RU2158739C2 - Thienopyrimidine compounds, method of preparation thereof, and pharmaceutical composition - Google Patents

Abstract

FIELD: pharmaceutical chemistry. SUBSTANCE: invention provides thienopyrimidine compounds with general formula I:

(I), in which Q is phenyl that can be substituted by one or several substituents from the group including halogen, alkoxy, and alkylthio groups; R² is C1-C16-alkyl optionally substituted by one or two alkoxy groups; phenyl radical optionally specified by one or two substituents selected from radicals alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halogen, hydroxy, and alkoxyalkoxy; benzyl; or C5-C6- cycloalkyl; R³ is amino group substituted by one or two substituents selected from benzyl optionally substituted by C1-C6-alkylthio group, and C1-C6-alkyl optionally substituted by pyridyl group; and R⁴ is phenyl radical substituted by C1-C6-alkoxy optionally substituted by C1- C6-acyl, C1-C6-alkenyl, or C3-C6-cycloalkyl; nitro group; alkylaminocarbonyl; N-C1-C6-alkyl-N-C1-C6-alkylaminocarbonyl; amino group; C1-C6-alkylamino group; C1-C6-acylamino group optionally substituted by 1-3 C1-C6-alkoxy or halogens; N-C1-C6-alkyl- N-C1-C6-acylamino group; benzoylamino group; C1-C6- alkylsulfonylamino group; formamido group; or C1-C6-alkenyl optionally substituted by C1-C6-alkoxycarbonyl or C1-C6-acyl; and salts of indicated compounds. Compounds of invention are effective as preventive or therapeutic agents in cases of some hormone-dependent diseases, for instance sexual hormone-dependent cancer. Compounds are also effective as agents controlling fecundation capacity in both sex species and as agents promoting fish spawning. EFFECT: expanded therapeutic possibilities. 11 cl, 8 tbl, 24 ex

Description

 The present invention relates to new derivatives of thienopyrimidine and their salts. In addition, the present invention relates to methods for producing thienopyrimidine derivatives and their salts, as well as to pharmaceutical compositions containing thienopyrimidine derivatives.

 Description of the prior art.

 The secretion of the anterior pituitary hormone is controlled by the peripheral hormones secreted by the target organs in relation to the corresponding hormones, as well as the secretory-accelerating or inhibitory hormone from the hypothalamus, which is the upper central organ of the anterior pituitary gland / in the description, such hormones are referred to by the general term “hypothalamic hormone” /. Currently, nine types of hormones are classified as hypothalamic hormones, including, for example, thyrotropin secreting hormone / TRH / or gonadotropin secreting hormone {GnRH: sometimes called IH-RH / hormone secreting luteinizing hormone /} / cm. Seirigaku 2, compiled by M. Iriku and K. Toyama, published by Bunkohdo, pp. 610-618, 1986 /. It is assumed that such hypothalamic hormones exert their effect through the receptor, which is supposed to exist in the anterior pituitary gland / cm. the link above / and research is currently being conducted on specific receptor genes for such hormones, including human genes / Receptor Kiso To Rinsho, compiled by H. Imura et al., published by Asakura Shoten, pp. 297-304, 1993 /. Accordingly, antagonists or agonists that specifically and selectively act on such receptors control the action of hypothalamic hormones and the secretion of the anterior pituitary hormone. As a result, such substances are expected to be valuable prophylactic and therapeutic agents for the treatment of diseases dependent on anterior pituitary hormone.

 Leiprorelin Acetate / Fujuno et al. Biological and Biophysical Res. Coimmun, T. 60, 00.406-413, 1974; Oliver R.T.D. with sotr. British Journal of Cancers, vol. 59, p. 823, 1989; and Toguchi et al. Journal of International Medical Research, t. 18, pp. 35-41 /, which is a very powerful derivative of the hormone secreting a gonadotropin hormone, one of the hypothalamic hormones / hereinafter sometimes abbreviated as GnRH / / Schally A.Y. with sotr. Journal of Biological Chem., T. 246, pp. 7230-7236, 1971; and Burgus R. et al. Proceeding of Natural Academic Science, USA, t. 69, pp. 278-282 / when used in multiple doses, lowers the secretion of gonadotropin in the pituitary gland, causing a decrease in the reactivity of gonadotropin in sperm and ovarian tissue, which inhibits the secretion of testosterone and estrogen. Therefore, it is known that leuprorelin acetate has antitumor activity against hormone-dependent cancers such as prostate cancer, and it is widely used in clinical practice. Leiprorelin acetate is widely used in clinical practice also as a therapeutic agent in the treatment of endometriosis and premature puberty. It is assumed that the high antitumor activity of leuprorelin acetate is associated with its high resistance to protease compared to natural GnRH and its high affinity for the GnRH receptor, which causes desensitization of GnRH due to a decrease in the number of receptors. However, since leuprorelin acetate is an ultra-agonist of GnRH receptors, it is known that immediately after the first application there is a temporary deterioration, accompanied by an increase in the concentration of serum testosterone associated with the pituitary-gonadotropic effect / acute effect /. In this regard, it is desirable to develop GnRH antagonistic drugs that would have almost the same therapeutic effect as described above, but would not cause the pituitary-gonadotropic effect mentioned above (acute effect). As compounds having such GnRH antagonistic activity, a number of compounds have been described, including, for example, derivatives of GnRH, such as normal peptides / US patent N 5140009 and N 5171835 /, derivatives of cyclic hexapeptide / Japanese Patent Application Laid-Open No. 61/1986 / - 191698 / or derivatives of a bicyclic peptide / Journal of medicinal Chem., Vol. 36, p. 3265-3273, 1993 /. However, all such compounds are peptides that exhibit a number of problems, including, for example, dosage forms, drug stability, duration of action and metabolic stability. To solve these problems, the creation of orally applicable GnRH antagonistic drugs, in particular of a non-peptide nature, is particularly desirable. However, to date, there are no reports of non-peptide GnRH antagonistic drugs.

 The purpose of the present invention is to provide new compounds with excellent gonadotropic hormone secreting hormone antagonistic activity, as well as excellent gonadotropic hormone secreting hormonal antagonistic agents.

 Description of the invention.

в которой R¹ представляет собой водород, алкильную группу или группу формулы:
Q-/CH₂/_p-
где Q представляет собой /1/ арильную группу, которая может быть замещена одной или более группами, выбранными из /I/ галогена, /II/ нитро, /III/ циано, /IV/ амино, /V/ необязательно замещенного карбоксила, /VI/ алкилендиокси и /VII/ группы формулы: -A-R⁵, в которой A представляет собой химическую связь или пространственную группу, a R⁵ представляет собой алкильную группу, /2/ необязательно замещенную циклоалкильную группу или /3/ необязательно замещенную гетероциклическую группу, а p представляет собой целое число в интервале 0-3;
R² представляет собой водород, алкильную группу, которая может быть замещена алкокси группой, необязательно замещенную арильную группу, необязательно замещенную аралкильную группу или необязательно замещенную циклоалкильную группу;
R³ представляет собой необязательно замещенную амино группу; r представляет собой целое число, имеющее значение в интервале 0-3; и R⁴ представляет собой необязательно замещенную арильную группу; или его соль;
/2/. Соединение по пункту /1/, в котором пространственная группа, представленная символом A, представляет собой -O- или -S/O/_m - где m - целое число в интервале 0-2;
/3/. Соединение по пункту /1/, в котором R¹ представляет собой группу формулы:
-O-/CH₂/_p-,
где Q представляет собой арильную группу, которая может быть замещена одним или более заместителями, выбранными из /1/ галогена и группы формулы: -A-R⁵, в которой A представляет собой -O- или -S/O/_m, где m представляет собой целое число в интервале 0-2, а R⁵ представляет собой алкильную группу; а p представляет собой целое число, имеющее значение в интервале 0-3;
/4/. Соединение по пункту /1/, в котором R² представляет собой /1/ алкильную группу, которая может быть замещена алкокси, /2/ арильную группу, которая может быть замещена одним или более заместителями, выбранными из /I/ амино, /II/ ацила, /III/ карбамоила, /IV/ карбокси, /V/ нитро, /VI/ гидрокси, /VII/ алкокси группы, которая может быть замещена алкокси, /VIII/ галогена и /IX/ группы формулы: -S/O/_n-R⁶, в которой n представляет собой целое число в интервале 0-2, a R⁶ - алкильную группу, /3/ аралкильную группу, которая может быть замещена галогеном, или /4/ циклоалкильную группу;
/5/. Соединение согласно пункту /4/, в котором R² представляет собой /1/ алкильную группу, которая может быть замещена алкокси, /2/ арильную группу, которая может быть замещена одним или более заместителями, выбранными из /I/ гидрокси, /II/ алкокси группы, которая может быть замещена алкокси, /III/ галогена и /IV/ группы формулы: S/O/_n-R⁶, в которой n представляет собой целое число в интервале 0-2, a R⁶ представляет собой алкильную группу, /3/ аралкильную группу или /4/ циклоалкильную группу;
/6/. Соединение согласно пункту /4/, в котором R² представляет собой арильную группу, которая может быть замещена одним или более заместителями, выбранными из /1/ алкокси группы, которая может быть замещена алкокси, /2/ галогена и /3/ группы формулы: -S/O/_n-R⁶, в которой n представляет собой целое число, имеющее значение в интервале 0-2, а R⁶ представляет собой алкильную группу;
/7/. Соединение по пункту /1/, в котором R³ представляет собой необязательно замещенную амино группу формулы:

где R^22' представляет собой /1/ арильную группу, которая может быть замещена одним или более заместителями, выбранными из /I/ амино, /II/ ацила, /III/ карбамоила, /IV/ карбокси, /V/ нитро, /VI/ гидрокси, /VII/ алкокси группы, которая может быть замещена алкокси, /VIII/ галогена, /IX/ алкила и /X/ группы формулы: -S/O/_n-R⁶, в которой n представляет собой целое число в интервале 0-2, a R⁶ представляет собой алкильную группу, /2/ гетероциклическую группу, которая может быть замещена одним или более заместителями, выбранными из /I/ амино, /II/ ацила, /III/ карбамоила, /IV/ карбокси, /V/ нитро, /VI/ гидрокси, /VII/ алкокси группы, /VIII/ галогена, /IX/ алкила и /X/ группы формулы: -S/O/_n-R⁶, в которой n представляет собой целое число, имеющее значение в интервале 0-2, a R⁶ представляет собой алкильную группу, /3/ аралкильную группу, которая может быть замещена галогеном, /4/ группу формулы:

в которой R²⁴ представляет собой водород, алкильную группу или арильную группу, R²⁵ представляет собой водород или алкильную группу, а R²⁴ и R²⁵ могут образовывать 5-7-членную циклическую аминогруппу, содержащую соседний атом азота, который может быть необязательно замещенным, а x представляет собой целое число, имеющее значение в интервале 0-3, или /5/ алкильную группу, которая может быть замещена алкилтио группой, w представляет собой целое число, имеющее значение в интервале 0-3; а R^23' представляет собой водород или алкильную группу;
/8/. Соединение по пункту /1/, в котором R³ представляет собой необязательно замещенную амино группу формулы:

в которой R^22'' представляет собой /1/ арильную группу, которая может быть замещена алкилтио, /2/ гетероциклическую группу, /3/ группу формулы:

в которой R^24' представляет собой водород или алкил, R^25' представляет собой водород или алкил, a R^24' и R^25' могут образовывать 5-7-членную циклическую аминогруппу, содержащую примыкающий атом азота, или /4/ алкильную группу, которая может быть замещенной алкилтио группой, w представляет собой целое число в интервале 0-3; а R^23''' представляет собой водород или алкильную группу;
/9/. Соединение по пункту /1/, в котором R⁴ представляет собой арильную группу, которая может быть замещена одним или более заместителями, выбранными из /1/ необязательно замещенной амино группы, /2/ ацила, /3/ необязательно замещенной карбамоильной группы, /4/ карбокси, /5/ нитро, /6/ гидрокси, /7/ необязательно замещенной алкокси группы и /8/ необязательно замещенной алкенильной группы;
10/. Соединение по пункту /1/, в котором R⁴ представляет собой арильную группу, которая может быть замещена одним или более заместителями, выбранными из /1/ группы формулы:

где R¹¹ представляет собой /I/ водород, /II/ алкил, /III/ необязательно замещенную алкокси группу, /IV/ необязательно замещенную ацильную группу или /V/ группу формулы: - S/O/_n-R⁶, в которой n представляет собой целое число, имеющее значение в интервале 0-2, a R⁶ представляет собой алкильную группу, а R^12' представляет собой водород или алкил, /2/ ацила, /3/ карбамоила, /4/ N-моно или диалкилкарбамоила, /5/ нитро, /6/ алкокси, которая может быть дополнительно замещена одним или более заместителями, выбранными из алкокси, алканоила, оксо, гидрокси, циклоалкила и галогена, /7/ алкенила, который может быть дополнительно замещен алкоксикарбонилом или алкилкарбонилом и /8/ алкенилокси;
/11/. Соединение согласно пункту /1/, в котором R⁴ представляет собой арильную группу, которая может быть замещена одним или более заместителями, выбранными из /1/ группы формулы:

в которой R^11'' представляет собой /I/ водород, /II/ алкил, /III/ алкокси, которая может быть замещена галогеном или алкокси, /IV/ формил, /V/ алканоил, который может быть замещен галогеном или алкокси, /VI/ бензоил или /VII/ группу формулы: -S/O/_n-R⁶, в которой n представляет собой целое число, имеющее значение в интервале 0-2, a R⁶ представляет собой алкильную группу, a R^12'' представляет собой водород или алкил, /2/ алкокси, которая может быть замещена алкокси, алканоилом или циклоалкилом, /3/ N-моно или диалкилкарбамоила, /4/ нитро, /5/ алкенила, который может быть замещен алкоксикарбонилом или алкилкарбонилом или /6/ алкенилокси;
12/. Соединение по пункту /1/, которое представляет собой 2,4/1H,3H/-диоксо-6-/4-метоксифенил/-3-фенил-1-/2-хлор-6-фторбензил/- 5-/N-бензил-N-метиламинометил[тиено.2,3-d]пиримидин или его соль;
13/. Соединение по пункту /1/, представляющее собой 2,4/1H,3H/-диоксо-1-/2,6-дифторбензил/-6-/4-пропиониламинофенил/-5-/ N-бензил-N-метиламинометил/-3-/3-метоксифенил/тиено[2,3-d]пиримидин или его соль;
14/. Соединение согласно пункту /1/, представляющее собой 2,4/1H,3H/-диоксо-1-/2,6-дифторбензил/-6-/4-изобутириламинофенил/-5-/ N-бензил-N-метиламинометил/-3-/3-метоксифенил/тиено[2.3-d]пиримидин или его соль;
15/. Способ получения соединения формулы /I/:

в которой R¹, R², R³, R⁴ и r имеют указанные выше значения, или его соли, заключающийся в реакции соединения формулы:

в которой R¹, R², R⁴ и r имеют указанные выше значения, X представляет собой уходящую группу, или его соли с соединением формулы:
R³-H,
в которой R³ имеет указанные выше значения, или его солью;
16/. Фармацевтическая композиция, содержащая соединение по пункту /1/, а также носитель, эксипиент или разбавитель такого соединения;
17/. Композиция по пункту /16/, представляющая собой антагонистическую композицию гормона, выделяющего гонадотропин;
18/. Композиция согласно пункту /16/, представляющая собой препарат для профилактики или лечения заболеваний, зависимых от полового гормона;
19/. Способ противодействия гонадотропин-секретирующему гормону у млекопитающих, заключающийся в применении эффективного количества соединения по пункту /1/ на млекопитающем, страдающем нарушениями, вызванными действием гонадотропин-секретирующего гормона;
/20/. Способ по пункту /19/, в котором нарушение, вызванное действием гонадотропин-секретирующего гормона, представляет собой гормонально-зависимое заболевание;
21/. Соединение по пункту /1/, предназначенное для медицинского применения;
22/. Применение соединения по пункту /1/ для получения гонадотропин-секретирующей гормональной антагонистической композиции, предназначенной для противодействия гонадотропин-секретирующему гормону у млекопитающих, страдающих нарушениями, вызванными действием гонадотропин-выделяющего гормона;
23/. Применение согласно пункту /22/, в котором нарушение, вызванное действием гонадотропин-секретирующего гормона, представляет собой заболевание, зависимое от полового гормона.The present invention provides / 1 /: a new thienopyrimidine derivative of the general formula / I /:

in which R ¹ represents hydrogen, an alkyl group or a group of the formula:
Q- / CH ₂ / _p -
where Q represents a / 1 / aryl group which may be substituted by one or more groups selected from / I / halogen, / II / nitro, / III / cyano, / IV / amino, / V / optionally substituted carboxyl, / VI / alkylenedioxy and / VII / groups of the formula: -AR ⁵ in which A represents a chemical bond or a space group, R ⁵ represents an alkyl group, / 2 / an optionally substituted cycloalkyl group or / 3 / an optionally substituted heterocyclic group, and p represents an integer in the range of 0-3;
R ² represents hydrogen, an alkyl group which may be substituted by an alkoxy group, an optionally substituted aryl group, an optionally substituted aralkyl group or an optionally substituted cycloalkyl group;
R ³ represents an optionally substituted amino group; r is an integer having a value in the range 0-3; and R ⁴ represents an optionally substituted aryl group; or its salt;
/ 2 /. The compound of claim 1, wherein the space group represented by A is —O— or —S / O / _m - where m is an integer in the range 0-2;
/ 3 /. The compound according to paragraph / 1 /, in which R ¹ represents a group of the formula:
-O- / CH ₂ / _p -,
where Q represents an aryl group which may be substituted by one or more substituents selected from / 1 / halogen and a group of the formula: —AR ⁵ in which A represents —O— or —S / O / _m , where m represents an integer in the range 0-2, and R ⁵ represents an alkyl group; and p is an integer having a value in the range 0-3;
/4/. The compound according to paragraph / 1 /, in which R ² represents / 1 / an alkyl group which may be substituted by an alkoxy, / 2 / aryl group which may be substituted by one or more substituents selected from / I / amino, / II / acyl, / III / carbamoyl, / IV / carboxy, / V / nitro, / VI / hydroxy, / VII / alkoxy groups, which may be substituted by alkoxy, / VIII / halogen and / IX / groups of the formula: -S / O / _n -R ⁶ in which n is an integer in the range 0-2, and R ⁶ is an alkyl group, / 3 / an aralkyl group which may be substituted with halogen, or / 4 / cycloalkyl group;
/5/. The compound according to paragraph / 4 /, in which R ² represents / 1 / an alkyl group which may be substituted by an alkoxy, / 2 / aryl group which may be substituted by one or more substituents selected from / I / hydroxy, / II / an alkoxy group which may be substituted with an alkoxy / III / halogen and / IV / group of the formula: S / O / _n -R ⁶ in which n is an integer in the range 0-2, and R ⁶ is an alkyl group, / 3 / an aralkyl group or / 4 / a cycloalkyl group;
/ 6 /. The compound according to paragraph / 4 /, in which R ² represents an aryl group, which may be substituted by one or more substituents selected from / 1 / alkoxy group, which may be substituted by alkoxy, / 2 / halogen and / 3 / groups of the formula: -S / O / _n -R ⁶ in which n is an integer having a value in the range 0-2 and R ⁶ is an alkyl group;
/ 7 /. The compound according to paragraph / 1 /, in which R ³ represents an optionally substituted amino group of the formula:

where R ^{22 '} represents a / 1 / aryl group which may be substituted by one or more substituents selected from / I / amino, / II / acyl, / III / carbamoyl, / IV / carboxy, / V / nitro, / VI / hydroxy, / VII / alkoxy group, which may be substituted by alkoxy, / VIII / halogen, / IX / alkyl and / X / groups of the formula: -S / O / _n -R ⁶ in which n is an integer in the range 0-2, a R ⁶ represents an alkyl group, / 2 / a heterocyclic group, which may be substituted by one or more substituents selected from / I / amino, / II / acyl, / III / carbamoyl, / IV / carboxy, / V / neither ro, / VI / hydroxy, / VII / alkoxy group, / VIII / halogen, / IX / alkyl and / X / group of formula: -S / O / _n -R ⁶ in which n is an integer having a value in the range 0-2, a R ⁶ represents an alkyl group, / 3 / an aralkyl group which may be substituted by halogen, / 4 / a group of the formula:

in which R ²⁴ represents hydrogen, an alkyl group or an aryl group, R ²⁵ represents hydrogen or an alkyl group, and R ²⁴ and R ²⁵ can form a 5-7 membered cyclic amino group containing an adjacent nitrogen atom, which may be optionally substituted, and x is an integer having a value in the range 0-3, or / 5 / an alkyl group which may be substituted with an alkylthio group, w is an integer having a value in the range 0-3; and R ^{23 ′} represents hydrogen or an alkyl group;
/eight/. The compound according to paragraph / 1 /, in which R ³ represents an optionally substituted amino group of the formula:

in which R ^{22 ″} represents a / 1 / aryl group which may be substituted by an alkylthio, / 2 / heterocyclic group, / 3 / a group of the formula:

in which R ^{24 '} represents hydrogen or alkyl, R ^25' represents hydrogen or alkyl, and R ^{24 '} and R ^25' can form a 5-7 membered cyclic amino group containing an adjacent nitrogen atom, or / 4 / alkyl group, which may be substituted by an alkylthio group, w is an integer in the range of 0-3; and R ^{23 ″ ″} represents hydrogen or an alkyl group;
/nine/. The compound according to paragraph / 1 /, in which R ⁴ represents an aryl group, which may be substituted by one or more substituents selected from / 1 / optionally substituted amino group, / 2 / acyl, / 3 / optionally substituted carbamoyl group, / 4 / carboxy, / 5 / nitro, / 6 / hydroxy, / 7 / optionally substituted alkoxy group and / 8 / optionally substituted alkenyl group;
ten/. The compound according to paragraph / 1 /, in which R ⁴ represents an aryl group which may be substituted by one or more substituents selected from / 1 / a group of the formula:

where R ¹¹ represents / I / hydrogen, / II / alkyl, / III / optionally substituted alkoxy group, / IV / optionally substituted acyl group or / V / group of the formula: - S / O / _n -R ⁶ in which n represents an integer having a value in the range 0-2, a R ⁶ represents an alkyl group, and R ^{12 '} represents hydrogen or alkyl, / 2 / acyl, / 3 / carbamoyl, / 4 / N-mono or dialkylcarbamoyl, (5) nitro, / 6 / alkoxy, which may be further substituted by one or more substituents selected from alkoxy, alkanoyl, oxo, hydroxy, cycloalkyl and halogen a, / 7 / alkenyl which may be further substituted by alkoxycarbonyl or alkylcarbonyl and / 8 / alkenyloxy;
/eleven/. The compound according to paragraph / 1 /, in which R ⁴ represents an aryl group, which may be substituted by one or more substituents selected from / 1 / a group of the formula:

in which R ^{11 ″} represents / I / hydrogen, / II / alkyl, / III / alkoxy, which may be substituted by halogen or alkoxy, / IV / formyl, / V / alkanoyl, which may be substituted by halogen or alkoxy, / VI / benzoyl or / VII / a group of the formula: -S / O / _n -R ⁶ in which n is an integer having a value in the range 0-2, a R ⁶ is an alkyl group, and R ^{12 ″} is hydrogen or alkyl, / 2 / alkoxy, which may be substituted by alkoxy, alkanoyl or cycloalkyl, / 3 / N-mono or dialkylcarbamoyl, / 4 / nitro, / 5 / alkenyl, which may be substituted n alkoxycarbonyl or alkylcarbonyl or / 6 / alkenyloxy;
12/. The compound according to paragraph / 1 /, which is 2,4 / 1H, 3H / -dioxo-6- / 4-methoxyphenyl / -3-phenyl-1- / 2-chloro-6-fluorobenzyl / - 5- / N- benzyl-N-methylaminomethyl [thieno 2,3-d] pyrimidine or a salt thereof;
13/. The compound according to paragraph / 1 /, which is 2,4 / 1H, 3H / -dioxo-1- / 2,6-difluorobenzyl / -6- / 4-propionylaminophenyl / -5- / N-benzyl-N-methylaminomethyl / - 3- / 3-methoxyphenyl / thieno [2,3-d] pyrimidine or a salt thereof;
fourteen/. The compound according to paragraph / 1 /, which is 2,4 / 1H, 3H / -dioxo-1- / 2,6-difluorobenzyl / -6- / 4-isobutyrylaminophenyl / -5- / N-benzyl-N-methylaminomethyl / - 3- / 3-methoxyphenyl / thieno [2.3-d] pyrimidine or a salt thereof;
fifteen/. The method of obtaining the compounds of formula / I /:

in which R ¹ , R ² , R ³ , R ⁴ and r have the above meanings, or its salts, consisting in the reaction of a compound of the formula:

in which R ¹ , R ² , R ⁴ and r have the above meanings, X represents a leaving group, or its salts with a compound of the formula:
R ³ -H,
in which R ³ has the above meanings, or its salt;
16/. A pharmaceutical composition comprising the compound of [1] as well as a carrier, excipient or diluent of such a compound;
17 /. The composition according to paragraph / 16 /, which is an antagonistic composition of the hormone secreting gonadotropin;
18/. The composition according to paragraph / 16 /, which is a drug for the prevention or treatment of diseases dependent on sex hormone;
19/. A method of counteracting a gonadotropin-secreting hormone in mammals, comprising applying an effective amount of the compound of [1] to a mammal suffering from disorders caused by the action of a gonadotropin-secreting hormone;
/20/. The method according to paragraph / 19 /, wherein the disorder caused by the action of a gonadotropin-secreting hormone is a hormone-dependent disease;
21 /. The compound according to paragraph / 1 / for medical use;
22 /. The use of the compound according to paragraph / 1 / to obtain a gonadotropin-secreting hormone antagonistic composition intended to counteract the gonadotropin-secreting hormone in mammals suffering from disorders caused by the action of gonadotropin-secreting hormone;
23 /. The use according to paragraph / 22 /, in which the violation caused by the action of gonadotropin-secreting hormone is a disease dependent on sex hormone.

Примерами алкильной группы, обозначенной индексами R¹, R² и алкила, который может быть замещен алкокси группой, представленного индексом R², могут служить, например, C_1-6 алкил /например, метил, этил, пропил, изопропил, бутил, втор. -бутил, трет.-бутил, пентил, гексил/. Среди них предпочтительной является алкильная группа, содержащая 1-3 углеродных атома.The core of the compound of the present invention, 2,4 / 1H, 3H / - dioxythieno [2,3-d] pyrimidine, is presented below:

Examples of an alkyl group indicated by the indices R ¹ , R ² and an alkyl which may be substituted by an alkoxy group represented by the index R ² are, for example, C _1-6 alkyl / for example methyl, ethyl, propyl, isopropyl, butyl, sec . -butyl, tert.-butyl, pentyl, hexyl. Among them, an alkyl group containing 1 to 3 carbon atoms is preferred.

As an example of an aryl group denoted by Q, or an optionally substituted aryl group denoted by R ² and R ⁴ , for example, monocyclic or fused polycyclic aromatic hydrocarbon residues can be given. Preferred examples thereof include C _6-14 aryl groups such as phenyl, naphthyl, antryl, phenanthryl, acenaphthylenyl and the like. Among them, phenyl, 1-naphthyl and 2-naphthyl are the most preferred groups.

в которой R¹¹ обозначает водород; алкил, например, C_1-6 алкил, который может быть замещен гидрокси группой; ацил /например, C_1-6 алкил-карбонил, формил; арилкарбонил/, который может быть замещен одним или более атомами галогена или алкокси группами; необязательно замещенную алкокси группу, упомянутую ниже; C_3-7циклоалкил, который может быть замещен одной или более гидрокси группами; группу формулы: -S/O/_n-R⁶, в которой n представляет собой целое число, имеющее значение в интервале 0-2, a R⁶ представляет собой алкильную группу, a R¹² обозначает водород или C_1-6 алкил, /9/ группа формулы:

в которой R²⁴ представляет собой водород, алкильную группу или арильную группу, R²⁵ представляет собой водород или алкильную группу и R²⁴ с R²⁵ могут образовывать необязательно замещенную 5-7-членную циклическую амино группу, содержащую соседний атом азота, а x представляет собой целое число в интервале 0-3, /10/ амидино, /II/ ацил /например, такой C_1-8 алканоил, как формил, ацетил, пропионил, бутирил, октаноил; такой C_1-8 алкокси-карбонил, как метоксикарбонил, этоксикарбонил, пропоксикарбонил, бутоксикарбонил; такой C_6-14 арил-карбонил, как бензоил; такой C_8-11 аралкил-карбонил, как бензилкарбонил; такой C_7-12 аралкилокси-карбонил, как бензилоксикарбонил/, который может быть необязательно замещен одним или более заместителями /например, галогеном, алкилтио, алкокси, оксо, гидрокси/, /12/ необязательно замещенная карбамоильная группа, например, карбамоил, N-монозамещенный карбамоил /например, такой N-/C_1-7 алкил/карбамоил, как метилкарбамоил, этилкарбамоил, пропилкарбамоил, изопропилкарбамоил/, N,N-дизамещенный карбамоил {например, N,N- ди/C_1-8 алкил/карбамоил, такой как диметил-карбамоил, диэтилкарбамоил, N-этил-N-метилкарбамоил, N-пропил-N- метилкарбамоил}, /13/ сульфамоил, /14/ N-монозамещенный сульфамоил { например, N-/C_1-6 алкил/сульфамоил, такой как метилсульфамоил, этилсульфамоил, пропилсульфамоил} , 15/ N,N- дизамещенный сульфамоил {например, N,N-ди/C_1-6 алкил/сульфамоил такой как диметилсульфамоил, диэтилсульфамоил}, /16/ карбокси, /17/ C_1-3 алкокси-карбонил /например, метоксикарбонил, этоксикарбонил, пропоксикарбонил, 18/ гидроксил, 19/ необязательно замещенная алкокси группа, например, C_1-6 алкокси /например, метокси, этокси, пропокси, изопропокси, бутокси, изобутокси, втор. -бутокси, трет.-бутокси, пентилокси, гексилокси/, которая может иметь один или более заместителей /например, C_1-6 алканоил, имеющий указанные выше значения, C_1-3 алкил галоген, C_1-3 алкилтио, C_1-3 алкокси, оксо, гидрокси, C_3-7 циклоалкил, который имеет указанные выше значения/, /20/ C_3-7 циклоалкилокси /например, циклопропилокси, циклопентилокси, циклогексилокси/, /22/ C_7-13 аралкилокси /например, бензилокси, бензгидрилокси/, /23/ C_6-14 арилокси /например, фенилокси, нафтилокси/, /24/ меркапто, /25/ C_7-13 аралкилтио /например, бензилтио, бензгидрилтио/, /26/ C_6-14 арилтио /например, фенилтио, нафтилтио/, /27/ группа формулы: S/O/_n -R⁶, в которой n представляет собой целое число, имеющее значение в интервале 0-2, а R⁶ представляет собой алкильную группу /например, метилтио, этилтио, пропилтио, метилсульфинил, этилсульфинил, пропилсульфинил, метилсульфонил, этилсульфонил, пропилсульфонил/, /28/ C_1-3 алкилендиокси /например, метилендиокси, этилендиокси, пропилендиокси/, /29/ сульфо, /30/ циано, /31/ азид, /32/ нитро, /33/ нитрозо, /34/ галоген /например, фтор, хлор, бром, иод/ и т.д.The number of substituents of the aryl group may be 1 or more, preferably 1-3. Examples of substituents of the aryl group denoted by R ² and R ⁴ are / 1 / C _1-6 alkyl /, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl, moreover, such alkyl groups may be substituted by alkyl carbonyl or alkoxycarbonyl /, / 2 / an optionally substituted alkenyl group such as a C _2-6 alkenyl / eg vinyl, allyl, 1-butenyl, 2-butenyl / which may be substituted by one or more C _{1 -10} acyl groups or C _1-6 alkoxy-carbonyl groups, / 3 / C _2-6 alkynyl / e.g. ethynyl, propargyl, 2-butynyl, 5-hexine il /, / 4 / C _3-7 cycloalkyl / for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl /, / 5 / C _6-14 aryl / for example phenyl, naphthyl /, which may be substituted by one or more substituents selected from (I) halogen, / II / alkyl, / III / alkoxy, which may be further substituted by an alkoxy group, / IV / nitro, / V / cyano, / VI / groups -S / O / _n -R ⁶ , in which n represents an integer having a value in the range 0-2, and R ⁶ represents alkyl or amino, (VII / amino, / VIII / acyl, / IX / carbamoyl, / X / carboxy and / XI / hydroxy, / 6 / heterocyclic group, for example, 5-9 membered an aromatic heterocyclic group containing 1-4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (for example, furyl, thienyl, pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl), or a 5-9 membered non-aromatic heterocyclic group containing 1 -4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom / for example, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl group, and pp can be substituted by one or more substituents selected from (I / halogen, / II / alkyl, / III / amino, / IV / acyl, / V / carbamoyl, / VI / carboxy, / VII / nitro, / VIII / hydroxy , / IX / alkoxy and / X / groups of the formula: -S / O / _n -R ⁶ in which n is an integer having a value in the range 0-2, and R ⁶ is an alkyl group, / 7 / C _7-13 aralkyl / for example benzyl, phenethyl, benzhydryl, which may be substituted by one or more halogen atoms, / 8 / an optionally substituted amino group, for example, groups of the formula:

in which R ¹¹ denotes hydrogen; alkyl, for example C _1-6 alkyl, which may be substituted with a hydroxy group; acyl / for example C _1-6 alkyl-carbonyl, formyl; arylcarbonyl / which may be substituted by one or more halogen atoms or alkoxy groups; optionally substituted alkoxy group mentioned below; C _3-7 cycloalkyl, which may be substituted with one or more hydroxy groups; a group of the formula: -S / O / _n -R ⁶ in which n is an integer having a value in the range 0-2, a R ⁶ is an alkyl group, a R ¹² is hydrogen or C _1-6 alkyl, / 9 / group of the formula:

in which R ²⁴ represents hydrogen, an alkyl group or an aryl group, R ²⁵ represents hydrogen or an alkyl group, and R ²⁴ with R ²⁵ may form an optionally substituted 5-7 membered cyclic amino group containing an adjacent nitrogen atom, and x represents an integer in the range 0-3, / 10 / amidino, / II / acyl / for example, a C _1-8 alkanoyl such as formyl, acetyl, propionyl, butyryl, octanoyl; C _1-8 alkoxy carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl; a C _6-14 aryl carbonyl such as benzoyl; a C _8-11 aralkyl carbonyl such as benzylcarbonyl; a C _7-12 aralkyloxy carbonyl such as benzyloxycarbonyl / which may optionally be substituted with one or more substituents / for example halogen, alkylthio, alkoxy, oxo, hydroxy /, / 12 / an optionally substituted carbamoyl group, for example, carbamoyl, N- monosubstituted carbamoyl / for example N- / C _1-7 alkyl / carbamoyl such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl /, N, N-disubstituted carbamoyl {e.g. N, N-di / C _1-8 alkyl / carbamoyl, such as dimethyl carbamoyl, diethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N-propyl-N-methyl arbamoyl}, / 13 / sulfamoyl, / 14 / N-monosubstituted sulfamoyl {for example, N- / C _1-6 alkyl / sulfamoyl such as methylsulfamoyl, ethylsulfamoyl, propylsulfamoyl}, 15 / N, N-disubstituted sulfamoyl {for example, N , N-di / C _1-6 alkyl / sulfamoyl such as dimethyl sulfamoyl, diethyl sulfamoyl}, / 16 / carboxy, / 17 / C _1-3 alkoxy carbonyl / for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 18 / hydroxyl, 19 / optional substituted alkoxy group, for example C _1-6 alkoxy / for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec. -butoxy, tert.-butoxy, pentyloxy, hexyloxy / which may have one or more substituents / for example C _1-6 alkanoyl having the above meanings, C _1-3 alkyl halogen, C _1-3 alkylthio, C _{1- 3} alkoxy, oxo, hydroxy, C _3-7 cycloalkyl, which has the above meanings /, / 20 / C _3-7 cycloalkyloxy / for example cyclopropyloxy, cyclopentyloxy, cyclohexyloxy /, / 22 / C _7-13 aralkyloxy / for example benzyloxy , benzhydryloxy /, / 23 / C _6-14 aryloxy / for example, phenyloxy, naphthyloxy /, / 24 / mercapto, / 25 / C _7-13 aralkylthio / for example, benzylthio, benzhydrylthio /, / 26 / C _6-14 arylthio / on the Reamer, phenylthio, naphthylthio /, / 27 / group of formula: S / O / _n -R ⁶ in which n is an integer having a value in the range 0-2, and R ⁶ represents an alkyl group / e.g., methylthio, ethylthio, propylthio, methylsulfinyl, ethylsulfinyl, propylsulfinyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl /, / 28 / C _1-3 alkylenedioxy / for example, methylenedioxy, ethylenedioxy, propylenedioxy /, / 29 / sulfo, / 30 / cyano, / 31 / azide / 32 / nitro, / 33 / nitroso, / 34 / halogen / e.g. fluorine, chlorine, bromine, iodine / etc.

Examples of cycloalkyl in the optionally substituted cycloalkyl group denoted by Q for R ¹ and R ² are, for example, C _3-10 cycloalkyl and C _3-10 bicycloalkyl. Preferred examples of such groups 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. Among these groups, cyclopentyl and cyclohexyl are preferred. Substituents may have the same meanings as indicated for aryl denoted by R ² and R ⁴ . Preferred examples of substituents are alkyl, alkoxy or halogen.

As examples of a heterocyclic group in an optionally substituted heterocyclic group denoted by Q for R ¹ , for example, a 5-13 membered aromatic heterocyclic group containing 1-4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom; or an unsaturated non-aromatic heterocyclic group.

 Examples of an aromatic heterocyclic group include an aromatic monocyclic heterocyclic group (for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3, 4-oxadiazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl /, an aromatic heterocyclic group with fused rings {e.g., benzofuranyl, isobenzofuranyl, nzo (b) thienyl, indolyl, isoindolyl, 1H-indazolyl, benzoimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinolininyl, quinolinyl vinyl purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthroinyl, indolisinyl, pyrrolo [1,2-b] pyridazole 5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazine yl, imidazo [1,2-a] pyridazinyl, 1,2,4-thiazolo [4,3a] pyridyl, 1,2,4-triazole [4,3-b] pyridazinyl}. Examples of a non-aromatic heterocyclic group include oxylanyl, azetisinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl. Among these groups, furyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, benzofuryl, indolyl and quinolyl are preferred.

A heterocyclic group may have one or more substituents, preferably one to three substituents. Such substituents have the same meanings as indicated for the optionally substituted aryl indicated by R ² and R ⁴ . Preferred examples of such substituents are halogen, alkyl, alkylthio or alkoxy.

 As an example of a halogen, which is a substituent of the aryl group indicated by Q, fluorine, chlorine, bromine, iodine should be noted.

 As examples of substituents of the optionally substituted carboxyl of the aryl group denoted by Q, alkyl, cycloalkyl, aryl, aralkyl and heterocyclic group, which has the same meanings as indicated above and below, should be noted.

As an example of a lower alkylenedioxy group which is a substituent of the aryl group denoted by Q, for example, C _1-6 alkylenedioxy. Examples of such alkylenedioxy groups are methylenedioxy, ethylenedioxy, propylenedioxy, 2,2-dimethylmethylenedioxy.

As the space group denoted by the symbol "A", for example, C _1-4 alkylene / for example methylene, ethylene /, C _2-6 alkenylene / for example vinylene, butadiene /; a group of the formula: - / CH ₂ / _c NR ²⁶ , in which c is 0-3, R ²⁶ represents hydrogen, C _1-6 alkyl / for example methyl, ethyl, butyl /; a group of the formula: —CO—; a group of the formula: —CONR ²⁷ in which R ²⁷ is hydrogen, C _1-6 alkyl / examples of alkyl are the above values of /, C _3-7 cycloalkyl / examples of the cycloalkyl are the above values of /, C _6-14 aryl / examples of such aryl are the above values /, a heterocyclic group / examples of such a heterocyclic group are given above /; a group of the formula: -S / O / _m , in which m is an integer having values in the range 0-2; -O-; a group of the formula: -NR ²⁷ S / O / _z , in which z is an integer in the range 0-2, R ²⁷ has the same meanings as above.

As an example of an alkoxy group, which may be a substituent of an alkyl group denoted by R ² , a C _1-6 alkoxy group may be mentioned.

As an example of an aralkyl group in an optionally substituted aralkyl group designated as R ² , mention may be made, for example, of aryl-alkyl. Such aryl has the same meanings as indicated above. Examples of alkyl include C _1-6 alkyl such as methyl, ethyl, propyl, butyl, pentyl, hexyl. The substituents on the aralkyl group designated as R ² have the same meanings as indicated for the substituents that the aryl group designated as R ² and R ^{4 may have} .

в которой R²² представляет собой алкил, циклоалкил, арил или гетероциклическую группу, и такие группы могут быть необязательно замещенными, w представляет собой целое число в интервале 0-3, R²³ представляет собой водород или необязательно замещенный алкил, или /2/ гексаметилентетрамино группу. Заместители на алкильной, циклоалкильной, арильной и гетероциклической группах в указанных выше R²² и R²³ имеют те же значения, что указаны выше для замещения арильной группы, обозначенной символами R² и R⁴.As an example of an optionally substituted amino group, denoted by the symbol R ³ , you can cite, for example, / 1 / group of the formula:

in which R ²² represents an alkyl, cycloalkyl, aryl or heterocyclic group, and such groups may be optionally substituted, w is an integer in the range 0-3, R ²³ is hydrogen or optionally substituted alkyl, or / 2 / hexamethylenetetramino group . The substituents on the alkyl, cycloalkyl, aryl and heterocyclic groups in the above R ²² and R ²³ have the same meanings as indicated above to replace the aryl group indicated by R ² and R ⁴ .

As a preferred spatial group, denoted by A in the definition of substituents of the aryl group Q in R ¹ , mention should be made of the group —O— or —S / O / _m , in which m is an integer having a value in the range 0-2.

As preferred examples of the above R ¹ group, a group of the formula: Q- / CH ₂ / _p in which Q and p are as defined above should be noted.

As preferred examples of the above R ¹ group, mention should be made of hydrogen or a group of the formula: - / CH ₂ / _p Q ', in which Q' is an aryl group which may be substituted by halogen, nitro, cyano, amino or a group of the formula: -A 'Is R ^15' / in which A 'is -O- or -S-, and R ^5' is alkyl /, and p is as defined above.

As more preferred examples of the above R ¹ group, a group of the formula should be mentioned:
Q- / CH ₂ / _p -,
in which Q represents an aryl group which may be substituted by one or more / I / halogen and / II / a group of the formula: —AR ⁵ , in which A represents —O— or —S / O / _m , where m represents an integer in the range 0-2, and R ⁵ represents an alkyl group; p is an integer in the range 0-3.

An even more preferred example of the group R ¹ is C _6-14 arylmethyl, which may be substituted with halogen or a group —A ″ - R ^{5 ″} , in which A ″ is —O— or —S—, and R ^{5 ″ '} represents alkyl.

A particularly preferred example of the group R ¹ is the group Q ″ ″ / CH ₂ / _p -, in which Q ″ ″ is an aryl group which may be substituted with halogen and p is an integer in the range 0-3. As preferred examples of the R ² group, it is worth mentioning / 1 / an alkyl group which may be substituted by an alkoxy, / 2 / an aryl group which may be substituted by one or more substituents selected from / I / amino, / II / acyl, / III / carbamoyl, / IV / carboxy, / V / nitro, / VI / hydroxy, / VII / alkoxy groups, which may be substituted by alkoxy, / VIII / halogen and / IV / groups of the formula: -S / O / _n -R ⁶ in which n is an integer in the range 0-2, and R ⁶ is an alkyl group, / 3 / an aralkyl group that may be substituted with halogen, or / 4 / c an alkloalkyl group.

As more preferred examples of the R ² group, mention is made of / 1 / C _1-6 alkyl, which may be substituted by C _1-3 alkoxy, / 2 / C _6-14 aryl, which may be substituted by one or more substituents selected from amino , acyl, carbamoyl, carboxyl, nitro, hydroxy, C _1-3 alkoxy, sulfo, halogen and a group of the formula: - S / O / _n -R ⁶ in which n is an integer in the range 0-2, and R ⁶ represents C _1-3 alkyl, or / 3 / C _3-10 cycloalkyl.

As even more preferred examples of the R ² group, a / 1 / alkyl group which may be substituted by an alkoxy, / 2 / aryl group, which may be substituted by one or more substituents selected from the / I / hydroxy, / II / alkoxy group should be mentioned which may be substituted by alkoxy, (III) halogen and / IV / groups of the formula: -S / O / _n -R ⁶ , in which n is an integer in the range 0-2, and R ⁶ is an alkyl group, / 3 / an aralkyl group or / 4 / a cycloalkyl group.

As more preferred examples of the R ² group, there can be mentioned / 1 / C _1-6 alkyl, which may be substituted by C _1-3 alkoxy, / 2 / C _6-14 aryl, which may be substituted by one or more C _1-3 alkoxy groups, and a group of the formula: -S / O / _n -R ⁶ in which n is an integer in the range 0-2, and R ⁶ is C _1-3 alkyl, or / 3 / C _3-10 cycloalkyl.

As the most preferred examples of the R ² group, an aryl group which may be substituted by one or more substituents selected from the / 1 / alkoxy group which may be substituted by an alkoxy, / 2 / halogen and / 3 / group of the formula: -S / O / _n -R ⁵ in which n is an integer in the range 0-2, and R ⁵ is an alkyl group.

в которой R^22' представляет собой /1/ арильную группу, которая может быть замещена одним или более заместителями, выбранными из /I/ амино, /II/ ацила, /III/ карбамоила, /IV/ карбокси, /V/ нитро, /VI/ гидрокси /VII/, алкокси группы, которая может быть замещена алкокси, /VIII/ галогена, /IX/ алкила или /X/ группы формулы: S/O/_n-R⁶, в которой n представляет собой целое число в интервале 0-2, a R⁶ представляет собой алькильную группу, /2/ гетероциклическую группу, которая может быть замещена одним или более заместителями, выбранными из /I/ амино, /II/ ацила, /III/ карбамоила, /IV/ карбокси, /V/ нитро, /VI/ гидрокси, /VII/ алкокси; /VIII/ галогена, /IX/ алкила или /X/ группы формулы: -S/O/_n-R⁶, в которой n представляет собой целое число в интервале 0-2, a R⁶ представляет собой алкильную группу, /3/ аралкильную группу, которая может быть замещенной галогеном, /4/ группу формулы:

в которой R²⁴ представляет собой водород, алкильную группу или арильную группу, R²⁵ представляет собой водород или алкильную группу, a R²⁴ и R²⁵ могут образовывать необязательно замещенную 5-7-членную циклическую амино группу, содержащую соседний атом азота, а x представляет собой целое число в интервале 0-3 или /5/ алкильную группу, которая может быть замещена алкилтио группой, w представляет собой целое число в интервале 0-3; а R^23' представляет собой водород или алкильную группу.As preferred examples of the above R ³ group, hexamethylenetetramino or a substituted amino group of the formula should be noted:

in which R ^{22 '} represents a / 1 / aryl group which may be substituted by one or more substituents selected from / I / amino, / II / acyl, / III / carbamoyl, / IV / carboxy, / V / nitro, / VI / hydroxy / VII /, an alkoxy group which may be substituted by alkoxy, / VIII / halogen, / IX / alkyl or / X / groups of the formula: S / O / _n -R ⁶ in which n is an integer in the range 0-2, a R ⁶ represents the alkyl group, a / 2 / a heterocyclic group which may be substituted with one or more substituents selected from / I / amino, / II / acyl, / III / carbamoyl, / IV / carbo B, / V / nitro, / VI / hydroxy, / VII / alkoxy; / VIII / halogen, / IX / alkyl or / X / groups of the formula: -S / O / _n -R ⁶ in which n is an integer in the range 0-2, and R ⁶ is an alkyl group, / 3 / an aralkyl group which may be substituted with halogen, / 4 / a group of the formula:

in which R ²⁴ represents hydrogen, an alkyl group or an aryl group, R ²⁵ represents hydrogen or an alkyl group, and R ²⁴ and R ²⁵ can form an optionally substituted 5-7 membered cyclic amino group containing an adjacent nitrogen atom, and x represents represents an integer in the range of 0-3 or / 5 / an alkyl group which may be substituted with an alkylthio group, w is an integer in the range of 0-3; and R ^{23 ′} represents hydrogen or an alkyl group.

/в которой R^22'' обозначает /1/ алкил, /2/ фенил, который может быть замещен одним или более заместителями, выбранными из галогена, нитро, алкила и группы формулы: -S/O/_n-R⁶, в которой n представляет собой целое число в интервале 0-2, a R⁶ представляет собой алкильную группу или амино группу, /3/ гетероциклическую группу, которая может быть замещена одним или более атомами галогена или алкильными группами, или /4/ N-алкилкарбамоил, w представляет собой целое число, имеющее значение в интервале 0-3; R^23'' обозначает водород или алкил/.As more preferred examples of the above R ³ group, mention may be made of hexamethylenetetramino or a group of the formula:

/ in which R ^{22 ″} is / 1 / alkyl, / 2 / phenyl, which may be substituted with one or more substituents selected from halogen, nitro, alkyl and a group of the formula: —S / O / _n —R ⁶ in which n is an integer in the range 0-2, and R ⁶ is an alkyl group or an amino group, / 3 / a heterocyclic group that may be substituted with one or more halogen atoms or alkyl groups, or / 4 / N-alkylcarbamoyl, w represents an integer having a value in the range 0-3; R ^{23 "} denotes hydrogen or alkyl /.

в которой R^22''' представляет собой арильную группу, которая может быть замещена алкилтио группой, /2/ гетероциклическую группу, /3/ группу формулы:

в которой R^24' представляет собой водород или алкил, а R^25' представляет собой водород или алкил и R^24' и R^25' могут образовывать 5-7-членную циклическую амино группу, содержащую соседний атом азота, или /4/ алкильную группу, которая может быть замещена алкилтио, w представляет собой целое число, имеющее значение в интервале 0-3; а R^23''' представляет собой водород или алкильную группу.As more preferred examples of the above R ³ group, a substituted amino group of the formula should be noted:

in which R ^{22 ″} represents an aryl group which may be substituted by an alkylthio group, / 2 / a heterocyclic group, / 3 / a group of the formula:

in which R ^{24 '} represents hydrogen or alkyl, and R ^25' represents hydrogen or alkyl, and R ^{24 '} and R ^25' can form a 5-7 membered cyclic amino group containing an adjacent nitrogen atom, or / 4 / alkyl group which may be substituted by alkylthio, w is an integer having a value in the range of 0-3; and R ^{23 ″ ″} represents hydrogen or an alkyl group.

/в которой R^23' представляет собой фенил или пиридил, причем эти группы могут быть незамещены или замещены группой формулы: -S/O/_n-R⁶, в которой n представляет собой целое число в интервале 0-2, а R⁶ представляет собой алкильную группу, w представляет собой целое число, имеющее значение в интервале 0-3. R^23' представляет собой водород или алкильную группу/.As preferred examples of the above R ³ group, mention should be made of a group of the formula:

/ in which R ^{23 '} represents phenyl or pyridyl, and these groups may be unsubstituted or substituted by a group of the formula: -S / O / _n -R ⁶ in which n is an integer in the range 0-2, and R ⁶ is represents an alkyl group, w is an integer having a value in the range of 0-3. R ^{23 '} represents hydrogen or an alkyl group /.

As preferred examples of the R ⁴ group, an aryl group may be mentioned which may be substituted with one or more substituents selected from / 1 / optionally substituted amino group, / 2 / acyl, / 3 / optionally substituted carbamoyl group, / 4 /, carboxy / 5 / nitro, / 6 / hydroxy, / 7 / optionally substituted alkoxy group and / 8 / optionally substituted alkenyl group.

в которой R^11' представляет собой /I/ водород, /II/ алкил, /III/ необязательно замещенную алкокси группу, /IV/ необязательно замещенную ацильную группу или /V/ группу формулы: -S/O/_n-R⁶, в которой n представляет собой целое число в интервале 0-2, a R⁶ представляет собой алкильную группу, a R^12' представляет собой водород или алкильную группу, /2/ ацила, /3/ карбамоила, /4/ N-моно- или диалкилкарбамоила, /5/ нитро, /6/ алкокси группы, которая может быть замещена одним или более заместителями, выбранными из алкокси, алканоила, оксо, гидрокси, циклоалкила и галогена, /7/ алкенила, который может быть замещен алкоксикарбонилом или алкилкарбонилом и /8/ алкенилокси.As more preferred examples of the above R ⁴ group, an aryl group which may be substituted with one or more substituents selected from the / 1 / group of the formula:

in which R ^{11 '} represents / I / hydrogen, / II / alkyl, / III / an optionally substituted alkoxy group, / IV / an optionally substituted acyl group or / V / a group of the formula: -S / O / _n -R ⁶ , which n is an integer in the range 0-2, a R ⁶ is an alkyl group, a R ^{12 '} is hydrogen or an alkyl group, / 2 / acyl, / 3 / carbamoyl, / 4 / N-mono- or dialkylcarbamoyl , / 5 / nitro, / 6 / alkoxy group which may be substituted by one or more substituents selected from alkoxy, alkanoyl, oxo, hydroxy, cycloalkyl and halogen, / 7 / alk phenyl, which may be substituted by alkoxycarbonyl or alkylcarbonyl and / 8 / alkenyloxy.

в которой R^11'' представляет собой /I/ водород, /II/ алкил, /III/ алкокси группу, которая может быть замещена галогеном или алкокси, /IV/ формил, /V/ алканоил, который может быть замещен галогеном или алкокси, /VI/ бензоил или /VII/ группу формулы: -S/O/_n-R⁶, в которой n представляет собой целое число, имеющее значение в интервале 0-2, а R⁶ представляет собой алкильную группу, a R^12'' представляет собой водород или алкил, /2/ алкокси группы, которая может быть замещена алкокси, алканоилом или циклоакилом, /3/ N-моно или ди-алкилкарбамоила, /4/ нитро, /5/ алкенила, который может быть замещен алкоксикарбонилом или алкилкарбонилом или /6/ алкенилокси.Other preferred examples of the above R ⁴ group include an aryl group which may be substituted with one or more substituents selected from / 1 / a group of the formula:

in which R ^{11 ″} represents / I / hydrogen, / II / alkyl, / III / alkoxy, which may be substituted by halogen or alkoxy, / IV / formyl, / V / alkanoyl, which may be substituted by halogen or alkoxy, (VI) benzoyl or / VII / a group of the formula: -S / O / _n -R ⁶ , in which n is an integer having a value in the range 0-2, and R ⁶ is an alkyl group, and R ^{12 ″} represents hydrogen or alkyl, / 2 / alkoxy, which may be substituted with alkoxy, alkanoyl or cycloakyl, / 3 / N-mono or di-alkylcarbamoyl, / 4 / nitro, / 5 / alkenyl, which may It is optionally substituted by alkoxycarbonyl or alkylcarbonyl or / 6 / alkenyloxy.

/в которой R³¹ обозначает C_1-6 алкил; C_1-3 алкокси, которая может быть замещена C_1-3 алкокси группой; или формил, R³² обозначает водород или C_1-6 алкил/, или C_2-4 алкенил, который может быть замещен алкокси-карбонилом или алкилкарбонилом.As another preferred example of an aryl group in the aforementioned optionally substituted aryl R ⁴ , phenyl is mentioned. As preferred examples of the substituents on the aryl group designated as R ⁴ , mention should be made of amino, acyl, carbamoyl, N-monosubstituted alkylcarbamoyl, carboxyl, nitro, hydroxy, C _1-3 alkoxy, which may be substituted by a C _1-3 alkoxy group, a group of the formula:

/ in which R ³¹ is C _1-6 alkyl; C _1-3 alkoxy, which may be substituted by a C _1-3 alkoxy group; or formyl, R ³² is hydrogen or C _1-6 alkyl /, or C _2-4 alkenyl, which may be substituted with alkoxy carbonyl or alkylcarbonyl.

где R³³ обозначает C_1-6 алкил, C_1-3 ацил, который может быть замещен C_1-3 алкокси; C_1-3 алкокси, которая может быть замещена C_1-4 ацилом; бензоил; или формил, R³⁴ обозначает водород или C_1-6 с алкил, C_2-4 алкенил, который может быть замещен C_1-3 алкокси-карбонилом или C_1-3 алкил-карбонилом.As a more preferred example of the aryl in the optionally substituted aryl of the group R ⁴ , phenyl is mentioned. As more preferred examples of the substituents on the aryl group designated as R ⁴ , amino may be mentioned; acyl; N-substituted alkylcarbamoyl; nitro C _1-3 alkoxy, which may be substituted by a C _1-3 alkoxy group; a group of the formula:

where R ³³ is C _1-6 alkyl, C _1-3 acyl, which may be substituted with C _1-3 alkoxy; C _1-3 alkoxy, which may be substituted with C _1-4 acyl; benzoyl; or formyl, R ³⁴ is hydrogen or C _1-6 with alkyl, C _2-4 alkenyl, which may be substituted with C _1-3 alkoxy carbonyl or C _1-3 alkyl carbonyl.

 In each of the above groups, the number of substituents is preferably 1-3, r is preferably 1, p is preferably 1, and w is preferably 1.

As examples of 5-7 membered cyclic amino groups containing a nitrogen atom, pyrrolidinyl, pyrrolinyl, pyrrolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, imidazolidinyl, imidazolinyl, imidazolyl, 1,2,3-triazinyl, 1,2,3-triazolidinyl should be mentioned , 1,2,3-triazolyl, 1,2,3,4-tetrazolyl, piperidinyl, piperazinyl, hexamethyleneamino, oxazolidino, morpholino, thiazolidino or thiomorpholino. As more
Preferred cyclic amino groups include pyrolidinyl, pyrazolinyl, pyrazolyl, piperidinyl, piperazinyl, morpholino and thiomorpholino.

Such a cyclic amino group may be substituted. Examples of substituents include C _1-6 alkyl, C _6-14 aryl, C _7-10 aralkyl, benzhydryl, C _1-6 alkyl carbonyl, C _6-14 aryl carbonyl, C _1-6 alkoxy carbonyl. As preferred substituents, C _1-6 alkyl, preferably C _1-3 alkyl, should be mentioned.

As a preferred alkyl in the above definition, for example, C _1-10 alkyl. Examples of alkyl include methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, tert.-butyl, pentyl, isopentyl, neopentyl and hexyl. Among these groups, the most preferred is an alkyl group containing 1-6 carbon atoms, and even more preferred is an alkyl group containing 1-3 carbon atoms.

As acyl, C _1-10 acyl can be mentioned, and examples of such acyl are, for example, alkanoyl, aryl carbonyl, aralkyl carbonyl and aralkyloxy carbonyl mentioned above.

 In this definition, alkyl carbonyl may be preferred acyl and alkanoyl, and alkyl is as defined above.

As a preferred alkoxy group in the above definition, C _1-6 alkoxy should be mentioned, and examples of such alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert. - butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy. Among these groups, alkoxy containing 1-3 carbon atoms is preferred.

A preferred alkenyl in the above definition is C _2-4 alkenyl. Examples of such alkenyl include vinyl, allyl, 1-butenyl, 2-butenyl.

As a preferred aryl in the above definition, C _6-14 aryl should be noted. Examples of such aryl include phenyl, naphthyl.

As a preferred aralkyl in the above definition, C _7-10 aralkyl should be mentioned. Examples of such aralkyl include benzyl, phenethyl.

 As halogen, fluorine, chlorine, bromine, iodine can be used.

 The compound / 1 / of the present invention can be easily obtained per se by known methods, examples of which are given in the following preparation methods, or by a similar method.

1. Method A: In accordance with the method described by K. Gewald, E. Schinke and H. Bottoher, Chem. Ber., 99, 94-100, / 1966 /, a reaction is carried out between the corresponding ketone or aldehyde containing an active methylene group / I / and an ester derivative of cyanoacetic acid, as well as sulfur, in order to obtain a 2-aminothiophene derivative / II /. More specifically, when the ketone / R '/ H / is used, it is heated under reflux together with an ester derivative of cyanoacetic acid, in the presence of acetic acid and ammonium acetate, in a medium of a suitable solvent such as toluene to form an ester derivative of alkylidene cyanoacetic acid, which is then heated in a suitable solvent, for example, ethanol in the presence of sulfur and a base to obtain a 2-aminothiophene derivative / II /. And in the case of the use of the aldehyde / R ^{3 '} = H /, it is heated in a suitable solvent, such as dimethylformamide, in the presence of an ester derivative of cyanoacetic acid, sulfur and a base to form a 2-aminothiophene derivative / II /.

Проводят реакцию между производным 2-аминотиофена /II/, полученным по способу, описанному в Способе получения 1, или его солью и производным изоцианата. Примером производного изоцианата могут служить производные, отвечающие общей формуле R²-NCO /в которой R² имеет указанные выше значения/. Реакцию соединения /II/ или его соли с производным изоцианата проводят в растворителе, не оказывающем нежелательного влияния на ход реакции /например, в тетрагидрофуране, пиридине, диоксане, бензоле, дихлорметане, 1,2-дихлорэтане, толуоле, ксилоле/ при температурах в интервале от примерно 15 до примерно 130^oC. Производное изоцианата используют в количестве примерно 1-5 эквивалентов, предпочтительно, 1,1-2,5 эквивалентов в расчете на 1 эквивалент соединения /II/. Продолжительность реакции составляет величину в интервале от нескольких часов до нескольких дней, предпочтительно, от примерно 15 минут до, примерно, двух дней.

A reaction is carried out between a 2-aminothiophene derivative / II / obtained by the method described in Production Method 1, or a salt thereof and an isocyanate derivative. An example of an isocyanate derivative can be derivatives corresponding to the general formula R ² —NCO / in which R ² has the above meanings /. The reaction of compound (II) or its salt with an isocyanate derivative is carried out in a solvent that does not undesirably affect the course of the reaction / for example, in tetrahydrofuran, pyridine, dioxane, benzene, dichloromethane, 1,2-dichloroethane, toluene, xylene / at temperatures in the range from about 15 to about 130 ^° C. The isocyanate derivative is used in an amount of about 1-5 equivalents, preferably 1.1-2.5 equivalents, based on 1 equivalent of compound / II /. The duration of the reaction is in the range from several hours to several days, preferably from about 15 minutes to about two days.

2. Method B: An amine (for example, a compound according to the formula R ² —NH ₂ / in which R ² has the above meanings) is subjected to a coupling reaction with an isocyanate derivative obtained by reacting a 2-aminothiophene derivative / II / or its salt with phosgene or its equivalent compound / for example, a diphosgene such as bis / trichloromethyl / carbonate, a triphosgene such as trichloromethylchloroformate /. The reaction of the compound [II] or its salt with phosgene or its equivalent compound is carried out in a solvent which does not adversely affect the reaction (for example, dioxane, tetrahydrofuran, benzene, toluene, xylene, 1,2-dichloroethane, chloroform) temperatures ranging from about 40 to 120 ^° C. Phosgene or an equivalent compound thereof is used in an amount in the range of from about 0.5 to 2 equivalents, preferably from about 0.9 to 1.1 equivalents. The reaction time is in the range from a few 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 undesirably affect the course of the reaction (for example, pyridine, tetrahydrofuran, dioxane, benzene, dichloromethane, 1,2-dichloroethane, toluene, xylene) at temperatures ranging from about 15 to 130 ^o C. The amine is used in an amount in the range of 1.1 to 5 equivalents, preferably 1.1-3 equivalents. The reaction time is from a few minutes to several days, preferably from about 15 minutes to about two days.

A reaction is carried out between the compound [XV] or its salt obtained above, with a base for carrying out a cycling reaction to obtain a thieno [2,3-d] pyrimidine derivative / XVI /. The cyclization reaction is carried out in a solvent which does not undesirably affect the course of the overall reaction. Alcohols such as methanol, ethanol or propanol, as well as ethers such as dioxane or tetrahydrofuran, can be used as a solvent. As the base, for example, bases such as alkali metal alkoxides such as sodium methylate, sodium ethylate or sodium isopropylate, as well as alkali metal hydrides such as sodium hydride can be used. The amount of base used is 1-5 equivalents, preferably 1.5-3 equivalents, based on 1 equivalent of compound / XV /. The reaction temperature ranges from about 10 ^° C. to the boiling point of the solvent, preferably from 25 ^° C. to the boiling point of the solvent used. The reaction time is from a few minutes to several days, preferably from about 10 minutes to two days.

Compound / XVI / and a halogenated aralkyl derivative are mixed in the presence of a base (for example, an organic base such as pyridine or triethylamine) in a solvent which does not undesirably affect the course of the reaction (for example, a solvent such as amides, for example dimethylformamide or dimethylacetamide /, in the temperature range 10-100 ^o C, to obtain 2,4-dioxothieno [2,3-d] - pyrimidine derivative / IIa /. Next, the compound / IIa / is mixed with N-bromosuccinamide / NBS / in a solvent which does not undesirably affect the course of the reaction / for example, such as halogenated hydrocarbons such as carbon tetrachloride or chloroform /, in the presence of α, α′- azobisisobutyronitrile, resulting in a compound of formula (II). Further, the compound (II) is mixed with various amines, in the presence of a base in a solvent which does not undesirably affect the course of the reaction / for example, in a solvent such as amides, for example dimethylformamide or dimethylacetamide, nitriles such as acetonitrile, such alcohols as ethanol /, at a temperature in the range of 10-100 ^o C for 0.5-6 hours, to obtain the compounds of formula / II /. If necessary, the compound / I / is converted into the corresponding salt using a suitable acid / for example, hydrochloric or oxalic acid /.

 The production method described above is represented by scheme 1 at the end of the description.

 The corresponding groups indicated in the above scheme have the above meanings. X represents a leaving group.

 As leaving groups indicated by the symbol X, mention may be made of groups capable of substitution by a nucleophilic reagent (for example, a hydrocarbon residue containing a hetero atom having a negative charge / for example, an oxygen atom, a sulfur atom and a nitrogen atom). Special mention should be made of a halogen atom (for example, atoms of iodine, bromine, chlorine), an alkanoyloxy group (for example, acetoxy, alkylsulfonyloxy / for example acetoxy, alkylsulfonyloxy / for example methanesulfonyloxy / and alkyl-arylsulfonyloxy / for example p-toluylsulfonyloxy) .

3. Method C: In addition to the method for producing compound / IIa / from compound / II / in accordance with the above scheme / 1 /, any per se conventional methods can be used, for example, those described below, which are used to convert compound / II / to the compound / IIa /. For example, the compound [II] is dissolved in an appropriate solvent, for example, methanol, ethanol, which do not have an undesirable effect on the reaction course, a 2N sodium hydroxide solution is added, and the resulting mixture is subjected to reaction at a temperature from room temperature to heating / to about 100 ^o C / for 1-12 hours. The resulting compound in which the -COOEt group is converted to -COOH is dissolved in an appropriate solvent, for example, dioxane, and an equivalent amount of triphosgene is added to the resulting solution and the reaction is carried out in the resulting mixture at a temperature of 80-150 ^° C. for 1- 10 hours with stirring. The resulting 1-hydroxy oxazine compound is treated in the same manner as used for the above conversion reaction of compound [XVI] to compound [IIa]. The oxazine compound thus obtained, in which the R ¹ group is introduced at the 1-position, was dissolved in a suitable solvent, for example, dichloromethane, an equivalent amount slightly exceeding the excess of an amine such as ammonia, alkylamine, arylamine was added to the resulting solution, and as a result of the mixture, the reaction was carried out in the temperature range from room to elevated / up to 100 ^° C / for 1-12 hours with stirring. Then, triphosgene and triethylamine as a base were added to the reaction mixture again, the reaction was carried out in the resulting mixture at about 100 ^° C under reflux for 1-6 hours to obtain a compound of formula (IIa).

4. Other methods:
The substituents on the compound / 1 / can be converted to other substituents using per se methods or conventional methods. Examples of such methods are described below.

 I /. The nitro group as a substituent can be converted to an amino group when the starting compound is dissolved in a suitable solvent such as ethanol, methanol, and palladium on carbon is added to the resulting solution, and the reaction is carried out at room temperature temperature for 1-12 hours in a hydrogen atmosphere, or b / iron powder and hydrochloric acid are added to the solution and the resulting mixture is reacted at room temperature for 1-12 hours.

 II / amino group can be converted to an acylated amino group when the starting compound is dissolved in a suitable solvent such as tetrahydrofuran, dimethylformamide, and potassium carbonate, pyridine and triethylamine as a base, as well as acid anhydride or acid halide are added to the resulting solution. . In the resulting mixture, the reaction is carried out at room temperature for 1-10 hours with stirring.

III / Using the amino compound as the starting compound, its amino group is converted to an alkyl-amino group. For example, the starting compound is dissolved in a suitable solvent such as acetic acid, dimethylformamide, dichloromethane, tetrahydrofuran, dioxane, acetonitrile, a diazonium agent, for example, sodium nitrite, isoamyl nitrite, is added to the resulting solution, and a palladium catalyst, for example, bis, is added to the resulting mixture. / dibenzilidenatsetonat / palladium and alkenyl derivative in an amount of one equivalent to an excess, and the resulting mixture was stirred at temperatures ranging from ambient to elevated / 80 ^o C / for 1-12 aces.

IV / The carbon atom can be introduced into the amino group, for example, by adding to the starting compound in the medium such an appropriate solvent as acetic acid, dimethylformamide, dichloromethane, tetrahydrofuran, dioxane, an acrylic acid derivative or oxirane, for example, an epoxy compound. The resulting mixture was stirred at a temperature of 0-80 ^o C for 6-24 hours.

V /. A sulfur atom can be introduced into the amino group of the compound, for example, into the starting compound in an appropriate solvent, for example, pyridine, dimethylformamide, dichloromethane, tetrahydrofuran, ethyl ether, dioxane, and a sulfur compound halide is added. The resulting mixture was stirred at 0-80 ^o C for 6-24 hours.

 VI / Substituent, a formyl group, can be converted to a methyl group by dissolving the starting compound in a suitable solvent such as tetrahydrofuran and adding an organic borane derivative, for example, borane dimethyl sulfide, to the resulting mixture and reacting the resulting mixture at room temperature increased in conditions of reflux for several hours, for example, 1-3 hours.

 VII / Acetonyloxy derivative can be obtained from a methoxy derivative by dissolving the starting material in a suitable solvent such as, for example, dimethylformamide, adding to the resulting solution an excess of Lewis acid, for example, aluminum chloride, and a sulfide derivative / for example dimethyl sulfide /, after which the reaction is carried out in the mixture in the temperature range from ice cooling to room temperature for 1-10 hours and after that the resulting hydroxide and the derivative is dissolved in a suitable solvent such as dimethylformamide, a base, for example sodium hydroxide or potassium carbonate and alkyl halide, is added to the solution. In the resulting mixture, the reaction is carried out at room temperature for 1-12 hours.

 VIII /. The methoxy group can be replaced by an isopropoxy group by dissolving the starting material in a suitable solvent such as dichloromethane, after which one equivalent or excess of a Lewis acid, for example, aluminum chloride, is added to the resulting solution and the reaction is carried out in the presence of a thiol compound or sulfide compound, for example, dimethyl sulfide and the resulting mixture at a temperature from room temperature to ice cooling for 1-10 hours.

 IX /. An aminocarbonyl group can be introduced by dissolving the starting compound containing a halogen atom in a suitable solvent such as dimethoxyethane, adding to the resulting solution an arylboronic acid derivative, such as sodium carbonate, a palladium compound, for example, tetrakis / triphenylphosphine / palladium / O /, as a catalyst and refluxing the resulting mixture for 1-6 hours.

 The X / Alkylthio compound may be converted to an alkylsulfinyl compound or an alkylsulfonyl compound by reacting the parent compound with an oxidizing agent such as methane chloroperbenzoic acid in a suitable solvent such as dichloromethane, at a temperature from ice-cooling to heating. With enhanced heating or treatment with excess oxidizing agent, an alkyl sulfonyl compound is obtained.

 Among the salts of the compounds (I) of the present invention obtained as described above, physiologically acceptable acid addition salts are preferred. Examples of such salts are salts of inorganic acids (for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid) or salts of organic acids / for example formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid maleic acid, citric acid, succinic acid, malic acid, methane sulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. In addition, in the case when the compound / I / of the present invention contains an acid group such as —COOH, the compound / 1 / can form a salt with an inorganic base /, for example, an alkali or alkaline earth metal such as sodium, potassium, calcium and magnesium ; ammonium / or with an organic base / for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine and N, N'-dibenzylethylenediamine /.

 The compounds of formula (I) or their salts of the present invention, obtained as described above, can be isolated and purified by such traditional means of separation as recrystallization, distillation and chromatography. In the case when the compound [I] is obtained in free form, it can be converted into its salt per se by conventional methods or by methods analogous to them. On the other hand, when such a compound is obtained in the form of a salt, it can be converted into the corresponding free form of the compound or into any other salt.

 In the case where the compound / I / or a salt thereof of the present invention is an optically active compound, such a compound can be separated into the d-form and 1-form using conventional optical splitting methods.

 Since the compound (I) of the present invention has GnRH antagonistic activity and low toxicity, such compounds can be safely used in the treatment of diseases dependent on male or female sex hormones, as well as in the treatment of diseases caused by excessive secretion of such hormones in mammals / for example, humans, monkeys , cows, horses, dogs, cats, rabbits, rats, mice, etc. /, inhibiting the secretion of gonadotropin hormone under the influence of the antagonistic effect of the GnRH receptor. More specifically, the compounds of the present invention are effective prophylactic or therapeutic agents for the prophylaxis or treatment of certain hormone-dependent diseases, for example, sex hormone-dependent cancer / for example, prostate cancer, cervical cancer, breast cancer, pituitary adenoma /, benign prostatic hypertrophy , uterine fibroids, endometriosis, premature puberty, ammenorrhea, premenstrual syndrome, polycystic ovary syndrome and acne vulgaris / inflammation sebaceous glands. In addition, the compounds of the present invention have efficacy as fertility regulating agents of both sexes (for example, pregnancy control agents and menstrual cycle regulating agents). The compounds of the invention can also be used as contraceptives for men or women, as an ovulation inducing agent in women. The compound of the present invention can be used as an agent for the treatment of infertility as a result of using the reactive effect associated with the cessation of its use. In addition, the compounds of the present invention are used as modulators of estrous cycles in farm animals and as an agent used to improve the quality of edible meat or to promote the growth of animals. In addition, the compounds of the present invention are useful for promoting fish spawning. Although the compounds of the invention can be used as such, they can also be effectively used by use in combination with a steroidal or non-steroidal antiandrogenic agent. The compound of the present invention can be used to suppress a temporary increase in the concentration of testosterone in the blood plasma, increases that occur when using a superantagonist such as leuprorelin acetate. The compound of the invention can be effectively used in combination with an anti-cancer chemotherapy agent. In the treatment of prostate cancer, examples of such a chemotherapeutic agent include Ifosfamide, YFT, Adriamycin, Peplomycin, Cisplatin and the like. In the treatment of breast cancer, examples of chemotherapeutic agents include Cyclofohamide, 5-FY /, YFT, Methotrexate, Andriamycin, Mitomycin C, Mitoxantrone, etc.

 Compounds (I) of the present invention demonstrate sufficient GnRH activity for subcutaneous or oral administration, are stably absorbed by oral administration, and exhibit GnRH activity for a long time.

 When using the compound [I] of the present invention in the field of livestock farming or fish farming as prophylactic and therapeutic agents of the above diseases, such compounds can be administered orally or non-orally in accordance with known methods. Such substances are mixed with a pharmaceutically acceptable carrier and are usually administered orally in the form of solid preparations such as tablets, capsules, granules or powder, or non-orally in the form of intravenous, subcutaneous or intramuscular injections, or in the form of a suppository or tablets for sublingual administration. In addition, such substances can be taken sublingually, subcutaneously or intramuscularly in the form of such sustained-release formulations as sublingually used tablets or microcapsules. The daily dosage of the compound (I) of the present invention may vary depending on the degree of damage; age, gender, body weight and differences in the sensitivity of the treatment object to the medication used; time and intervals between use, properties, dosage forms and nature of the drug; as well as the nature of the effective components, the dosage ranges usually being, without special restrictions, 0.01-10 mg, preferably from about 0.02 to 2 mg, more preferably from about 0.01 to 1 mg, per 1 kg the body weight of the mammal of the animal, and, as a rule, such dosages are used once a day or in 2-4 separate doses. The daily dosage when used in the field of livestock farming or fish farming can vary depending on conditions similar to those mentioned above, and they are in the range from about 0.001 to 5 mg, preferably from about 0.002 to 2, per 1 kg of animal or fish body weight mg, when applied in the form of one or 2-3 separate dosages.

 As the aforementioned pharmaceutically acceptable carriers, various conventional organic or inorganic carriers may be used which are introduced as fillers, lubricants, binders and disintegrants into solid compositions; and in the form of solvents, solubilizers, suspending agents, isotonic agents, buffering agents and pain-relieving agents in liquid compositions. If necessary, other additives such as preservatives, antioxidants, coloring agents and flavoring agents can be used.

 Preferred examples of the above excipients include lactose, sugar, D-mannitol, starch, crystalline cellulose and more volatile silica. Preferred examples of the aforementioned lubricants include magnesium stearate, calcium stearate, talc and colloidal silicon oxide. Preferred examples of the binding agents mentioned above include crystalline cellulose, sugar, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxymethyl cellulose and polyvinyl pyrrolidone. Preferred examples of these disintegrants include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium cross-carmellose and sodium carboxymethyl starch. Preferred examples of the above solvents include water for injection, alcohol, propylene glycol, macrogol, sesame oil and corn oil. Preferred examples of the solubilizers mentioned above include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, tris-aminomethane, cholesterol, triethanolamine, sodium carbonate and sodium citrate. Preferred examples of the above suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride and glycerol monostearic ester; as well as hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose. Preferred examples of the above-mentioned isotonic agents include sodium chloride, glyceryl and D-mannitol. Preferred examples of the buffering agents mentioned above include buffering solutions such as phosphate, acetate, carbonate and citrate. Preferred examples of the above pain relief agents include benzyl alcohol. Preferred examples of the preservatives mentioned above are para-hydroxy benzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid. Preferred examples of the above anti-oxidizing agents include sulfite and ascorbic acid.

 To the compound [I] of the present invention, for example, a suspending agent, a solubilizer, a stabilizer, an isotonic agent and a protective agent are added, then the mixture is molded in accordance with the per se known method to obtain preparations for intravenous, subcutaneous and intramuscular injections. Such injectable formulations can be processed into lyophilized preparations, if necessary, using a per se known method.

 Examples of the aforementioned pharmaceutical compositions are oral agents (for example, diluted powders, granules, capsules and tablets), injectable preparations, drip injection preparations, external agents (for example, transnasal preparations, subcutaneous preparations, etc.), ointments (for example, rectal ointment, vaginal ointment, etc. / and other drugs.

 Such pharmaceutical compositions can be produced using per se a known method conventionally used to prepare pharmaceutical compositions.

 The compound / I / of the present invention or its salt can be used in injectable preparations in the form of an aqueous preparation for injection together with dispersing agents / for example, Tween 80 / Atlas Powde, USA /, HCO 80 / Nikko Kamikals, Japan /, polyethylene glycol, carboxymethyl celluloses, alginate sodium and the like /, protective agents for example methyl paraben, propyl paraben, benzyl alcohol and the like /, isotonic agents / for example, sodium chloride, mannitol, sorbitol, glucose, etc. / and other agents or in the form of an oil injection prep ata by dissolving, suspending or emulsifying in vegetable oil / e.g., olive oil, sesame oil, cotton seed oil, corn oil and the like /, propylene glycol, etc.

 In the preparation of an oral pharmaceutical composition, the compound (I) of the present invention or its salt is formed by compression, for example, with excipients (for example, lactose, sucrose, starch, etc.), disintegrating agents (for example, starch, calcium carbonate, etc.). n / with binding agents / for example with starch, gum arabic, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose and the like / or lubricants / for example with talc, magnesium stearate, polyethylene glycol 6000, etc. / etc. / and so on. d. If necessary, the composition is coated per se in a known manner in order to mask taste, gastric coating or prolonged action. Examples of a coating agent include hydroxypropyl methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, pluronic F68, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, and hydroxymethyl cellulose acetate succinate; manufactured by Rum, Germany /, red iron oxide and the like. A subcover layer may be provided between the gastric coating and the core according to a per se known method.

 To prepare an external composition for use, the compound (I) of the present invention or its salt, as such, or its salt is treated in a manner known per se to obtain a solid, semi-solid or liquid external agent. For example, a solid preparation is prepared as follows. The compound of the present invention, as such, or after adding / mixing with fillers / for example glycerin, mannitol, starch, microcrystalline cellulose and the like /, thickeners / for example, natural resins, cellulose derivatives, acrylic acid polymers, etc. / and other substances are converted into a powder composition. In the case of a liquid composition, an oily or aqueous suspension is prepared in substantially the same way as the injection preparation. In the case of a semi-solid composition, the preferred preparation is an aqueous or oily gel or ointment. Each of these preparations can be combined with a pH adjusting agent (for example, carboxylic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), an antiseptic agent (for example, with p-hydroxybenzoate, chlorobutanol, benzalkonium chloride and the like / and other substances.

 In the preparation of the ointment, the compound / I / of the present invention or its salt can be converted into an oily or aqueous solid, semi-solid or liquid ointment. Examples of the oil bases used in the above compositions are glycerides of higher fatty acids (for example, cocoa butter, Witepsols), manufactured by Dynamite-Nobel, etc. medium fatty acids (for example, Migliols / manufactured by Dynamite-Nobel / etc.), as well as vegetable oil / for example, sesame oil, soybean oil, cottonseed oil, etc. /, as well as other substances. Examples of water-based materials are polyethylene glycols and propylene glycol, and examples of the aqueous gel base material are natural resins, cellulose derivatives, vinyl polymers, acrylic acid polymers, and the like.

 The best way to implement the invention.

 Further, the present invention is described in more detail using the following Reference examples and Working examples, which do not limit the scope of the invention.

¹ H-NMR spectra were recorded on a Variant Gemini 200/200 MHz /, Jeol Lambda 300/300 MHz / or Brucker AM 500/500 MHz / type spectrometer using tetramethylsilane as the internal standard. All delta values are expressed in ppm.

The symbols used to describe the spectra in the present description have the following meanings:
s: singlet, d: doublet, t: triplet, dt: double triplet, m: multiplet, br: wide.

Reference example 1
Obtaining ethyl 2-amino-5-phenylthiophene-3-carboxylic acid.

To a mixture consisting of ethyl cyanoacetate / 6.1 g, 50 mmol /, sulfur / 1.61 g 50 mmol /, triethylamine / 3.5 ml, 25 mmol / and dimethylformamide / 10 ml /, was added dropwise with stirring at 45 ^o C, for 20 minutes phenylacetaldehyde / 50% diethyl phthalate solution; 12.05 g, 50 mmol /. The resulting mixture was stirred for 9 hours at 45 ^° C. and the reaction mixture was concentrated. The resulting residue was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, which was further dried (MgSO ₄ ), followed by distillation of the solvent under reduced pressure. The residue was chromatographed on silica gel, followed by recrystallization from ether-hexane to give yellowish plates (5.55 g, 45%), mp 124.5-125.5 ^o C / literary value 123-124 ^o C /.

Elemental analysis for C ₁₃ H ₁₃ NO ₂ S:
(C,%; H,%; N,%)
Calculated: 63.13; 5.30; 5.66
Found: 62.99; 5.05; 5.63
Spectrum ¹ H-NMR / 200 MHz, CDCl ₃ / δ: 1.37 / 3H, triplet, J = 7.1 Hz /, 4.30 / 2H, doublet, J = 7.1 Hz /, 5.97 / 2H, broad (7.17 - 7.46 / 6H, multiplet).

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

Reference example 2
Obtaining ethyl 2-amino-4-methyl-5- / 4-methoxy-phenyl / thiophene-3-carboxylic acid:
A mixture consisting of 4-methoxyphenylacetone / 16.5 g, 0.10 mol /, ethyl cyanoacetate / 12.2 g, 0.10 mol /, ammonium acetate / 1.55 g, 20 mmol /, acetic acid / 4, 6 ml, 80 mmol / and benzene / 20 ml / was heated for 24 hours under reflux, removing the water formed in the reaction using a Dean-Stark device. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane and an aqueous solution of sodium bicarbonate. The organic layer was washed with an aqueous solution of sodium chloride, which was then dried (MgSO ₄ ), after which the solvent was distilled off under reduced pressure. Sulfur (3.21 g, 0.10 mol) and diethylamine (10.4 ml, 0.10 mol) were added to the ethanol (30 ml) solution of the residue. The resulting mixture was stirred for 2 hours at 50-60 ^o C and then concentrated and the concentrate was extracted with ethyl acetate. The extract obtained was washed with an aqueous solution of sodium chloride and dried (MgSO ₄ ), after which the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography and recrystallized from ether-hexane to give light yellow plates (11.5 g, 40%), mp 79-80 ^o C.

Elemental analysis for C ₁₅ H ₁₇ NO ₃ S:
(C,%; H,%; N,%; S,%)
Calculated: 61.83; 5.88; 4.81; 11.01
Found: 61.81; 5.75; 4.74; 10.82
Spectrum ¹ H-NMR / 200 MHz, CDCl ₃ / δ: 1.37 / 3H, triplet, J = 7.1 Hz /, 2.28 / 3H, singlet /, 3.83 / 3H, singlet /, 4, 31 / 2H, quartet, J = 7.1 Hz /, 6.05 / 2H, wide /, 6.91 / 2H, doublet, J = 8.8 Hz /, 7.27 / 2H, doublet, J = 8 , 8 Hz /,
IR spectrum / KBr /: 3426, 3328, 1651, 1586, 1550, 1505, 1485 cm ^-1 .

FAB mass spectrum m / z: 291 / M ⁺ /.

Reference example 3
Using various derivatives of acetone instead of 4-methoxyphenylacetone, the compounds shown in Table 1 were obtained in accordance with a substantially similar method to that described in Reference Example 2,
Reference Example 4
Obtaining ethyl 3-amino-4-methyl-5- / 4-nitrophenyl / thiophene-3-carboxylic acid:
By the method, almost similar to that described in Reference example 1, using 4-nitrophenylacetone / 35.0 g, 195 mmol / instead of 4-methoxyphenyl acetone, ethyl cyanoacetate / 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 / 16.0 ml, 160 mmol / received the target compound as colorless crystals / 22.2 g , 52% /. Mp 168-170 ^o C / recrystallization from a mixture of ether-hexane /.

Elemental analysis for C ₁₄ H ₁₄ N ₂ O ₄ S:
(C,%; H,%; N,%)
Calculated: 54.89; 4.61; 9.14
Found: 54.83; 4.90; 9.09
Spectrum ¹ H-NMR / 200 MHz, CDCl ₃ / δ: 1.39 / 3H, triplet, J = 7.1 Hz /, 2.40 / 3H, singlet /, 4.34 / 2H, quartet, J = 7 1 Hz /, 6.27 / 2H, broad /, 7.48 / 2H, doublet, J = 8.7 Hz /, 8.23 / 2H, doublet, J = 8.7 Hz /.

IR spectrum / KBr /: 3446, 3324, 1667, 1580, 1545, 1506, 1491, 1475, 1410, 1332 cm ^-1 .

Reference Example 5
Obtaining ethyl ester of 2,4 / 1H, 3H / -dioxo-5-methyl-6- / 4-methoxyphenyl / thieno [2,3-d] pyrimidine-3-acetic acid:
Ethyl isocyanoacetate (2.90 ml, 25.80 mmol) was added to a solution of the compound obtained in Reference Example 1 / 5.00 g, 17.20 mmol /. The resulting mixture was stirred for 6 hours at 45 ^° C. and then concentrated under reduced pressure. The concentrate was dissolved in ethanol / 6 ml / and sodium ethoxide {prepared from ethanol / 30 ml / and sodium / 0.79 g, 34.30 mmol /} was added to the solution. The resulting mixture was stirred for 24 hours at room temperature and 2N HCl (18 ml, 36 mmol) was added. Ethanol was distilled off under reduced pressure and the residue was filtered, washed with water-ethanol and dried under reduced pressure, followed by recrystallization from ethanol to give white needles / 5.70 g, 89% /. Mp 164-165 ^o C.

Elemental analysis for C ₁₈ H ₁₈ N ₂ O ₂ S:
(C,%; H,%; N,%)
Calculated: 57.74; 4.85; 7.48
Found: 57.78; 5.03; 7.45
Spectrum ¹ H-NMR / 200 MHz, CDCl ₃ / δ: 1.30 / 3H, triplet, J = 7.2 Hz /, 2.45 / 3H, singlet /, 3.85 / 3H, singlet /, 4, 26 / 2H, quartet, J = 7.2 Hz /, 4.78 / 2H, singlet /, 6.95 / 2H, doublet, J = 8.8 Hz /, 7.31 / 2H, doublet, J = 8 , 8Hz /, 10.58 / 1H, singlet /.

IR spectrum / KBr /: 2914, 1742, 1713, 1655, 1605, 1568, 1528, 1499 cm ^-1 .

Reference Example 6
Using, as starting materials, the compounds obtained in Reference Examples 2, 3 or 4, in a manner similar to that described in Reference Example 5, the compounds shown in Table 2 were obtained.

Reference example 7
Obtaining ethyl ester of 2,4- / 1H, 3H / -dioxo-6- / 4-nitrophenyl / - 5-methylthieno [2,3-d] pyrimidin-3-acetic acid:
Concentrated sulfuric acid (12 ml) was added to compound 1 obtained in Reference Example 6 / 2.20 g, 6.39 mmol /. A solution of sodium nitrate (550 mg, 6.47 mmol) in conc. Was added dropwise to the resulting mixture under ice cooling. sulfuric acid, after which the mixture was stirred for one hour while cooling the system with ice. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried (MgSO ₄ ), after which 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, mp 277-280 ^° C.

Elemental analysis for C ₁₇ H ₁₅ N ₃ O ₆ S • 0.4H ₂ O:
(C,%; H,%; N,%)
Calculated: 51.48; 4.01; 10.59
Found: 51.64; 3.79; 10.61
Spectrum ¹ H-NMR / 200 MHz, CDCl ₃ / δ: 1.33 / 3H, triplet, J = 7.2 Hz /, 2.56 / 3H, singlet /, 4.28 / 2H, quartet, J = 7 , 2 Hz /, 4.79 / 2H, singlet /, 7.57 / 2H, doublet, J = 8.8 Hz /, 8.30 / 2H, doublet, J = 8.8 Hz /, 10.30 / 1H, singlet.

IR spectrum / KBr /: 1748, 1719, 1663, 1522, 1460 cm ^-1 .

Reference example 8
Obtaining ethyl ester of 2,4 / 1H, 3H / -dioxo-1- / 2-fluorobenzyl / - 6- / 4-nitrophenyl / -5-methylthieno [2,3-d] pyrimidine-3-acetic acid:
To a solution of the compound obtained in Reference Example 7/700 mg, 1.80 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 resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated and the concentrate was partitioned between ethyl acetate and an aqueous solution of sodium chloride. The aqueous layer was extracted with ethyl acetate. The combined extract was washed with an aqueous solution of sodium chloride, dried (MgSO ₄ ) and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography to give a white powder / 500 mg, 56% /. Mp 155-158 ^o C.

Elemental analysis for C ₂₄ H ₂₀ N ₃ O ₆ SF • 0.5H ₂ O:
(C,%; H,%; N,%)
Calculated: 56.91; 4.18; 8.30
Found: 56.74; 3.84; 8.25
Spectrum ¹ H-NMR / 200 MHz, CDCl ₃ / δ: 1.32 / 3H, triplet, J = 7.2 Hz /, 3.84 / 3H, singlet /, 4.27 / 2H, quartet, J = 7 , 2 Hz /, 4.84 / 2H, singlet /, 5.30 / 2H, singlet /, 7.06 - 7.33 / 4H, multiplet /, 7.54 / 2H, doublet, J = 8.9 / 7.27 (2H, doublet, J = 8.9 Hz).

IR spectrum / KBr /: 1748, 1711, 1673, 1520, 1491 cm ^-1 .

Reference example 9
Using as starting materials the substances obtained in Reference example 6, in accordance with the method described in Reference example 8, the compounds shown in Table 3 were obtained.

Reference Example 10
Obtaining ethyl 5-bromomethyl-2,4 / 1H, 3H / -dioxo-1- / 2-fluorobenzyl / -6- / 4-nitrophenyl / thieno [2,3-d] pyrimidine-3-acetic acid:
A mixture consisting of the compound obtained in example 8 / 0.300 g, 0.603 mmol /, N-bromosuccinamide / 0.107 g, 0.603 mmol /, α, α′-azobisisobutyronitrile / 10 mg, 0.60 mmol / and carbon tetrachloride / 15 ml /, heated under reflux for 2 hours. After cooling, insoluble compounds formed as a result of the reaction were filtered off from the reaction mixture. The filtrate was diluted with chloroform. The organic layer was washed with an aqueous solution of sodium chloride and dried (MgSO ₄ ), then the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 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.

Spectrum ¹ H-NMR / 200 MHz, CDCl ₃ / δ: 1.31 / 3H, triplet, J = 7.1 Hz /, 4.26 / 2H, quartet, J = 7.1 Hz /, 4.78 / 2H, singlet /, 4.86 / 2H, singlet /, 5.30 / 2H, singlet /, 7.07-7.37 / 4H, multiplet /, 7.75 / 2H, doublet, J = 8.8 Hz /, 8.33 (2H, doublet, J = 8.8 Hz).

IR spectrum / KBr /: 1713, 1673, 1524, 1477 cm ^-1 .

Reference example 11
Using, as starting materials, the compounds obtained in Reference Example 9, in a manner similar to that described in Reference Example 10, the compounds shown in Table 4 were obtained. Compounds 30-33 were prepared from compounds 30 or 31 of Reference Example 9 according to the method of Example 18,
Reference example 12
Preparation of 5- / N-benzyl-N-methylaminomethyl / -2.4- / 1H, 3H / -dioxo-1- / 2-fluorobenzyl / -6- / 4-nitrophenyl / thieno / 2,3-d ethyl hydrochloride / pyrimidine-3-acetic acid
Ethyl diisopropylamine / 0.12 ml, 0.710 mmol / and benzylmethylamine / 0.07 ml, 0, were added to a solution of the compound obtained in Reference Example 10 / 0.270 g, 0.47 mmol / in dimethylformamide / 10 ml / 56 mmol. The resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated and the concentrate was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried (MgSO ₄ ), after which the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel to give a colorless oil (0.29 g, 100%). To a solution of the obtained oil in ethyl acetate, a 1N solution of hydrogen chloride in ether was added under ice cooling. The resulting mixture was stirred for 10 minutes at the same temperature. The reaction mixture was concentrated under reduced pressure, and the concentrate was recrystallized from ethyl acetate-ether to give the corresponding hydrochloride (0.084 g) as white crystals. Mp 120-128 ^o C.

Elemental analysis for C ₁₂ 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.

IR spectrum / KBr /: 1711, 1665, 1522, 1493 cm ^-1 .

Reference Example 13
Preparation of 3-isobutyl-2,4 / 1H, 3H / -dioxo-5-methyl-6-N-methoxyphenyl / thieno [2,3-d] pyrimidine:
A mixture consisting of isovaleric acid / 1.15 ml, 10.03 mmol /, diphenylphosphoryl azide / 2.85 g, 10.30 mmol /, triethylamine / 1.45 ml, 10.03 mmol / and benzene / 15 ml / , heated for 1.5 hours under reflux until isobutyl isocyanate was isolated. To the resulting mixture was added the compound obtained in Reference example 2 / 2.00 g, 6.85 mmol / and benzene / 5 ml /; the resulting mixture was heated under reflux for 4 days. The reaction mixture was partitioned between ethyl acetate and an aqueous solution of sodium chloride. The aqueous layer was extracted with ethyl acetate, and the combined extracts were washed with an aqueous solution of sodium chloride and dried with MgSO ₄ , after which the solvent was removed under reduced pressure. The residue was chromatographed on silica gel to give a white powder (2.64 g, 99%). The obtained urea derivative was dissolved in ethanol (30 ml), 28% sodium methylate / 3.93 g, 20.37 mmol / was added to the solution, the resulting mixture was stirred at room temperature for 16 hours, and 1N hydrochloric acid / 22 ml, 22 was added. mmol. Solvent, ethanol was removed by distillation under reduced pressure. The resulting residue was filtered off, washed with water-ethanol, dried under reduced pressure, and then recrystallized from ethanol to give white needles / 1.61 g, 70% /.

Mp 215-216 ^o C.

Elemental analysis for C ₁₈ H ₂₀ N ₂ O ₂ S:
Calculated,%: C 62.77; H 5.85; N, 8.13.

 Found,%: C 62.75; H 15.82; N, 8.04.

Spectrum ¹ H-NMR / 300 MHz, CDCl ₃ / δ: 0.96 / 6H, doublet, J = 6.8 Hz /, 2.20 / 1H, septet, J = 6.8 Hz /, 2.50 / 3H, singlet /, 3.85-3.87 / 5H, multiplet /, 6.96 / 2H, doublet, J = 8.8 Hz /, 7.33 / 2H, doublet, J = 8.8 Hz /, 9.50 (1H, singlet).

IR spectrum / KBr /: 1711, 1657, 1537, 1499, 1458 cm ^-1 .

Reference Example 14
Using, as starting materials, the compounds obtained in Reference Example 2 or 4, in accordance with the method described in Reference Example 13, the compounds shown in Table 5 were obtained.

Reference Example 15
Preparation of 2-amino-4-methyl-5- / 4-methoxyphenyl / thiophene-3-carboxylic acid:
To an ethanol solution / 60 ml / of the compound obtained in Reference Example 2 / 3.0 g, 10.3 mmol /, 2N sodium hydroxide solution / 20.0 ml, 40.0 mmol / was added and the resulting mixture was heated under reflux for 1,5 hour. After cooling, 2N hydrochloric acid (20.1 ml, 40.0 mmol) was added to the reaction mixture to neutralize, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium chloride and dried over MgSO ₄ . The solvent was removed by distillation under reduced pressure, and the residue was washed with ether-hexane to give a light yellow powder (2.2 g, 91%).

Mp 142-145 ^o C.

Spectrum ¹ H-NMR / 200 MHz, DMSO-d ₆ / δ: 2.22 / 3H, singlet /, 3.79 / 3H, singlet /, 6.98 / 2H, doublet, J = 8.8 Hz /, 7.25 / 2H, doublet, J = 8.8 Hz /, 7.39 / 2H, singlet /.

IR spectrum / KBr /: 3470, 1647, 1576, 1508, 1475 cm ^-1 .

Reference example 16
Preparation of 2,4 / 1H / -dioxo-6- / 4-methoxyphenyl / -5-methylthieno [2,3-d] oxazine:
To the dioxane solution (10 ml) of the compound / 6.00 g, 22.8 mmol / obtained in Reference Example 15, triphosgene / 6.76 g, 22.8 mmol / was added and the resulting mixture was stirred at 100 ^° C. for 4 hours. After completion of the reaction, the reaction solution was concentrated, the residue was filtered and washed with ether to obtain a light yellow powder / 596 g, 90% /.

Mp 209-210 ^o C.

Spectrum ¹ H-NMR / 200 MHz, DMSO-d ₆ / δ: 2.36 / 3H, singlet /, 3.82 / 3H, singlet /, 7.06 / 2H, doublet, J = 8.8 Hz /, 7.41 / 2H, doublet, J = 8.8 Hz /, 10.50 / 1H, singlet /.

IR spectrum / KBr /: 1779, 1709, 1533, 1497 cm ^-1 .

Reference example 17
Preparation of 2,4 / 1H / -dioxo-1- / 2-fluorobenzyl / -6- / 4-methoxyphenyl / -5-methylthieno [2,3-d] oxazine:
To the dimethylformamide solution / 30 ml / of the compound / 4.80 g, 16.59 mmol / obtained in Reference Example 16, was added potassium carbonate / 3.43 g, 24.88 mmol /, potassium iodide / 2.75 g, 16 , 59 mmol / and 2-fluorobenzyl chloride / 2.96 ml, 24.88 mmol /, after which the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and an aqueous solution of sodium chloride. The aqueous layer was extracted with ethyl acetate, the extracts were combined and washed with an aqueous solution of sodium chloride and dried over MgSO ₄ , after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel chromatography to give the product as white crystals / 4.87 g, 74% /.

Mp 162-163 ^o C.

Spectrum ¹ H-NMR / 200 MHz, CDCl ₃ / δ: 2.43 / 3H, singlet /, 3.84 / 3H, singlet /, 5.21 / 2H, singlet /, 6.95 / 2H, doublet, J = 8.8 Hz /, 7.05-7.44 / 6H, multiplet /.

IR spectrum / KBr /: 1769, 1719, 1562, 1531, 1493 cm ^-1 .

FAB-MS m / z: 398.1 / MH ⁺ /.

Reference Example 18
Preparation of 2,4 / 1H / -dioxo-1- / 2,6-difluorobenzyl / -6- / 4-methoxyphenyl / -5-methylthieno [2,3-d] oxazine:
According to a method practically similar to that described in Reference example 17, using 2,6-difluorobenzyl chloride / 1.18 g, 7.26 mmol / instead of 2-fluorobenzyl chloride, from the compound / 2.00 g, 6.91 mmol / obtained in the Reference example 17, potassium carbonate / 0.95 g, 6.91 mmol / and potassium iodide / 1.15 g, 6.91 mmol / received the target compound as colorless crystals / 2.34 g, 82% /.

Mp 189-190 ^o C / recrystallization from a mixture of ethyl acetate-hexane /.

Spectrum ¹ H-NMR / 300 MHz, CDCl ₃ / δ: 2.42 / 3H, singlet /, 3.84 / 3H, singlet /, 5.27 / 2H, singlet /, 6.90-6.96 / 4H multiplet /, 7.24 - 7.36 / 3H, multiplet.

IR spectrum / KBr /: 1775, 1731, 1528, 1468 cm ^-1 .

Reference example 19
Preparation of 2,4- (1H, 3H) dioxo-1- (2-fluorobenzyl) -6- / 4-methoxyphenyl / - 3-3-methoxypropyl / -5-methylthieno [2,3-d] pyrimidine:
To a dichloromethane / 12 ml / solution of the compound obtained in Reference Example 17, 3-methoxypropylamine / 0.17 ml, 1.67 mmol / was added while cooling the system with ice, and the resulting mixture was stirred at room temperature for 1 hour. The residue obtained by concentrating the reaction mixture was partitioned between dichloromethane and an aqueous solution of sodium chloride. The aqueous layer was extracted with dichloromethane, the obtained extracts were combined, washed with an aqueous solution of sodium chloride and dried over MgSO _4, and then the solvent was distilled off. The residue thus obtained was purified by silica gel column chromatography to obtain a white powder / 524 mg, 78% /. The resulting amine derivative was dissolved in tetrahydrofuran / 20 ml / and triphosgene / 351 mg, 1.18 mmol / and triethylamine / 0.15 ml, 2.37 mmol / were added to the resulting solution, after which the mixture was stirred for 1, 5 hours when heated. After cooling, the reaction mixture was extracted with ethyl acetate, the organic layer was washed with an aqueous solution of sodium chloride and dried over MgSO _4, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography and, after drying, it was recrystallized from ethyl acetate-hexane to give a white crystalline plate (398 mg, 72%).

Mp 113-115 ^o C.

Elemental analysis for C ₂₅ H ₂₅ N ₂ O ₄ SF:
Calculated,%: C 64.09; H 5.38; N, 5.98.

 Found,%: C 63.89; H 5.39; N, 5.92.

Spectrum ¹ H-NMR / 300 MHz, CDCl ₃ / δ: 2.00 / 2H, quintet, J = 6.7 Hz /, 2.50 / 3H, singlet /, 3.34 / 3H, singlet /, 3, 50 / 2H, triplet, J = 6.7 Hz /, 3.83 / 3H, singlet /, 4.18 / 2H, triplet, J = 6.7 Hz /, 5.26 / 2H, singlet /, 6, 93 / 2H, doublet, J = 8.8 Hz /, 7.07-7.12 / 2H, multiplet /, 7.24-7.29 / 4H, multiplet /.

IR spectrum / KBr /: 1700, 1659, 1473 cm ^-1 .

Reference Example 20
Using, as starting compounds, which were obtained in Reference Example 18 by a method similar to that described in Reference Example 15, the substances shown in Table 6 were obtained.

Reference example 21
Preparation of 2,4 / 1H, 3H / dioxo-3-phenyl-5-methyl-6/4-methoxyphenyl / thieno [2,3-d] pyrimidine:
Phenyl isocyanate (2.66 ml, 24.48 mmol) was added to the pyridine solution (30 ml) of the compound / 5.00 g, 16.32 mmol / obtained in Reference Example 4. The resulting mixture was stirred for 6 hours at 45 ^o C, the reaction mixture was concentrated under reduced pressure to obtain a residue. This residue was dissolved in ethanol / 6 ml /. To the resulting solution was added 28% sodium methylate / 7.86 g, 40.80 mmol /, the resulting mixture was stirred for 2 hours at room temperature and 2N hydrochloric acid / 25 ml, 50 mmol / was added to the resulting mixture, followed by the solvent, ethanol was removed under reduced pressure. The resulting residue was filtered, washed with water-ethanol, dried under reduced pressure and recrystallized from ethanol to give a yellow powder / 6.09 g, 98% /.

Mp > 300 ^o C.

Elemental analysis for C ₁₉ H ₁₃ N ₃ O ₄ S • 0.3H ₂ O
Calculated,%: C 59.30; H 3.56; N, 10.92.

 Found,%: C 59.56; H 3.52; N, 10.93.

Spectrum ¹ H-NMR / 300 MHz, DMSO-d ₆ / δ: 2.50 / 3H, singlet /, 7.31-7.46 / 5H, multiplet /, 7.78 / 2H, doublet, J = 8, 8 Hz /, 8.32 / 2H, doublet, J = 8.8 Hz /, 12.50 / 1H, singlet /.

IR Spectrum / KBr /: 1715, 1657, 1593, 1510 cm ^-1 .

Reference Example 22
Preparation of 2,4 / 1H, 3H / -dioxo-5-methyl-3- / 3-methoxyphenyl / -6- / 4-methoxyphenyl / thieno [2,3-d] pyrimidine:
According to a method similar to that described in Reference example 21, using 3-methoxyphenyl isocyanate / 1.57 ml, 12.0 mmol / instead of phenyl isocyanate, from the compound / 3.06 g, 10.00 mmol / obtained in Reference example 4, and 28% sodium methylate / 4.82 g, 25.00 mmol / received the target compound as colorless crystals / 3.15 g, 77% /.

Mp > 300 ^o C.

Elemental analysis for C ₂₀ H ₁₅ N ₃ O ₅ • S:
Calculated,%: C 58.67; H 3.69; N, 10.26.

 Found,%: C 58.76; H 3.67; N, 10.32.

Spectrum ¹ H-NMR / 300 MHz, CDCl ₃ / δ: 2.50 / 3H, singlet /, 3.78 / 3H, singlet /, 6.87 / 1H, doublet, J = 8.1 Hz /, 6, 92 / 1H, singlet /, 7.00 / 1H, doublet, J = 8.1 Hz /, 7.38 / 1H, triplet, J = 8.1 Hz /, 7.77 / 1H, doublet, J = 8 7 Hz /, 8.31 / 2H, doublet, J = 8.7 Hz /, 12.48 / 1H, singlet /.

IR spectrum / KBr /: 1717, 1661, 1593, 1510, 1429 cm ^-1 .

Reference example 23
Preparation of 2,4 / 1H, 3H / -dioxo-1- / 2,6-difluorobenzyl / -5-methyl-3- / 3-methylsulfinyl phenyl / -6- / 4-methoxyphenyl / thieno [2,3-d] pyrimidine :
To the dichloromethane solution (20 ml) of compound 2/200 mg, 0.37 mmol / obtained in Reference Example 20 / Table 6 /, m-chloroperbenzoic acid / 129 mg, 0.37 mmol / was added under ice-cooling. The resulting mixture was stirred for 30 minutes and the reaction mixture was partitioned between dichloromethane and an aqueous solution of sodium chloride. The aqueous layer was extracted with dichloromethane, the combined extracts were dried, treated with an aqueous solution of sodium chloride and dried over MgSO ₄ , after which the solvent was removed under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give a white powder / 183 mg, 89% /.

Mp 267-268 ^o C.

Spectrum ¹ H-NMR / 300 MHz, CDCl ₃ / δ: 2.46 / 3H, singlet /, 2.79 / 3H, singlet /, 3.85 / 3H, singlet /, 5.35 / 2H, singlet /, 6.90 - 6.97 / 4H, multiplet /, 7.33-7.72 / 7H, multiplet /.

IR spectrum / KBr /: 1717, 1667, 1628, 1562, 1533 cm ^-1 .

EAB-MS m / z: 553.1 / MH ⁺ /.

Reference Example 24
Preparation of 2,4 / 1H, 3H / -dioxo-1- [2,6-difluorobenzyl] -5-methyl-3- / 3-methylsulfonylphenyl / -6- / 4-methoxyphenyl / thieno [2,3-d] pyrimidine :
By a method similar to that described in Reference example 23, again using m-chloroperbenzoic acid / 62 mg, 0.18 mmol /, from the compound / 100 mg, 0.18 mmol / obtained in Reference example 23, the title compound was obtained as colorless crystals / 98 mg, 95% /.

Mp 256-257 ^o C.

Spectrum ¹ H-NMR / 300 MHz, CDCl ₃ / δ: 2.46 / 3H, singlet /, 3.10 / 3H, singlet /, 3.85 / 3H, singlet /, 5.36 / 2H, singlet /, 6.90 - 6.97 / 4H, multiplet /, 7.29 - 8.01 / 7H, multiplet /.

IR spectrum / KBr /: 1719, 1665, 1531, 1473 cm ^-1 .

FAB-MS m / z: 569.1 / MH ⁺ /.

Reference example 25
Using, as starting materials, the compounds obtained in accordance with the methods described in Reference Examples 13, 14, 21 or 22, the compounds were obtained in accordance with the method described in Reference Example 17, which are presented in Table 7.

Reference example 26
Preparation of 2,4 / 1H, 3H / dioxo-1- [2-fluorobenzyl] -5-bromomethyl-6- / 4-methoxyphenyl / -3- / 3-methoxypropyl / thieno [2,3-d] pyrimidine:
A mixture consisting of compound / 270 mg, 0.576 mmol / obtained in Reference Example 19, N-bromosuccinimide / 103 mg, 0.576 mmol /, α, α′-azobisisobutyronitrile / 10 mg, 0.058 mmol / and carbon tetrachloride / 10 ml / heated under reflux. After cooling, insoluble matter was removed by filtration, the filtrate was diluted with chloroform. The organic layer was washed with an aqueous solution of sodium chloride and dried over MgSO ₄ , after which the solvent was distilled off under reduced pressure. The residue thus obtained was recrystallized from ethyl acetate to obtain a colorless powder / 249 mg, 93% /.

Mp 105-107 ^o C.

Spectrum ¹ H-NMR / 300 MHz, CDCl ₃ / δ: 2.01 / 2H, quintet, J = 6.7 Hz /, 3.33 / 3H, singlet /, 3.50 / 2H, triplet, J = 6 7 Hz /, 3.85 / 3H, singlet /, 4.21 / 2H, triplet, J = 6.7 Hz /, 4.81 / 2H, singlet /, 5.27 / 2H, singlet /, 6, 98 / 2H, doublet, J = 8.8 Hz /, 7.09-7.34 / 4H, multiplet /, 7.49 / 2H, doublet, J = 8.8 Hz /.

IR spectrum / KBr /: 1713, 1661, 1628, 1541 cm ^-1 .

FAB-MS m / z: 548.1 / MH ⁺ /.

Reference example 27
Using the compounds obtained in Reference Examples 19, 20, 23, 24 or 25 as starting materials, the compounds were prepared in accordance with the method described in Reference Example 26, which are presented in Table 8.

 Example 1

Preparation of 2,4 / 1H, 3H / -dioxo-6- / 4-methoxyphenyl / - 3-phenyl-1- / 2-fluorobenzyl / -5- / N-benzyl-N-methylaminomethyl / thieno hydrochloride [2,3- d] pyrimidine:
Ethyl diisopropylamine (0.08 ml, 0.460 mmol) and methylbenzylamine (0.05 ml, 0.370 mmol) were added to a solution of compound 5 obtained in Reference Example 11 (0.150 g, 0.310 mmol) in dimethylformamide (10 ml). After stirring for 2 hours at room temperature, the reaction mixture was concentrated. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried (MgSO ₄ ). 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%). To a solution of the obtained oil in ethyl acetate / 4 ml / was added, under ice-cooling, a 1N solution of hydrogen chloride in ether / 0.3 ml /. After stirring for 10 minutes under ice cooling, the reaction mixture was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-ether to give the desired hydrochloride salt (0.144 g) as white crystals.

Mp 140-143 ^o C.

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.

IR spectrum / KBr /: 1711, 1665, 1543, 1477 cm ^-1 .

 Example 2

 Using as the starting compounds the substances obtained in Reference Example 11, according to the method described in Example 1, the compounds listed in Table 9 were obtained.

 Example 3

Preparation of 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 Example 2 (0.15 g, 0.247 mmol) was dissolved in ethanol / 15 ml /, and 10% palladium on carbon / 15 mg / was added to the resulting mixture. The mixture was hydrogenated for 8 hours at room temperature under atmospheric pressure in a hydrogen atmosphere. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The concentrate was subjected to chromatographic purification on a silica gel column to obtain a yellow crystalline amorphous substance (0.046 g, 32%).

Spectrum ¹ H-NMR / 300 MHz, CDCl ₃ / δ: 2.05 / 3H, singlet /, 3.57 / 2H, singlet /, 3.81 / 2H, broad singlet /, 3.89 / 2H, singlet / , 5.29 / 2H, singlet /, 6.69 / 2H, doublet, J = 8.7 Hz /, 7.05 - 7.56 / 16H, multiplet /.

FAB-Macc spectrum m / z: 577 / MH ⁺ /.

 Example 4

Preparation of 6- / aminophenyl / -2,4- / 1H, 3H / -dioxo-1- / 2,6-difluorobenzyl / -5- / N-methyl-N-benzylaminomethyl / -3-phenylthieno [2,3-d ] pyrimidine:
Using as starting material the compound N 17 obtained in Example 2, in accordance with the method described in Example 3, the desired compound was obtained in the form of a crystalline amorphous material / 65% /.

Spectrum ¹ H-NMR / 300 MHz, CDCl ₃ / δ: 2.05 / 3H, singlet /, 3.56 / 2H, singlet / 3.81 / 2H, broad singlet /, 3.88 / 2H, singlet /, 5.36 / 2H, singlet /, 6.71 / 2H, doublet, J = 8.7 Hz /, 6.91 / 2H, triplet, J = 8.7 Hz /, 7.21-7.53 / 13H multiplet.

 Example 5

Preparation of 6- / 4-acetylaminophenyl / -2.4 / 1H, 3H / dioxo-1- / 2-fluorobenzyl / -5- / N-methyl-N-benzylaminomethyl / -3-phenylthieno [2,3-d] pyrimidine:
The compound obtained in Example 3 (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 resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The concentrate was distributed between methylene chloride / 30 ml / and a saturated aqueous solution of sodium chloride / 10 ml /. The aqueous layer was again extracted with methylene chloride / 30 ml /. The combined organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The resulting concentrate was purified by silica gel column chromatography to obtain a colorless solid / 0.01 g, 15% /.

Spectrum ¹ H-NMR / 300 MHz, CDCl ₃ / δ: 2.06 / 3H, singlet /, 2.19 / 3H, singlet /, 3.57 / 2H, singlet /, 3.90 / 2H, singlet /, 5.30 / 2H, singlet /, 7.04-7.57 / 16H singlet /, 7.70 / 2H, doublet, J = 8.4 Hz /.

 Example 6

 Using as starting materials the compound obtained in example 3 by a method similar to that described in Example 5, the following compounds were obtained.

N 1: Hydrochloride 2,4 / 2H, 3H / -dioxo-1- / 2-fluorobenzyl / -5- / N-methyl-N-benzylaminomethyl / -3-phenyl-6- / 4-propionylaminophenyl / thieno [2, 3-d] pyrimidine / yield: 86%, mp. 172-175 ^o C /.

N 2: Hydrochloride 2,4 / 2H, 3H / -dioxo-1- / 2-fluorobenzyl / -6- / 4-isobutyrylaminophenyl / -5- / N-methyl-N-benzylaminomethyl / -3-phenylthieno [2,3 -d] pyrimidine / yield: 77%, mp. 185-188 ^o 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 ^o C /.

 Example 7

Preparation of 2,4 / 1H, 3H / -dioxo-1- / 2-fluorobenzyl / -5- / N-benzyl-N-methylaminomethyl / -6- / 4-methoxyphenyl / -3- / 3-methoxy-propyl / thieno [2,3-d] pyrimidine:
Ethyl diisopropylamine (0.140 ml, 0.780 mmol) and methylbenzylamine (0.080 ml, 0.620 mmol) were added to the dimethylformamide / 10 ml / compound solution / 284 mg, 0.519 mmol / obtained in Reference Example 26. The resulting mixture was stirred at room temperature for 2 hours, then it was concentrated and the resulting residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate. The extract and the organic layer were combined, dried with MgSO ₄ , and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to obtain a colorless oily substance / 280 mg, 92% /. This oily substance was dissolved in ethyl acetate / 4 ml / and a 1N solution of hydrogen chloride in ether / 0.3 ml / was added to the resulting solution while cooling the system with ice. The resulting mixture was stirred under ice cooling, and the reaction mixture was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-ether to give the hydrochloride salt of the target compound (220 mg) as white crystals.

Mp 95-100 ^o C.

Elemental analysis for C ₃₅ H ₃₄ N ₃ O ₄ SF • 1.0HCl • 0.5H ₂ O:
Calculated,%: C 62.60; H 5.73; N, 6.64.

 Found,%: C 62.73; H 5.67; N, 6.56.

IR spectrum / KBr /: 1702, 1657, 1562, 1543, 1489 cm ^-1 .

 Example 8

Using, as starting materials, the compounds obtained in Reference Example 27, in accordance with the method described in Example 7, the compounds listed in Table 10 were obtained. Compounds 19 and 20 were obtained by hydrolysis of compound 21 to obtain compound 22 and reaction of the compound
22 with alkyl halide in the presence of a base.

Example 9
Preparation of 6- / 4-aminophenyl / -2,4- / 1H, 3H / -dioxo-1- / 2,6-difluorobenzyl / -5 - / - benzyl-N-methylaminomethyl / -3- / 3-methoxyphenyl hydrochloride thieno [2,3-d] pyrimidine:
To formic acid / 200 ml / was added, under ice-cooling, a solution of compound 13 obtained in Example 8, 50% palladium-carbon in powder form / 0.90 g /, and the resulting mixture was stirred for 2 hours in a hydrogen atmosphere at room temperature. The reaction mixture was concentrated and the residue was partitioned between dichloromethane and saturated sodium bicarbonate. The aqueous layer was extracted with dichloromethane and the extract was combined with the organic layer. The resulting mixture was dried with MgSO ₄ and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain a colorless powder / 5.13 g, 60% /. The compound thus obtained (100 mg) was dissolved in ethyl acetate / 4 ml /, and a 1N solution of hydrogen chloride in ether / 0.3 ml / was added to the resulting solution under ice cooling, and the resulting mixture was stirred for 10 minutes while cooling the system with ice . The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-ether to give the desired compound hydrochloride (95 mg) as white crystals.

Mp 162-165 ^o C.

Elemental analysis for C ₃₅ H ₃₀ N ₄ O ₃ SF ₂ • 2.0HCl • 1.0H ₂ O:
Calculated,%: C 58.74; H 4.79; N, 7.83.

 Found,%: C 58.44; H 4.72; N, 7.66.

IR spectrum / KBr /: 1715, 1659, 1537, 1473 cm ^-1 .

Example 10
Using as the starting compounds the substances obtained in Example 8, in accordance with the method described in Example 9, the compounds listed in Table 11 were obtained.

Example 11
Preparation of 2,4 / 1H, 3H / -dioxo-1- / 2,6-difluorobenzyl / -5- / N-benzyl-N-methylaminomethyl / -6- / 4-formamidophenyl / -3-phenylthieno [2,3- d] pyrimidine.

Formic acid (0.5 ml, 13.3 mmol) was added to acetic anhydride (1.0 ml, 10.6 mmol) under ice-cooling, the resulting mixture was stirred for one hour at 50 ^° C. to obtain a mixed formic anhydride and acetic acid . To a tetrahydrofuran (10 ml) solution of compound 2/200 ml, 0.34 mmol / obtained in Example 10, mixed formic acetic anhydride / 0.3 ml / was added under ice-cooling, and the mixture was stirred for 30 minutes. The resulting mixture was stirred for one hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a colorless solid (125 mg), which is the target compound.

Mp 194-196 ^o C.

Elemental analysis for C ₃₅ H ₃₀ N ₄ O ₃ SF ₂ • 0.5H ₂ O:
Calculated,%: C 66.55; H 4.63; N, 8.87.

 Found,%: C 66.74; H 4.56; N, 8.88.

Spectrum ¹ H-NMR / 300 MHz, CDCl ₃ / δ: 3.57 / 2H, singlet /, 3.90 / 2H, singlet /, 5.37 / 2H, singlet /, 6.90-7.30 / 12H multiplet /, 7.34-7.79 / 6H, multiplet /, 8.42 / 1H, singlet /.

IR spectrum / KBr /: 1715, 1665, 1531, 1467 cm ^-1 .

Example 12
Using as the starting materials the compounds obtained in Example 9 or 10 in accordance with the method described in Example 1: 1, the compounds listed in Table 12 were obtained.

Example 13
Preparation of 2,4 / 1H, 3H / -dioxo-1- / 2,6-difluorobenzyl / - 5- / N-benzyl-N-methylaminomethyl yl / -6- / 4-methylaminophenyl / -3- / 3- methoxyphenyl hydrochloride / thieno [2,3-d] pyrimidine:
To a tetrahydrofuran (30 ml) solution of compound 2 (730 mg, 1.12 mmol) obtained in Example 12, borane dimethyl sulfide (0.28 ml, 2.8 mmol) was added under ice-cooling, and the resulting mixture was heated for 2 hours reflux condenser. After adding hydrochloric acid (pH <2) and subsequent heating under reflux for 1 hour, the resulting solution was concentrated and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane, the extract was combined with the organic layer, the resulting mixture was dried over MgSO ₄ and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain a colorless powder / 610 mg, 85% /. To an ethyl acetate / 4 ml / solution of the compound thus obtained was added a 1N solution of hydrogen chloride in ether / 0.3 ml / while cooling the system with ice, and the resulting mixture was stirred for 10 minutes under ice cooling. The residue obtained by concentrating the reaction mixture under reduced pressure was recrystallized to give white crystals / 95 mg / of the target compound hydrochloride.

Mp 155-160 ^o C.

Elemental analysis for C ₃₅ H ₃₀ N ₄ O ₃ FS ₂ • 2.0HCl, 0.5 AcOEt • 3.0H ₂ O
Calculated,%: C 56.36; H 5.47; N, 6.91.

 Found,%: C 56.08; H 5.22; N, 6.86.

IR spectrum / KBr /: 1715, 1663, 1607, 1543, 1475 cm ^-1 .

Example 14
Preparation of 2,4 / 1H, 3H / -dioxo-1- / 2,6-difluorobenzyl / 6- / 4-propionylaminophenyl / -5 - / - benzyl-N-methylaminomethyl / -3- / 3-methoxyphenyl / thieno hydrochloride [ 2,3-d] pyrimidine:
To dichloromethane / 10 ml / solution of the compound / 250 mg, 0.38 mmol / obtained in Example 9 was added triethylamine / 0.053 mg, 0.38 mmol / and propionyl chloride / 0.033 ml, 0.38 mmol / while cooling the system with ice and the resulting mixture was stirred for one hour. The reaction mixture was partitioned between dichloromethane and saturated sodium bicarbonate. The aqueous layer was extracted with dichloromethane, the extracts were combined and washed with an aqueous solution of sodium chloride and then dried over MgSO ₄ , then, under reduced pressure, the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain a colorless oily substance / 220 mg, 82% /. To an ethyl acetate / 4 ml / solution of the acyl derivative thus obtained was added a 1N solution of hydrogen chloride in ether / 0.3 ml / while cooling the system with ice, and the resulting mixture was stirred for 10 minutes under ice cooling. The reaction mixture was concentrated under reduced pressure, the residue was recrystallized to obtain white crystals of hydrochloride / 213 mg / of the target compound.

Mp 218-224 ^o C.

IR Spectrum / KBr /: 1713, 1665, 1601, 1543, 1475 cm ^-1 .

Example 15
Using as starting materials the compounds obtained in Example 9 or 10 in accordance with the method described in Example 14, the compounds are listed in Table 13.

Example 16
Using a procedure similar to that described in Example 14, and using the compound obtained in Example 9 or 10, as well as anhydrous trifluoroacetic acid instead of propionyl chloride, a trifluoroacetylamino derivative was obtained. To the resulting derivative was added a halogenated derivative (for example, propyl bromide, isopropyl bromide) in the presence of an appropriate base / for example potassium carbonate / in a solvent / for example in dimethylformamide /, which does not undesirably affect the course of the reaction and the resulting mixture was stirred for 1-6 hours at room temperature. A 2N aqueous sodium hydroxide solution was added to the reaction mixture to effect hydrolysis for 1 to 2 hours to obtain the compounds listed in Table 14.

Example 17
Using the compounds obtained in Example 9 or 10 as starting materials, the compounds listed in Table 15 were obtained by reacting the starting compounds with isoamyl nitrite, a vinyl compound and a palladium compound (for example, palladium tetrakistriphenylphosphine, palladium dibenzylideneacetone) in acetic acid with stirring at room temperature or when heated for 1-6 hours.

Example 18
To a mixture of compound 30 or 31, which were obtained in Reference Example 9, a small amount of an arylboric acid derivative, a 2M aqueous solution of sodium carbonate and 1,2-dimethoxyethane, as well as a catalytic amount of tetrakis / triphenylphosphine / palladium / O / were added and the resulting the mixture was stirred under reflux for 2 hours. An N-methylbenzylamino group was introduced into the resulting compound in accordance with the method described in Reference Example 26 and Example 1 to obtain the compounds listed in Table 16.

Example 19
To the compounds obtained in Example 2, 3 equivalents of dimethyl sulfide and 3 equivalents of aluminum chloride were added in dichloromethane under ice cooling. The resulting mixture was stirred for 1-4 hours to obtain an R ⁴ phenol derivative. The compound thus obtained, a small amount of alkyl halide (for example, chlorine acetone) and a base (for example, potassium carbonate) were mixed in dimethylformamide to give the compounds listed in Table 17.

Example 20
Using the compound obtained in Example 4/100 mg /, lactose / 165 mg /, corn starch / 5 mg /, polyvinyl alcohol / 4 mg / and magnesium stearate / 1 mg /, a tablet was conventionally prepared.

Example 21
The compound obtained in Example 4/5 g / was dissolved in distilled water for injection to obtain a preparation in a total volume of 100 ml. The resulting solution was subjected to sterilization filtration using a 0.22 μm membrane filter / manufactured by Sumitomo Electric Industries Ltd. or Zartolius Inc. /, 2 ml volumes of each of the preparations were placed in sterilized ampoules, after which lyophilization was carried out using standard methods to obtain a lyophilized solution for injection in an amount of 100 mg / ampoule.

Example 22
Using the compound 1 obtained in Example 15/100 mg /, lactose / 165 mg /, corn starch / 25 mg /, polyvinyl alcohol / 4 mg / and magnesium stearate / 1 mg /, tablets were conventionally prepared.

Example 23
Compound 1 obtained in example 15/5 g / was dissolved in distilled water for injection, bringing the volume to 100 ml. The resulting solution was subjected to sterilization filtration using a 0.22 μm membrane filter / manufactured by Sumitomo Electric Industries, Ltd. or Zartolius, Inc. /, 2 ml volumes were placed in sterile ampoules, and then lyophilization was carried out by standard methods to obtain a lyophilized solution for injection in an amount of 100 mg / ampoule.

Example 24
The compound obtained in Example 4, or the compound 1 of Example 15 to 5 g
/ 2 / Lactose, crystalline cellulose / granules / - 330 g
/ 3 / D-mannitol - 29 g
/ 4 / Low-substituted hydroxypropyl cellulose - 20 g
/ 5 / Talc - 25 g
/ 6 / Hydroxypropyl cellulose - 50 g
/ 7 / Aspartame - 3 g
/ 8 / Dipotassium glycyrrhetinate - 3 g
/ 9 / Hydroxypropylmethyl cellulose 2910 - 30 g
/ 10 / Titanium oxide - 3.5 g
/ 11 / Yellow iron semi-oxide - 0.5 g
/ 12 / Light silicic anhydride - 1 g
Suspended or dissolved in purified water / 1 /, / 3 /, / 4 /, / 5 /, / 7 / and / 8 /. The core of the granules / 2 / was coated with a suspension or solution to obtain crude fine granules, which were coated with materials / 9 / - / 11 / to obtain coated fine granules, which were mixed with / 12 / to obtain 500 g of small granules containing 1% of the compound obtained in Example 4, or the compound 1 of Example 15. 500 mg packaging was prepared from the thus obtained small granules.

 Industrial applicability.

 The thienopyrimidine derivative / 1 / of the present invention is an effective prophylactic or therapeutic agent for preventing or treating certain hormone-dependent diseases, for example, sex hormone-dependent cancer / for example, prostate cancer, cervical cancer, breast cancer, pituitary adenoma /, benign prostatic hypertrophy, uterine fibroids, endometriosis, premature puberty, amenorrhea, premenstrual syndrome, polycystic ovary syndrome and acne ; they are effective agents for controlling fertility in both sexes (for example, agents that control pregnancy and the menstrual cycle); these substances can be used as a contraceptive for men or women, as agents that induce ovulation in women; they can be used as agents for the treatment of infertility using the effect of the response to discontinuation of the drug; these substances can be used as modulators of estrous cycles in animals in the field of livestock farming, as an agent that improves the quality of edible meat or promotes the growth of animals; as well as an agent that promotes fish spawning.

Claims (11)

1. The compound of thienopyrimidine of General formula

where Q is phenyl, which may be substituted by one or more substituents selected from the group consisting of halogen, alkoxy and alkylthio;
R ² represents (i) a C _1-6 alkyl group which may be substituted by one or two alkoxy group (s), (ii) a phenyl group which may be substituted by one or two substituents selected from the group consisting of alkoxy group, alkylthio group an alkylsulfinyl group, an alkylsulfonyl group, a halogen atom, a hydroxy group and an alkoxyalkoxy group, (iii) a benzyl group or (iv) a C _5-6 cycloalkyl group;
R ³ represents an amino group substituted by one or two substituents selected from the group consisting of (i) a benzyl group which may be substituted by a C _1-6 alkylthio group, and (ii) a C _1-6 alkyl group which may be substituted by a pyridyl group a group, a di-alkylamino group or a pyrrolidinyl group; and
R ⁴ represents a phenyl group substituted by (i) a C _1-6 alkoxy group which may be substituted by a C _1-6 acyl group, a C _1-6 alkenyl group or a C _3-6 cycloalkyl group (ii) a nitro group, (iii) C _1-6 alkylamino-carbonyl group, (iv) NC _1-6 alkyl-NC _1-6 alkylaminocarbonyl group, (v) amino group, (vi) C _1-6 alkylamino group, (vii) C _1-6 acylamino group, which may be substituted by one to three C _1-6 alkoxy or halogen (s), (viii) NC _1-6 alkyl-NC _1-6 acylamino group, (ix) benzoylamino group, (x) C _1-6 alkylsulfonylamino group, (xi) formamide group or (xii) a C _1-6 alkenyl group substituted with a C _1-6 alkoxy carbonyl or a C _1-6 acyl; or its salt.  2. The compound according to claim 1, which is 2,4- (1H, 3H) -dioxo-6- (4-methoxyphenyl) -3-phenyl-1- (2-chloro-6-fluoro-benzyl) -5 - (N-benzyl-N-methylaminomethyl) thieno [2,3-d] pyrimidine or a salt thereof.  3. The compound according to claim 1, which is 2,4- (1H, 3H) -dioxo-1- (2,6-difluorobenzyl) -6- (4-propionylaminophenyl) -5- (N-benzyl-N- methylaminomethyl) -3- (3-methoxyphenyl) thieno [2,3-d] pyrimidine or a salt thereof.  4. The compound according to claim 1, which is 2,4- (1H, 3H) -dioxo-1- (2,6-difluorobenzyl) -6- (4-isobutyrylaminophenyl) -5- (N-benzyl-N- methylaminomethyl) -3- (3-methoxyphenyl) thieno [2,3-d] pyrimidine or a salt thereof.  5. The compound according to claim 1, which is 5- (N-benzyl-N-methylaminomethyl) -1- (2,6-difluorobenzyl) -2,4- (1H, 3H) dioxo-6- (4- propionylaminophenyl) -3-phenylthieno [2,3-d] pyrimidine or a salt thereof. 6. A method for producing a compound according to claim 1, which comprises reacting a compound of the formula

where X - represents a leaving group, and other symbols have the meanings defined in claim 1, or its salts with a compound of the formula R ³ - H, where R ³ has the meaning defined in claim 1, or its salt.  7. A pharmaceutical composition having hormonal antagonistic activity of gonadotropin hormone secretion, containing the compound according to claim 1, and, in addition, a carrier, excipient or diluent.  8. The composition according to claim 7, which is a gonadotropin-releasing hormone antagonistic composition.  9. The compound according to claim 1, having a gonadotropin-releasing hormone antagonistic activity.  10. The compound according to claim 1 for producing a gonadotropin-releasing hormone antagonistic composition for antagonizing a gonadotropin-releasing hormone in a mammal suffering from a disease caused by a gonadotropin-releasing hormone.  11. The compound of claim 9, wherein the gonadotropin-releasing hormone disorder is a sex hormone dependent disease. Priority on points:
02/08/1995 according to claims 1, 2, 6 - 11;
02/19/1995 - according to paragraphs 3 - 5.

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