydro-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -4-oxo-thieno [2,3-b] pyridine-5-carboxylic acid or a salt thereof.  6. The compound according to claim 1, which is an ethyl ester of 2- (4-acetylaminophenyl) -3- (N-benzyl-N-methylaminomethyl) -4,7-dihydro-7- (2-fluorobenzyl) -4-oxothieno [2,3-b] pyridine-5-carboxylic acid or a salt thereof.  7. The compound according to claim 1, which is 5-benzoyl-3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-4-oxo-2- ( 4-propionylaminophenyl) -4-oxo-thieno [2,3-b] pyridine or a salt thereof.  8. The compound according to claim 1, which is 5-benzoyl-3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-2- (4-N ' -methylureidophenyl) -4-oxo-thieno [2,3-b] pyridine or a salt thereof.  9. The compound according to claim 1, which is 3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-5-isobutyryl-4-oxo-2- ( 4-propionylaminophenyl) thieno [2,3-b] pyridine or a salt thereof.  10. The compound according to claim 1, which is 3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-5-isobutyryl-2- (4-N ' -methylureidophenyl) -4-oxo-thieno [2,3-b] pyridine or a salt thereof.  11. The compound according to claim 1, which is 3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-2- (4-N'-methylureidophenyl) - 4-oxothieno- [2,3-b] pyridin-5- (N-isopropyl) carboxamide or a salt thereof.  12. The compound according to claim 1, which is 3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-2- (4-N'-methylureidophenyl) - 4-oxothieno- [2,3-b] pyridin-5- (N-isopropyl-N-methyl) carboxamide or a salt thereof.  13. The compound according to claim 1, which is 3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-2- (4-N'-methylureidophenyl) - 4-oxothieno- [2,3-b] pyridin-5- (N-benzyl-N-methyl) carboxamide or a salt thereof.  14. The compound according to claim 1, which is 7- (2,6-difluorobenzyl) -4,7-dihydro-5-isobutyryl-2- (4-isobutyrylaminophenyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxothieno- [2,3-b] pyridine or a salt thereof.  15. The compound according to claim 1, which is 5-acetyl-4,7-dihydro-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -3-methyl-4-oxo-thieno [2,3-b ] pyridine or its salt. 16. A method of obtaining a compound according to claim 3, which includes the interaction of the compounds of formula

where R ⁴ , R ⁵ and n have the meanings indicated in claim 1;
R ⁷ and R ⁸ have the meanings indicated in claim 2;
R ¹⁰ and m have the meanings indicated in claim 3;
X represents a leaving group,
or its salt with a compound of the formula
R ⁹ H
where R ⁹ has the meaning indicated in claim 3,
or its salt.  17. A composition exhibiting antagonistic activity against gonadotropin-releasing hormone, characterized in that it comprises a compound of general formula I according to any one of claims 1 to 15 and a carrier, excipient or diluent.  18. The compound of general formula I according to any one of claims 1 to 15, exhibiting antagonistic activity against gonadotropin-releasing hormone. Priority on points:
04/19/94 according to claims 2 to 4;
08/19/94 according to claims 5 and 6;
11/04/94 according to claim 15;
02/28/95 according to claims 7 to 13;
04/14/95 (PCT) according to claims 1 and 14.

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