CZ290723B6 - Condensed bicyclic thiophene derivatives, process of their preparation, pharmaceutical preparations in which they are comprised as well as their use - Google Patents

Abstract

Gonadotropin releasing hormone antagonistic (GnRH-A) compsn. comprises a condensed bicyclic cpd. (opt. substd.) consisting of two homo or hetero 5-7 membered rings, a carrier, and a diluent or excipient.

Description

Technical field

The invention relates to fused bicyclic thiophene derivatives, a process for their preparation, a pharmaceutical composition comprising them and their use.

The thiophene derivatives of the present invention are effective for the antagonist-acting hormone that releases gonadotropin.

BACKGROUND OF THE INVENTION

The anterior pituitary hormone secretion is regulated by peripheral hormone secreted from the target organs of the respective hormones and secreted by the hypothalamic hormone, which is the upper central organ of the anterior pituitary gland (referred to collectively as "hypothalamic hormones"). Nowadays, there are nine types of hormones confirmed as hypothalamic hormones including, for example, thyrotropin releasing hormone (TRH) or gonadotropin releasing hormone [GnRH: sometimes called LH-RH (luteinizing hormone releasing hormone)] [see Seirigaku2 by M. Iriku and K. Toyama , Bunkohdo, pp. 610-618 (1968).]. These hypothalamic hormones are believed to act through receptors believed to exist in the anterior pituitary gland (see above). Studies have been developed to observe receptor genes specific for these hormones, including human studies [Kiso To Rins Receptor by H. Imura et al., Published by Asakura Shoten, pp. 297-304, 1993.]. Antagonists or agonists specifically and selectively acting on these receptors regulating the action of the hypothalamic hormone and regulate the secretion of the anterior pituitary lobe. As a result, they are expected to be useful for the prophylactic and therapeutic agents of anterior pituitary lobe diseases.

Leuprorelin acetate [Fujino et al .: Biological and Biophysical Research Communications 60, 00.406 (1974), Oliver RTD et al .: British Joumal of Cancers 59, 823 (1989) and Toguchi et al .: Joumal of Intemational Medical Research 18, 35. ], which is a highly potent derivative of the gonadotropic hormone releasing hormone, one of the hypothalamic hormones (hereinafter sometimes referred to as GnRH) [Schally AV et al., Joumal of Biological Chemistry 246, 7230 (1971) and Burgus R. et al. Proceeding of Natural Academic Science, USA 69, 278 (1972).] Reduces the production of gonadotropic hormone release in the pituitary when administered at multiple doses. This causes a decrease in the reactivity of the gonadotropic hormone in the testes and ovaries and suppresses the secretion of testosterone and estrogen. Thus, leuprorelin acetate is known to exhibit antitumor activity on hormone-dependent cancers such as prostate cancer. Leuprorelin acetate is widely used in the clinical field. Leuprorelin acetate is also widely used clinically as a therapeutic agent, for example in endometriosis and premature puberty. The high antitumor activity of leuprorelin acetate is believed to exist due to its high resistance to the protease as compared to natural GnRH and its high affinity for the GnRH receptor, causing desensitization of GnRH by reducing the number of receptors. However, since leuprorelin acetate is an ultra-agonist at the GnRH receptor, it is known that transient aggravation (worsening) is observed immediately after the first administration with an increase in serum testosterone concentration due to the gonadotropic action of the pituitary gland (acute effect). In view of the above, GnRH antagonist medicaments that are expected to have substantially the same therapeutic effects described above but which do not cause the above-mentioned transient gonadotropic pituitary action (acute effect) are desirable. Compounds having this GnRH antagonist activity include numerous compounds including, for example, GnRH derivatives such as straight chain peptides (US Patents 5140009 and 5171835), cyclic hexapeptide derivatives (Japanese

Patent application S61 (1966) -191698.) Or bicyclic peptide derivatives [Joumal of Medicinal Chemistry 36, 3265 (1993).]. However, all of these compounds are peptides which present many problems regarding, for example, dosage forms, drug stability, durability of action and metabolic stability. Orally administrable GnRH antagonist drugs, especially non-peptide drugs, are highly desirable to address these problems. However, there is currently no report of non-peptide GnRH antagonist drugs.

It is an object of the present invention to provide novel compounds having excellent gonadotropic hormone releasing hormone antagonist activity as well as excellent gonadotropic hormone releasing hormone antagonists.

SUMMARY OF THE INVENTION

The present invention provides fused bicyclic thiophene derivatives of formula (I)

(I) in which:

- R ¹¹ is hydrogen, C _1-6 alkyl, a group of formula Q- (CH 2) p -, wherein p is 1 or 2 and Q is

C 6-14 aryl, optionally substituted

a) halogen,

(b) nitro;

(c) cyano;

d) amino,

e) carboxyl optionally substituted with (1) C 1-6 alkyl, (2) C 1-6 cycloalkyl, (3) C 6-14 aryl, (4) C 6-14 aryl-C 1-6 alkyl, (5) a 5-membered cyclic group selected from 2- or 3-thienyl , 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl,

2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or 5- (1,2,4-thiadiazolyl), 1, 3,4-thiadiazolyl, 4- or 5- (1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl and 1H- or 2H- (6) a 6-membered cyclic group selected from the group consisting of N-oxido-2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxido-2-, 4- or 5-pyrimidinyl, 2- or 3-thiomorpholinyl, 2- or 3-morpholinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, 2- or 3-piperazinyl , triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl and N-oxido-3- or 4-pyridazinyl, or (7) a 5-8 membered cyclic group or a fused ring thereof selected from benzofuryl benzothiazolyl, benzoxazolyl, tetrazolo [ 1,5-b] pyridine zinyl, triazolo [4,5-b] pyridazinyl, benzoimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indosinyl, quinolizinyl, 1,8-naphthylisinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, phenazinyl, phenazinyl, phenazinyl, phenazinyl, phenazinyl, phenazinyl, phenol, phenothiazinyl and phenoxazinyl,

-2GB 290723 B6

f) _C1-6 alkylenedioxy;

g) a group of the formula -AR ¹⁵ wherein A is

a) chemical bond,

b) C ₂ _4alkylen,

c) C ₂ _ ₆ alkenylene,

d) a group of the formula - (CH ₂ ) _c NR ²⁴ wherein c is 0 to 3 and R ²⁴ is hydrogen or C 1-6 alkyl,

e) a group of the formula -CO-,

f) a group of the formula -CONR ²² wherein R ²² is (1) hydrogen, (2) C ^ alkyl, (3) C ₃ _éCykloalkyl (4) Ce-uaryl, (5) a 5-membered cyclic group selected from the group consisting of 2- or

3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl,

2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl,

3- or 5- (1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or 5- (1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2, 3-triazolyl, 1,2,4-triazolyl and 1H- or 2H-tetrazolyl, (6) a 6-membered cyclic group selected from the group consisting of N-oxido-2-, 3- or 4-pyridyl, 2-, 4- or 5 -pyrimidinyl, N-oxido-2-, 4- or 5-pyrimidinyl, 2- or 3-thiomorpholinyl, 2- or 3-morpholinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl,

1,4-thiazinyl, 1,3-thiazinyl, 2- or 3-piperazinyl, triazinyl, oxotriazinyl, 3- or

4-pyridazinyl, pyrazinyl and N-oxido-3- or 4-pyridazinyl, (7) a 5-8 membered cyclic group or a fused ring thereof selected from benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzoimidazolyl, quinolyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl,

1,8-naphthylisinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl and phenoxazinyl, or (8) a -SO _P - group in which p is 1 or 2,

g) -o-

(h) —S— or

(i) a group of the formula NR ²² S (O) _e - in which e is 0 to 2 and R ²² is as above;

R ¹⁵ is C 1-6 alkyl,

^R12 is i) hydrogen, ii) C] _ ₆ alkyl, iii) a Ce-uaryl, optionally substituted, iv) C ₆ ..i _4-aryl-C 1 alkyl, optionally substituted, or v) C3 _{'to 4} or cycloalkyl C ₃ _ ₁₀ bicycloalkyl, optionally substituted,

- R ¹³ is a group of the formula -NR ²² R ²³ 'wherein R ²² is (1) C ^ alkyl, optionally substituted, (2) C ₃ _ ₆ cycloalkyl, optionally substituted, (3) ₄ C6_i aryl, optionally substituted (4) an optionally substituted 5-membered cyclic group selected from 2 or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4 or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl,

3- or 5- (1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or 5- (1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2, 3-triazolyl, 1,2,4-triazolyl and 1H- or 2H-tetrazolyl, (5) an optionally substituted 6-membered cyclic group selected from the group consisting of N-oxido-2-, 3- or 4-pyridyl, 2-,

4- or 5-pyrimidinyl, N-oxido-2-, 4- or 5-pyrimidinyl, 2- or 3-thiomorpholinyl, 2- or

3-morpholinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, 2- or 3-piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl and N-oxido-3- or 4-pyridazinyl, or (6) an optionally substituted 5- to 8-membered cyclic group or fused ring thereof selected from benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4] , 5-b] pyridazinyl, benzoimidazolyl, quinolyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8-naphthylisinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acrydinyl, phenanthridinyl, phenanthridinyl, phenanthridinyl, phenanthridinyl, phenanthridinyl and phenoxazinyl, and R ²³ is hydrogen or optionally substituted C 1-4 alkyl,

R ¹⁴ is optionally substituted C 6 -C 8 aryl, the substituents for the above

Ci_6alkyl, C ₃ _iocykloalkyl, C _{3 _] 0} bicycloalkyl, _C6 _i ₄ aryl, Ce-uaryl-C ^ alkyl, 5-membered cyclic group membered cyclic group and a 5 to 8-membered cyclic group, or a fused ring are individually 1-6 substituents selected from the group consisting of

a) C ₆ -C 18 aryl, optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, amino, mono- or di-C _1-6 alkylamino, C _1-6 alkoxy and halogen,

b) a mono- or di-C 1-6 alkylamino group,

c) C1-4 acylamino,

(d) hydroxyl;

e) carboxyl,

(f) nitro;

g) C _M alkoxy,

h) C 1-6 alkylcarbonyloxy,

(i) halogen; and

j) a group of the formula -NR ²² R ²³ wherein R ²² is (1) hydrogen, (2) CXalkyl, (3) C ₃ _6cykloalkyl (4) Ce-uaryl, (5) a 5-membered cyclic group selected from the group consisting of 2- or

3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl,

2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or

5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl,

3- or 5- (1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or 5- (1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2, 3-triazolyl, 1,2,4-triazolyl and 1H- or 2H-tetrazolyl, (6) a 6-membered cyclic group selected from the group consisting of N-oxido-2-, 3- or 4-pyridyl, 2-, 4- or 5 -pyrimidinyl, N-oxido-2-, 4- or 5-pyrimidinyl, 2- or 3-thiomorpholinyl, 2- or 3-morpholinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1 , 4-thiazinyl, 1,3-thiazinyl, 2- or 3-piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl and N -oxido-3- or 4-pyridazinyl, (7) a 5-8 membered cyclic group, or a fused ring thereof selected from benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzoimidazolyl, quinolyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, indolizinyl, quinolinyl, quinolinyl, quinolinyl, quinolinyl 8-naphthylisinyl, purinyl, pteridinyl, dibenzofuranyl, carbazo (8) a -SOp- group in which p is 1 or 2, and R ²³ is hydrogen or C 1-6 alkyl, wherein the group of the formula -NR ²² R ²³ is optionally substituted with 1-6 substituents selected from the group consisting of (1) C ^ alkyl), (2) C ₂ _6alkenyl, (3 ') C ^ alkynyl, (4) C ₃ ^ cycloalkyl, (5' ) C ₅ _ ₇ cycloalkenyl, (6 ') C7_naralkyl, (7') C6_ ₁₄ aryl, (8) C ^ alkoxy, (9 ')

-4GB 290723 B6

C ^ aryloxy, (10 ') Ci_6alkanoyl (1 Γ) C ₆ _i4arylkarbonyl, (12') C _g alkanoyloxy, (13) C ^ uarylkarbonyloxyl, (14 ') carboxy, (15') C ^ alkoxycarbonyl, (16 ') carbamoyl, (17') N-monoC 1-4 alkylcarbamoyl, (18 ') N, N-di-C 1-4 alkylcarbamoyl, (19') cyclic aminocarbonyl selected from the group consisting of 1-aziridinylcarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl,

1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl and morpholinocarbonyl, (20 ') halogen, (2Γ) mono- to trihalogen-C | ₍₄ ') alkyl, (22') oxo, (23 ') amidino, (24') imino, (25 ') amino, (26') mono- or di-C 1-6 alkylamino, (27 ') 3-6 membered cyclic amino, containing, in addition to the carbon atom and one nitrogen atom, 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, (28 ') C 1-6 alkanoylamino, (29') benzamido, (30 ') carbamoylamino, (31') N-C 1-4 alkylcarbamoylamino, (32 ') N, N-di-C 1-4 alkylcarbamoylamino, (33') C _1-3 alkylenedioxy, (34 ') -B (OH) ₂ , (35') hydroxyl, (36 ') epoxy, (37') ') nitro, (38') cyano, (39 ') mercapto, (40') sulfo, (4Γ) sulfino, (42 ') phosphono, (43') sulfamoyl, (44 ') C 1-6 alkylsulfamoyl, (45') di -C 1-6 alkylsulfamoyl, (46 ') C _1-6 alkylthio, (47') phenylthio, (48 ') C _1-6 alkylsulfinyl, (49') phenylsulfinyl, (50 ') C _1-6 alkylsulfonyl and (51') phenylsulfonyl, ar is 0 to 3, or salts thereof.

One preferred class of derivatives of the invention of formula I wherein R ¹¹ is a group of formula Q- (CH _{2) p} - in which p is 1 or 2 and Q is Ce-uaryl, optionally substituted

a) halogen,

(b) nitro, (c) cyano,

d) amino,

e) carboxy, optionally substituted (1) C | _ ₆ alkyl, (2) C ₃ _6cykloalkylem, (3) C ₆ _i4arylem, (4) C-uaryl-C n alkyl, (5) 5-membered cyclic group selected from the group consisting of 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl,

2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or

5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or 5- (1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or 5- (1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1 2,4-triazolyl and 1H- or 2H-tetrazolyl, (6) a 6-membered cyclic group selected from the group consisting of N-oxido-2-, 3- or 4-pyridyl,

2-, 4- or 5-pyrimidinyl, N-oxido-2-, 4- or 5-pyrimidinyl, 2- or 3-thiomorpholinyl, 2- or 3-morpholinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, 2- or 3-piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl and N-oxido-3- or 4-pyridazinyl, or (7) a 5- to 8-membered cyclic group or a fused ring thereof selected from benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzoimidazolyl, quinolyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinazolinyl , quinoxalinyl, indolizinyl, quinolizinyl, 1,8-naphthylisinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acrydinyl, phenathridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl and phenoxazinyl,

f) C 1-6 alkylenedioxy;

g) a group of the formula -AR ¹⁵ wherein A is

a) chemical bond,

-5GB 290723 B6

b) C 1-4 alkylene,

c) C ₂ . ₆ alkenylene,

d) a group of the formula - (CH ₂ ) c NR ²⁴ , wherein c is 0 to 3 and R ²⁴ is hydrogen or C 1-6 alkyl,

e) -CO- group,

f) a group of the formula -CONR ²² wherein R ²² is (1) hydrogen, (2) C 1-4 alkyl, (3) C 1-4 cycloalkyl, (4) C 1-4 aryl, (5) a 5-membered cyclic group selected from the group consisting of:

2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl , 3-, 4- or 5-pyrazolyl, 2-, 4-, or 5-imidazolyl, 3-,

4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or 5- (1,2, 4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or 5- (1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4- (6) a 6-membered cyclic group selected from the group consisting of N-oxido-2-, 3- or 4-pyridyl, 2-, 4- or triazolyl;

5-pyrimidinyl, N-oxido-2-, 4- or 5-pyrimidinyl, 2- or 3-thiomorpholinyl, 2- or

3-morpholinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl,

1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, 2- or 3-piperazinyl, triazinyl, oxotriazinyl, 3-or

4-pyridazinyl, pyrazinyl and N-oxido-3- or 4-pyridazinyl, (7) a 5-8 membered cyclic group or a fused ring thereof selected from benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzoimidazolyl, quinolyl, isoquinolinyl, quinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl,

1,8-naphthylisinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acrydinyl, phenthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl and phenoxazinyl, or (8) a -SO _p- group wherein p is 1 to 2

g) -θ ^-

h) -S- or

i) a group of the formula -NR ²² S (O) _e , wherein e is 0 to 2, R ²² is as defined above, R ¹ 'is C 1-6 alkyl, and the other substituents are as above.

A second preferred group of derivatives of the present invention of Formula I in which Q in the meaning of R ¹¹ is ₄ C6_i aryl, optionally substituted by halogen and the other substituents are as above.

A third preferred group of derivatives of the invention of Formula I wherein R ¹³ is a _mono-aryl-4 C6_i C] _6alkylaminoskupina optionally substituted with 1-5 substituents selected from the group consisting of

a) ₄ C6_i aryl, optionally substituted with 1-4 substituents selected from the group consisting of hydroxyl, amino, mono- or di-C ^ alkylamino, C | _ ₆ alkoxy and halogen,

b) a mono- or di-C 1-6 alkylamino group,

c) C1-4 acylamino,

(d) hydroxyl;

e) carboxyl,

(f) nitro;

-6GB 290723 B6

g) C 1-6 alkoxy,

h) C 1-6 alkylcarbonyloxy,

(i) halogen; and

j) a group of the formula -NR ²² R ²³ wherein R ²² is (1) hydrogen, (2) C ₁₆ alkyl, (3) C; _v6 cycloalkyl, (4) C 5-6 aryl, (5) a 5-membered cyclic group selected from the group consisting of:

2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or

5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4 or 5-isoxazolyl, 3-, 4- or 5- isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl,

3- or 5- (1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or 5- (1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2, 3-triazolyl, 1,2,4-triazolyl and 1H- or 2H-tetrazolyl, (6) a 6-membered cyclic group selected from the group consisting of N-oxido-2-, 3- or 4-pyridyl, 2-, 4- or 5 -pyrimidinyl, N-oxido-2-, 4- or 5-pyrimidinyl, 2- or 3-thiomorpholinyl, 2- or 3-morpholinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl,

1,4-thiazinyl, 1,3-thiazinyl, 2- or 3-piperazinyl, triazinyl, oxotriazinyl, 3- or

4-pyridazinyl, pyrazinyl and N-oxido-3- or 4-pyridazinyl; (7) a 5-8 membered cyclic group 20 or a fused ring thereof selected from benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl , triazolo [4,5-b] pyridazinyl, benzoimidazolyl, quinolyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl,

1,8-naphthylisinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acrydinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl and phenoxazinyl, or (8) a group of the formula -SO _P- , 25 wherein p is 1-2 and R ²³ is hydrogen or C 1-6 alkyl, wherein the group -R ²² R ²³ is optionally substituted with 1 to 6 substituents selected from the group consisting of (1 ') C _1-6 alkyl, (2') C 2-6 alkenyl, (3 ') C 2-6 alkynyl, (4 ') C _3-6 cycloalkyl, (5') C _{5 7} cycloalkenyl, (6 ') C ₇ -naralkyl, (7') C 6-6 aryl, (8 ') C _1-6 alkoxy, (9') C ₆ _] ₄ aryloxy, (10 ') C 1-6. ₆ alkanoyl, (11) C ₆ _ | ₄ arylcarbonyl, (12 ') C 1-6 alkanoyloxy, (13') C 6-14 arylcarbonyloxy, (14 ') carboxyl, (15') C 1-4 alkoxycarbonyl, (16 ') carbamoyl, (17') N-mono-C 1-4 alkylcarbamoyl, ( 18 ') N, N-di-C 1-4 alkylcarbamoyl, (19') cyclic aminocarbonyl selected from the group consisting of 1-aziridinylcarbonyl, 1-azetidinylcarbonyl,

1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl and morpholinocarbonyl, (20 ') halogen, (21') mono- to trihalo-C 1-6 alkyl, (22 ') oxo, (23') amidino, (24 ') imino (25 ') amino, (26') mono- or di-C 1-6 alkylamino, (27 ') a 3 to 6-membered cyclic amino group containing up to 3 heteroatoms selected from oxygen, sulfur and nitrogen in addition to carbon and one nitrogen atom, (28 ') C _1-6 alkanoylamino, (29') benzamido, (30 ') carbamoylamino, (31') NC 1-4 alkylcarbamoylamino, (32 ') Ν, Ν-di-C _1-4 alkylcarbamoylamino, (33') C 1-3 alkylenedioxy, ( 34 ') -B (OH) ₂ , (35') hydroxyl, (36 ') epoxy, (37') nitro, (38 ') cyano, (39') mercapto, (40 ') sulfo, (4Γ) sulfino (42 ') phosphono, (43') sulfamoyl, (44 ') C _1-6 alkylsulfamoyl, (45') di-C 1-6 alkylsulfamoyl, (46 ') C 1-6 alkylthio, (47') phenylthio, (48 ') C 1-6 alkylsulfinyl (49 ') phenylsulfinyl, (50 ') C 1-4 alkylsulfonyl and (51') phenylsulfonyl, and the other substituents are as above.

A fourth preferred group of compounds of the present invention is those of Formula I wherein R ¹³ is benzylamino optionally substituted with 1 to 6 substituents selected from the group consisting of:

a) ₄ C6_i aryl, optionally substituted with 1-4 substituents selected from the group consisting of 50 hydroxy, amino, mono- or dC | _ ₆ alkylamino, and halogen Ci_6alkoxyl,

b) a mono- or di-C 1-6 alkylamino group,

c) C 1-4 acylamino,

-7EN 290723 B6

(d) hydroxyl;

e) carboxyl,

(f) nitro;

g) C 1-6 alkoxy,

h) C 1-6 alkylcarbonyloxy,

(i) halogen; and

j) a group of the formula -NR ²² R ²³ , wherein R ²² is (1) hydrogen, (2) C 1-4 alkyl, (3) C 1-4 cycloalkyl, (4) C 6 aryl, 5-membered cyclic group selected from the group consisting of 2 - or 3-thienyl,

2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or

5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4 or 5-isothiazolyl, 3- or 5- (1, 2, 3, 4, 5 or 5-isothiazolyl); 2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 2- or 5- (1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or 5- (1,2,3- thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl,

1,2,4-triazolyl and 1H or 2H-tetrazolyl; (6) a 6-membered cyclic group selected from the group consisting of N-oxido-2,3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxido -2-, 4- or 5-pyrimidinyl, 2- or 3-thiomorpholinyl, 2- or 3-morpholinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1 , 3-thiazinyl, 2- or 3-piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl and N-oxido-3 or 4-pyridazinyl, (7) a 5-8 membered cyclic group or a fused ring thereof selected from the group of including benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzoimidazolyl, quinolyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8-naphthylisinyl , purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acrydinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl and phenoxazinyl, or (8) a group of the formula -SO _P - wherein p is 1-2 and R ²³ is hydrogen or C 1-6 alkyl, wherein the group -R ²² R ²³ is optionally substituted with 1 to 6 substituents selected from the group consisting of (Γ) C 1-6 alkyl, (2 ') C2_íalkenyl, (3 ') C 2-6 alkynyl, (4') C3_écykloalkyl, (5) C ₅ _ ₇ cycloalkenyl, (6) C ₇ _ _H aralkyl, (7 ') C6_ ₁₄ aryl, (8) C ^ alkoxy, (9 ') C 6-14 aryloxy, (10') C 1-6 alkanoyl, (11 ') C 6-14 arylcarbonyl, (12') C 1-6 alkanoyloxy, (13 ') C 1-6 arylcarbonyloxy, (14') carboxyl, (15 ') C 1-6 alkoxycarbonyl, (16') carbamoyl, (17 ') N-monoC ₁₄ alkylcarbamoyl, (18') N, N-di-C _1-4 alkylcarbamoyl, (19 ') cyclic aminocarbonyl selected from the group consisting of 1-aziridinylcarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl,

1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl and morpholinocarbonyl, (20 ') halogen, (2') mono- to trihalo-C 1-4 alkyl, (22 ') oxo, (23') amidino, (24 ') imino, (25') amino, (26 ') a mono- or di-C 1-4 alkylamino group, (27') a 3 to 6-membered cyclic amino group containing in addition to carbon and one nitrogen atom 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, (28 ') C 1-6 alkanoylamino, (29') ') benzamido, (30') carbamoylamino, (3 ') N - C 1-4 alkylcarbamoylamino, (32') N, N-di-C 1-4 alkylcarbamoylamino, (33 ') C _1-3 alkylenedioxy, (34') -B (OH) 2, (35 ') hydroxyl, (36') epoxy, (37 ') nitro, (38') cyano, (39 ') mercapto, (40') sulfo, (41 ') sulfino, (42') phosphono, (43 ') sulfamoyl, (44') C 1-6 alkylsulfamoyl, (45 ') di-C 1-6 alkylsulfamoyl, (46') C _1-6 alkylthio, (47 ') phenylthio, (48') C 1-6 alkylsulfinyl, (49 ') phenylsulfinyl, (50 ') C 1-6 alkylsulf onyl and (51 ') phenylsulfonyl, and the other substituents are as above.

-8GB 290723 B6

A fifth preferred group is a compound of formula I wherein R ¹⁴ is phenyl optionally substituted with 1 to 6 substituents selected from the group consisting of:

a) ₄ C6_i aryl which is optionally substituted with 1-4 substituents selected from the group consisting of hydroxyl, amino, mono- or dC | _6alkylaminoskupinu, Ci_6alkoxyl and halogen,

b) a mono- or di-C 1-6 alkylamino group,

c) C1-4 acylamino,

(d) hydroxyl;

e) carboxyl,

(f) nitro;

g) C 1-6 alkoxy,

h) C 1-6 alkylcarbonyloxy,

(i) halogen; and

j) a group of the formula -NR ²² R ²³ wherein R ²² is (1) hydrogen, (2) C ₄ _ ₆ alkyl, (3) C _{3 6} cycloalkyl, (4) ₄ C6_i aryl, (5) a 5-membered cyclic a group selected from 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl,

2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl,

2- or 5- (1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or 5- (1,2,3-thiadiazolyl),

1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl and 1H or 2H-tetrazolyl, (6) a 6-membered cyclic group selected from the group consisting of N-oxido-2, 3- or 4 -pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxido-2-, 4- or 5-pyrimidinyl, 2- or 3-thiomorpholinyl, 2- or

3-morpholinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl,

1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, 2- or 3-piperazinyl, triazinyl, oxotriazinyl, 3-or

4-pyridazinyl, pyrazinyl and N-oxido-3- or 4-pyridazinyl, (7) a 5-8 membered cyclic group or a fused ring thereof selected from benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzoimidazolyl, quinolyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl,

1,8-naphthylisinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acrydinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl and phenoxazinyl, or (8) a group of the formula -SO _P - in which p is 1 or 2, and R ²³ is hydrogen or Cbéalkyl, wherein the group of formula -R ²² R ²³ is optionally substituted with 1-6 substituents selected from the group consisting of (Γ) C ^ alkyl, (2 ') C2-6 alkenyl, (3) C ₂ _ ₆ alkynyl, (4 ) C ₃ _6cykloalkyl, (5) C ₅ _ ₇ cycloalkenyl, (6) C ₇ -naralkyl, (7 ') C ₆ -] ₄ aryl, (8) C] _6alkoxyl, (9') _{C6_) 4} aryloxy, (10) C] _6alkanoyl, (11) C / ₁₄ arylcarbonyl, (12 ') Ci_6alkanoyloxyl (13') of 6-and ₄ arylkarbonyloxyl, (14 ') carboxy, (15) C ^ alkoxycarbonyl, (16 ') carbamoyl, (17') N-mono-C _1-4 alkylcarbamoyl, (18 ') N, N-di-C _1-4 alkylcarbamoyl, (19') cyclic aminocarbonyl selected from the group consisting of 1-aziridinylcarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl and morpholinocarbonyl, ( 20 ') halogen, (2') mono- to trihaloC 1-6 alkyl, (22 ') oxo, (23') amidino, (24 ') imino, (25') amino, (26 ') mono- or di- C _b . ₄ alkylamino, (27 ') a 3 to 6-membered cyclic amino group containing, in addition to a carbon atom and one nitrogen atom, 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, (28') C 1-4 alkanoylamino, (29 ') benzamido, (30') ') carbamoylamino, (31') N-C 1-4 alkylcarbamoylamino, (32 ') Ν, Ν-di-C 1-4 alkylcarbamoylamino, (33') C _1-3 alkylene

-9E 290723 B6 Dioxo, (34 ') -B (OH) ₂ , (35') hydroxyl, (36 ') epoxy, (37') nitro, (38 ') cyano, (39') mercapto, (40 ') ) sulfo, (4Γ) sulfino, (42 ') phosphono, (43') sulfamoyl, (44 ') C _1-6 alkylsulfamoyl, (45') di-C _1-6 alkylsulfamoyl, (46 ') C _1-6 alkylthio, (47') ') phenylthio, (48') C _1-6 alkylsulfinyl, (49 ') phenylsulfinyl, (50') C _1-6 alkylsulfonyl and (51 ') phenylsulfonyl, and the other substituents are as above.

A sixth preferred group of derivatives of the invention of Formula I wherein R ¹² is i) C] _ ₆ alkyl, ii) C6_i ₄ aryl, iii) a _C6 _i ₄ aryl-C ^ alkyl one or iv) C ₃ _i ₀ cycloalkyl or C ₃ _iobicykloalkyl, wherein the substituents ii) to iv) are optionally substituted by 1-6 substituents selected from the group consisting of

a) C ₁ -C ₄ aryl which is optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, amino, mono- or C 1 -C 6 alkylamino, C 1-6 alkoxy and halogen,

b) a mono- or di-C 1-4 alkylamino group,

c) C1-4 acylamino,

(d) hydroxyl;

e) carboxyl,

(f) nitro;

(g) C 1-6 alkoxy,

h) C 1-4 alkylcarbonyloxy,

(i) halogen; and

j) a group of the formula -NR ²² R ²³ wherein R ²² is (1) hydrogen, (2) C ₆ alkyl, (3) Cfycykloalkyl, (4) ₄ C6_i aryl, (5) a 5-membered cyclic group selected from the group consisting of 2- or

3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3- , 4- or 5-pyrazolyl, 2-, 4-, or 5-imidazolyl, 3-, 4- or

5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 2- or 5- (1,2,4-thiadiazolyl) 1,3,4-thiadiazolyl, 4- or 5- (1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl and 1H or 2H-tetrazolyl, (6) a 6-membered cyclic group selected from the group consisting of N-oxido-2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxido-2-, 4- or 5 -pyrimidinyl, 2- or 3-thiomorpholinyl, 2- or 3-morpholinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl,

1,4-thiazinyl, 1,3-thiazinyl, 2- or 3-piperazinyl, triazinyl, oxotriazinyl, 3- or

4-pyridazinyl, pyrazinyl and N-oxido-3- or 4-pyridazinyl, (7) a 5-8 membered cyclic group or a fused ring thereof selected from benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzoimidazolyl, quinolyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl,

1,8-naphthylisinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acrydinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl and phenoxazinyl, or (8) a group of formula -SO _P - in which p is 1 or 2, and R ²³ is hydrogen or C₁₋₄ alkyl, the group of formula -R ²² R ²³ is optionally substituted with 1-6 substituents selected from the group consisting of (1 ') C ^ alkyl, (2) C ₂ _6alkenyl, (3') C ₂ _6alkinyl , (4) C ₃ _6cykloalkyl, (5) C ₅ _7cykloalkenyl, (6) C ₇ _naralkyl, (7 ') C6_i ₄ aryl, (8) C ^ alkoxy, (9') C ₆ -i ₄ aryloxy, (10 ') C ^ alkanoyl, (11') C6_i ₄ arylcarbonyl, (12 ') Cfyalkanoyloxyl, (13') C6_i ₄ arylkarbonyloxyl, (14 ') carboxy, (15) C ₁₆ alkoxycarbonyl, (16') carbamoyl, (17 ') N-mono-C 1-6 alkylcarbamoyl, (18') N, N-di-C 1-6 alkylcarbamoyl, (19 ') cyclic

-10CZ 290723 B6 aminocarbonyl selected from the group consisting of 1-aziridinylcarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl and morpholinocarbonyl, (20 ') halogen, (2Γ) mono- to trihalo-C _b4 alkyl, ( 22 ') oxo, (23') amidino, (24 ') imino, (25') amino, (26 ') mono- or di-C 1-6 alkylamino, (27') 3- to 6-membered cyclic amino group containing in addition to carbon and one nitrogen atom having 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, (28 ') C 1-6 alkanoylamino, (29') benzamido, (30 ') carbamoylamino, (31') N-C 1-6 alkylcarbamoylamino, (32 ') N, N-di-C 1-6 alkylcarbamoylamino, (33 ') C 1-3 alkylenedioxy, (34') -B (OH) ₂ , (35 ') hydroxyl, (36') epoxy, (37 ') nitro, (38') cyano, (39 ') mercapto, (40') sulfo, (41 ') sulfino, (42') phosphono, (43 ') sulfamoyl, (44') C 1-6 alkylsulfamoyl, (45 ') di-C 1-6 alkylsulfamoyl, (46 ') C 1-6 alkylthio, (47') phenylthio, (48 ') C _1-6 alkylsulfinyl, (49') phenylsulfinyl, (50 ') C 1-6 alkylsulfonyl and (51') phenylsulfonyl, and the other substituents are as above.

In particular, a preferred derivative of the invention is 5-benzylaminomethyl-1- (2-chloro-6-fluorobenzyl) -2,4 (1H, 3H) -dioxo-6- (4-methoxyphenyl) -3-phenylthieno [2,3-d] ] pyrimidine or a salt thereof.

The present invention also relates to a process for the preparation of derivatives according to the sixth preferred group, wherein the thiophene derivative of the general formula II

in which

R. is a group of formula Q- (CH ₂ ) _p - wherein Q is as in claim 1 and p is 1 or 2,

R ¹² is i) C _1-6 alkyl, ii) C 1-6 aryl, iii) C 1-6 -C 1-6 alkyl or iv) C 3-10 cycloalkyl or C 3-10 bicycloalkyl, wherein all substituents i) to iv) are optionally substituted with 1-6 substituents selected from groups including

a) ₄ and C6 aryl, optionally substituted with 1-4 substituents selected from the group consisting of hydroxyl, amino, mono- or di-Ci_6alkylaminoskupinu, C ^ alkoxy, and halogen,

b) a mono- or di-C 1-6 alkylamino group,

c) C]. ₄ acylamino,

(d) hydroxyl;

e) carboxyl,

(f) nitro;

g) C 1-6 alkoxy,

h) C 1-6 alkylcarbonyloxy,

(i) halogen; and

- 11 GB 290723 B6

j) a group of the formula -NR ²² R ²³ wherein R ²² is (1) hydrogen, (2) C _1-6 alkyl, (3) C 1-6 cycloalkyl, (4) C 1-6 aryl, (5) 5-membered cyclic group selected from 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl,

2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or

5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl,

3- or 5- (1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or 5- (1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2, 3-triazolyl, 1,2,4-triazolyl and 1H- or 2H-tetrazolyl, (6) a 6-membered cyclic group selected from the group consisting of N-oxido-2-, 4- or 4-pyridyl, 2-, 4- or 5 -pyrimidinyl, N-oxido-2-, 4- or 5-pyrimidinyl, 2- or 3-thiomorpholinyl, 2- or 3-morpholinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl,

1,4-thiazinyl, 1,3-thiazinyl, 2- or 3-piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl and N-oxido-3- or 4-pyridazinyl, (7) 5-8 membered cyclic or a fused ring group selected from benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzoimidazolyl, quinolyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8-naphthylisinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acrydinyl, phenthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl and phenoxazinyl, or (8) a -SO _P - group wherein p is 1 or 2, and R ²³ is hydrogen or C 1-6 alkyl, wherein the group -NR ²² R ²³ is optionally substituted with 1 to 6 substituents selected from the group consisting of (1 ') C _1-6 alkyl, (2') C 1-6 alkenyl, (3 ') ') CXalkinyl, (4) C ₃ _ ₆ cycloalkyl, (5) C ₅ _ ₇ cycloalkenyl, (6) C ₇ naralkyl, (7) C ^ uaryl, (8') CXalkoxyl ( 9 ') C6 i4aryloxyl, (10) C ₆ alkanoyl, (1 Γ) C ₆ _i ₄ arylcarbonyl, (12') C galkanoyloxyl, (13 ') C6_i ₄ arylkarbonyloxyl, (14') carboxy, (15 ' ) Ci_6alkoxykarbonyl, (16 ') carbamoyl, (17') N-mono ₁ _ ₄ alkylcarbamoyl, (18 ') njn-di-C ^ alkylcarbamoyl, (19') a cyclic aminocarbonyl selected from the group consisting of 1-aziridinylcarbonyl, 1-azetidinylcarbonyl , 1-pyrrolidinylcarbonyl,

1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl and morpholinocarbonyl, (20 ') halogen, (2') mono- to trihalo-C 1-6 alkyl, (22 ') oxo, (23') amidino, (24 ') imino, (25') (26 ') a mono- or di-C 1-6 alkylamino group, (27') a 3-6 membered cyclic amino group containing, in addition to a carbon atom and one nitrogen atom, 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, (28 ') ) Ci_6alkanoylaminoskupina (29 ") benzamido, (30") carbamoylamino, (31 ') NC-alkylkarbamoylaminoskupina, (32'), Ν, Ν-di-C ^ alkylkarbamoylaminoskupina, (33 ') C ₃ alkylenedioxy, (34') - B (OH) ₂ , (35 ') hydroxyl, (36') epoxy, (37 ') nitro, (38') cyano, (39 ') mercapto, (40') sulfo, (4Γ) sulfino, (42 ') ) phosphono, (43 ') sulfamoyl, (44') C 1-6 alkylsulfamoyl, (45 ') di-C _1-6 alkylsulfamoyl, (46') C 1-6 alkylthio, (47 ') phenylthio, (48') C 1-6 alkylsulfamoyl; ₆ alkylsulfinyl, (49 ') phenylsulfinyl, (50') C 1-4 alkylsul fonyl and (51 ') phenylsulfonyl,

R ¹⁴ and r are as above and

X is a leaving group, or a salt thereof, in reaction with a compound of formula R ¹³ H wherein R ¹³ is as above, or a salt thereof.

It is a further object of the present invention to provide a gonadotropin releasing hormone antagonist pharmaceutical composition comprising as an active ingredient at least one derivative of the invention, or a salt thereof, in association with a carrier, excipient, or diluent.

In one embodiment, the pharmaceutical composition is for the prevention or treatment of sex hormone dependent diseases. As an active ingredient, it comprises in an effective amount at least one derivative of the invention, or a salt thereof, in association with a carrier, excipient or diluent.

In a second embodiment, the pharmaceutical composition is intended for the prevention or treatment of sex hormone dependent cancer, benign prostatic hypertrophy or uterine fibroid. As

The active ingredient comprises in an effective amount at least one derivative according to the invention, or a salt thereof, in association with a carrier, excipient or diluent.

A third embodiment is a pharmaceutical composition for the prevention or treatment of sex hormone dependent cancer selected from the group consisting of prostate cancer, uterine cancer, breast cancer, and mucosal adenoma. As an active ingredient, it comprises in an effective amount at least one derivative of the invention, or a salt thereof, in association with a carrier, excipient or diluent.

A fourth embodiment is a pharmaceutical composition for the prevention or treatment of sex hormone dependent diseases selected from the group consisting of prostatauxi, endometriosis, uterine fibroid and premature puberty. As an active ingredient, it contains in an effective amount at least one derivative according to this, or a salt thereof, in association with a carrier, excipient or diluent.

In a fifth embodiment, the pharmaceutical composition is suitable for controlling pregnancy. As an active ingredient, it comprises in an effective amount at least one derivative of the invention, or a salt thereof, in association with a carrier, excipient or diluent.

Another embodiment of the pharmaceutical composition is for controlling the menstrual cycle. As an active ingredient, it comprises in an effective amount at least one derivative of the invention, or a salt thereof, in association with a carrier, excipient or diluent.

The last embodiment is a pharmaceutical composition for contraception. As an active ingredient, it comprises in an effective amount at least one derivative of the invention, or a salt thereof, in association with a carrier, excipient or diluent.

The present invention also provides the use of the derivatives of the invention, or salts thereof, for the manufacture of a pharmaceutical composition for antagonizing gonadotropin releasing hormone in a mammal suffering from gonadotropin releasing hormone production disorders.

One use of the derivatives of the invention, or salts thereof, is for the manufacture of a pharmaceutical composition for the treatment of sex hormone dependent diseases.

Another use of the derivatives of the invention, or salts thereof, is contemplated for the manufacture of a pharmaceutical composition for the treatment of sex hormone dependent cancer, benign prostatic hypertrophy or uterine fibroid.

Another use of the derivatives of the invention, or salts thereof, is for the manufacture of a pharmaceutical composition for the treatment of sex hormone dependent cancer selected from the group consisting of prostate cancer, uterine cancer, breast cancer and mucosal adenoma.

Yet another use of the derivatives of the invention, or salts thereof, is contemplated for the manufacture of a pharmaceutical composition for the treatment of sex hormone dependent diseases selected from the group consisting of prostatauxi, endometriosis, uterine fibroid and premature puberty.

A further use of the derivatives of the invention, or salts thereof, is suitable for the manufacture of a pharmaceutical composition antagonizing the gonadotropin releasing hormone for controlling pregnancy in mammals.

Another use of the derivatives of the invention, or salts thereof, is for the manufacture of a pharmaceutical composition antagonizing the gonadotropin releasing hormone for controlling the menstrual cycle in mammals.

And the last possibility of using the derivatives of the invention, or salts thereof, is for the manufacture of a pharmaceutical composition antagonizing gonadotropin releasing hormone for contraception in mammals.

-13GB 290723 B6

Examples of the carbon atoms R ¹ , R ² , R ³ and R ⁷ include, each optionally substituted, an alkyl group (e.g., an alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl), cycloalkyl (e.g. cycloalkyl of 3 to 6 carbon atoms such as cyclopropyl, cyclopentyl and cyclohexyl), alkoxyalkyl (e.g. alkoxy (1 to 3 carbon atoms)) alkyl (s) (C 1 -C 6 alkyl such as methoxymethyl, ethoxymethyl, ethoxybutyl and propoxyhexyl), hydroxyalkyl (e.g., C 1 -C 6 alkyl such as hydroxymethyl, hydroxyethyl, hydroxybutyl and hydroxypropyl). alkenyl (e.g. C 2 -C 6 alkenyl such as vinyl, butadienyl and hexatrienyl), formyl, carboxyl, alkoxycarbonyl (e.g. C 1 -C 6 alkoxycarbonyl, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl), cyano amide, mono- and di-alkylcarbamoyl (e.g., mono- and di-C 1 -C 4 alkyl) carboamoyl, such as methylcarbamoyl, ethylcarbamoyl, hexylcarbamoyl, dimethylcarbamoyl and methylethylcarbamoyl), amidine, aryl (e.g. 14 carbon atoms such as phenyl, naphthyl and anthracenyl), aralkyl (e.g. aralkyl of up to 20 carbon atoms such as benzyl, benzhydryl and trityl) and heterocyclic groups bonded to a carbon atom (e.g., 5-membered cyclic groups containing, in addition to the carbon atom, 1 to 4 heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen, such as

2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl , 3-, 4- or 5-pyrazolyl. 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4oxadiazolyl), 1,3,4- oxadiazolyl, 3- or 5- (1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or 5- (1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl and 1H- or 2H-tetrazolyl, 6-membered cyclic groups containing in addition to the carbon atom 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen such as N-oxido-2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxido2-, 4- or 5-pyrimidinyl, 2- or 3-thiomorpholinyl, 2- or 3 -morpholinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxadinyl, 1,4-thiazinyl, 1,3-thiazinyl, 2- or 3-piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl , pyrazinyl and N-oxido-3- or

A 4-pyrazinyl group; and a 5- to 8-membered cyclic group or a fused ring containing 1 to 4 heteroatoms in addition to a carbon atom, eg, oxygen, sulfur or nitrogen, for example bicyclic or tricyclic fused cyclic groups containing 1 to 4 heteroatoms -atoms selected from the group consisting of oxygen, sulfur and nitrogen, such as benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzoimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8-naphthyllizinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl and phenothiazinyl).

Examples of substituents which may have the above-mentioned carbon-linked groups include an aryl group of 6 to 14 carbon atoms (e.g., phenyl and naphthyl), optionally substituted with 1 to 4 substituents selected for example from the group consisting of a) hydroxyl, b) (c) mono- or di-alkyl (C 1 -C 6) amine (e.g., methylamine, ethylamine, propylamine, dimethylamine, and diethylamino); and d) C 1 -C 6 alkoxy (e.g., methoxy, ethoxy, propoxy, and amine); and e) a halogen atom (fluorine, chlorine, bromine, iodine), a mono- or dialkyl (C 1 -C 6) amino group (e.g., methylamino, ethylamino, propylamino, dimethylamino, and diethylamino), acylamino of 1 to 4 atoms carbon (e.g. formylamino and acetylamino), hydroxyl, carboxyl, nitro, C 1 -C 6 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy and butoxy) and alkyl (C 1 -C 6) carbonyloxy (e.g. acetoxy and ethylcarbonyloxy), halogen (e.g. fluorine, chlorine, bromine and iodine) and optionally substituted groups described below attached to a nitrogen atom. The number of substituents ranges from 1 to 6, preferably from 1 to 3.

-14GB 290723 B6

Examples of the groups R ¹ , R ² , R ⁷ , R ⁹ and R ¹⁷ attached to the nitrogen atom include groups, each optionally substituted, of the general formula

NR "R ²³ wherein R ²² is hydrogen, alkyl, cycloalkyl, aryl, a heterocyclic group, and an -SO _P - (wherein p is an integer of 1-2) and R ¹⁴ represents a hydrogen atom, an alkyl group or heterocyclic groups bonded to a nitrogen atom (e.g., ΙΗ-1-pyrrolyl, 1-imidazolyl, pyrazolyl, indolyl, ΙΗ-1-indazolyl,

7-purinyl, 1-pyrrolidinyl, 1-pyrrolinyl, 1-imidazolidinyl, pyrazolidinyl, piperazinyl, pyrazolidinyl, 4-morpholinyl and 4-thiomorpholinyl groups). Said alkyl, cycloalkyl, aryl and heterocyclic groups are as defined above.

Examples of substituents that may be attached to a nitrogen atom include an alkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl), a 2-alkenyl group. up to 6 carbon atoms (e.g., vinyl, 1-methylvinyl, 1-propenyl and allyl), alkynyl of 2 to 6 carbon atoms (eg, ethynyl, 1-propynyl and propargyl), cycloalkyl of 3 to 6 carbon atoms (eg. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), C 5 -C 7 cycloalkenyl (e.g. cyclopentenyl and cyclohexenyl), C 7-11 aralkyl (e.g. benzyl, α-methylbenzyl and phenethyl), aryl 6 up to 14 carbon atoms (eg phenyl and naphthyl), alkoxy of 1 to 6 carbon atoms (eg methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec. butoxy and tert-butoxy) C 6 -C 14 aryloxy (e.g. phenoxy), C 1 -C 6 alkanoyl (e.g. formyl, acetyl, propionyl, butyryl and isobutyryl), aryl (C 6 -C 14) carbonyl (eg benzoyl), C 1 -C 6 alkanoyloxy (eg formyloxy, acetyloxy, propionyloxy and isobutyryloxy), aryl (s) Carbonyloxy (e.g., benzoyloxy), carboxyl, alkoxy (C1-C6) carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, tert-butoxycarbonyl, tert-butoxycarbonyl, tert-butoxycarbonyl, tert-butoxycarbonyl) N-mono-alkyl (C 1 -C 4) carbamoyl (e.g., N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl and N-butylcarboamoyl), N, N-dialkyl (C 1 -C 4) carbamoyl (e.g. N-isopropylcarboamyl and N-butylcarbamoyl), N, N-dialkyl (C 1 -C 4) carbamoyl (e.g. Ν, Ν-dimethylcarbamoyl, N, N-diethylcarbamoyl, Ν, Ν -dipropylcarbamoyl and Ν, Ν-dibutylcarbamoyl), cyclic aminocarbonyl (e.g. 1-aziridinylcarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl and morpholinocarbonyl), a halogen atom (fluorine, chlorine, bromine and iodine), a mono- or trihalomethyl (1-4C) alkyl group; , dichloromethyl, trifluoromethyl and trifluoroethyl), oxo, amidino, imino, amino, mono- or di-C 1 -C 4 -alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino , diisopropylamine and dibutylamino), a 3- to 6-membered cyclic amine group containing, in addition to a carbon atom and one nitrogen atom, 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen (e.g. aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, imidaz olidinyl, piperidine, morpholine, dihydropyridyl, N-methylpiperazinyl and N-ethylpiperazinyl), C 1 -C 6 alkanoylamino (e.g. formamide, acetamide, trifluoroacetamide, propionylamide, butyrylamide and isobutyrylamide), benzamide, carbamoylamino, N-alkyl (C 1 -C 4) carbamoylamino (e.g., N-methylcarbamoylamino, N-ethylcarbamoylamino, N-propylcarbamino) and N-butylcarbamoylamino), N, N-dialkyl (C 1 -C 4) carbamoylamino group

(E.g., N, N-methylcarbamoylamino, Ν, Ν-diethylcarbamoylamino, N, N-dipropylcarbamoylamino and Ν, Ν-dibutylcarbamoylamino), (C 1 -C 3) alkylenedioxy (e.g., methylenedioxy and ethylenedioxy), B (OH) 2, hydroxyl, epoxy (-O-), nitro, cyano, mercapto, sulfo, sulfin, phosphone, dihydroxyboryl, sulfamoyl, alkylsulfamoyl of 1 to 6 carbon atoms (e.g., N- methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl and N-butylsulfamoyl), dialkyl (1 to 6 carbon atoms) sulfamoyl group (e.g. Ν, Ν-dimethylsulfamoyl, N, N-diethylsulfamoyl, Ν, Νsulfamoyl) and Ν, Ν-dibutylsulfamoyl), (C 1 -C 6) alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, and tert-butylthio), phenylthio, (1-6C) alkylsulfin, and carbon atoms (e.g., methylsulfinyl, ethylsulfinyl, propylsulfinyl and butylsulfinyl), phenylsulfinyl, C 1 -C 6 alkylsulfonyl (e.g. methylsulfonyl, ethylsulfonyl, propylsulfonyl and butylsulfonyl) and phenylsulfonyl groups. The number of substituents ranges from 1 to 6, preferably from 1 to 3.

Examples of the groups R ¹ , R ² and R ⁷ attached to an oxygen atom include a hydroxyl group, each optionally substituted, alkoxy, cycloalkoxy, aryloxy, aralkyloxy and heterocyclic hydroxyl group. Alkyl, cycloalkyl, aryl, aralkyl and heterocyclic groups in said alkoxy, cycloalkoxy, aryloxy, aralkyloxy and heterocyclic hydroxyl groups are as defined above.

Substituents which may carry an oxygen atom are as defined above for the groups attached to the nitrogen atom.

Examples of the sulfur atom R ¹ , R ² , R ⁷ and R ¹² include mercapto, alkylthio, cycloalkylthio, arylthio, aralkylthio and heterocyclic thio. Alkyl, cycloalkyl, aryl, aralkyl and heterocyclic groups in said alkylthio group, cycloalkylthio group, arylthio group, aralkylthio group and heterocyclic thio group are as defined above.

The substituents which may be carried by the sulfur atom are those mentioned above for the optionally substituted groups attached to the nitrogen atom.

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

Examples of substituents of said homocyclic groups include an alkyl group having 1 to 15 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and pentadecyl), C 3 -C 10 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), C 2 -C 10 alkenyl (e.g., vinyl, allyl, 2-methylallyl, 2-butenyl, 3-butenyl and 3-octenyl), a (C 2 -C 10) alkynyl group (e.g., ethynyl, 2-propynyl and 3-hexinyl), a C 3 -C 10 cycloalkyl group (eg, cyclopropenyl, cyclopentenyl, and cyclohexenyl), (C 6 -C 10) aryl (e.g. phenyl and naphthyl), (C 1 -C 19) aralkyl (e.g., benzyl, phenyl) thyl and trityl), nitro, hydroxyl, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, alkoxy (C 1 -C 5) carbonyl (e.g. methoxycarbonyl and ethoxycarbonyl), sulfo group, halogen atom (e.g. fluorine, chlorine, bromine and iodine);

Carbon atoms (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy), aryloxy of 6 to 10 carbon atoms (eg, phenoxy), alkylthio of 1 to 6 carbon atoms (e.g. methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio and tert-butylthio), arylthio of 6 to 10 carbon atoms (e.g. phenylthio), alkylsulfinyl of 1 to 6 carbon atoms (e.g. methylsulfinyl and ethylsulfinyl) , arylsulfinyl group having 6 to 10 carbon atoms (e.g., phenylsulfinyl), an alkylsulfonyl group having 1 to 6 carbon atoms (e.g., methylsulfonyl and ethylsulfonyl), an arylsulfonyl group having 6 to 10 carbon atoms (e.g., phenylsulfonyl), an amino group, an acylamino group (C 1 -C 6) acetylamino (e.g., acetylamino and propylamine), (C 1 -C 4) mono- or di-alkylamino (e.g. methylamino, ethylamino, propylamino, isopropylamino, butylamino, dime) thylamino and diethylamino), a C 3 -C 8 cycloalkylamino group (e.g. cyclopropylamine, cyclobutylamine, cyclopentylamine and cyclohexylamine), arylamino group of 6 to 10 carbon atoms (eg aniline), aralkyl group of 1 to 6 carbon atoms (eg formyl, acetyl and hexanoyl), aryl (6 to 10 carbon atoms) carbonyl (e.g. benzoyl) and a 5- to 6-membered heterocyclic group containing, in addition to a carbon atom, 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen (e.g. 2- or 3-thienyl, 2- or 3-thienyl) -furyl, 3-, 4- or 5-pyrazolyl, 2-, 4 or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or

5-isoxazolyl, 2-, 4- or 5-imidazolyl, 1,2,3- or 1,2,4-triazolyl, 1H- or 2H-tetrazolyl, 2-, 3- or 4-pyridyl, 2-, 4 - or 5-pyrimidyl, 3- or

4-pyridazinyl, quinolyl, isoquinolyl and indolyl). The number of substituents ranges from 1 to 6, preferably from 1 to 3.

Examples of the above-mentioned optionally substituted heterocyclic R ³ groups include

5- to 8-membered cyclic groups or fused rings thereof containing from 1 to 4 heteroatoms in addition to a carbon atom, such as oxygen, sulfur and nitrogen, for example 5-membered cyclic groups containing 1 to 4-heteroatoms in addition to a carbon atom from the group consisting of oxygen, sulfur and nitrogen, for example 2- or 3-thienyl, 2- or 3-furyl, 2- or

3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-Oxadiazolyl), 1,3,4-oxadiazolyl, 3- or 5- (1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4-or 5- (1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2, 3-triazolyl, 1,2,4-triazolyl and 1H- or 2H-tetrazolyl, 6-membered cyclic groups containing in addition to the carbon atom 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, such as N -oxido-2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxido-2-, 4- or 5-pyrimidinyl, thiomorpholinyl, morpholinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperazinyl, pyranyl , thiopyranyl, 1,4-oxadinyl, 1,4-thiazinyl, 1,3-thiazinyl, piperazinyl, triazinyl, oxotriazinyl, 3- n or a 4-pyridazinyl, pyrazinyl and N-oxido-3- or 4-pyridazinyl group, a bicyclic or tricyclic fused ring group containing, in addition to a carbon atom, 1-4 heteroatoms selected from the group consisting of oxygen, sulfur or nitrogen, such as benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,4-b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzoimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phtaladinyl, quinazolinyl, quinoxalinyl, indolidinyl, quinolidinyl, 1,8-naphthyllidinyl, purinynyl, purinyl, purinyl dibenzofuranyl, carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxadinyl, phenazinyl, phenothiazinyl and phenoxazinyl groups.

Examples of substituents that may have said heterocyclic groups include an alkyl group of 1 to 6 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl), alkenyl of 2 to 6 atoms carbon (e.g., vinyl, 1-methylvinyl, 1-propenyl and allyl), alkynyl of 2 to 6 carbon atoms (e.g., ethynyl, 1-propynyl and propargyl), cycloalkyl of 3 to 6 carbon atoms (e.g., cyclopropyl, cyclobutyl) , cyclopentyl and cyclohexyl), C 5 -C 7 cycloalkenyl (e.g., cyclopentenyl and cyclohexenyl), C 7 -C 7 aralkyl

- 17C 290723 B6 carbon atoms (eg benzyl, α-methylbenzyl and phenethyl), (C 6 -C 14) aryl (eg phenyl and naphthyl), (C 1 -C 6) alkoxy (eg methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy), aryloxy group of 6 to 14 carbon atoms (e.g. phenoxy), alkanoyl of 1 to 6 carbon atoms (e.g. formyl, acetyl, propionyl, butyryl and isobutyryl), aryl (C 6 -C 14) carbonyl (e.g., benzoyl), C 1 -C 6 alkanoyloxy (e.g., formyloxy, acetyloxy, propionyloxy, butyryloxy, and isobutyryloxy), aryl (C 6 -C 14) carbonyloxy (e.g. benzoyloxy), carboxyl, alkoxy (C 1 -C 6) carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl and tert-butoxycarbonyl), carbamoyl, Nm ono-alkyl (C 1 -C 4) carbamoyl, N-mono-alkyl (C 1 -C 4) carbamoyl (e.g. N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl and N-butylcarbamoyl), N, N-dialkyl (C 1 -C 4) carbamoyl (e.g. Ν, Ν-dimethylcarbamoyl, N, N-diethylcarbamoyl) , Ν, Ν-dipropylcarbamoyl and N, N-dibutylcarbamoyl), cyclic aminocarbonyl (e.g., 1-aziridinylcarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl, fluorophenyl, fluorophenyl, carbonyl, fluorophenyl, carbonyl, fluorophenyl) and iodo), mono-, di-or trihaloalkyl of 1 to 4 carbon atoms (e.g., chloromethyl, dichloromethyl, trifluoromethyl and trifluoroethyl), oxo, amidino, imino, amino, mono- or di-alkylamino of 1 to 4 carbon atoms (e.g., chloromethyl, dichloromethyl, trifluoromethyl and trifluoroethyl), oxo, amidino, imino, amino, mono- or di-alkylamine a C 1 -C 4 group (e.g., methylamine, ethylamine, propylamine, isopropylamine, butylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, and dibutylamine),

A 6-membered cyclic amine group optionally containing, in addition to carbon atoms and 1 nitrogen atom, 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen (e.g. aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, imidazolidinyl, piperidine, morpholine, dihydropyridyl, pyridyl, N-methylpiperazinyl and N-ethylpiperazinyl), C 1 -C 6 alkanoylamino (e.g., formamide, acetamide, trifluoroacetamide, propionylamide, butylamide and isobutyrylamide, benzamoyrylamide, benzamoyl, benzamoyl, benzamoyl, -alkyl (C 1 -C 4) carbamoylamino (e.g., N-methylcarbamoylamino, N-ethylcarbamoylamino, N-propylcarbamoylamino, N-isopropylcarbamoylamino and N-butylcarbamoylamino), N, N-dialkyl (C 1 -C 4) carbamoylamino a group (eg, N, N-dimethylcarbamoylamine, Ν, Ν-diethylcarbamoylamine) ω, N, N-dipropylcarbamoylamino and Ν, Ν-dibutylcarbamoylamino), C 1 -C 3 alkylenedioxy (e.g. methylenedioxy and ethylenedioxy), -B (OH) ₂ , hydroxyl, epoxy (-O-), nitro, cyano, mercapto, sulfo, sulfin, phosphone, dihydroxyboryl, sulfamoyl, alkylsulfamoyl of 1 to 6 carbon atoms (e.g., N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl and N-butylsulfamoyl), dialkyl (C 1 -C 6) sulfamoyl group (e.g. N, N-dimethylsulfamoyl, Ν, Ν- diethylsulfamoyl, N, N-dipropylsulfamoyl and Ν, Ν-dibutylsulfamoyl), (C 1 -C 6) alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio and tert-butylthio), phenylthio, alkylthio up to 6 carbon atoms (e.g. methylsulfinyl, ethylsulfinyl, propylsulfinyl and butylsulfinyl), phenylsulfinyl, alkylsulfonyl of 1 to 6 carbon atoms (e.g. methylsulfonyl, ethylsulfonyl, propylsulfonyl and butylsulfonyl) and phenylsulfonyl. The number of substituents ranges from 1 to 6, preferably from 1 to 3.

The ester group in the optionally esterified carboxyl group R ⁴ includes, for example, the alkyl, cycloalkyl, aryl and heterocyclic groups, as defined above.

-18GB 290723 B6

Examples of amidated carboxyl groups R ⁴ include those of the formula -CONR ²² R ²³ (wherein R ²² and R ²³ are as defined above).

As the lower alkyl group in the lower alkyl group substituted by the sulfur bonded group referred to as R ⁴ , for example, an alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, hexyl and the like. A group attached to a sulfur atom is as defined above.

A lower alkyl group in a lower alkyl group substituted with an optionally substituted hydroxyl, R ⁴ , is as defined above.

As the substituent of the lower alkyl group with optionally substituted hydroxyl, mentioned above as R ⁴ , for example, an alkyl group of 1 to 6 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl and tert-butyl) with optionally 1 to 4 substituents selected from halogen atoms (e.g., chlorine, bromine and fluorine), aryl groups of 6 to 10 carbon atoms (e.g., phenyl and naphthyl), aralkyl groups of 7 to 12 carbon atoms (e.g., benzyl and phenethyl) and nitro, C 6 -C 10 aryl (e.g. phenyl and naphthyl) optionally with 1 to 3 substituents selected from halogen (e.g. chlorine, bromine and fluorine), C 1-6 alkyl (e.g. methyl , ethyl and propyl) and aryl groups of 1 to 10 carbon atoms (e.g. phenyl and naphthyl), aralkyl of 7 to 12 carbon atoms (e.g. benzyl, phenylethyl and naphthylmethyl) a) optionally with 1 to 4 substituents selected from a halogen atom (e.g. chlorine, bromine and fluorine groups), (C1-C6) alkyl groups (e.g., methyl, ethyl and propyl), (C6-C10) aryl groups (e.g., phenyl and naphthyl), (C1-C12) aralkyl groups (e.g., benzyl and phenethyl) and nitro, alkyl (C1-C6) carbonyl (e.g., acetyl and propionyl) with optionally 1 to 3 substituents selected from formyl, halogen (e.g., chlorine, bromo and fluoro), (C 1 -C 6) alkyl (e.g., methyl, ethyl, and propyl), (C 6 -C 10) aryl (e.g., phenyl and naphthyl), C 7 -C 12 aralkyl (e.g. benzyl and phenethyl) and nitro, aryl (C 6 -C 10) oxycarbonyl (e.g. phenyloxycarbonyl and naphthyloxycarbonyl) optionally having 1 to 4 substituents selected from a halogen atom (e.g. chlorine, bromine and (C 1 -C 6) alkyl (e.g., methyl, ethyl, and propyl), (C 6 -C 10) aryl (e.g. phenyl and naphthyl), aralkyl groups of 7 to 12 carbon atoms (e.g. benzyl and phenylethyl) and nitro groups, aryl (6 to 10 carbon atoms) carbonyl (e.g. benzoyl and naphthylcarbonyl) optionally having 1 to 4 substituents which are selected from a halogen atom (e.g., chlorine, bromine and fluorine), an alkyl group having 1 to 6 carbon atoms (e.g. methyl, ethyl and propyl), an aryl group having 6 to 10 carbon atoms (e.g. phenyl and naphthyl), (C7 -C12) aralkyl groups (e.g., benzyl and phenylethyl) and nitro groups; (C7 -C12) aralkyl (e.g., benzylcarbonyl and phenethylcarbonyl) optionally having 1 to 4 substituents selected from a halogen atom (e.g., chlorine, bromine and fluorine), (C1-C6) alkyl (e.g., methyl, ethyl and propyl), (C6-C10) aryl (e.g., phenyl and naphthyl), aral C 7 -C 12 alkyl (e.g., benzyl and phenethyl) and nitro, pyranyl or furanyl, tri (C 1 -C 4 alkyl) silyl (e.g. trimethylsilyl and triethylsilyl) optionally having 1 to 4 substituents selected from a halogen atom (e.g., chlorine, bromine and fluorine), an alkyl group having 1 to 6 carbon atoms (e.g. methyl, ethyl and propyl), an aryl group having 6 to 6 C uhlíku-C (ar (eg phenyl and naphthyl), C až-C ar ar aralkyl groups (eg, benzyl and phenethyl) and nitro groups.

The hydrocarbon group in the carbonyl group optionally substituted by the hydrocarbon group R ⁴ is, for example, a saturated or unsaturated hydrocarbon group having up to 25 carbon atoms. Examples include an alkyl group (eg, a C 1 -C 8 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, target, butyl, pentyl)

-9C 290723 B6 and hexyl), cycloalkyl (cycloalkyl of 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), alkoxyalkyl (e.g. alkoxy (of 1 to 3 carbon atoms)) alkyl (of 1 to 6 carbon atoms) carbon atoms such as methoxymethyl, ethoxymethyl, ethoxybutyl and propoxyhexyl), alkenyl (e.g. alkenyl of up to 6 carbon atoms such as vinyl, butenyl, butadienyl and hexatrienyl), aryl (e.g. aryl of 6 to 14 atoms) carbon (such as phenyl, naphthyl and anthracenyl) and aralkyl (e.g., C7-20 aralkyl such as benzyl, benzhydryl and trityl).

An optionally substituted 5- to 7-membered heterocyclic group having a ring-forming, carbonyl, thiocarbonyl or optionally oxidized sulfur atom, or a group convertible thereto, R ⁶ , is as set forth on page 5, lines 45 to 9, line 6. 35, European patent applications 0520423.

Examples of the anionic or amine-convertible group mentioned above as R ⁶ include carboxyl, alkoxy (C 1 -C 4) carbonyl, cyano, tetrazolyl, trifluoromethanesulfonic acid, phosphoric acid and sulfonic acid. As the spacer arm V, for example, ~ (C = O) -, -O-, -S-, -NH-, - (C = O) -NH- -O-CH ₂ - -S-CH is mentioned. , and -CH = CH-.

An optionally substituted aromatic hydrocarbon group optionally containing heteroatoms and an optionally substituted heterocyclic group indicated as ring Z is as defined on page 5, lines 38-44 of European patent application 0520423.

As the aryl group R ¹¹ or in the optionally substituted aryl groups R ¹² and R ¹⁴ , for example, monocyclic or fused polycyclic aromatic hydrocarbon groups can be mentioned. Preferred examples include C 6 -C 14 aryl such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like. More preferred is phenyl, 1-naphthyl and 2-naphthyl.

The number of substituents is one or more, preferably one to three. Examples of substituents include C 1 -C 3 alkyl (e.g., methyl, ethyl, propyl), C 2 -C 4 alkenyl (e.g., vinyl, allyl, 2-butenyl), C 4 -C 4 alkynyl ( such as propargyl and 2-butynyl), cycloalkyl of 3 to 7 carbon atoms (e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), aryl (e.g. phenyl and naphthyl), 5- to 9-membered aromatic heterocyclic group with 1 to heteroatoms selected from nitrogen, oxygen, and sulfur (e.g., furyl, thienyl, pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, and pyridyl), 5- to 9-membered non-aromatic heterocyclic group with 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur (e.g., oxiranyl, azetidinyl, oxethanyl, thitanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidinyl, tetrahydropyranyl, morpholinyl, th (morpholinyl and piperazinyl), C7 -C10 aralkyl (e.g. benzyl and phenethyl), amino group, N-monosubstituted amino group (e.g., N-alkyl (C 1 -C 6) amino, such as methylamine, ethylamine and propylamine), N, N-disubstituted amino [e.g. N, N-di (C 1 -C 6 alkyl) amino, such as dimethylamine and diethylamino], amidine, acyl (e.g., C 1 -C 8 alkyl) carbonyl such as acetyl, propionyl and butyryl, aryl ( (C 6 -C 14) carbonyl such as benzoyl, aralkyloxy (C 7 -C 12) carbonyl, such as benzyloxycarbonyl), carbamoyl, N-monosubstituted carbamoyl [e.g. N-alkyl (C 1 -C 6) carbamoyl group such as methylcarbamoyl, ethylcarbamoyl and propylcarbamoyl], Ν, Ν-disubstituted carbamoyl group [e.g. N, N-dialkyl (C 1 -C 6) carbamoyl such as dimethylcarbamoyl and diethylcarbamoyl], sulfamoyl, N-monosubstituted sulfamoyl [e.g. N- (C 1 -C 6 alkyl) sulfamoyl such as methylsulfamoyl, ethylsulfamoyl and propylsulfamoyl], Ν, Ν-disubstituted sulfamoyl [e.g. N, N-di (C 1 -C 6 alkyl) sulfamoyl, such as

-20EN 290723 B6 dimethylsulfamoyl and diethylsulfamoyl], carboxyl, alkoxy (C 1 -C 3) carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl), hydroxyl, C 1 -C 3 alkoxy (e.g. methoxy, ethoxy and propoxy) which it may carry a substituent (e.g., C 1 -C 3 alkyl, halogen, C 1 -C 3 alkylthio and hydroxyl), C 2 -C 4 alkenyloxy (e.g., vinyloxy and allyloxy), cycloalkyloxy (e.g., cycloalkyloxy) (C 3 -C 7) atoms such as cyclopropyloxy and cyclobutyloxy), aralkyloxy (eg C 7 -C 10 aralkyloxy), aryloxy (eg phenyloxy and naphthyloxy), mercapto, (C 1 -C 3) alkylthio (eg. methylthio, ethylthio and propylthio), aralkylthio (e.g., C7 -C10 aralkylthio) such as benzylthio), arylthio (e.g. phenylthio and naphthylthio), alkyl lendioxy having 1 to 3 carbon atoms (e.g. methylenedioxy, ethylenedioxy and propylenedioxy), sulfo, cyano, azide, nitro, nitro, halogen (fluoro, chloro, bromo iodo) and the like.

As the aralkyl group in the optionally substituted aralkyl group R ¹² , for example, an aryl-alkyl group may be mentioned. Aryl is as defined above. Examples of the alkyl group include an alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl and hexyl. The substituents are the same as defined above for the aryl group substituents R ^12th

As the cycloalkyl group in the optionally substituted cycloalkyl groups R ¹¹ and R ¹² , for example, a cycloalkyl group having 3 to 10 carbon atoms and a bicycloalkyl group having 3 to 10 carbon atoms can be mentioned. Preferred examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3] 1,2,1] nonyl, bicyclo [4,2,1] nonyl and bicyclo [4,3,1] decyl. More preferred are cyclopentyl and cyclohexyl. The substituents are the same as defined above for the aryl group substituents R ^12th

As the heterocyclic group in the optionally substituted heterocyclic group R ¹¹ , for example, a 5- to 13-membered aromatic heterocyclic group having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen or a saturated or unsaturated non-aromatic heterocyclic group may be mentioned.

Examples of the aromatic heterocyclic group include a monocyclic heterocyclic group (e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3, 4-oxadiazolyl, furazanyl, 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 and triazinyl), a fused ring aromatic hetocyclic group (e.g., benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indoryl, isoindoryl, 1H-indazolyl, benzoimidazolyl, benzoxazolyl, 1,2-benzoisothiazyl, 2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthylidinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, aridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazinyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyridazinyl, 1,2,4-triazolo [4, 3-a] pyridyl and 1,2,4-triazolo [4,3-b] pyridazinyl].

Examples of the non-aromatic heterocyclic group include oxylanyl, azetidinyl, oxethanyl, thiethanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and piperazinyl groups.

-21 GB 290723 B6

The heterocyclic group may have one or more substituents, preferably one to three substituents. These substituents represent the same substituents as the optionally substituted aryl group R ¹² .

The substituents in the optionally substituted carboxyl group Q include, for example, alkyl, cycloalkyl, aryl, aralkyl and heterocyclic groups. These groups are as defined above.

Lower alkylenedioxy Q includes, for example, C 1 -C 6 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy, propylenedioxy, and 2,2-dimethylmethylenedioxy).

The lower alkyl group R ¹¹ is, for example, an alkyl group having 1 to 6 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl).

An optionally substituted amino group R ¹⁵ is, for example, a group of the formula -NR ²² R ²³ wherein R ²² is an optionally substituted aryl or an optionally substituted heterocyclic group and R ²³ is a hydrogen atom, an optionally substituted alkyl group. Optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heterocyclic groups are as defined above.

The arm group under the symbol "A" includes, for example, a C 1 -C 4 alkylene group (eg, methylene and ethylene) of 2 to 6 carbon atoms (eg vinylene and butadienyl), a group of the formula - (CH ₂ ) c NR ²⁴ - wherein c is 0 to 3, R ²⁴ is hydrogen, C 1 -C 6 alkyl (e.g. methyl, ethyl and butyl), -CO-, -CONR ²² -, wherein R ²² is as defined above, -O-, -S-, a group of the formula -NR ²² S (O) e - wherein e is a number from 0 to 2 and R ²² is as defined above.

Preferred examples of a 5- to 7-membered homo- or hetero-cyclic group (Ring W ') in an optionally substituted fused bicyclic compound containing a 5- to 7-membered homo- or hetero-cyclic group (Ring W') and 5- to 7-membered The 7-membered homo- or heterocyclic group (Ring Y ') includes a 5- or 6-membered homo- or heterocyclic group, more preferably a 5- or 6-membered heterocyclic group. Specific examples of ring W 'include cyclic groups of the following formulas:

-22GB 290723 B6

gi o:

II

Cl or Cl c

H

H

AT

etc.

Particularly preferred is a cyclic group of formula yc

-23 GB 290723 B6

The most preferred example of ring W is a group of formula

wherein R ¹ and R ² are as defined above.

Preferred examples of a 5- to 7-membered homo- or hetero-cyclic group (Ring Y ') in an optionally substituted fused bicyclic compound containing a 5- to 7-membered homo- or hetero-cyclic group (Ring W') and 5- to 7-membered A 7-membered homo- or hetero-cyclic group (Ring Y ') includes a 6-membered homo- or hetero-cyclic group, more preferably a 6-membered hetero-cyclic group. Specific examples of ring W 'include cyclic groups of the formula:

O II

Y «H

H

Among these cyclic groups, the following groups are preferred:

-24GB 290723 B6

More preferred are cyclic groups of the formula:

^ 0

More preferred examples of said ring Y 'are cyclic groups of the general formula

wherein R ¹⁶ is an optionally substituted hydrocarbon group, R ¹⁷ is a hydrogen atom or a group attached to a carbon, nitrogen, oxygen or sulfur atom and o is 1 or 2, or a cyclic group of the formula

wherein R ²⁰ and R ²¹ are each independently hydrogen or optionally substituted hydrocarbon.

Examples of hydrocarbon groups in the optionally substituted hydrocarbon groups R ¹⁶ , R ²⁰ and R ²¹ include the alkyl, cycloalkyl, aryl and aralkyl groups described above.

Examples of substituents that may optionally have said hydrocarbon groups include optionally 1 to 5 substituents selected from, for example, the following: nitro, hydroxyl, oxo, thioxo, cyano, carbamoyl, carboxyl, alkoxy (C 1 -C 4) ) carbonyl group (eg methoxycarbonyl and ethoxycarbonyl), sulfo group, halogen atom (fluorine, chlorine, bromine and iodine), alkoxy group having 1 to 6 carbon atoms (eg methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, 2-butoxy and tert-butoxy), aryloxy group of 6 to 12 carbon atoms (e.g. phenoxy), a haloaryl group of 6 to 16 carbon atoms (e.g. o-, m- or p-chlorophenoxy and o-, m- or p-bromophenoxy) , (C 1 -C 6) alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, and tert-butylthio), (C 6 -C 12) arylthio (e.g., phenylthio), (C 1 -C 6) alkylsulfinyl 6 carbon atoms (e.g. methylsulfinyl and ethylsulfinyl), alkylsulfonyl group having 1 to 6 carbon atoms (e.g. methylsulfonyl and ethylsulfonyl), amino, C 1 -C 6 acylamino (e.g., formylamino, acetylamino and propylamino), C 1 -C 4 mono- or di-alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino and diethylamino), C 1 -C 6 acyl (e.g., formyl,

(Acetyl and hexanoyl), aryl (6 to 12 carbon atoms) carbonyl (eg benzoyl), 5- or 6-membered heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from the group consisting of oxygen , sulfur and nitrogen (e.g. 2- or 3-thienyl, 2- or 3-thienyl);

3-furyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-imidazolyl, 1,2,3- or 1,2,4-triazolyl, 1H- or 2H-tetrazolyl, 2-, 3- or

4-pyridyl, 2-, 4- or 5-pyrimidyl, 3- or 4-pyridazinyl, quinolyl, isoquinolyl and indolyl, haloalkyl of 1 to 10 carbon atoms (e.g. difluoromethyl, trifluoromethyl, trifluoroethyl and trichloroethyl) and in the case of hydrocarbon groups are cycloalkyl, cycloalkenyl, aryl or aralkyl and alkyl of 1 to 6 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl and butyl). The number of substituents ranges from 1 to 6, preferably from 1 to 3.

The group R ¹⁷ bonded to a carbon, nitrogen, oxygen or sulfur atom is as defined above.

One of R ¹ and R ² is preferably a radical of formula

R ⁹ - (CH ₂ ) m -, wherein R ⁹ is a group attached to a nitrogen atom and m is a number from 0 to 3, and a second group of the general formula

wherein R ¹⁰ represents an optionally substituted phenyl group and A represents a hanger group.

The optionally substituted R ⁹ group mentioned above attached to the nitrogen atom is as defined above.

Examples of substituents in the optionally substituted phenyl group listed above as R ¹⁰ include halogen (fluoro, chloro, bromo and iodo), alkyl of 1 to 8 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl, tert-butyl, pentyl, isopentyl and neopentyl), optionally substituted with 1 to 3 halogens (fluorine, chlorine, bromine and iodine), alkoxy of 1 to 8 carbon atoms (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy), optionally substituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine and iodine), alkylthio of 1 to 8 carbon atoms (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio , pentylthio, isopentylthio and neopentylthio), optionally substituted with 1 to 3 halogen atoms (fluoro, chloro, bromo and iodo), (C 1 -C 6) alkyloxy (e.g. formyloxy, acetoxy and propionyloxy), hydroxyl, carbo xyl, alkoxy (C 1 -C 6) carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl), cyano, nitro, amide, and mono- or di (C 1 -C 6) -carbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl and dimethylcarbamoyl). The number of substituents ranges from 1 to 5, preferably from 1 to 3.

Arm groups A are as defined above.

R ³ is preferably a group of formula

R ⁷

Wherein R ⁷ represents a hydrogen atom or a group bonded to a carbon, nitrogen, oxygen or sulfur atom and R ⁸ represents a halogen atom, a nitro group, a cyano group or an optionally substituted aliphatic hydrocarbon group bonded to an oxygen, nitrogen or sulfur atom.

The above-mentioned optionally substituted R ⁷ group attached to a carbon, nitrogen, oxygen or sulfur atom is as defined above.

Examples of an optionally substituted aliphatic hydrocarbon group in an optionally substituted aliphatic hydrocarbon group bonded to an oxygen, nitrogen or sulfur atom as mentioned above as R ⁸ include an alkyl group having 1 to 15 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl) , isobutyl, sec-butyl, target, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and pentadecyl), C 3 -C 8 cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclopentyl and cyclohexyl), (C 2 -C 10) alkenyl (e.g., vinyl, allyl, 2-methylallyl, 2-butenyl, 3-butenyl, and 3-octenyl), (C 2 -C 10) alkynyl (e.g. (propynyl and 3-hexynyl) and alkoxy of 1 to 6 carbon atoms (e.g. methoxy, ethoxy, propoxy and butoxy). Examples of substituents which the hydrocarbon group may carry include nitro, hydroxyl, oxo, thioxo, cyano, carbamoyl, carboxyl, alkoxy (C 1 -C 4 -carbonyl) (e.g., methoxycarbonyl and ethoxycarbonyl), sulfo, halogen (fluorine, chlorine, bromine and iodine), (C1-C4) alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy), (C1-C4) alkylthio (e.g. methylthio, ethylthio, propylthio, isopropylthio, butylthio and tert-butylthio), amino, (C 1 -C 6) alkanoylamino (eg acetylamino and propionylamino), mono- or di (C 1 -C 4) alkyl a group (e.g., methylamine, ethylamine, propylamine, isopropylamine, butylamine, dimethylamine, and diethylamine), a (C 1 -C 4) alkanoyl group (eg, formyl, acetic) aryl and propionyl), a 5- or 6-membered heterocyclic group which, in addition to carbon atoms, contains 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, which may optionally have 1 to 4 substituents selected from a) halogen atom (e.g. . and (b) C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, and isopropyl) such as 2- or 2- (C 1 -C 4) alkyl;

3-thienyl, 2- or 3-furyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-,

4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or

5-imidazolyl, 1,2,3- or 1,2,4-triazolyl, 1H- or 2H-tetrazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 3- or 4 pyridazinyl, quinolyl, isoquinolinyl, indolyl, and haloalkyl of 1 to 6 carbon atoms (e.g., difluoromethyl, trifluoromethyl, trifluoroethyl and trichloroethyl). The number of substituents ranges from 1 to 4, preferably from 1 to 3.

R ¹¹ is preferably a group of the formula

4CH ₂ ) pQ ', wherein p is an integer from 1 to 3 and Q' is an aryl group which may be substituted with a halogen atom, a nitro group, a cyano group, an amino group, an optionally substituted carboxyl group, a lower alkylenedioxy group or -AR ¹⁶ wherein R ¹⁵ is lower alkyl and A is as defined above.

The aryl group may be substituted by a halogen atom, a nitro group, a cyano group, an amino group, optionally substituted by a carboxyl group, a lower alkylenedioxy group or a group of the formula -AR ¹⁶ , referred to as Q ', wherein A and R ¹⁶ are as defined above. Lower alkyl is as defined above.

-27GB 290723 B6

Preferably Q 'represents an aryl group which may be substituted by a halogen atom (fluorine, chlorine, bromine, nitrogen).

Preferably, R ¹³ is an optionally substituted monoaralkylamino group. An optionally substituted aralkyl group in an optionally substituted monoaralkylamino group is as defined above, the aralkyl group preferably being a benzyl group.

R ¹⁴ preferably represents an optionally substituted phenyl group as defined above.

An optionally substituted fused bicyclic compound containing a 5- to 7-membered homone or heterocyclic group and a 5- to 7-membered homo- or heterocyclic group is preferably a compound of formula V (V) wherein ring W, R ¹⁶ , R ¹⁷ α is as defined above, or a compound of formula VII (VII) wherein R ¹⁸ and R ¹⁹ independently of each other are an optionally substituted hydrocarbon group and the ring Y is as defined above.

An optionally substituted hydrocarbon group R ¹⁸ or R ¹⁹ is as defined above.

Ring Y represents an optionally substituted 5- to 7-membered hetero-ring except for 4-pyridone. More preferably, ring Y is a cyclic group of formula VIII

(VIII) wherein R ²⁰ and R ²¹ are as defined above.

The ring W is preferably a cyclic group of formula VI (VI),

Wherein R ¹ and R ² are as defined above.

The compounds of formula (I), (II) and (VI) and salts thereof can be readily prepared by known methods, as exemplified in the following Production Methods 1 to 16.

The abovementioned optionally substituted fused bicyclic compound containing 5- to 2-carboxylic acid

A 7-membered homo- or heterocyclic group and a 5- to 7-membered homo- or heterocyclic group can be produced according to production methods 1 to 16.

Production Method 1: According to the method described by K. Gewald, E. Schink and H. Bottcher: Chem. Ber. 99, 94 (1966), the corresponding ketone or aldehyde with active methylene of formula (I) is reacted with a cyanoacetic acid ester derivative and sulfur to be converted to the 2-aminothiophene derivative of formula (ii). More particularly - in the case of using ketone (R ¹ is not hydrogen), the ketone is heated under reflux together with a cyanoacetic acid ester derivative in the presence of acetic acid and ammonium acetate in an appropriate solvent such as toluene. There is thus obtained an alkylidene cyanoacetic acid ester derivative which is then heated in an appropriate solvent, for example ethanol, in the presence of sulfur and a base. There was thus obtained a 2-aminothiophene derivative of formula (ii). In the case of using aldehyde (R ¹ = H), the aldehyde is heated in an appropriate solvent, for example dimethylformamide, in the presence of a cyanoacetic ester derivative, sulfur and a base to give a 2-aminothiophene derivative of general formula II. The compound of formula (ii) thus obtained is heated according to the method described by Kuwatou et al. [see German patent 2,435,025] with ethoxymethylenemalonic acid diethyl ester. An adduct of formula (iii) is obtained. The adduct is stirred in a solvent that does not adversely affect the reaction (e.g., an alcohol such as ethanol and methanol) in the presence of a base (e.g., an alkali metal hydroxide such as potassium hydroxide and sodium hydroxide) at temperatures ranging from 10 to 70 ° C. This gives the carboxylic acid of the general formula iv subjected to ring closure by heating in a polyphosphoric acid ester (PPE). The compound of formula (v) is stirred in a solvent that does not adversely affect the reaction (e.g., in amides such as dimethylformamide and dimethylacetamide) in the presence of a halogenated aralkyl derivative and a base. (e.g., organic bases such as pyridine and triethylamine) at a temperature ranging from 10 to 100 ° C. There was thus obtained a 4,7-dihydro-4-oxothieno [2,3-b] pyridine-5-carboxylic acid ester derivative of the formula Ia. Thereafter, compound 1a is mixed together with N-bromosuccinimide (NBS) in a solvent that does not adversely affect the reaction (e.g., halogenated hydrocarbons such as carbon tetrachloride and chloroform) in the presence of α, α'-azobisisobutyronitrile at temperatures ranging from 30 to 100 Deň: 32 ° C. The compound of formula (1b) is obtained. The compound of formula 1b is mixed together with various amines in a solvent that does not adversely affect the reaction (e.g., amides such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile, and alcohols such as ethanol) in the presence of a base at a temperature in the range from 10 to 100 ° C. The production method 1 is described in the following Scheme 1:

-29GB 290723 B6

Scheme 1

DNCCIUCOiR '

NlltOAc AcOll

2) S lINEtj (R * '# 11)

NCCIhCOtť

S NEtj (R · '= 11)

(Hive)

KOll-EtOII ——--—>

(and/)

wherein R ¹ is a hydrogen atom or an alkyl group, R 1 is an alkyl group, X is a leaving group, Xa is a halogen atom and R ² , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ⁹ , m and n are as defined above .

Alkyl groups R ¹ and R 'are as defined above.

-30GB 290723 B6

The leaving group X includes, for example, a group that is potentially substituted with a nucleophilic reagent, such as a hydrocarbon group with a heteroatom (e.g., oxygen, sulfur, nitrogen) that is negatively charged. Preferred examples of the leaving group include a halogen atom (e.g. iodine, bromine and chlorine), alkanoyloxy (e.g. acetoxy), alkylsulfonyloxy (e.g. methanesulfonyloxy) and alkyl-arylsulfonyloxy (e.g. p-toluenesulfonyloxy).

Halogen Xa is fluorine, iodine, bromine and chlorine. A bromine atom is preferred.

Production Method 2: In essentially the same manner as Production Method 1, a 2-aminothiophene derivative whose position 5 is unsubstituted is of the general formula vi, which can be synthesized according to the method described by K. Gewald [K. Gewald, Chem. Ber. 98, 3571 (1965), K. Gewald et al. Schinke: Chem. Ber. 99, 2712 (1966).] Is reacted with ethoxymethylene malonic acid diethyl ester with heating according to the method described by Kuwata et al. [Germany Patent 2,435,025]. An adduct of formula (ii) is obtained. This adduct is stirred at a temperature of from 10 to 60 ° C in a solvent that does not adversely affect the reaction (e.g., alcohols such as ethanol and methanol) in the presence of a suitable base (e.g., an alkali metal hydroxide such as potassium hydroxide and sodium hydroxide). to form a carboxylic acid of formula (viii). The compound of formula (viii) is subjected to various cationic substitution reactions and, if appropriate, to a suitable functional group change to introduce a substituent R, which is then subjected to a ring-closing reaction by heating in a polyphosphoric acid ester (PPE). There was thus obtained a thieno [2,3-b] pyridine derivative of the general formula ix. The compound of formula (ix) is mixed with the halogenated aralkyl derivative in a solvent that does not adversely affect the reaction (e.g., amides such as dimethylformamide and dimethylacetamide) in the presence of a base at temperatures ranging from 10 to 100 ° C. There was thus obtained a 4,7-dihydro-4-oxothieno [2,3-b] pyridine- ester ester derivative.

5-carboxylic acids of formula Ia. As for the cationic reaction, for example, nitration (fuming nitric acid - concentrated sulfuric acid, sodium nitrate, concentrated sulfuric acid), acylation (acid chloride - aluminum chloride), formylation (phosphorus oxychloride - dimethylformamide or N-methylformanilide) and bromination (N- bromosuccinimide, bromo-pyridine). The compound of formula (Ia) is then treated in essentially the same manner as in Production Method 1. This yields compounds of Formula (Ib) and (I). Production Method 2 is shown in Scheme 2:

-31 GB 290723 B6 /

Scheme 2

(vO

R ¹ '

KOll-EtOll

- (Vi)

Production Method 3: An alanic acid derivative of formula (x) is stirred at a temperature in the range of from 5 ° C to 110 ° C together with an equivalent or excess of triphosgene relative to the compound of formula (x) in a solvent that does not adversely affect the reaction. 1,4-dioxane). There is thus obtained an isatoic anhydride derivative of the formula (xi). Thereafter, the halogenated derivative of formula (xii) is stirred at a temperature ranging from

-32GB 290723 B6 to 130 ° C. in a solvent that does not adversely affect the reaction (ethers such as tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbons such as benzene and toluene, amides such as Ν, Ν-dimethylformamide and Ν, Ν-dimethylacetamide, and alkylsulfoxides such as is dimethylsulfoxide) in the presence of a base (e.g., an alkali metal carbonate such as potassium carbonate, an alkali metal hydride such as sodium hydride and potassium hydride, and an alkali metal alkoxide such as potassium butoxide). There was thus obtained a substituted derivative of the formula (xiii). This derivative of formula (xiii) is reacted with an equivalent or a small excess (relative to the compound of formula (xiii) (e.g. 1.1 to 1.5 equivalents)) of the β-ketoacid ester derivative of formula (xiv) at a temperature ranging from 40 to 110 ° C in a solvent that does not adversely affect the reaction (e.g., ethers such as tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbons such as benzene and toluene, amides such as Ν, Ν-dimethylformamide and Ν, Ν-dimethylacetamide, and an alkyl sulfoxide such as dimethyl sulfoxide) in the presence of a base (e.g. an alkali metal carbonate such as potassium carbonate, an alkali metal hydride such as sodium hydride and potassium hydride, and an alkali metal alkoxide such as potassium butoxide). Compound 15 of formula (Va) is obtained. The previous production method 3 is shown in Scheme 3:

-33GB 290723 B6

Scheme 3

wherein each symbol is as defined above.

Production Method 4: The pyridine derivative of formula (xv) is mixed with an equivalent or 5 of excess triphosgene relative to the compound of formula (xv) in a solvent that does not adversely affect the reaction (e.g., ethers such as tetrahydrofuran and 1,4-dioxane) at range from 30 to 110 ° C. An acid anhydride derivative of formula (xvi) is thus obtained. Then

The halogenated derivative of formula (xii) is stirred in a solvent that does not adversely affect the reaction (e.g., ethers such as tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbons such as benzene and toluene, amides such as Ν, Ν -dimethylformamide and N, N-dimethylacetamide, and alkyl sulfoxides such as dimethyl sulfoxide) at a temperature ranging from 40 to 130 ° C 5 in the presence of a base (eg an alkali metal carbonate such as potassium carbonate, an alkali metal hydride such as sodium hydride and potassium hydride, and an alkali metal alkoxide such as potassium butoxide). There was thus obtained a substituted derivative of the formula (xvii). This derivative of formula (xvii) is reacted with an equivalent or a small excess (e.g., 1.1 to 1.5 equivalents) of a β-ketoacid ester derivative of formula (xiv) in a solvent that does not adversely affect the reaction (e.g., ethers such as tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbons such as benzene and toluene, amides such as Ν, Ν-dimethylformamide and N, N-dimethylacetamide, and alkyl sulfoxides such as dimethyl sulfoxide) in the presence of a base (eg an alkali metal carbonate such as potassium carbonate, an alkali metal hydride such as sodium hydride and potassium hydride, and an alkali metal alkoxide such as potassium butoxide) at temperatures ranging from 15 to 110 ° C. A compound of formula Vb is thus obtained. The previous production method 4 is shown in Scheme 4:

-35GB 290723 B6

Scheme 4

(CH ₂ ) n · (xvii) wherein each symbol is as defined above.

-36GB 290723 B6

Production Method 5: A 4,7-dihydro-4-oxothieno [2,3-b] pyridine-5-carboxylic acid ester derivative is stirred in an appropriate solvent that does not adversely affect the reaction (e.g., an ether such as tetrahydrofuran, ethyl ether and dioxane). % of the acid together with a suitable reducing agent (e.g. lithium aluminum hydride) at a temperature in the range of 0 to 80 ° C. There was thus obtained a 4,7-dihydro-thieno [2,3-b] pyridin-4-one derivative of formula Ic. This derivative is mixed with a suitable oxidizing agent (eg, manganese dioxide) in an appropriate solvent (eg, dichloromethane or chloroform) at a temperature in the range of 10 to 80 ° C. There was thus obtained a 5-formyl derivative. The thus obtained derivative of the general formula (Id) is stirred together with the Grignard reagent at a temperature ranging from 0 to 80 ° C in a solvent which does not adversely affect the reaction (e.g. ethers such as tetrahydrofuran and ethyl ether). The corresponding secondary alcohol derivative of formula (Ie) is thus obtained. The compound of formula (Ie) is mixed with a suitable oxidizing agent (eg, a metal oxide such as manganese dioxide) in an appropriate solvent (eg, halogenated hydrocarbons such as dichloromethane and chloroform) at a temperature in the range of 10 to 80 ° C. There was thus obtained a 5-carbonyl derivative of the general formula If. The previous production method 5 is shown in Scheme 5:

Scheme 5

LiAlH ₄ -------> THF

activated ------- »Un0 ₂

activated

----—>

Manure

wherein R ²⁵ is a hydrocarbon group and the other symbols are as defined above.

The aforementioned hydrocarbon group R ²⁵ represents the same hydrocarbon group as the hydrocarbon group in the carbonyl group optionally substituted by a hydrocarbon group as described above as R ⁴ .

-37GB 290723 B6

Production Method 6: The 4,7-dihydro-4-oxothieno [2,3-b] pyridine-5-carboxylic acid ester derivative of formula (Ia ') is stirred at a temperature between 10 and 100 ° C together with the aluminum amide derivative beforehand prepared from an appropriate aluminum reagent [(e.g., trimethylaluminum and diisobutylaluminum hydride (DIBAL)) and an amine in a suitable solvent that does not adversely affect the reaction (e.g., halogenated hydrocarbons such as dichloromethane and ethers such as tetrahydrofuran, ethyl ether and dioxane). The compound of formula (Ia) is mixed together with the Grignard reagent in an appropriate solvent which does not adversely affect the reaction ( (e.g. tetrahydrofuran and ethyl ether) at a temperature in the range of -78 to 80 ° C to give the corresponding ketone derivative of formula (If). in scheme 6:

Scheme 6

Customs ') (Ia')

R ¹⁴ MgXq or R ¹⁴ Li

(L1) wherein R @ ²⁶ is alkyl or aryl, R @ ²⁷ and R @ ²⁸ are each independently hydrogen or hydrocarbon, and the other symbols are as defined above.

Alkyl and aryl R ²⁶ are as defined above.

-38GB 290723 B6

The hydrocarbon groups R ²⁷ and R ²⁸ represent the same hydrocarbon group as the hydrocarbon group in the carbonyl group optionally substituted by a hydrocarbon group as mentioned above as R ⁴ .

Production Method 7: A 4,7-dihydro-5-hydroxymethylthieno [2, a] derivative is stirred in an appropriate solvent that does not adversely affect the reaction (e.g., halogenated hydrocarbons such as dichloromethane, ethers such as tetrahydrofuran, ethyl ether and dioxane, and pyridine). 3-b] pyridin-4-one of formula Ia 'together with a suitable halogenating agent (e.g., thionyl chloride and methanesulfonyl chloride) at a temperature ranging from 0 to 100 ° C. There was thus obtained a 4,7-dihydro-10-thieno [2,3-b] pyridine derivative of the general formula Ig. This derivative of formula (Ig) is mixed with a suitable nucleophilic reagent in an appropriate solvent that does not adversely affect the reaction (e.g., ethers such as tetrahydrofuran and ethyl ether, and amides such as dimethylformamide). There was thus obtained the corresponding 5-substituted derivative of the formula Ih. The above production method 7 is shown in Scheme 7:

Scheme 7

OH- »X’

-------->

conversion

wherein X 'is a leaving group, Z is an oxygen, sulfur or nitrogen atom optionally substituted by a hydrocarbon group, and the other symbols are as defined above.

The leaving group X 'may be, for example, groups that are susceptible to nucleophilic agent substitution [e.g. a negative-charged heteroatomic hydrocarbon group (eg, oxygen, sulfur, and nitrogen) referred to above as "YR ¹⁶ ]. More specifically, for example, aralkyloxy (e.g., acetoxy), alkylsulfonyloxy (e.g., methanesulfonyloxy), and alkyl-arylsulfonyloxy (e.g., p-toluenesulfonyloxy).

The hydrocarbon group in the above-mentioned nitrogen atom group optionally substituted by a hydrocarbon group means the same hydrocarbon group as the hydrocarbon group in the carbonyl group optionally substituted by a hydrocarbon group, as mentioned above as R ⁴ .

-39GB 290723 B6

Production Method 8: A 4,7-dihydro-5-formylthieno [2,3-b] pyridin-4-one derivative is stirred in an appropriate solvent that does not adversely affect the reaction (e.g., ethers such as tetrahydrofuran, ethyl ether and dioxane, and pyridine). of formula Ih together with a suitable Wittig reagent at a temperature in the range of 0 to 100 ° C. There was thus obtained a 4,7-dihydrothieno [2,3-b] pyridin-4-one derivative of the formula Ij. This derivative of formula (Ij) is stirred at a temperature in the range of 10 to 100 ° C together with a suitable reducing agent [e.g. hydrogenation in a hydrogen stream using a catalyst (e.g. palladium on carbon)] in an appropriate solvent that does not adversely affect the reaction (e.g. alcohols such as ethyl alcohol, esters such as ethyl acetate, ethers such as tetrahydrofuran, ethyl ether and dimethylformamide). There was thus obtained the corresponding 5-substituted derivative of the formula Ik. The above production method 8 is shown in Scheme 8:

Scheme 8

catalytic

------->

reduction

(Ik) wherein R ²⁹ and R ³⁰ are hydrogen or a hydrocarbon group and the other symbols are as defined above.

The above hydrocarbon groups R ²⁹ and R ³⁰ represent the same hydrocarbon group as the hydrocarbon group in the carbonyl group optionally substituted by a hydrocarbon group as mentioned above as R ⁴ .

-40GB 290723 B6

Production Method 9: In an appropriate solvent that does not adversely affect the reaction (e.g., ethers such as tetrahydrofuran and dioxane, and alcohols such as ethyl alcohol), the 4,7-dihydro-4-oxothieno [2,3-b] ester derivative pyridine-5-carboxylic acids of formula Ia 'undergo hydrolysis under stirring at a temperature ranging from 0 to 100 ° C by addition of an acid (e.g. an inorganic acid such as hydrochloric acid) or in an alkaline aqueous solution (e.g. 1 to 4N aqueous solution) alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide). The resulting 5-carboxylic acid derivative is heated at a temperature ranging from 50 to 200 ° C in an appropriate solvent that does not adversely affect the reaction. The corresponding decarboxylated derivative of formula (In) is thus obtained. The previous production method 9 is shown in Scheme 9:

wherein all symbols mean as above.

Production Method 10: Starting from a 2-aminothiophene derivative of formula (ii). The urea derivative of the general formula (II) is prepared according to process A or B.

Process A: A 2-aminothiophene derivative of general formula (ii) produced by the process described in Production Method 1, or a salt thereof, is reacted with an isocyanate derivative. Examples of isocyanate derivatives are those of formula R ¹² -NCO (wherein R ¹² is as defined above). The reaction of the compound of formula (ii) or a salt thereof with an isocyanate derivative is carried out in a solvent which does not adversely affect the reaction (e.g. tetrahydrofuran, pyridine, dioxane, benzene, dichloromethane, 1,2-dichloroethane, toluene, xylene). to 130 ° C. The isocyanate derivative is used in an amount of 1 to 5 equivalents, preferably 1.1 to 2.5 equivalents per 1 equivalent of the compound of formula (ii). The reaction time is from a few minutes to several days, preferably from 15 minutes to 2 days.

2. Method B: Amin [e.g. a compound of formula R ¹² -NH ₂ (wherein R ¹² is as defined above)] is added to an isocyanate derivative prepared by reacting a 2-aminothiophene derivative of formula ii or a salt thereof with phosgene or an equivalent compound

[Eg. diphosgene such as bis (trichloromethyl) carbonate, triphosgene such as trichloromethyl chlorophonate]. The reaction of the compound of formula (ii) or a salt thereof with phosgene or an equivalent thereof is carried out in a solvent which does not adversely affect the reaction (e.g. dioxane, tetrahydrofuran, benzene, toluene, xylene, 1,2-dichloroethane or chloroform) at a temperature ranging from 40 to 120 ° C. The phosgene or equivalent compound is used in an amount of from 0.5 to 2 equivalents, preferably from 0.9 to 1.1 equivalents. The reaction time is from a few minutes to several days, preferably from 15 minutes to 2 days. The amine addition reaction is carried out in a solvent that does not adversely affect the reaction (e.g., pyridine, tetrahydrofuran, dioxane, benzene, dichloromethane, 1,2-dichloroethane, toluene, xylene) at a temperature in the range of 15 to 130 ° C. The amine is used in an amount of 1 to 5 equivalents, preferably from 1.1 to 3 equivalents. The reaction time is from a few minutes to several days, preferably from 15 minutes to two days.

The compound of formula (XV) thus produced or a salt thereof is reacted with a base. This results in ring closure and the thieno [2,3-d] pyrimidine derivative of formula XVI is prepared. The ring closure reaction is carried out in a solvent which does not adversely affect the reaction. Examples of solvents are alcohols such as methanol, ethanol and isopropanol, and ethers such as dioxane and tetrahydrofuran.

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

The base is used in an amount of 1 to 5 equivalents, preferably 1.5 to 3 equivalents per equivalent of the compound of formula (XV).

The reaction temperature ranges from 10 ° C to the boiling point of the solvent used, 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 10 minutes to 2 days.

The compound of formula XVI and the halogenated aralkyl derivative are stirred in the presence of a base (e.g. an organic base such as pyridine or triethylamine) in a solvent that does not adversely affect the reaction (e.g., amides such as dimethylformamide or dimethylacetamide) at 10 to 100 ° C. . Thus, a 2,4-dioxothieno [2,3-d] pyrimidine derivative of the formula IIa is prepared. Then, the compound of formula IIa is mixed with N-bromosuccinimide (NBS) in a solvent that does not adversely affect the reaction (e.g., halogenated hydrocarbons such as carbon tetrachloride or chloroform) in the presence of α, α'-azobisisobutyronitrile. A compound of formula IIb is prepared. This compound is mixed with various amines in the presence of a base in a solvent that does not adversely affect the reaction (e.g., amides such as dimethylformamide or dimethylacetamide, nitriles such as acetonitrile, and alcohols such as ethanol) at temperatures ranging from 10 to 100. Deň: 32 ° C. A compound of formula (II) is thus prepared. If necessary, this compound is converted to the corresponding salt by a suitable acid (e.g., hydrochloric acid or oxalic acid). The foregoing manufacturing method 10 is shown in Scheme 10:

-42GB 290723 B6

Scheme 10

ω o <9 from u

S o <«z w

ca

OF

From ca <

wherein each symbol is as defined above.

Production method 11: The amino group of the 2-aminothiophene derivative of formula (xvii) is protected, e.g. as a Boc derivative. This derivative is stirred according to T. Hirohashi et al. [German patent

-43GB 290723 B6

2155403 (1972), inter alia] or by the method of M. Nakanishi et al. [Japanese Pat. 73-01664 (1974), inter alia] with a halogenated acyl derivative in the presence of a base in a solvent that does not adversely affect the reaction (e.g., amides such as dimethylformamide or dimethylacetamide) at temperatures ranging from 10 to 100 ° C. This yields a derivative of formula (xviii) which is mixed with a suitable salt (e.g., lithium iodide) in a suitable solvent (e.g., acetone or methyl ethyl ketone). There is thus obtained a derivative of the formula (xiv), which is subjected to a substitution reaction with a suitable amine (e.g. ammonia). This yields a derivative of the formula (xx) which is stirred in a solvent that does not adversely affect the reaction (e.g. toluene, dimethylformamide, dimethylacetamide, methanol or ethanol) in the presence of a suitable catalyst (e.g. sodium ethoxide or toluenesulfonic acid), if necessary , at temperatures ranging from 30 to 120 ° C. Dehydro-cyclization thus produces a derivative of the formula (VIIa). This compound is mixed with a halogenated aralkyl derivative in the presence of a base (e.g., an organic base including potassium carbonate, pyridine and triethylamine) in a solvent that does not adversely affect the reaction (e.g., amides such as dimethylformamide or dimethylacetamide) at temperatures ranging from 10 to 100. Deň: 32 ° C. There was thus obtained the 2-oxothieno [2,3-e] azepine derivative of the formula VIIb. Then, the compound of formula VIIIb is mixed with N-bromosuccinimide (NBS) in a solvent (eg, halogenated hydrocarbons including carbon tetrachloride and chloroform) in the presence of α, α'-azobisisobutyronitrile at temperatures ranging from 30 to 100 ° C. There was thus obtained the compound of formula (Vile). This compound is mixed with various amines in the presence of a base in a solvent that does not adversely affect the reaction (e.g., amides such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile, and alcohols such as ethanol) at temperatures ranging from 10 to 100 ° C. A compound of formula Vid is thus obtained. If necessary, the compound is converted with a suitable acid (e.g., hydrochloric or oxalic acid) into the corresponding salt. The foregoing manufacturing method 11 is shown in Scheme 11:

-44GB 290723 B6

Scheme 11

wherein each symbol is as defined above.

Production Method 12: The amino group of the 2-aminothiophene derivative that can be produced according to the method described in Production Method 1 is protected, e.g., Boc. This derivative is mixed with a halogenated aralkyl derivative in the presence of a base (eg, an organic base including potassium carbonate, pyridine and triethylamine) in a solvent that does not adversely affect the reaction (eg, amides such as dimethylformamide and dimethylacetamide) at temperatures

-45GB 290723 B6 from 10 to 100 ° C. There is thus obtained a derivative of the formula (xxi) which is subjected to alkaline hydrolysis with a suitable alkali (e.g. sodium hydroxide) in a suitable solvent (e.g. methanol, tetrahydrofuran). The derivative so produced is mixed with DPPA in a solvent that does not adversely affect the reaction (e.g., toluene, tetrahydrofuran, dimethylformamide, dimethylacetamide, or ethanol) at temperatures in the range of 10 to 100 ° C. The resulting compound is converted to a carbamic acid ester derivative of formula (xxii) with a suitable alcohol (e.g. ethanol). This derivative is stirred in the presence of a base (e.g. sodium ethoxide) in a solvent that does not adversely affect the reaction (e.g. dimethylformamide and dimethylacetamide) at temperatures ranging from 10 to 100 ° C. There was thus obtained a thieno [2,3-d] imidazol-2-one derivative of the general formula Vile. This compound is mixed with a halogenated alkyl derivative in the presence of a base in a solvent that does not adversely affect the reaction (e.g., amides such as dimethylformamide and dimethylacetamide) at temperatures ranging from 10 to 100 ° C. There was thus obtained a compound of formula VIIf. The compound of formula VIIIf is mixed together with N-bromosuccinimide (NBS) in a solvent that does not adversely affect the reaction (e.g., halogenated hydrocarbons such as carbon tetrachloride and chloroform) in the presence of α, α'-azobisisobutyronitrile at temperatures ranging from 30 to 100 ° C. There was thus obtained a compound of formula VIIg. This compound is further mixed with various amines in the presence of a base in a solvent that does not adversely affect the reaction (e.g., amides such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile, and alcohols such as ethanol) at temperatures ranging from 10 to 100. Deň: 32 ° C. There was thus obtained a compound of formula VIIh. The compound obtained is converted, if necessary, into the corresponding salt with a suitable acid (e.g., hydrochloric acid or oxalic acid). The foregoing manufacturing method 12 is shown in Scheme 12:

-46GB 290723 B6

Scheme 12

Wherein each symbol is as defined above.

Production Method 13: From the 2-aminothiophene derivative of formula (ii), which can be produced according to the method described in Production Method 1, or from a salt thereof, an ethyl ester derivative is prepared

4,5-dihydro-7-hydroxy-5-oxothieno [3,2-b] pyridine-6-carboxylic acid according to the method of J. M. Baker et al. [J. Chem. Res. (M) 1980,113, J. Chem. Res. (s) 6 (1980)]. More specifically, the 2-aminothiophene derivative of formula (ii) or a salt thereof is reacted with a malonic ester. This provides a compound of formula xxii which is stirred in the presence of a suitable base (e.g. sodium hydride) in a solvent that does not adversely affect the reaction (e.g., amides such as dimethylformamide and dimethylacetamide) at temperatures ranging from 10 to 100 ° C. . There was thus obtained a compound of the formula VIIIa. This derivative of formula VIIIa is mixed with a halogenated aralkyl derivative in the presence of a base (e.g., organic bases including potassium carbonate, pyridine and triethylamine) in a solvent that does not adversely affect the reaction (e.g., amides such as dimethylformamide and dimethylacetamide) at temperatures ranging from 10 to 100 ° C. There was thus obtained a compound of formula VIIk. This derivative is mixed with N-bromosuccinimide (NBS) in a solvent that does not adversely affect the reaction (e.g., halogenated hydrocarbons such as carbon tetrachloride and chloroform) in the presence of α, α'-azobiisobutyronitrile at temperatures ranging from 30 to 100 ° C. This gives a compound of formula Vilm. This compound is mixed with various amines in the presence of a base in a solvent that does not adversely affect the reaction (e.g., amides such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile, and alcohols such as ethanol) at temperatures ranging from 10 to 100. Deň: 32 ° C. There was thus obtained a compound of formula VIIn. If necessary, this compound is converted to the corresponding salt by a suitable acid (e.g., hydrochloric acid or oxalic acid). The previous production method 13 is shown in Scheme 13:

-48GB 290723 B6

Scheme 13 w o

Cl. with

Q ω o o o

d +> <0

/TO

1) HR ^u

2) HCl ether wherein each symbol is as defined above.

-49GB 290723 B6

Production Method 14: 1,4-Dihydro-4-oxoquinoline-3- ester derivative is stirred in a suitable solvent that does not adversely affect the reaction (e.g., halogenated hydrocarbons such as dichloromethane and ethers such as tetrahydrofuran, ethyl ether and dioxane). carboxylic acids of formula Va 'with an aluminum amide derivative made from a suitable aluminum reagent [e.g.

trimethylaluminum, triethylaluminum or diisobutylaluminum hydride (DIBAL) J; and amines at temperatures ranging from 10 to 100 ° C. There is thus obtained a 1,4-dihydro-4-oxoquinoline-3-carboxylic acid amide derivative of the formula Va. This derivative is mixed with the Grignard reagent in a suitable solvent that does not adversely affect the reaction (e.g., tetrahydrofuran and ethyl ether) at temperatures ranging from 0 to 80 ° C. There is thus obtained a derivative of the corresponding ketone 10 of the formula Vc. The foregoing manufacturing method 14 is shown in Scheme 14:

Scheme 14

R * R ** NH

R ^for MgXa> or R ^{1 <} Li

Wherein R ²⁶ is an alkyl or aryl group, R ²⁷ and R ²⁸ are each independently hydrogen or a hydrocarbon group and the other symbols are as defined above.

Alkyl and aryl R ²⁶ are as defined above.

The hydrocarbon groups R ²⁷ and R ²⁸ represent the same hydrocarbon group as the hydrocarbon group in the carbonyl group optionally substituted by a hydrocarbon group as mentioned above as R '.

Production Method 15: 1,4-Dihydro-4-oxopyrido ester derivative [2,3] is stirred in an appropriate solvent that does not adversely affect the reaction (e.g., halogenated hydrocarbons such as dichloromethane and ethers such as tetrahydrofuran, ethyl ether and dioxane). -b] pyridine-3-carboxylic acids of formula Vd with an aluminum amide derivative made from a suitable aluminum reagent [e.g. trimethylaluminum, triethylaluminum or diisobutylaluminum hydride (DIBAL)] and amines at temperatures ranging from 10 to 100 ° C. There was thus obtained 1,4-dihydro-4-oxopyrido [2,3-b] pyridine-3-carboxylic acid amide derivative of the formula VId. This derivative is mixed with the Grignard reagent in a suitable solvent that does not adversely affect the reaction (e.g., tetrahydrofuran and ether) at temperatures ranging from 0 to 80 ° C. A derivative of the corresponding ketone of formula Ve is obtained. The production method is shown in Scheme 15:

-51 CZ 290723 B6

R ”R” NH ^

D I BAL · *

wherein R ²⁶ is an alkyl or aryl group, R ²⁷ and R ²⁸ are each independently hydrogen or a hydrocarbon group, and the other symbols are as defined above.

Alkyl and aryl R ²⁶ are as defined above.

The hydrocarbon groups R ²⁷ and R ²⁸ represent the same hydrocarbon group as the hydrocarbon group in the carbonyl group optionally substituted by a hydrocarbon group as mentioned above as R '.

Production Method 16: In a suitable solvent that does not adversely affect the reaction (e.g., ethers such as 1,2-dimethoxyethane, tetrahydrofuran and dioxane, and alcohols such as ethyl alcohol), the compound of formula (Ip) is dissolved. To this solution is added in the presence of an equimolar amount to an excess (2 to 10 equivalents) of a suitable base (e.g., sodium carbonate) a suitable allyl boronic acid derivative (e.g., phenylboronic acid, 3-methoxyphenylboronic acid and 4-ethoxycarbonylphenylboronic acid). To this mixture is added in an inert gas stream (e.g. argon) suitable

Catalyst [e.g. palladium metal including tetrakis (triphenylphosphine) palladium]. The mixture is stirred for a few minutes to several hours at a temperature ranging from 10 to 100 ° C. Remove the insoluble matter. The desired derivative of formula (Iq) remains. The foregoing manufacturing method 16 is shown in Scheme 16:

Scheme 16

wherein R ³⁰ is an optionally substituted aryl group and the other symbols are as defined above.

Physiologically acceptable acid addition salts are preferred as the salts of the compounds of the invention obtained as above. Examples of such salts include salts with inorganic acids (e.g., hydrochloric, hydrobromic, nitric, sulfuric, and phosphoric acids) or with organic acids (e.g., formic, acetic, trifluoroacetic, fumaric, oxalic, tartaric, maleic, citric, succinic, malic acids) , methanesulfonic, benzenesulfonic and p-toluenesulfonic). When a compound of formula I of the present invention has an acid group such as -COOH, it may form salts with an inorganic base (e.g., an alkali metal or alkaline earth metal such as sodium, potassium, calcium and magnesium, or ammonia) or an organic bases (e.g., trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine and Ν, Ν'-dibenzylethylenediamine).

Particularly preferred examples of the compounds or salts thereof of this invention include 3- (N-benzyl-N-methylaminomethyl) -4,7-dihydro-7- (2-methoxybenzyl) -2- (4-methoxyphenyl) -4-oxothieno ethyl ester [2,3-b] pyridine-5-carboxylic acid 3- (N-benzyl-N-methylaminomethyl) -4,7-dihydro-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -4 ethyl ester -4 oxothieno [2,3-b] pyridine-5-carboxylic acid 2- (4-acetylaminophenyl) -3- (N-benzyl-N) ethyl ester

-53EN 290723 B6 methylaminomethyl) -4,7-dihydro-7- (2-fluorobenzyl) -4-oxothieno [2,3-b] pyridine-5-carboxylic acid, 5-benzylmethylaminomethyl-1- (2-chloro-6) -fluorobenzyl) -2,4 (1H, 3H) -dioxo-6- (4-methoxyphenyl) -3-phenylthieno [2,3-d] pyrimidine, 5-benzoyl-3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-4-oxo-2- (4-propionylaminophenyl) thieno [2,3-b] pyridine, 5-benzoyl-3- (N-benzyl-N) -methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-2- (4-N'-methylureidophenyl) -4-oxothieno [2,3-b] pyridine, 3- (N-benzyl-N-) methylaminomethyl) 7- (2,6-difluorobenzyl) -4,7-dihydro-5-isobutyryl-4-oxo-2- (4-propionylaminophenyl) thieno [2,3b] pyridine, 3- (N-benzyl-N- methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-2-5-isobutyryl-2- (4-N'-methylureidophenyl) -4-oxothieno [2,3-b] pyridine, 3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-2- (4-N ' -methylureidophenyl) -4-oxothieno [2,3-b] pyridine-5 - (N-isopropyl) carboxamide, 3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-2- (4-N'-methylureidopheny l) -4-oxothieno [2,3-b] pyridine-5- (N-isopropyl-N-methyl) carboxamide; 3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) 4 7-dihydro-2- (4-N'-methylureidophenyl) -4-oxothieno [2,3-b] pyridine-5- (N-benzyl-N-methyl) carboxamide or a salt thereof.

The compounds or salts thereof of the present invention produced as above can be isolated and purified by conventional resolution methods such as recrystallization, distillation and chromatography.

When the compound of formula (I) is produced in free form, it can be converted to its salt by known conventional methods or analogous methods. Conversely, when obtained in the form of a salt, it can be converted to the free form or to any other salt.

When the compound or salt thereof of the present invention is an optically active compound, it can be separated into the d-compound and the 1-compound by conventional optical resolution techniques.

Since the compounds of the invention have GnRH antagonist activity and low toxicity, they can be safely used to treat male or female hormone-dependent diseases as well as to treat diseases caused by excessive secretion of these hormones in warm-blooded animals (e.g., humans, monkeys, cows, horses, dogs, cats, rabbits, rats, and mice) by suppressing gonadotropic hormone secretion by exerting a GnRH receptor antagonist effect. In particular, the compounds of the invention are effective as prophylactic or therapeutic agents for the prevention or treatment of several hormone-dependent diseases, for example sex hormone-dependent cancers (e.g., prostate cancer, cervical cancer, breast cancer, pituitary adenoma), benign prostatic hypertrophy, uterine myoma, endometriosis, premature puberty, amenorrhea, premenstrual syndrome, polycystic ovary syndrome, and acne vulgaris. The compounds of this invention are also effective as a fertility control agent in both sexes (e.g., pregnancy control agents and menstrual cycle control agents). The compounds of the invention may further be used as a contraceptive for both sexes and in women as an ovulation inducing agent. The compound of the invention can be used as an agent for treating infertility by utilizing a retroactive effect after stopping its administration. The compounds of this invention are useful as estrogen cycle modifiers in livestock and as an agent for improving edible meat quality or for promoting animal growth. In addition, the compounds of the invention are useful as a spawning agent in fish. While the compounds of this invention may be used alone, they may also be effectively used when administered in combination with a steroidal or non-steroidal antiandrogenic agent. The compound of the invention can be used to suppress a transient increase in plasma testosterone concentration, an increase that occurs when a GnRH superantagonist such as leuprorelin acetate is administered. The compound of the invention is effectively administered in combination with a chemotherapeutic agent for the treatment of cancer. In the treatment of prostate cancer, chemotherapeutic agents include Ifosfamide, UFT, Adriamycin, Peplomycin, Cisplatin and the like. In the treatment of breast cancer, examples of chemotherapeutic agents include Cyclophohamide, 5-FU-, UFT, Methotraxate, Adriamycin, Mitomycin C, Mitoxantrone and the like.

-54GB 290723 B6

When a compound of the present invention is used in the livestock or fish farming field, it can be administered orally or neorally as a prophylactic and therapeutic agent of the aforementioned diseases according to known methods. The compound is admixed with a pharmaceutically acceptable carrier and is usually administered orally as a solid composition, such as a tablet, capsule, granule or powder, or neorally, such as intravenous, subcutaneous or intramuscular injection, or as a suppository or sublingual tablet to be administered under language. Further, sublingual, subcutaneous or intramuscular administration may be by sustained release, such as sublingually administered tablets or microcapsules. The daily dose depends on the degree of affliction, age, sex, body weight, differences in susceptibility of the subject to be administered, the time and intervals of administration, the properties, dosage forms and types of the medicinal product, and the types of active ingredients. The daily dose is usually in the range, although not specifically limited, from 0.01 to 10 mg, preferably from 0.02 to 2 mg, more preferably from 0.01 to 1 mg per kg of body weight of the warm-blooded animal to be administered. once daily or divided into 2 to 4 doses. The daily ration, when used in livestock or fish farming, depends on similar conditions as above. It varies from 0.001 to 5 mg, preferably from 0.002 to 2 mg per kg of body weight, in a single dose or in 2-3 doses, depending on the species of animal or fish.

Conventional various organic or inorganic carriers are used as the above-mentioned pharmaceutically acceptable carriers. They are used as excipients, lubricants, binders and disintegrants in solid compositions, such as solvents, solubilizing agents, suspending agents, isotonizing agents, buffering agents, suspending agents, isotonizing agents, buffering agents, and pain relieving agents in liquid compositions. Other additives such as preservatives, antioxidants, coloring agents and sweeteners may also be used as necessary.

Preferred examples of the above-mentioned excipients include lactose, sugar, D-mannitol, starch, crystalline cellulose and more volatile silica. Preferred examples of the above lubricants include magnesium stearate, calcium stearate, talc and colloidal silica. Preferred examples of the above binding agents include crystalline cellulose, sugar, D-mannitol, dextrin, hydroxypropylcellulose, hydroxymethylcellulose and polyvinylpyrrolidone. Preferred examples of the above disintegrants include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium and sodium starch glycolate. Preferred examples of the above solvents include water for injection, alcohol, propylene glycol, macrogol, sesame oil and corn oil. Preferred examples of the above solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate and sodium citrate. Preferred examples of the above suspending agents include surfactants such as stearyl-triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzetonium chloride and stearic acid monoglycerylester, and hydrophilic polymers such as polyvinyl alcohol, polyvinyl cellulose, polyvinylpyrrolidone hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose. Preferred examples of the above isotonizing agents include sodium chloride, glycerin and D-mannitol. Preferred examples of the above buffering agents include buffer solutions such as phosphate, acetate, carbonate and citrate. Preferred examples of the above pain relieving agents include benzyl alcohol. Preferred examples of the above protecting agents include para-hydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid. Preferred examples of the above-mentioned antioxidants include sulfite and ascorbic acid.

For example, a suspending agent, a solubilizing agent, a stabilizing agent, an isotonizing agent, and a preservative are added to the compound of the invention; then the mixture is treated in a known manner to give intravenous, subcutaneous or intramuscular injection. These injections can then be processed by known methods into lyophilized preparations, if necessary.

-55GB 290723 B6

Examples of the above pharmaceutical compositions are oral agents (e.g., diluted powders, granules, capsules and tablets), injections, drip solution, external agents such as transnasal preparations, percutaneous preparations, etc.), ointments (e.g. rectal ointment, vaginal) ointment, etc.) and the like.

These pharmaceutical compositions can be manufactured by known methods used for the manufacture of pharmaceutical compositions.

The compound of the present invention or a salt thereof may be prepared as an injection in the form of an aqueous injection together with dispersing agents [e.g. Tween 80 (Atlas Powder, USA), HCO 80 (Nikko Chemicals, Japan), polyethylene glycol, carboxymethylcellulose, sodium alginate, etc.], preservatives (eg methylparaben, propylparaben, benzyl alcohol, etc.), isotonizing agents (eg sodium chloride, mannitol, sorbitol, glucose, etc.) and the like or in the form of an oil injection by dissolving, suspending or emulsifying in a vegetable oil (eg olive oil, sesame oil, cottonseed oil, corn oil, etc.), propylene glycol and the like.

In preparing a pharmaceutical composition for oral use, the compound of the present invention or a salt thereof is kneaded by compression, e.g., with fillers (e.g., lactose, sucrose, starch, etc.), disintegrants (e.g., starch, calcium carbonate, etc.), binders (e.g. starch, acacia, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or lubricants (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) and the like. If necessary, the composition is coated in a known manner with a taste masking agent, an enteric coating or a coating for prolonged action. Examples of coating agents include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, pluronic F 68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (a copolymer of red and methacrylic acid), iron and the like. There may also be a subcoating layer between the enteric coating and the core, which is obtained in a known manner.

In preparing the composition for external use, the compound of the present invention or a salt thereof is converted into a solid, semi-solid, or liquid agent for external use in a known manner. For example, a solid preparation is prepared as follows. As such, or after addition / mixing with a filler (eg, glycol, mannitol, starch, microcrystalline cellulose, etc.), thickening agents (eg, natural gums, cellulose derivatives, acrylic acid polymers, etc.) and the like are converted to a powdered compound means. In the case of a liquid formulation, an oily or aqueous suspension is made in a manner almost identical to that in which injections are prepared. In the case of a semi-solid composition, the preferred composition is an aqueous or oily gel or ointment. In all cases, a pH adjusting agent (eg, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), an antiseptic agent (eg, p-hydroxybenzoates, chlorobutanol, benzalkonium chloride, etc.) and the like can be added.

In the manufacture of an ointment, for example, the compound of the present invention or a salt thereof may be formulated as an oily or aqueous solid, semi-solid or liquid ointment. Examples of the oily base applicable to the above composition include higher fatty acid glycerides [e.g. cocoa butter, Witepsols (manufactured by Dynamite-Nobel), etc.], medium fatty acids [e.g. Miglyols (manufactured by Dynamite-Nobel) etc.] and vegetable oil (eg sesame oil, soybean oil, cottonseed oil, etc.) and the like. Examples of the aqueous base include polyethylene glycols and propylene glycol. Bases for aqueous gel include natural gums, cellulose derivatives, vinyl polymers, polymers of acrylic acid, etc.

-56GB 290723 B6

DETAILED DESCRIPTION OF THE INVENTION

By way of reference examples, working examples and test examples, the present invention will be described in more detail. However, this detailed description is not intended to limit the scope of the invention.

* HNMR spectra were measured on a Varian GEMINI 200 (200 MHz) spectrometer, a JEOL LAMBDA300 (300 MHz) spectrometer, and a Brucker AM 500 (500 MHz) spectrometer with tetramethylsilane as an internal standard. All delta values are expressed in ppm.

The symbols used herein have the following meanings: s means singlet, d means doublet, t means triplet, dt means triplet doublet, m means multiplet, br means broad signal.

Reference Example 1

2-Amino-5-phenylthiophene-3-carboxylic acid ethyl ester

To a mixture 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 ° C phenylacetaldehyde (50% (w / w) diethyl phthalate solution, 12.05 g, 50 mmol) over 20 minutes. The mixture was stirred at 45 ° C for 9 h. The reaction mixture was concentrated. The resulting residue was extracted with ethyl acetate. The extract was washed with brine, which was then dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is chromatographed on silica gel. Crystallization from ether / hexane gave slightly yellow plates (55 g, 45%), mp 124.5-125.5 ° C (123-124 ° C according to literature). For C ₃ H ₁₃ NO ₂ S Calculated: 63.13% C 5.30% H 5.66% N Found: 62.99% C 5.05% H 5.63% N H Nuclear Magnetic Resonance Spectrum (200 MHz, CDCl ₃ , δ): 1.37 (3H, t, J = 7.1 Hz), 4.30 (2H, d, J = 7.1 Hz), 5.97 (2H, br), 7.17-7.46 (6H, m). IR (KBr): 3448, 3320, 1667, 1590, and 1549 cm @ ^-1 .

Reference Example 2

2-Amino-4-methyl-5- (4-methoxy-phenyl) -thiophene-3-carboxylic acid ethyl ester

A mixture of 4-methoxyphenylacetone (16.5 g, 0.10 mol), cyanoacetic acid ethyl ester (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 at reflux for 24 h while the water formed in the reaction mixture was removed with a Dean-Stark apparatus. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane and aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. To the ethanol solution of the residue (30 mL) was added sulfur (3.21 g, 0.10 mmol) and diethylamine (10.4 mL, 0.120 mmol). The mixture was stirred at 50-60 ° C for 2 h, then concentrated and the concentrate was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue which was chromatographed on silica gel was recrystallized from ether-hexane. This gave pale yellow plates (11.5 g, 40% by weight), mp 79-80 ° C. For C ₅ H ₁₇ NO ₃ S Calculated: 61.83% C 5.88% H 4.81% N 11.01% S Found: 61.81% C, 5.75% H, 4 74% N, 10.82% S. 1 HNMR spectrum (200 MHz, CDCl ₃ , δ): 1.37 (3H, t, J = 7.1 Hz), 2.28 (3H, s), 3, 83 (3H, s), 4.31 (2H, q, J = 7.1 Hz), 6.05 (2H, brs), 6.91 (2H, d, J = 8.8 Hz), 7, 27 (2H, d, J = 8.8Hz). IR (KBr): 3426, 3328, 1651, 1586, 1550, 1505, and 1485 cm @ ^-1 . FAB-MS m / z 291 (M ^& lt ^{; +} & gt ^; ).

-57GB 290723 B6

Reference Example 3

When various acetone derivatives are used instead of 4-methoxyphenylacetone, the compounds listed in Table 1 are prepared in substantially the same manner as above in Reference Example 2.

Table 1

ref 3 comb. C. Ř ²⁵ R ²¹ yield (% by weight) m.p. (° C) 1 methyl phenyl 40 64-65 2 methyl 2-methoxyphenyl 12 70-71

Reference Example 4

[3-Ethoxycarbonyl-5- (4-methoxy-phenyl) -4-methyl-thiophen-2-yl] -aminomethylene-malonic acid diethyl ester

To the compound produced in Reference Example 2 (10 g, 343.3 mmol) was added diethylethoxymethylene malonate (7.45 g, 34.5 mmol). The mixture was stirred at 120 ° C for 2 h. After cooling, crystals precipitated by adding ether to the reaction mixture. The crystals are filtered off, washed once with ether and dried under reduced pressure over phosphorus pentoxide. Light yellow crystals (14.2 g, 90% by weight) are obtained, mp 122-123 ° C. 1 H NMR (200 MHz, CDCl ₃ , δ): 1.32 (3H, t, J = 7.1 Hz), 1.38 (3H, t, J = 7.2 Hz), 1.41 (3H) t, J = 7.2 Hz), 2.34 (3H, s), 3.85 (3H, s), 4.25 (2H, q, J = 7.1 Hz), 4.38 (2H δ, J = 7.2 Hz), 4.45 (2H, q, J = 7.2 Hz), 6.95 (2H, d, J = 8.8 Hz), 7.31 (2H, d J = 8.8 Hz), 8.22 (1H, d, J = 13.4 Hz), 12.74 (1H, d, J = 13.1 Hz). IR (KBr): 2984, 1720, 1707, 1688, 1653, 1599, 1518, and 1499 cm @ ^-1 .

Reference Example 5

When the compounds of Reference Example 3 or commercially available various thiophene compounds are used as starting materials, the compounds of Table 2 are prepared in substantially the same manner as above in Reference Example 4.

Table 2 _R 2 »

R

HDDCiHj

ΓCOCO 3 H 3 NH-CH-CH 2 COOC 3 H 3

ref. C. R ^2U 7 yield (% w / w) m.p. (° C) 1 methyl phenyl 92 108-109 2 phenyl methyl 92 137-138 3 methyl H 92 132-133 4 methyl 2-methoxyphenyl 100 ALIGN! amorphous

-58GB 290723 B6

Reference Example 6

[3-Carboxy-5- (4-methoxy-phenyl) -4-methyl-thiophen-2-yl] -aminomethylene-malonic acid diethyl ester

To a solution of the compound prepared in Reference Example 4 (7.0 g, 15.2 mmol) in dioxane (20 mL) was added a solution of potassium hydroxide (5.0 g, 75.7 mmol) in ethanol (30 mL) at 60-60 ° C. 70 ° C with stirring. The mixture was stirred at the same temperature for 1 h, allowed to stand at room temperature for 1 h, 2N HCl (40 mL, 80 mmol) was added under ice-cooling, and the reaction mixture was concentrated under reduced pressure. The resulting yellow precipitate was filtered off, washed with a mixture of cold water and ethanol and dried under reduced pressure over phosphorus pentoxide. A yellow powder (6.1 g, 93%) was obtained, mp 184-187 ° C. 1 H NMR (200 MHz, DMSO-4 ₆ , δ): 1.24 (3H, t, J = 7.1 Hz), 1.28 (3H, t, J = 7.2 Hz), 2.30 (3H, s), 3.80 (3H, s), 4.15 (2H, q, J = 7.1Hz), 4.24 (2H, q, J = 7.2Hz), 7.03 (2H, d, J = 8.7 Hz), 7.37 (2H, d, J = 8.7 Hz), 8.08 (1H, d, J = 13.6 Hz), 12.41 (1H , d, J = 13.6 Hz). IR (KBr): 3422, 2980, 1719, 1653, 1607, 1551 and 1512 cm @ ^-1 .

Reference Example 7

If the compounds produced in Reference Example 5 were used as starting materials, the compounds listed in Table 3 were prepared in substantially the same manner as above in Reference Example 6.

Table 3: oon

XOOCiHj

NH-CH = CH 2 CCl 3

ref 7 ex. C. Ř® F yield (% w / w) m.p. (° C) 1 methyl phenyl 98 187-190 2 phenyl methyl 65 173-175 3 methyl H 94 187-189 4 methyl 2-methoxyphenyl 88 167-169

Reference Example 8

4-Hydroxy-2- (4-methoxyphenyl) -4-methylthieno [2,3-b] pyridine-5-carboxylic acid ethyl ester

To the polyphosphoric acid ester (PPE) (90 mL) was added in small portions with stirring at 190 ° C the compound produced in Reference Example 6 (6.0 g, 13.8 mmol). The mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extracted solution was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is chromatographed on silica gel. A yellow powder (3.65 g, 77%) was obtained. For analysis, the powder was recrystallized from ethanol. Yellow crystals are obtained, mp 162-163 ° C. H, 4.99; N, 4.08; S, 9.34. Found: C, 62.89; H, 5.04; N, 4.01. 34% S. Ή NMR spectrum (200 MHz, CDCl ₃ , δ): 1.47 (3H, t, J = 7.1 Hz), 2.63 (3H, s), 4.87 (3H, s) , 4.49

-59EN 290723 B6 (2H, q, J = 7.1 Hz), 6.99 (2H, d, J = 8.8 Hz), 7.44 (2H, d, J = 8.8 Hz), 8 84 (1H, s), 12.11 (1 H, s). IR (KBr) 3434, 2992, 1692, 1601, 1582, 1535, and 1504 cm ^-1 . FAB-MS m / z 344 (MH ^&lt; ^{+ &gt;} ).

Reference Example 9

If the compounds produced in Reference Example 7 were used as starting materials, the compounds listed in Table 4 were prepared in substantially the same manner as above in Reference Example 8.

Table 4

ref 9 comb. C. _R 20 R ²¹ yield (% by weight) m.p. (° C) 1 methyl phenyl 60 155-157 2 phenyl methyl 69 146-147 3 methyl H 21 175-177 4 methyl 2-methoxyphenyl 73 amorphous

Reference Example 10

4-Hydroxy-2- (4-nitrophenyl) -3-methylthiopheno [2,3-b] pyridine-5-carboxylic acid ethyl ester

To a solution of Compound 1 prepared in Reference Example 9 (3.76 g, 12.0 mmol) in concentrated sulfuric acid (10 mL) was added dropwise a solution of sodium nitrate (1.27 g, 15.0 mmol) in concentrated acid while cooling with ice. sulfuric acid (5 ml). The mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into ice water and extracted with chloroform. The extracted solution was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is chromatographed on silica gel. A yellow powder is obtained which is recrystallized from ethanol. Yellow crystals (1.75 g, 41%) were obtained, mp 260-261 ° C. For C 17 H 14 N 2 O 5 S calculated: 56.98% C, 3.94% H, 7.82% N, found: C 56.66%, 3.91% H, 7.86% N. 1 H NMR (200 MHz, CDCl 3)? ₃ , δ): 1.49 (3H, t, J = 7.1 Hz), 2.70 (3H, s), 4.51 (2H, q, J = 7.1 Hz), 7.70 (3H, s); 2H, d, J = 8.8 Hz), 8.34 (2H, d, J = 8.8 Hz), 8.89 (1H, s), 12.27 (1H, s). IR (KBr): 3002, 1692, 1605, 1514, 1350 and 1290 cm ^'1. FAB-MS m / z 358 (MH +).

Reference Example 11

4-Hydroxy-5-hydroxymethyl-2- (4-methoxyphenyl) -3-methylthieno [2,3-b] pyridine

To a suspension (6 mL) of lithium aluminum hydride (0.0326 g, 0.87 mmol) in anhydrous tetrahydrofuran was added dropwise a solution of the compound produced in Reference Example 8 (0.20 g, 0.58 mmol) in anhydrous tetrahydrofuran (3 mL) with room temperature (15 to 35 ° C, the same range is used in the next section)

-60GB 290723 B6). The mixture was then stirred at room temperature for 30 minutes. Roche's salt was added to the mixture. The resulting precipitate was removed by filtration. In this procedure, if necessary to complete the reaction, the reaction mixture is heated to reflux. The precipitate was washed with ethyl alcohol and chloroform, the organics were combined, concentrated under reduced pressure, and the concentrate was partitioned between ethyl acetate and aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. White crystals (0.13 g, 74%) were obtained. Tt greater than 300 ° C. * H NMR (200 MHz, DMSO-d6, _.delta .): 2.55 (3H, s), 3.81 (3H, s), 4.41 (2H, s), 7.03 (2H, d, J = 8.8 Hz), 7.40 (2H, d, J = 8.8 Hz), 7.75 (1H, s). IR (KBr): 3210, 2930, 1613, 1506 and 1255 cm @ ^-1 . FAB-MS m / z 302 (MH ^&lt; ^{+ &gt;} ).

Reference Example 12

2-Benzoyl-N-hydroxy-3-methylthieno [2,3-b] pyridine-5-carboxylic acid ethyl ester

To a mixture of compound 3 produced in Reference Example 7 (5.0 g, 15.3 mmol) and anhydrous aluminum chloride (8.6 g, 64.5 mmol) in nitromethane (100 mL) was gradually added dropwise under nitrogen atmosphere under ice-cooling. benzoyl chloride (3.6 mL, 31.0 mmol). The mixture was stirred at room temperature for 1 h, then at 50 ° C for 14 h. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. A brownish powder (7.58 g) was obtained. This powder is added in small portions to the polyphosphoric acid ester (PPE) with stirring at 120 ° C. The mixture was stirred at the same temperature for 90 minutes, poured into ice water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is chromatographed on silica gel. A yellow powder (0.82 g, 16 wt%) was obtained. As a sample for analysis, part is recrystallized from chloroform-ethanol. Yellow crystals are obtained, mp 241-243 ° C. For C ₈ H ₁₅ NO ₄ S.0,25 H ₂ O: calculated: 62.51% C 4.52% H 4.05% N Found: 62.77% C, 4.22% H, 4 1 H NMR spectrum (200 MHz, CDCl ₃ -CD ₃ OD, δ): 1.49 (3H, t, J = 7.1 Hz), 2.71 (3H, s), 4, 53 (2H, q, J = 7.1 Hz), 7.49-7.70 (3H, m), 8.96 (1H, s). IR (KBr): 3004, 1692, 1638, 1603, 1582, 1537, and 1431 cm @ ^-1 .

Reference Example 13

2-Phenylacetyl-4-hydroxy-3-methylthieno [2,3-b] pyridine-5-carboxylic acid ethyl ester

If compound 3 (10.0 g, 30.55 mmol) produced in Reference Example 7 was used, essentially in the same manner as in Reference Example 12 using phenylacetyl chloride instead of benzoyl chloride, the title compound (1.47 g, 14% by weight) was produced. m.p. 208-204 ° C. For C ₁₉ H ₇ NO ₄ S.0.1 EtOAc calculated: 63.98% C, 4.93% H, 3.85% N, found: 64.25% C, 4.66% H, 3.52 ¹ H NMR spectrum (200 MHz, CDCl ₃ -CD ₃ OD, δ): 1.47 (3H, t, J = 7.1 Hz), 2.99 (3H, s), 4.20 ( 2H, s), 4.49 (2H, q, J = 7.1 Hz), 7.26-7.41 (5H, m), 8.96 (1H, s), 12.50 (1H, s) ). IR (KBr): 3424, 2986, 1694, 1601, 1580, 1535, 1495 and 1439 cm @ ^-1 .

Reference Example 14

2-Bromo-4-hydroxy-3-methylthieno [2,3-b] pyridine-5-carboxylic acid ethyl ester

To a solution of compound 3 produced in Reference Example 7 (17.8 g, 54.4 mol) and pyridine (22 mL, 0.272 mmol) in chloroform (120 mL) was gradually added dropwise a solution of bromine (3.4 mL, 66.0 mmol). ) in chloroform (30 mL). The mixture was stirred at room temperature for 40 minutes, then concentrated under reduced pressure. Dilute hydrochloric acid was added to the concentrate. The resulting crystalline

The precipitate is filtered off, washed with water and a small amount of cold ether and dried over phosphorus pentoxide under reduced pressure. A brown powder (20 g) was obtained. This powder was added in small portions to a polyphosphoric acid ester (PPE) (100 mL) at 120 ° C with stirring. The mixture was stirred at the same temperature for 90 minutes. The reaction mixture was then poured onto ice with water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is chromatographed on silica gel. A pale yellow powder (9.53 g, 58%) was obtained. As a sample for analysis, part of the powder was recrystallized from chloroform-methanol. Colorless needles were obtained, mp 214-216 ° C. For C ₁₁ H ₁₀ NO ₃ SBr calculated: C 41.79, H 3.19, N 4.43, found: C 41.55, H 3.14, N 4.53. 1 H NMR (200 MHz, CDCl ₃ -CD ₃ OD, δ): 1.47 (3H, t, J = 7.1 Hz), 2.60 (3H, s), 4.50 (2H, q, J = 7.1 Hz), 8.82 (1H, s). IR (KBr): 2990, 1694, 1605, 1578, and 1533 cm @ ^-1 .

Reference Example 15

2-Bromo-4-hydroxy-3-methylthieno [2,3-b] pyridine-5-carboxylic acid ethyl ester (another method for producing the compound of Reference Example 14)

A mixture of compound 3 produced in Reference Example 9 (0.24 g, 1.01 mmol), N-bromosuccinimide (10.198 g, 1.11 mmol) and chloroform (10 mL) was refluxed for 3 h. After cooling, the reaction mixture was poured into aqueous sodium chloride solution and extracted with chloroform. The extract was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is chromatographed on silica gel. A yellow powder is obtained. Recrystallization from chloroform-methanol gave colorless needles (0.29 g, 91%), m.p. Mp 214-216 ° C.

Reference Example 16

7-Benzoyl-4,7-dihydro-2- (4-methoxyphenyl) -3-methyl-4-oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester

To a solution of the compound prepared in Reference Example 8 (5 g, 14.6 mmol) in pyridine (100 mL) was added benzoyl chloride (1.78 mL, 15.3 mmol) under ice-cooling. After stirring at room temperature for 150 minutes, ethanol (1 mL) was added to the reaction mixture. The mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane and saturated aqueous sodium chloride solution. The aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is chromatographed on silica gel. Crystallization from ethanol gave white crystals (6.41 g, 98%), mp 110-112 ° C. H, 4.73; N, 3.13. Found: C, 66.95; H, 4.68; N, 2.93. @ 1 H NMR spectrum (200 MHz, CDCl3). ₃ , δ): 1.14 (3H, t, J = 7.7 Hz), 2.42 (3H, s), 3.85 (3H, s), 4.26 (2H, q, J = 7, 2 Hz), 6.98 (2H, d, J = 6.7 Hz), 7.40 (2H, d, J = 8.9 Hz), 7.57 (2H, t, J = 7.6 Hz) 7.70 (1H, t, J = 5.9 Hz), 8.27 (2H, d, J = 7.0 Hz), 9.14 (1H, s). IR (KBr): 2972, 1717, 1607, 1580, 1552 and 1502 cm @ ^-1 .

Reference Example 17

7-Benzoyl-3-bromomethyl-4,7-dihydro-2- (4-methoxyphenyl) -4-oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester

A mixture of the compound produced in Reference Example 16 (6.39 g, 14.3 mmol), N-bromosuccinimide (2.67 g, 15 mmol), α, α'-azobisisobutyronitrile (0.47 g, 2.86 mmol) and of carbon tetrachloride (100 mL) was refluxed for 1 h. Insoluble matter is filtered off after cooling. The filtrate is diluted

-62EN 290723 B6 with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate. Colorless needles (7.02 g, 93%) were obtained, mp 124-126 ° C. For C ₂₅ H ₂₀ NO ₃ SBr calculated: 57.04% C, 3.83% H, 2.66% N, found: 57.16% C, 3.85% H, 2.70% N. * HNMR spectrum (200 MHz, CDCl ₃ , δ): 1.14 (3H, t, J = 7.2 Hz), 3.88 (3H, s), 4.26 (2H, q, J = 7.2 Hz) ), 4.68 (2H, s), 7.04 (2H, d, J = 8.8 Hz), 7.53-7.75 (5H, m), 8.35 (2H, d, J = 7.0 Hz), 9.20 (1H, s). IR (KBr): 2984, 1717, 1605 and 1502 cm @ ^-1 .

Reference Example 18

3- (N-Benzoyl-N-methylaminomethyl) -4-hydroxy-2- (4-methoxyphenyl) -thieno [2,23-b] pyridine-5-carboxylic acid ethyl ester

A mixture of the compound prepared in Reference Example 17 (6.73 g, 12.8 mmol), N-ethyldiisopropylamine (2.30 mL, 13.4 mmol), N-benzylmethylamine (1.73 mL, 13.4 mmol) and dimethylformamide. (100 mL) was stirred at room temperature for 40 min. The solvent was distilled off under reduced pressure. The residue was partitioned between dichloromethane and saturated aqueous sodium chloride solution. The organic layer was washed with water, dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was dissolved in a mixture of dichloromethane (100 mL) and ethanol (50 mL). To this solution was added a solution of sodium ethoxide (0.88 g, 13 mmol) in ethanol (50 mL) under ice-cooling, and the mixture was stirred at room temperature for 4 h. The reaction mixture was then neutralized with acetic acid, the solvent was distilled off under reduced pressure, and the residue was partitioned between dichloromethane and water. The organic layer was washed with water, dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue is chromatographed on silica gel. The product was recrystallized from ethanol. Colorless needles (4.32 g, 73%) were obtained, mp 175-177 ° C. For C ₂₆ H ₂₆ N ₂ O ₄ S calculated: 67.51% C, 5.67% H, 6.06% N, found: 67.43% C, 5.72% H, 6.06% N. 1 H NMR (200 MHz, CDCl 3, δ): 1.45 (3H, t, J = 7.2 Hz), 2.35 (3H, s), 3.75 (2H, brs), 3.89 ( 3H, s), 3.92 (2H, s), 4.44 (2H, q, J = 7.2 Hz), 7.01 (2H, d, J = 6.7 Hz), 7.21- 7.37 (7H, m); 8.87 (1H, s). IR (KBr): 3424, 3000, 1686, 1607 and 1504 cm ^1st

Reference Example 19

2-Amino-4-methyl-5- (4-nitrophenyl) -thiophene-3-carboxylic acid ethyl ester

In essentially the same manner as described in Reference Example 1 above, using 4-nitrophenylacetone (35.0 g, 195 mmol) instead of 4-methoxyphenylacetone, cyanoacetic acid ethyl ester (23 g, 19.5 mmol), ammonium acetate (3.times. 1 g, 40 mmol), acetic acid (9.1 mL, 159 mmol), sulfur (5.0 g, 160 mmol) and diethylamine (16.0 mL, 160 mmol) to give the title compound as colorless crystals (22.2 mp 168-170 ° C (recrystallized from ether-hexane). For C ₁₄ H ₁₄ N ₂ O ₄ S calculated: 54.89% C, 4.61% H, 9.14% N, found: 54.83% C, 4.90% H, 9.09% N. 1 H NMR (200 MHz, CDCl ₃ , δ): 1.39 (3H, t, J = 7.1 Hz), 2.40 (3H, s), 4.34 (2H, q, J = 7, 1 Hz), 6.27 (2H, brs), 7.48 (2H, d, J = 8.7 Hz), 8.23 (2H, d, J = 8.7 Hz). IR (KBr): 3446, 3324, 1667, 1580, 1545, 1506, 1491, 1475, 1410 and 1332 cm @ ^-1 .

Reference Example 20

2,4 (1H, 3H) -Dioxo-5-methyl-6- (4-methoxyphenyl) -thieno [2,3-b] pyrimidine-3-acetic acid ethyl ester

To a solution of the compound prepared in Reference Example 1 (5.00 g, 17.20 mmol) was added isocyanatoacetic acid ethyl ester (2.90 mL, 25.80 mmol). The mixture was stirred at 45 ° C for 6 h, then stirred at room temperature for 1 h

The concentrate was dissolved in ethanol (6 ml) to which was added sodium ethoxide [prepared from ethanol (30 ml) and sodium (0.79 g, 34.30 mmol)]. The mixture was stirred at room temperature for 24 h. To the mixture was added 2N HCl (18 mL, 36 mmol). Ethanol was distilled off under reduced pressure. The residue is filtered, washed with a mixture of water and ethanol and dried under reduced pressure. Recrystallization from ethanol followed. White needles (5.70 g, 89%) were obtained with mp 164-165 ° C. For C ₈ H ₁₈ N ₂ O ₅ S Calculated: 57.74% C 4.85% H 7.48% N Found: 57.78% C, 5.03% H, 7.45% N. 1 H NMR spectrum (200 MHz, CDCl ₃ , δ): 1.30 (3H, t, J = 7.2 Hz), 2.45 (3H, s), 3.85 (3H, s), 4, 26 (2H, q, J = 7.2Hz), 4.78 (2H, s), 6.95 (2H, d, J = 8.8Hz), 7.31 (2H, d, J = 8) 8 Hz), 10.58 (1H, s). IR (KBr): 2914, 1742, 1713, 1655, 10 1605, 1568, 1528, and 1499 cm @ ^-1 .

Reference Example 21

When the compounds produced in Reference Examples 2, 3 and 19 were used as starting materials, the compounds listed in Table 5 were prepared in substantially the same manner as above in Reference Example 20.

Table 5

ref 21 comb. C. _R - P yield (% by weight) m.p. (° C) 1 ethyl acetate H 85 119-120 2 methyl methoxy 84 273-276 3 phenyl methoxy 85 > 300 4 phenyl nitro 84 > 300 5 benzyl methoxy 92 241-242 6 4-methoxyphenyl methoxy 99 > 300 7 cyclohexyl methoxy 84 275-276 8 2-methoxyphenyl methoxy 81 257-258 9 3-methoxyphenyl methoxy 93 > 300 10 2-chlorophenyl methoxy 95 285-286 11 3-chlorophenyl methoxy 97 > 300 12 4-chlorophenyl methoxy 95 > 300

Reference Example 22

2,4 (1H, 3H) -Dioxo-6- (4-nitrophenyl) -5-methylthieno [2,3-d] pyrimidine-3-acetic acid ethyl ester

To a solution of compound 1 produced in Reference Example 21 (2.20 g, 6.39 mmol) was added 30 concentrated sulfuric acid (12 mL). A solution of sodium nitrate (550 mg, 6.47 mmol) in concentrated sulfuric acid was added dropwise under ice-cooling. The mixture was stirred under ice-cooling for 1 h. The reaction mixture was poured on ice with water and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4) and the solvent was evaporated

-64GB 290723 B6 distills off the reduced pressure. The residue is chromatographed on silica gel. A yellowish powder (1.30 g, 52%) was obtained, which was recrystallized from ethyl acetate-hexane. Yellow crystals are obtained, mp 277-280 ° C. For C ₁₇ H ₁₅ N ₃ O ₆ S.0.4 H ₂ O calculated: C 51.48, H 4.01, N 10.59, found: C 51.64, H 3.79, 10.61 % N. 1 H NMR (200 MHz, CDCl 3, δ): 1.33 (3H, t, J = 7.2 Hz), 2.56 (3H, s), 4.28 (2H, q, J = 7.2 Hz), 4.79 (2H, s), 7.57 (2H, d, J = 8.8 Hz), 8.30 (2H, d, J = 8.8 Hz), 10.30 (1H, s). IR (KBr): 1748, 1719, 1663, 1522 and 1460 cm @ ^-1 .

Reference Example 23

2,4 (1H, 3H) -Dioxo-1- (2-fluorobenzyl) -6- (4-nitrophenyl) -5-methylthieno [2,3-d] pyrimidine-3-acetic acid ethyl ester

To a solution of the compound prepared in Reference Example 22 (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 mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated, and the concentrate was partitioned between ethyl acetate and brine. The aqueous layer was extracted with ethyl acetate. The combined extract was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is chromatographed on silica gel. A white powder (500 mg, 56%) was obtained, mp 155-158 ° C. For C ₂₄ H ₂ ON ₃ 06SF.O 5 H ₂ O: calculated: 56.91% C 4.18% H 8.30% N Found: 56.74% C, 3.84% H, 8 25% N. 1 H NMR spectrum (200 MHz, CDCl 3, δ):

1.32 (3H, t, J = 7.2 Hz), 3.84 (3H, s), 4.27 (2H, q, J = 7.2 Hz), 4.84 (2H, s), 5, 30 (2H, s), 7.06-7

7.33 (4H, m), 7.54 (2H, d, J = 8.9Hz), 7.27 (2H, d, J = 8.9Hz). IR (KBr): 1748, 1711, 1673, 1520, and 1491 cm @ ^-1 .

Reference Example 24

Starting from the compounds produced in Reference Example 21, the compounds listed in Table 6 were prepared as described in Reference Example 23 above.

Table 6

ref. C. R ³ ' ir ^: yield (% by weight) m.p. (° C) 1 ethyl acetate 2-fluoro methoxy 85 127-128 2 methyl 2-methoxy methoxy 91 174-175 3 methyl 2-fluoro methoxy 97 179-180 4 phenyl 2-methoxy methoxy 93 240-241 5 phenyl 2-fluoro methoxy 96 252-253 6 phenyl 2-fluoro nitro 87 294-295 7 phenyl 3-fluoro methoxy 88 215-217 8 phenyl 4-fluoro methoxy 66 209-212

-65GB 290723 B6

Table 6 - continued

ref. C. R ^JJ P R * yield (% by weight) m.p. (° C) 9 phenyl 2,4-difluoro methoxy 73 227-228 10 phenyl 2,4-difluoro methoxy 87 291-292 11 phenyl 2-chloro-6-fluoro methoxy 91 287-288 12 phenyl 2-methylthio methoxy 81 239-240 13 benzyl 2-fluoro methoxy 86 124-126 14 benzyl 2,6-difluoro methoxy 82 161-163 15 Dec 4-methoxyphenyl 2-fluoro methoxy 87 270-272 16 4-methoxyphenyl 2,6-difluoro methoxy 83 > 300 17 cyclohexyl 2-fluoro methoxy 79 172-173 18 cyclohexyl 2,6-difluoro methoxy 73 207-208 19 Dec phenyl 2,6-difluoro nitro 93 280-282 20 May 2-methoxyphenyl 2-fluoro methoxy 84 195-198 21 2-methoxyphenyl 2,6-difluoro methoxy 86 205-208 22nd 3-methoxyphenyl 2-fluoro methoxy 89 241-242 23 3-methoxyphenyl 2,6-difluoro methoxy 85 253-255 24 2-chlorophenyl 2-fluoro methoxy 91 220-221 25 2-chlorophenyl 2,6-difluoro methoxy 83 178-182 26 3-chlorophenyl 2-fluoro methoxy 90 247-248 27 Mar: 3-chlorophenyl 2,6-difluoro methoxy 93 278-279 28 4-chlorophenyl 2-fluoro methoxy 79 269-270 29 4-chlorophenyl 2,6-difluoro methoxy 91 > 300

Reference Example 25

5-Bromomethyl-2,4 (1H, 3H) -dioxo-1- (2-fluorobenzyl) -6- (4-nitrophenyl) thieno [2,3-d] pyrimidine-3-acetic acid ethyl ester

A mixture of the compound prepared in Reference Example 23 (0.300 g, 0.603 mmol), N-bromosuccinimide (0.107 g, 0.603 mmol), α, α'-azobisisobutyronitrile (10 mg, 0.60 mmol) and carbon tetrachloride (15 mL) was boiled 2. h under reflux. After cooling, the resulting insoluble material was filtered from the reaction mixture. The filtrate was diluted with chloroform. The organic layer was washed with 15 aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate. Colorless needles (0.284 g, 82% by weight), mp 165-167 ° C are obtained. For C ₂ 4 H _l9 N ₃ O6SBrF calculated: 50.01% C 3.32% H 7.29% N Found: 49.87% C, 3.27% H, 7.23% N. NMR spectrum (200 MHz, CDCl ₃ , δ): 1.31 (3H, t, J = 7.1 Hz), 4.26 (2H, q, J = 7.1 Hz), 4.78 (2H, s) 4.86 (2H, s), 5.30 (2H, s), 7.07-7.37 (4H, m), 7.75 (2H, d, J = 8.8 Hz), 8.33 (2H, d, J = 8.8Hz). IR (KBr): 1713, 1673, 1524, and 1477 cm @ ^-1 .

Reference Example 26

If the compounds produced in Reference Example 24 were used as starting materials, then the compounds listed in Table 7 were prepared as described in Reference Example 25 above.

-66GB 290723 B6

Table 7

ref. C. R ³³ Ø ³³ R ³⁴ yield (% by weight) m.p. (° C) 1 ethyl acetate 2-fluoro methoxy 70 152-153 2 methyl 2-methoxy methoxy 63 173-176 3 methyl 2-fluoro methoxy 82 175-177 4 phenyl 2-methoxy methoxy 93 240-241 5 phenyl 2-fluoro methoxy 86 230-233 6 phenyl 2-fluoro nitro 86 224-225 7 phenyl 3-fluoro methoxy 84 215-216 8 phenyl 4-fluoro methoxy 84 232-233 9 phenyl 2,4-difluoro methoxy 84 230-231 10 phenyl 2,6-difluoro methoxy 87 250-252 11 phenyl 2-chloro-6-fluoro methoxy 86 255-257 12 phenyl 2-methylthio methoxy 90 212-214 13 benzyl 2-fluoro methoxy 83 132-134 14 benzyl 2,6-difluoro methoxy 89 154-155 15 Dec 4-methoxyphenyl 2-fluoro methoxy 88 226-228 16 4-methoxyphenyl 2,6-difluoro methoxy 80 249-251 17 cyclohexyl 2-fluoro methoxy 86 149-151 18 cyclohexyl 2,6-difluoro methoxy 77 192-194 19 Dec phenyl 2,6-difluoro nitro 94 228-229 20 May 2-methoxyphenyl 2-fluoro methoxy 77 180-181 21 2-methoxyphenyl 2,6-difluoro methoxy 79 212-214 22nd 3-methoxyphenyl 2-fluoro methoxy 82 234-235 23 3-chlorophenyl 2,6-difluoro methoxy 88 255-256 24 2-chlorophenyl 2-fluoro methoxy 85 175-178 25 2-chlorophenyl 2,6-difluoro methoxy 88 191-193 26 3-chlorophenyl 2-fluoro methoxy 81 243-246 27 Mar: 3-chlorophenyl 2,6-difluoro methoxy 92 270-273 28 4-chlorophenyl 2-fluoro methoxy 84 271-274 29 4-chlorophenyl 2,6-difluoro methoxy 78 265-268

Reference Example 27

5-Benzylmethylaminomethyl-2,4 (1H, 3H) -dioxo-1- (2-fluorobenzyl} -6-nitrophenyl) thieno [2,3-d] pyrimidine-3-acetic acid ethyl ester hydrochloride ίο To a solution of the compound produced in Reference Example 25 Ethyl diisopropylamine (0.12 mL, 0.710 mmol) and benzylmethylamine (0.07 mL, 0.56 mmol) were added under ice-cooling with ice (0.270 g, 0.47 mmol) in dimethylformamide (10 mL). The mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated, and the concentrate was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over magnesium sulfate, then the solvent was distilled off under reduced pressure, and the residue was evaporated.

-67GB 290723 B6 is chromatographed on silica gel. A colorless oil was obtained (0.297 g, 100 wt%). To a solution of this oil in ethyl acetate was added IN ethereal hydrochloric acid under ice-cooling. The mixture was stirred at the same temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the concentrate was recrystallized from ethyl acetate-ether. The corresponding hydrochloride (0.084 g) was obtained as white crystals, mp 120-128 ° C (hydrochloride). For C32H29N4O6SF.HCl.H2O calculated C 57.27, H 4.81, N 8.35, found: C 57.23, H 4.55, 8.42% N. 1 H NMR spectrum ( 200 MHz, CDCl3 free amine δ): 1.31 (3H, t, J = 7.1 Hz), 2.16 (3H, s), 3.61 (2H, s), 3.97 (2H, s) 4.27 (2H, q, J = 7.1 Hz), 4.87 (2H, s), 5.31 (2H, s), 7.10-7.35 (9H, m), 7 97 (2H, d, J = 8.8Hz), 8.23 (2H, d, J = 8.8Hz). IR (KBr, hydrochloride): 1711, 1665, 1522 and 1492 cm ^{@ 4} .

Working example 1

4,7-Dihydro-7- (2-methoxybenzyl) -2- (4-methoxyphenyl) -3-methyl-4-oxothieno [2,3b] pyridine-5-carboxylic acid ethyl ester

To a suspension of sodium hydride (60% w / w in oil; 123 mg, 3.08 mmol) in dimethylformamide (3 mL) was added dropwise a solution of the compound produced in Reference Example 8 (1.0 g, 2) under nitrogen atmosphere under ice-cooling. , 91 mmol) in dimethylformamide (20 mL). A solution of 2-methoxybenzyl chloride (0.92 g, 5.87 mmol) in dimethylformamide (3 mL) was added dropwise and the mixture was stirred at room temperature for 23 h then at 70 ° C for 2 h. C. The reaction mixture was then concentrated and the concentrate was partitioned between ethyl acetate and aqueous ammonium chloride solution. The aqueous layer was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel. A pale yellow amorphous solid was obtained (0.95 g, 70%). For analysis, a sample of amorphous material was recrystallized from dichloromethane-ether. Yellow fries were obtained, mp 165-167 ° C. For C 6 H ₂₅ NO ₂ S.0,5 ₅ H ₂ O calculated 66.08% C 5.55% H 2.96% N Found: 66.33% C, 5.44% H 2, 74% N. 1 H NMR spectrum (200 MHz, CDCl 3, δ): 1.41 (3H, t, J = 7.1 Hz), 2.65 (3H, s), 3.85 (3H, s) 3.86 (3H, s), 4.39 (2H, q, J = 7.1 Hz), 5.16 (2H, s), 6.92-7.00 (4H, m), 21 to 7.41 (4H, m), 8.41 (1H, s). IR (KBr): 2980, 1727, 1684, 1609, 1590, 1497, and 1464 cm ^{@ 4} .

Working Example 2

When the compound produced in Reference Example 8 is used as the starting material, the compounds listed in Table 8 are prepared in substantially the same manner as in Working Example 1.

Table 8

-68GB 290723 B6

pr. Ex. C. R yield (% by weight) m.p. (° C) 1 H 49 170-172 2 3-methoxy 71 153-155 3 4-methoxy 72 132-134 4 2-methyl 63 199-201 5 2-acetoxy 52 154-156 6 2-methylthio 49 152-154 7 4-nitro 97 98-99 8 4- (2-cyanophenyl) 62 134-136 9 4- (2-tert-butoxycarbonyl) phenyl 76 120-122

Working example 3

When the compounds produced in Reference Examples 9 and 10 were used as starting materials, the compounds listed in Table 9 were prepared in substantially the same manner as in Working Example 1.

Table 9

r> 36

pr. Ex 3 comb. C. Ί? ¹ ~ Ř ²² _R 36 yield (% by weight) m.p. (° C) 1 methyl 4-nitrophenyl 2-methoxybenzyl 69 194-195 2 methyl phenyl 2-methoxybenzyl 91 amorphous 3 phenyl methyl 2-methoxybenzyl 73 184-186 4 methyl benzyl 2-methoxyphenyl 47 65-70 5 methyl phenylacetyl 2-methoxyphenyl 64 167-170 6 methyl 2-methoxyphenyl 2-methoxyphenyl 57 194-196 7 methyl bromine 2-methoxyphenyl 90 161-163 8 methyl 4-nitrophenyl 2-fluorobenzyl 90 184-186 9 methyl 4-methoxyphenyl 2-fluorobenzyl 81 117-120 10 methyl 4-methoxyphenyl 2,6-difluorobenzyl 80 amorphous 11 methyl 4-nitrophenyl 2,6-difluorobenzyl 81 215-217 12 methyl 4-nitrophenyl 2-chloro-6-fluorobenzyl 80 211-213 13 methyl phenyl 2,6-difluorobenzyl 90 184-186 14 methyl phenyl 2-chloro-6-fluorobenzyl 86 171-173 15 Dec methyl 4-methoxyphenyl 1-diesel 1 74 193-195 16 methyl 4-methoxyphenyl 2-methoxyphenethyl 50 134-136 17 methyl 4-methoxyphenyl fenethyl 54 182-184 18 methyl 4-methoxyphenyl 3-phenylpropyl 62 147-149 19 Dec methyl 4-methoxyphenyl cinnamyl 64 170-172 20 May methyl 4-methoxyphenyl 3-picolyl 28 142-144 21 methyl bromine 2-fluorobenzyl 78 211-213 22nd methyl bromine 2,6-difluorobenzyl 73 175-176

-69GB 290723 B6

Working example 4

4,7-Dihydro-5-hydroxymethyl-7- (2-methoxybenzyl) -2- (4-methoxyphenyl) -3-methyl-4-oxothieno [2,3-b] pyridine

To a solution of the compound prepared from Reference Example 11 (0.12 g, 0.40 mmol) in dimethylformamide (10 mL) was added potassium carbonate (0.083 g, 0.60 mmol), 2-methoxybenzyl chloride (0.094 g, 0) at room temperature. , 60 mol) and potassium iodide (0.033 g, 0.20 mol). The mixture was stirred at room temperature for 90 minutes and at 50 ° C for 2 hours. The reaction mixture was concentrated and the concentrate was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane. The extract was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel. A pale yellow amorphous solid is obtained which is recrystallized from ethyl acetate. Colorless crystals are obtained, mp 153-156 ° C. For C ₂₄ H ₂₃ NO ₄ S Calculated 68.39% C 5.50% H 3.32% N Found: 68.11% C 5.58% H 3.24% N * H NMR spectrum (200 MHz, CDCl ₃ , δ): 2.67 (3H, s), 3.85 (3H, s), 3.86 (3H, s), 4.59 (2H, s), 5.12 (2H, s), 6.90-7.00 (4H, m), 7.15 (1H, d), 7.3-7.4 (3H, m), 7.45 (1H, s). IR (KBr) 3400, 2936, 2838, 1618, 1547, 1504 and 1249 cm @ ^-1 .

Working example 5

5-Acetoxymethyl-7-dihydro-7- (2-methoxybenzyl) -2- (4-methoxyphenyl) -3-methyl-4-oxothieno [2,3-b] pyridine

To a solution of the compound prepared in Working Example 4 in pyridine (0.400 g, 0.96 mmol) at room temperature was added anhydrous acetic acid (1.78 g, 19.0 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated. The concentrate was partitioned between ethyl acetate and dilute hydrochloric acid. The aqueous layer was extracted with ethyl acetate. The extract is chromatographed on silica gel. An amorphous colorless solid is obtained, which is recrystallized from ethyl ether. Colorless crystals (0.46 g, 100% by weight), mp 158-159 ° C, are obtained. H, 5.44; N, 3.02. Found: C, 67.09; H, 5.09; N, 3.06. @ 1 H NMR Spectrum (200 MHz, CDCl3). δ): 2.07 (3H, s), 2.67 (3H, s), 3.84 (3H, s), 3.86 (3H, s), 5.11 (2H, s), 5 12 (2H, s), 6.90-7.00 (4H, m), 7.18 (1H, d, J = 7.7 Hz), 7.3-7.4 (3H, m), 7.69 (1 H, s). IR spectrum (KBr); 1752, 1626, 1578, 1508, 1506 and 1255 cm ^-1 .

Working example 6

3-Bromomethyl-4,7-dihydro-7- (2-methoxybenzyl) -2- (4-methoxyphenyl) -4-oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester

A mixture of the compound produced in Working Example 1 (0.35 g, 0.755 mmol), N-bromosuccinimide (0.135 g, 0.758 mmol), α, α'-azobisisobutyronitrile (13 mg, 0.079 mmol) and carbon tetrachloride (5 mL) was boiled 2. h under reflux. After cooling, the resulting insoluble material was filtered from the reaction mixture and the filtrate was diluted with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from ethyl acetate. Colorless needles (0.272 g, 66% by weight), mp 200-201 ° C are obtained. For C 6 H ₂₄ NO ₂ SBr ₅ Calculated 57.57% C 4.66% H 2.58% N Found: 57.75% C 4.31% H 2.31% N * H NMR spectrum (200 MHz, CDCl ₃ , δ): 1.40 (3H, t, J = 7.1 Hz), 3.86 (6H, s), 4.40 (2H, q, J = 7.1 Hz) ), 5.05 (2H, s), 5.16 (2H, s), 6.92-7.04 (4H, m), 7.23-7.28 (1H, m), 7.34-7 7.43 (1H, m), 7.57 (2H, d, J = 8.9 Hz), 8.46 (1H, s). IR (KBr): 2980, 1725, 1607, 1588, and 1497 cm @ ^-1 .

-70GB 290723 B6

Working example 7

If the compounds produced in Working Examples 3, 4, 19, 65, 66 and 73 were used as starting materials, then the compounds 5 listed in Table 10 were prepared in substantially the same manner as in Working Example 6.

Table 10

173-175 bromomethyl

4-nitrophenyl bromomethyl bromomethyl

4-methoxyphenyl phenyl phenyl bromomethyl bromomethyl bromomethyl bromomethyl bromomethyl bromomethyl bromomethyl bromomethyl bromomethyl bromomethyl bromomethyl bromomethyl bromomethyl benzoyl

2-methoxyphenyl bromide

3-methoxyphenyl

4-nitrophenyl

4-methoxyphenyl 4-nitrophenyl

4-nitrophenyl

4-methoxyphenyl 4-nitrophenyl

4-nitrophenyl

4-methoxyphenyl 4-methoxyphenyl

2-methoxybenzyl

2-methoxybenzyl

2-methoxybenzyl

2-methoxybenzyl

2-methoxybenzyl 2-methoxybenzyl 2-methoxybenzyl

2-methoxybenzyl 2-fluorobenzyl

2-fluorobenzyl

2,6-difluorobenzyl 2-chloro-6-fluorobenzyl 2-fluorobenzyl

2,6-difluorobenzyl 2,6-difluorobenzyl 2,6-difluorobenzyl 2-fluorobenzyl ethoxycarbonyl acetoxymethyl ethoxycarbonyl ethoxycarbonyl ethoxycarbonyl ethoxycarbonyl ethoxycarbonyl ethoxycarbonyl ethoxycarbonyl ethoxycarbonyl ethoxycarbonyl ethoxycarbonyl ethoxycarbonyl

100 ALIGN!

131-133

194-196 amorphous amorphous

174-175

83-86

202-204 amorphous

200-202

175-177 amorphous

236-238

123-124

226-228

186-187

-71 CZ 290723 B6

Table 10 - continued

prac. Ex. C. Ø ³² r36 R ³⁷ yield (% by weight) m.p. (° C) 18 bromomethyl 4-methoxyphenyl 2-fluorobenzyl propionyl 45 165-166 19 Dec bromomethyl 4-methoxyphenyl 2-fluorobenzyl butyryl 65 165-166 20 May bromomethyl 4-methoxyphenyl 2-fluorobenzyl hexanoyl 55 168-169 21 bromomethyl 4-methoxyphenyl 2-fluorobenzyl valeryl 63 173-174 22nd bromomethyl 4-methoxyphenyl 2-fluorobenzyl heptanoyl 54 145-147 23 bromomethyl 4-methoxyphenyl 2-fluorobenzyl isovaleryl 74 187-189 24 bromomethyl 4-methoxyphenyl 2-fluorobenzyl benzoyl 75 145-147 25 bromomethyl 4-ethoxycarbonylphenyl 2-methoxybenzyl ethoxycarbonyl 98 196-198 26 bromomethyl 4-methoxyphenyl 2-fluorobenzyl ethoxycarbonyl 77 115-120 27 Mar: bromomethyl 4-diethylaminocarbonylphenyl 2-fluorobenzyl ethoxycarbonyl 40 amorphous 28 bromomethyl 4-ethoxycarbonylphenyl 2,6-difluorobenzyl benzoyl 88 190-192 29 bromomethyl 4-butoxyphenyl 2-fluorobenzyl ethoxycarbonyl 40 138-140 30 bromomethyl 4-methoxy- 2-fluorobenzyl cyano- 100 ALIGN! 216-218

phenyl

Working example 8

3-Benzylaminomethyl-4,7-dihydro-7- (2-methoxybenzyl) -3- (4-methoxyphenyl) -4-oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester hydrochloride

To a solution of the compound produced in Working Example 6 (0.245 g, 0.452 mmol) in dimethylformamide (5 mL) was added triethylamine (0.10 mL, 0.717 mmol) and benzylamine (80 μΐ, 0.732 mmol) under ice-cooling. The mixture was stirred at room temperature for 90 minutes. The reaction mixture was concentrated and the concentrate was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel. A colorless oil is obtained (0.135 g, 53% by weight). To a solution of this oil in ethanol (4 mL) was added IN ethanolic hydrochloric acid (0.2 mL) under ice-cooling. The mixture was stirred for 10 minutes under ice-cooling. The reaction mixture was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate and ether. The corresponding hydrochloride (0.133 g) was obtained as white crystals, mp 118-119 ° C. For C ₃₃ H ₃₂ N ₂ O ₅ S.HCl.0.9 H ₂ O calculated C 63.79, H 5.64, N 4.51, Found: C 64.03%, 5.44% H, 4.51% N. 1 H NMR spectrum (200 MHz, CDCl ₃ , free amine, δ): 1.40 (3H, t, J = 7.1 Hz), 2.05 (1H, br), 3.81 (3H, s), 3.86 (3H, s), 3.87 (2H, s), 3.94 (2H, s), 4.40 (2H, q, J = 7.1 Hz) 5.18 (2H, s), 6.80 (2H, d, J = 8.8 Hz), 6.91-6.99 (2H, m), 7.20-7.42 (9H, m), 8.45 (1H, s). IR (KBr, hydrochloride) 3422, 2938, 1719, 1605, 1560, 1545, 1502 and 1460 cm @ ^-1 .

-72GB 290723 B6

Working example 9

When the compound produced in Working Example 6 is used as the starting material, the compounds listed in Table 11 are prepared in substantially the same manner as in Working Example 8.

Table 11

och ₃

prac. Ex. C. -Ř ³¹ yield (% by weight) m.p. (° C) 1 anilinomethyl 44 173-174 2 phenethylaminomethyl 34 148-145 (oxalate) 3 phenylpropylaminomethyl 36 116-118 (hydrochloride) 4 N'-methylpiperazinylmethyl 63 138-139 5 N'-phenylpiperazinylmethyl 61 189-190 6 4-phenylpiperidinomethyl 52 165-167 7 N'-benzylpiperazinylmethyl 86 109-110 (oxalate) 8 phthalamidomethyl 46 221-223 9 1,2,3,4-tetrahydroisoquinolinylmethyl 49 156-158 (hydrochloride) 10 benzhydrylaminomethyl 52 133-135 (hydrochloride) 11 N-phenyl-N-benzylaminomethyl 20 May 93-95 (hydrochloride) 12 methylaminomethyl 100 ALIGN! 118-120 (hydrobromide) 13 ethylaminomethyl 100 ALIGN! 114-116 (hydrobromide) 14 N-benzyl-N-methylaminomethyl 69 96-98 (oxalate) 15 Dec N-benzyl-N-methylaminomethyl 77 147-152 (hydrochloride) 16 2-methoxybenzylaminomethyl 40 108-110 (hydrochloride) 17 3-methylbenzylaminomethyl 28 110-112 (hydrochloride) 18 3,4-dimethoxybenzylaminomethyl 10 129-131 (hydrochloride) 19 Dec 2-phenylimidazo-1-ylmethyl 49 130-132 20 May aminomethyl 89 104-106 (hydrobromide) 21 N-benzyl-N-dimethylammoniummethyl 40 135-137 (bromide) 22nd N-methyl-N- (2,3,4-trimethoxybenzyl) aminomethyl 31 113-115 (hydrochloride) 23 N-methyl-N- (N-methylindol-3-yl) ethylaminomethyl 43 151-153 (hydrochloride) 24 N-methyl-N-phenylpropylaminomethyl 64 103-105 (hydrochloride) 25 N-methyl-N- (2-thiomethylbenzyl) aminomethyl 77 115-117 (hydrochloride) 26 N-methyl-N- (3,5-trifluoromethylbenzyl) aminomethyl 53 130-132 (hydrochloride) 27 Mar: N-methyl-N- (2,6-dichlorobenzyl) aminomethyl 75 124—126 (hydrochloride) 28 N-methyl-N- (2-nitrobenzyl) aminomethyl 76 139-141 (hydrochloride) 29 tert-butylaminomethyl 80 126-128 (hydrobromide)

-73GB 290723 B6

Table 11 - continued

prac. Ex. C. ~ 17 yield (% by weight) m.p. (° C) 30 dimethylaminomethyl 98 117-119 (hydrobromide) 31 N-methyl-N- (2-chlorobenzyl) aminomethyl 64 143-145 (hydrochloride) 32 N-methyl-N- (3-chlorobenzyl) aminomethyl 75 203-205 (hydrochloride) 33 N-methyl-N- (4-chlorobenzyl) aminomethyl 67 197-199 (hydrochloride) 34 N-methyl-N- (2-fluorobenzyl) aminomethyl 38 120-122 (hydrochloride) 35 dibenzylaminomethyl 55 155-157 (hydrochloride) 36 N-hydroxyethyl-N-benzylaminomethyl 60 112-114 (hydrochloride) 37 N-ethoxycarbonylethyl-N-benzylaminomethyl 50 78-80 (hydrochloride) 38 N-benzyl-N-acetamidomethyl 17 78-82 (hydrochloride) 39 N-propyl-N-benzylaminomethyl 64 103-107 (hydrochloride) 40 N-benzyl-N-phenethylaminomethyl 67 105-111 (hydrochloride) 41 2-indanylaminomethyl 56 128-132 (hydrochloride) 42 N-methyl-N- (2-indanyl) aminomethyl 24 121-125 (hydrochloride) 43 N-methyl-N- (3-nitrobenzyl) aminomethyl 80 209-211 (hydrochloride) 44 N-methyl-N- (4-nitrobenzyl) aminomethyl 80 199-201 (hydrochloride) 45 N-methyl-N- (2-phenylbenzyl) aminomethyl 70 112-114 (hydrochloride)

Working example 10

When the compound produced in Working Example 7 is used as the starting material, the compounds listed in Table 12 are prepared in substantially the same manner as in Working Example 8.

Table 12

-74GB 290723 B6

prac. Ex. C. —J ^ n Ø ³⁵ Ø ⁷⁷ yield (% by weight) m.p. (° C) 1 N-benzyl-N- 4-nitro-2-methoxy methylamino-phenyl methyl ethoxycarbonyl 73 124-126 (• HCI) 2 N-benzyl-N- 4-methoxy-2-methoxy methylamino-phenyl methyl ethoxycarbonyl 30 108-117 (, HCl) 3 N-benzylphenyl 2-methoxy aminomethyl ethoxycarbonyl 25 167-169 (• HCI) 4 N-benzyl-N- phenyl 2-methoxy methylamino- methyl ethoxycarbonyl 94 117-120 (.HCI) 5 phenyl N-benzyl-2-methoxy aminomethyl ethoxycarbonyl 40 195-197 (.HCI) 6 N-benzyl-N-benzoyl 2-methoxy methylaminomethyl ethoxycarbonyl 70 90-95 (.HCI) 7 N-benzyl-2-methoxy-2-methoxy aminomethyl phenyl ethoxycarbonyl 18 114-118 (.HCI) 8 N-benzyl-N- 2-methoxy-2-methoxy-methylamino-phenyl methyl ethoxycarbonyl 57 119-122 9 N-benzyl-bromo 2-methoxy aminomethyl ethoxycarbonyl 60 207-211 (oxalate) 10 N-benzyl-N-bromo-2-methoxy methylaminomethyl ethoxycarbonyl 78 112-116 (oxalate) 11 N-benzyl-N- 3-methoxy-2-methoxy methylamino phenyl methyl ethoxycarbonyl 71 115-120 (.HCI) 12 N-benzyl-N- 4-methoxy-2-methoxy methylaminocarbonyl methyl phenyl ethoxycarbonyl 94 122-125 (.HCI) 13 N-benzyl-N- 4-methoxy-2-fluoro methylamino phenyl methyl cyano 94 203-206 (.HCI)

Working example 11

4,7-Dihydro-7- (2-methoxybenzyl) -2- (4-methoxyphenyl) -3-methyl-4-oxothieno [2,3-b] pyridine-N-benzylpiperazinyl-5-carboxamide

To 1 benzylpiperazine (0.77 g, 4.37 mmol) was added dropwise a solution of diisobutyl10 aluminum hydride (1.5N, 2.9 mL, 4.37 mmol) in toluene under ice-cooling. The mixture was allowed to warm to room temperature and stirred at this temperature for 30 minutes. A solution of the compound prepared in Working Example 1 (0.50 g, 1.08 mmol) in toluene (5 mL) was added to the solution at the same temperature. After stirring at room temperature for 15 h, methylene chloride (30 mL) was added to the reaction mixture. The mixture was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure and the residue (1.03 g of 15 solid) was recrystallized from methylene chloride-hexane. The above title compound (0.48 g, 78%) was obtained, mp 233-235 ° C. For C ₃ H ₃ N ₃ O ₄ S · 0.5 H ₂ O calculated

-75GB 290723 B6

% C, 69.75;% H, 6.02;% N, 6.97;% S, 5.32%. Found:% C, 69.88;% H, 6.06;% S, 5.98. 1 H NMR spectrum (200 MHz, CDCl ₃ , δ): 2.45 to 2.55 (4H, m), 2.63 (3H, s), 3.43 to 3.49 (2H, m), 3 55 (2H, s), 3.73-3.82 (2H, m), 3.84 (6H, s), 5.11 (2H, s), 6.89-6.98 (4H, m), 7.21 to 7.40 (9H, m), 7.79 (1H, s).

Working example 12

When the compound produced in Working Example 1 is used as the starting material, the compounds listed in Table 13 are prepared in substantially the same manner as in Working Example 11.

Table 13 0 _R3B A, CON-R ³⁹ | 15 Dec 1 R ³⁶ prac. Ί? ² R ³⁹ yield m.p. Ex. C. (% by weight) (° C) 1 4-methoxy-2-methoxy-3-pyridyl phenyl benzyl hydrogen 54 214-216 2 4-Methoxy-2-methoxy-dimethyl-phenyl-benzyl-aminopropyl hydrogen 59 160-164 3 4-methoxy-2-methoxy-3-pyridylphenyl benzyl methyl hydrogen 60 168-170 4 4-nitrophenyl 2,6-dimethyl methoxy 80 223-224 fluorobenzyl 5 phenyl 2,6-dimethyl methoxy 85 amorphous fluorobenzyl

Working example 13

4,7-Dihydro-7- (2-methoxybenzyl) -2- (4-methoxyphenyl) -3- [N-methyl-N- (2-methoxybenzyl) aminomethyl] -4-oxothieno [2,3-b] pyridine ethyl ester hydrochloride -5-carboxylic acids

To a solution of compound 12 produced in Working Example 9 (0.30 g, 0.52 mmol) in ethanol 25 (5 mL) was added triethylamine (0.21 g, 2.1 mmol) and 2-methoxybenzyl chloride (0) at room temperature. , 16 g, 1.0 mmol). The mixture was stirred at room temperature for 60 h. The reaction mixture was concentrated, and the concentrate was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel. A yellow oil (0.23 g, 72%) was obtained. To a solution of this oil (0.07 g, 0.10 mmol) in ethyl acetate (5 mL) was added IN ethereal hydrochloric acid solution (0.2 mL, 0.20 mmol) under ice-cooling. The mixture was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate with ether. The corresponding hydrochloride (0.07 g, 100%) was obtained as white crystals, m.p. 107

-76E 290723 B6 to 109 ° C. For C ₃₅ H ₃₆ N ₂ O ₆ Calculated S.HC1.H ₂ O 63.01% C 5.89% H 4.30% N Found: 63.57% C, 6.05% H, 3 88% N. 1 H NMR spectrum (200 MHz, CDCl ₃ , free amine δ): 1.39 (3H, t, J = 7.2 Hz), 2.38 (3H, s), 3.71 ( 3H, s), 3.85 (2H, s), 3.87 (2H, s), 3.88 (2H, s), 4.30 (2H, s), 4.39 (2H, q, J) = 7.2 Hz), 5.21 (2H, s), 6.77-7.70 (12H, m), 8.44 (1H, s). IR (KBr, hydrochloride) 3422, 2944, 1721, 1605, 1499, 1464, 1383, 1294 and 1253 cm ^-1 . Mass Spectrum (FAB) m / z 613 (M).

Working example 14

When compound 12 produced in Working Example 9 is used as the starting material, the compounds listed in Table 14 are prepared in substantially the same manner as in Working Example 13.

Table 14

0CH ₃

prac. ex 14 com. C. RT yield (% by weight) m.p. (° C) 1 2-methylbenzyl methyl 84 120-122 2 3-methoxybenzyl methyl 78 74-76 3 4-methoxybenzyl methyl 55 126-128 4 2,3-dimethoxybenzyl methyl 91 99-101 5 2-bromobenzyl methyl 24 141-143 6 fenethyl ethyl 53 133-135 7 2-methoxyphenethyl methyl 31 154-156 8 2-cyanobiphenyl-4-methyl methyl 87 120-122 9 phenylcarbamoyl methyl 91 89-91 10 2-phenyl-2-propenyl methyl 13 152-154 11 allyl methyl 36 138-140 12 3-pyridylmethyl methyl 20 May 160-162 13 1-naphthylmethyl methyl 47 161-163 14 2-naphthyl methyl methyl 47 148-150 15 Dec α-methylbenzyl methyl 35 149-151 16 2-hydroxybenzyl methyl 18 178-180 17 2-methoxycarbonylbenzyl methyl 36 129-131 18 2-trifluoromethylbenzyl methyl 33 129-123 19 Dec 2-thenyl methyl 26 133-135

Working example 15

2- (4-Aminophenyl) -4,7-dihydro-7- (2-methoxybenzyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester acid

-77 GB 290723 B6

To a solution of compound 1 produced in Working Example 10 (0.60 g, 1.00 mmol) in methanol (10 mL) was added powdered iron (0.22 g, 4.0 mmol). The mixture was stirred vigorously with ice cooling. The reaction mixture was poured into ice-water, the product was neutralized with sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel. Crystallization from chloroform-ether gave yellow needles (0.40 g, 71%), mp 120-122 ° C. For C33H33N3O4S.HCI.3 / 2 H ₂ O calculated 66.65% C, 6.10% H 7.07% N Found: 66.16% C, 5.76% H, 7.13% N. 1 H NMR (200 MHz, CDCl 3, free amine δ): 1.38 (3H, t, J = 7.2 Hz), 2.14 (3H, s), 3.68 (3H, s), 3.87 ( 3H, s), 4.17 (2H, s), 4.39 (2H, q, J = 7.2Hz), 5.21 (2H, s), 6.72 (2H, d), 6.96 ( 2H, t), 7.20 (4H, m), 7.35 (1H, t), 7.64 (2H, d), 8.37 (1H, s). IR (KBr, HCl salt): 3454, 1690, 1603, 1499, 1386 and 1317 cm ^1st Mass Spectrum (FAB) m / z 568 (M ^& lt ^{; +} & gt ^; ).

Working Example 16

4,7-Dihydro-5-hydroxymethyl-3- (N-methyl-N-benzylaminomethyl) -7- (2-methoxybenzyl) -2- (4-methoxyphenyl) -4-oxothieno [2,3-b] pyridine hydrochloride

To a solution of compound 2 prepared in Working Example 10 (0.390 g, 0.67 mmol) in methanol (40 mL) was added aqueous potassium carbonate solution [prepared from potassium carbonate (0.185 g, 1.34 mmol) and water (8 mL). ]. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated and the concentrate was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure. A pale yellow oil (0.36 g, 100%) was obtained. To a solution of this oil (0.10 g) in tetrahydrofuran (5 mL) was added 1 N hydrochloric acid ether solution (0.37 mL, 0.37 mmol) under ice-cooling. The mixture was stirred for 10 minutes under ice-cooling. The reaction mixture was concentrated under reduced pressure. Crystallization from ether gave the corresponding hydrochloride (0.105 g, 100%) as white crystals, mp 135-140 ° C. For C ₃₂ H33N ₂ O ₄ SC1 calculated 66.60% C 5.76% H 4.85% N Found: 66.57% C, 5.90% H, 4.54% N. 1 H NMR spectrum (500 MHz, CDCl ₃ , free amine δ): 2.76 (3H, s), 3.86 (3H, s), 3.80 (3H, s), 4.37 (2H, s) 4.45 (1H, brs), 4.55 (1H, brs), 4.77 (2H, s), 5.53 (2H, s), 6.94 (2H, d, J = 8.2) Hz), 6.98 (1H, t, J = 7.4 Hz), 7.06 (2H, brd), 7.3-7.45 (7H, m), 7.50 (1H, m), 8.27 (1 H, s). IR (KBr, HCl salt): 3388, 1607, 1499 and 1253 cm ^1st Mass Spectrum (FAB) m / z 541 (M ^& lt ^{; +} & gt ^; ).

Working example 17

4,7-Dihydro-7- (2-methoxybenzyl) -2- (4-methoxyphenyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxothieno [2,3-b] pyridine-5-carboxamide hydrochloride

Anhydrous ammonia (22 mL) was dissolved in toluene (5 mL) at -78 ° C. To this solution was added a toluene solution of diisobutylaluminum hydride at the same temperature. The mixture was then warmed to room temperature and stirred for an additional 30 minutes. To this solution was added a solution of compound 15 produced in Reference Example 9 (0.25 g, 0.425 mmol) in toluene (4 mL) at room temperature. The mixture was stirred for an additional 1 h at room temperature and then partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water, dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue is chromatographed on silica gel. Colorless crystals are obtained. To a solution of these crystals (0.130 g, 0.23 mmol) in tetrahydrofuran (5 mL) was added 1 N hydrochloric acid in ether (0.46 mL, 0.46 mmol) under ice-cooling, and the mixture was stirred for 10 minutes under ice-cooling. . The reaction mixture was concentrated under reduced pressure. Crystallization from ether gave white crystals of the corresponding hydrochloride (0.143 g, 100%), mp 152-157 ° C. For C3 ₂ H3 ₂ N ₃ O ₄ SC1

Found: C, 66.28; H, 5.80; N, 4.51. Found: C, 66.71; H, 5.60; N, 4.86. Found: C, 66.28; H, 5.80; MHz, CDCl 3, free amine δ): 2.84 (3H, s), 3.87 (3H, s), 3.88 (3H, s). 4.35 (1H, q, J = 4.8Hz), 4.6-4.8 (3H, m), 5.31 (2H, s), 6.09 (1H, s), 6.95 (1H, t, J = 7.6Hz). 6.99 (1H, t, J = 7.6Hz), 7.03 (2H, d, J = 8.0Hz), 7.30-7.36 (4H, m), 7.40-7 50 (5H, m). 8.94 (1H, s), 9.70 (1H, br), 11.61 (1H, br). IR (KBr, HCl salt): 1663, 1605, 1578, 1502 and 1255 cm ^1st Mass Spectrum (FAB) m / z 554 (MH) ^&lt; ^{+ &gt;} .

Working Example 18

The compound 15 produced in Working Example 9 is reacted with various amine derivatives in substantially the same manner as above in Working Example 17. This produces the compounds shown in Table 15.

Table 15

pr. ex. C. ic ' yield (% by weight) m.p. (° C) 1 N, N-dimethylamino 51 136-144 (hydrochloride) 2 N'-benzylpiperazino 26 168-174 (hydrochloride) 3 piperidino 38 133-142 (hydrochloride)

Working example 19

4,7-Dihydro-7- (2-methoxybenzyl) -2- (3-methoxyphenyl) -3-N-methyl-oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester

To a mixture of compound 7 prepared in Working Example 3 (0.615 g, 1.41 mmol), 3-methoxyphenylboronic acid (9.321 g, 2.11 mmol), 2M sodium carbonate (3.53 mL, 7.06 mmol) and 1, 2-Dimethoxyethane (30 mL) was added tetrakis (triphenylphosphine) palladium (0.163 g, 0.141 mmol) under argon and the mixture was refluxed for 24 h. After cooling, ethyl acetate was added to the reaction mixture and the insolubles were filtered off through celite. The filtrate was partitioned between ethyl acetate and brine. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is chromatographed on silica gel. An amorphous substance (0.446 g, 68% by weight) was obtained. For C2ďH25NO S.0,5 ₅ H ₂ O: calculated: 66.08% C 5.55% H 2.96% N Found: 66.33% C 5.40% H 2.91% N 1 H NMR (200 MHz, CDCl 3, δ): 1.41 (3H, t, J = 7.1 Hz), 2.69 (3H, s), 3.84 (3H, s), 3.87 (3H, s), 4.39 (2H, q, J = 7.1 Hz), 5.16 (2H, s), 6.87-7.02 (5H, m), 7.22-7, 42 (3H, m), 8.42 (1 H, s). IR (KBr): 3440, 2938, 1727, 1688, 1607, 1493 and 1465 cm ^1st

-79GB 290723 B6

Working Example 20

4,7-Dihydro-2- (4-methoxyphenyl) -3- (N-methyl-N-benzylaminomethyl) -7- (2-methylthiobenzyl) -4-oxothieno [2,3-b] pyridine-5- ethyl ester hydrochloride carboxylic acids

A mixture of the compound prepared in Reference Example 18 (0.12 g, 0.26 mmol), potassium carbonate (54 mg, 0.39 mmol) of 2-methylthiobenzyl chloride (54 mg, 0.31 mmol), potassium iodide (18 mg, 0 , 1 mmol) and dimethylformamide (3 mL) was stirred at 50 ° C for 3 h. After cooling, the solvent was distilled off under reduced pressure. The residue is chromatographed on silica gel, dissolved in ethyl acetate 10 (20 ml) and to this solution is added 1N hydrochloric acid in ether (0.33 ml), which is concentrated under reduced pressure. The concentrate by crystallization from ether gave pale yellow crystals of the corresponding hydrochloride (0.1 g, 64%), mp 118-120 ° C. For C34H34N7O4S2.HC1.0,4H ₂ O: calculated: 63.57% C 5.62% H 4.36% N Found: 63.81% C 5.82% H 4.49% N 1 H NMR (200 MHz, CDCl ₃ , δ): 1.38 (3H, t, J = 7.1 Hz), 2.52 (3H, s), 2.94 15 (3H, s), 3, 88 (3H, s), 4.38 (3H, q-like signal, J = 7.1 Hz), 4.60 (1H, brs), 4.75 (2H, brs), 5.39 (2H, s 7.04 (2H, d, J = 8.7 Hz), 7.23-7.53 (11H, m), 8.39 (1H, s), 11.82 (1H, brs). IR (KBr): 3406, 2980, 1719, 1605 and 1502 cm @ ^-1 .

Working example 21

When the compound produced in Reference Example 18 is used as the starting material and the reaction is carried out with various halogen compounds in substantially the same manner as in Working Example 20, it produces the compounds listed in Table 16.

Table 16

prac. Ex 21 consolid. C. r36 yield (% by weight) m.p. (° C) 1 2-methoxybenzyl 65 109-113 (hydrochloride) 2 4-methoxybenzyl 65 200-204 (hydrochloride) 3 3-fluorobenzyl 61 203-207 (hydrochloride) 4 1-naphthylmethyl 62 187-192 (hydrochloride) 5 2-naphthylmethyl 77 122-125 (hydrochloride) 6 2-methoxyphenethyl 57 76-81 (hydrochloride) 7 2-trifluoromethylbenzyl 66 189-194 (hydrochloride)

Working example 22

4,7-Dihydro-5-formyl-7- (2-methoxybenzyl) -2- (4-methoxyphenyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxothieno [2,3-b] pyridine

To a solution of the compound produced in Working Example 16 (0.54 g, 0.10 mmol) in chloroform (10 mL) was added active manganese dioxide (0.27 g) and the mixture was stirred at room temperature for 1 h.

-80GB 290723 B6

The reaction mixture was filtered through celite and the celite was washed with chloroform. The combined filtrate was concentrated. The concentrate is chromatographed on silica gel. Crystallization from ethyl acetate-ether gave white crystals (0.014 g, 25%), mp 181-185 ° C. For C ₃₂ H ₃₀ N ₂ O ₄ S.0.8 SiO ₂ calculated: 65.51% C, 5.15% H, 4.77% N, found: 63.25% C, 5.13% H, 5.25% N. 1 H NMR spectrum (200 MHz, CDCl ₃ , δ): 2.40 (3H, s), 3.85 (3H, s), 3.87 (3H, s), 3.8- 4.0 (2H, br), 4.33 (2H, s), 5.23 (2H, s), 6.9 to 7.1 (5H, m), 7.2 to 7.4 (7H, m), 7.64 (1H, d, J = 9.7 Hz), 8.31 (1H, s), 10.45 (1H, s). IR (KBr): 2934, 1688, 1603, 1502, 1386 and 1255 cm ^'1. Mass Spectrum (FAB) m / z 539 (MH) ^&lt; ^{+ &gt;} .

Working example 23

2- (4-Acetylaminophenyl) -4,7-dihydro-7- (2-methoxybenzyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester acid

To a solution of the compound prepared in Working Example 15 (0.11 g, 0.20 mmol) was added acetic anhydride (1 mL) and pyridine (0.29 g, 10.0 mmol) under ice-cooling. The mixture was stirred at room temperature for 8 h. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate, which was extracted with dichloromethane. The extract was washed with brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue is chromatographed on silica gel. The product was crystallized from ether. This gave a white crystalline powder (0.07 g, 58%), mp 161-163 ° C. 1 H NMR (500 MHz, DMSO-d ₆ , δ): 1.35 (3H, t, J = 7.2 Hz), 2.10 (3H, s), 2.58 (3H, s), 3 82 (3H, s), 4.2-4.4 (4H, m), 4.42 (1H, d), 4.58 (1H, d), 5.51 (2H, s), 6, 70 (1H, t), 7.05 (1H, d), 7.1-7.3 (1H, m), 7.3-7.5 (7H, m), 7.68 (1H, s) 7.78 (2H, d), 8.88 (1H, s), 10.33 (1H, s). IR (KBr): 3258, 1717, 1686, 1605, 1495, 1317 and 1253 cm ^'1. Mass Spectrum (FAB) m / z 610 (MH) ^&lt; ^{+ &gt;} .

Working example 24

4,7-Dihydro-2- (4-formylaminophenyl) -7- (2-methoxybenzyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxothieno [2,3-b] pyridine-carboxylic acid ethyl ester

To a solution of the compound produced in Working Example 15 (0.23 g, 4.00 mmol) in dichloromethane (5 mL) was added a mixture of acetic anhydride and formic acid [which was prepared by adding formic acid [99% (w / w). , 6.00 mmol) to acetic anhydride (0.41 g, 4.00 mmol) under ice-cooling and stirring the resulting mixture at 60 ° C for 2 h]. The mixture was then stirred at room temperature for 8 h.

The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate, which was extracted with dichloromethane. The extract was washed with brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue is chromatographed on silica gel. Crystallization from chloroform-ether gave white needles (0.17 g, 72%), mp 185-187 ° C. For C ₃₄ H ₃₃ N ₃ O ₅ S.0.5 H ₂ O calculated: 67.53% C, 5.67% H, 6.95% N, found: 67.04% C, 5.28% H 6.97% N. 1 H NMR (200 MHz, CDCl ₃ , δ): 1.38 (3H, t, J = 7.2 Hz), 2.13 (3H, s), 3.65 (3H) , s), 3.87 (3H, s), 4.17 (2H, s), 4.38 (2H, q), 5.18 (2H, s), 6.97 (1H, t), 7 1 to 7.7 (8H, m), 7.38 (1H, t), 7.5 to 7.7 (2H, m), 7.9 to 7.9 (2H, m), 8.40 (1H, s) 8.44 (1H, s). IR (KBr): 3336, 2978, 1723, 1605, 1495, 1439 and 1305 cm ^'1. Mass Spectrum (FAB) m / z 596 (MH) ^&lt; ^{+ &gt;} .

Working example 25

When the compound produced in Reference Example 11 and the compound derived from the compound in Reference Example 18 are used as starting compounds by reduction according to substantially

In the same manner as in Reference Example 11, in essentially the same manner as in Working Example 4, the compounds listed in Table 17 were prepared.

Table 17

prac. Ex. C. R ³¹ R ³² Ø ³⁵ yield (% by weight) m.p. (° C) 1 methyl 4-methoxyphenyl 2-fluorobenzyl 76 184-185 2 N-methyl- N-benzylaminomethyl 4-methoxyphenyl 2-fluorobenzyl 92 amorphous

Working example 26

When the compound produced in Working Example 7 is used as the starting compound, essentially the same method as in Working Example 8 produces the compounds shown in Table 18.

Table 18

prac. ex. C. R ³² R ³⁵ yield (% by weight) m.p. (° C) 1 4-nitrophenyl 2-fluorobenzyl 83 140-144 2 4-nitrophenyl 2,6-difluorobenzyl 91 145-147 3 4-nitrophenyl 2-chloro-6-fluorobenzyl 78 175-177

-82GB 290723 B6

Working example 27

When the compound produced in Working Example 26 is used as the starting compound, essentially the same reaction as in Working Example 15 produces the compound shown in Table 19.

Table 19

Example 27 (% w / w) (° C) C.

1 4-aminophenyl 2-fluorobenzyl 79 158-160 2 4-aminophenyl 2,6-difluorobenzyl 96 195-196 3 4-aminophenyl 2-chloro-6-fluoro- 71 144-146 benzyl

Working example 28

4,7-Dihydro-7- (2-fluorobenzyl) -5-formyl-2- (4-methoxyphenyl) -3-methyl-4-oxothieno [2,3-b] pyridine

The compound produced in Working Example 25 (4.10 g) was stirred with manganese dioxide (20.5 g) in chloroform (120 mL) at room temperature for 1 h. The reaction mixture was filtered through celite. The filtrate is concentrated to dryness. The concentrate was chromatographed on silica gel. Recrystallization from methylene chloride-ethyl acetate gave colorless crystals (3.72 g, 83%). 1 H NMR (200 MHz, CDCl ₃ , δ): 2.66 (3H, s), 3.85 (3H, s), 5.26 (2H, s), 6.96 (2H, d), 7 1 to 7.4 (6H, m), 8.17 (1H, s), 10.44 (1H, s).

Working example 29

4,7-Dihydro-7- (2-fluorobenzyl) -5- (1-hydroxyethyl) -2- (4-methoxyphenyl) -3-methyl-4-oxothieno [2,3-b] pyridine

The compound produced in Working Example 28 (1.0 g) was dissolved in anhydrous tetrahydrofuran (50 mL). To this solution was added methylmagnesium bromide (0.35 g) under ice-cooling, and the mixture was allowed to warm to room temperature. Stirring is continued for 3 h. The reaction mixture is filtered through celite. The filtrate is concentrated to dryness. Saturated aqueous ammonium chloride solution (20 mL) and ethyl acetate (20 mL) were added to the concentrate. The mixture was stirred, the aqueous layer was extracted with ethyl acetate (20 mL), and the combined organic layer was dried. The solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel. This afforded a yellow amorphous substance (1.10 g, 100%). 1 H NMR spectrum (200 MHz, CDCl ₃ , δ): 1.55 (3H, d), 2.66 (3H, s), 3.84 (3H, s), 4.94 (1H, q), 5.20 (2H, s), 6.95 (2H, d), 7.1-7.2 (3H, m), 7.3-7.4 (3H, m), 7.44 (1H, with).

-83GB 290723 B6

Working example 30

If the compound produced in Working Example 28 is reacted with Grignard reagents instead of methylmagnesium bromide according to essentially the same method as in Working Example 29, the compounds shown in Table 20 are obtained.

Table 20

prac. Ex. C. R R ' yield (% by weight) m.p. (° C) 1 2-methoxy methyl 100 ALIGN! amorphous 2 2-fluoro ethyl 97 amorphous 3 2-fluoro propyl 92 amorphous 4 2-fluoro phenyl 71 amorphous 5 2-fluoro isopropyl 85 amorphous 6 2-fluoro butyl 95 amorphous 7 2-fluoro sek.butyl 72 amorphous 8 2-fluoro tert-butyl 77 amorphous 9 2-fluoro pentyl 75 amorphous 10 2-fluoro cyclopentyl 75 amorphous 11 2-fluoro hexyl 68 amorphous 12 2-fluoro cyclohexyl 100 ALIGN! amorphous 13 2-fluoro 4-fluorophenyl 92 amorphous 14 2-fluoro benzyl 46 amorphous

Working example 31

5-Acetyl-4,7-dihydro-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -3-methyl-4-oxothieno [2,3-b] pyridine

The compound produced in Working Example 29 (0.50 g) was stirred for 3 h at 40 ° C with manganese dioxide in chloroform (50 mL). The reaction mixture was filtered through celite. The filtrate is concentrated to dryness. Recrystallization of the residue from hexane-ethyl acetate gave colorless crystals (0.35 g, 70%), mp 215-216 ° C. For C ₂₄ H ₂₀ NO ₃ S calculated: 68.44% C, 4.78% H, 3.33% N, found: 68.35% C, 4.70% H, 3.41% N. 1 HNMR spectrum (200MHz, CDCl ₃ , δ): 2.26 (3H, s), 2.78 (3H, s), 3.85 (3H, s), 5.25 (2H, s), 6.96 ( 2H, d), 7.1-7.5 (6H, m), 8.37 (1H, s). Mass Spectrum (FAB) m / z 422 (MH) ^&lt; ^{+ &gt;} .

Working example 32

When using the compound produced in Working Example 30, following essentially the same procedure as in Working Example 31, the compounds shown in Table 21 were obtained.

-84GB 290723 B6

Table 21

prac. Ex. C. R R ' yield (% by weight) m.p. (° C) 1 2-methoxy methyl 80 156-157 2 2-fluoro ethyl 67 180-181 3 2-fluoro propyl 65 170-171 4 2-fluoro phenyl 84 183-184 5 2-fluoro isopropyl 70 172-174 6 2-fluoro butyl 83 162-163 7 2-fluoro sek.butyl 75 132-133 8 2-fluoro tert.butyl 44 141-144 9 2-fluoro pentyl 88 145-144 10 2-fluoro cyclopentyl 62 182-183 11 2-fluoro hexyl 66 125-126 12 2-fluoro cyclohexyl 69 191-192 13 2-fluoro 4-fluorophenyl 86 187-188

Working example 33

5-Acetyl-3-bromomethyl-1,7-dihydro-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -4-oxothieno [2,3-b] pyridine

The compound produced in Working Example 31 (0.32 g) was dissolved in carbon tetrachloride (60 ml). This solution was refluxed for 2h together with N-bromosuccinimide (0.144 g) and α, α'-azobisisobutyronitrile (0.013 g). After cooling, chloroform was added to the reaction mixture. The mixture was washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was dried. The solvent was distilled off under reduced pressure. The residue is chromatographed on silica gel. A yellow amorphous solid is obtained, which is recrystallized from chloroform-isopropyl alcohol-ethyl acetate. Colorless needles (0.29 g, 75% by weight) are obtained, mp 226-228 ° C. 1 H NMR (200 MHz, CDCl ₃ , δ): 2.81 (3H, s), 3.86 (3H, s), 5.03 (2H, s), 5.26 (2H, d), 7 03 (2H, d), 7.1-7.5 (4H, m), 7.55 (2H, d), 8.38 (1H, s).

Working example 34

When compounds prepared in Working Example 32 were used as starting materials, the compounds listed in Table 22 were prepared according to essentially the same reactions as described in Working Example 33 above.

-85GB 290723 B6

Table 22

prac. Ex. C. R R ' yield (% by weight) m.p. (° C) 1 2-methoxy methyl 68 206-208 2 2-fluoro ethyl 48 186-187 3 2-fluoro propyl 65 165-166 4 2-fluoro phenyl 75 145-147 5 2-fluoro isopropyl 81 123-124 6 2-fluoro butyl 63 173-174 7 2-fluoro sek.butyl 68 146-148 8 2-fluoro target, butyl 80 98-99 9 2-fluoro isobutyl 74 187-189 10 2-fluoro pentyl 55 168-169 11 2-fluoro cyclopentyl 45 166-167 12 2-fluoro hexyl 54 146-147 13 2-fluoro cyclohexyl 61 169-170 14 2-fluoro 4-fluorophenyl 94 135-136

Working example 35

5-Acetyl-4,7-dihydro-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxothieno [2,3-b] pyridine

The compound produced in Working Example 33 (0.25 g) was dissolved in dimethylformamide (20 ml). To this solution were added diisopropylethylamine (0.079 g) and N-benzylmethylamine (0.074 g) at room temperature. The mixture was stirred at room temperature for 90 minutes. The reaction mixture was concentrated to dryness under reduced pressure. The residue was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was dried. The solvent was distilled off and the residue was chromatographed on silica gel to give a yellow amorphous compound (0.27 g). This amorphous compound was dissolved in methylene chloride (5 ml) and treated with 1N hydrochloric acid in ether (1 ml) under ice-cooling. The resulting crystalline precipitate was filtered off. There was thus obtained the title compound (0.22 g, yield 77%), mp 185-193 ° C. For C32H30N2O3SCIF.2 H ₂ O: calculated: 62.68% C 5.59% H 4.57% N Found: 63.16% C 5.62% H 4.56% N Ή NMR (200 MHz, CDCl 3, δ): 2.80 (3H, s), 2.87 (3H, s), 3.88 (3H, s), 4.3 to 4.44 (1H, m), 4 6-4.8 (3H, m), 5.35 (2H, s), 7.03 (2H, d), 7.2-7.5 (11H, m), 8.48 (1H, s) 11.8 (1H, brs). Mass Spectrum (FAB) m / z 541 (MH) ^&lt; ^{+ &gt;} .

Working example 36

When the compounds produced in Working Example 34 are used as starting materials, the compounds shown in Table 23 are obtained according to essentially the same reactions as in Working Example.

-86GB 290723 B6

Table 23

0 > VCOR · Λ xy - ^ci Chao ^ ¹

prac. Ex. C. R R ' yield (% by weight) m.p. (° C) 1 2-methoxy methyl 100 ALIGN! 124-130 2 2-fluoro ethyl 83 163-172 3 2-fluoro propyl 62 145-150 4 2-fluoro phenyl 50 154-161

Working Example 37

4,7-Dihydro-7- (2-fluorobenzyl) -3- (N-methyl-N-benzylaminomethyl) -2- (4-N'-methylureidophenyl) -4-oxothieno [2,3-b] pyridine-5-ethyl ester -carboxylic acids

To a solution of the compound produced in Working Example 26 (0.11 g, 0.20 mmol) in tetrahydrofuran (5 mL) was added pyridine (0.5 mL). To this mixture, methyl isocyanate (0.064 mL) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure. The concentrate was dissolved in chloroform, washed with brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue is chromatographed on silica gel. Crystallization from ethanol-ethyl acetate gave white needles (0.09 g, 73%), mp 216-220 ° C. For C34H33N4O4SF.2H2O Calculated: C 62.95, H 5.75, N 8.64. Found: C 63.22, H 5.60, 8.39% N. 1 H NMR spectrum (500 MHz) DMSO-d 6, 1.44 (3H, t), 2.25 (3H, brs), 2.84 (3H, s), 4.35 (2H, brs), 4.43 (2H, q), 4.90 (2H, brs), 5.62 (2H, s), 7.20-7.32 (7H, m), 7.45-7.60 (6H, m), 8.85 (1 H, s). IR (KBr): 3308, 1698, 1605, 1499, 1319, 1236 and 1183 cm ^1st Mass spectrum m / z 613 (MH) ⁺ .

Working example 38

If the compounds prepared in Working Example 27 were used as starting materials, the compounds listed in Table 22 were prepared as the corresponding hydrochlorides according to essentially the same reactions as described in Working Examples 23, 24 and 37 above.

Table 24

-87GB 290723 B6

prac. 38 ' C. F Ř ²² yield (% by weight) m.p. (° C) 1 4-acetyl- 4-aminophenyl 2-fluorobenzyl 84 118-120 2 4-propionyl- 4-aminophenyl 2-fluorobenzyl 74 221-223 4-isobutyryl- 4-aminophenyl 2-fluorobenzyl 72 118-192 4 4-benzoyl- 4-aminophenyl 2-fluorobenzyl 53 141-143 5 4-methanesulfonamidophenyl 2-fluorobenzyl 95 > 300

Working example 39

5-Benzylmethylaminomethyl-2,4 (1H, 3H) -dioxo-1- (2-fluorobenzyl) -6- (4-methoxyphenyl) -3-phenylthieno [2,3-d] pyrimidine hydrochloride

To a solution of compound 15 produced in Reference Example 29 (0.150 g, 0.310 mmol) in dimethylformamide (10 mL) was added ethyldiisopropylamine (0.08 mL, 0.460 mmol) and methylbenzylamine (0.05 mL, 0.370 mmol) under ice-cooling. After stirring at room temperature, the reaction mixture was concentrated. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue is chromatographed on silica gel. This gave a colorless oil (0.159 g, 97%). To a solution of this oil in ethyl acetate (4 mL) was added 1 N hydrogen chloride in ether (0.3 mL) under ice-cooling. After stirring under ice-cooling for 10 minutes, the reaction mixture was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-ether. The title hydrochloride (0.144 g) was obtained as white crystals. Tt 140-143. For C35H30N3O3SF.HCl.H2O calculated: 65.05% C, 5.14% H, 6.50% N, found: 65.14% C, 5.03% H, 6.37% N 1 H NMR (200 MHz, CDCl 3, free amine, δ): 2.07 (3H, s), 3.57 (2H, s), 3.86 (3H, s), 3.90 (3H, s). 5.30 (2H, s), 6.94 (2H, d, J = 8.8 Hz), 7.05 to 7.60 (14H, m), 7.66 (2H, d, J = 8.8 Hz). IR (KBr, hydrochloride) 1711, 1665, 1543 and 1477 cm @ ^-1 .

Working example 40

Starting from the compounds produced in Reference Example 28, the compounds listed in Table 25 were prepared as described in Working Example 39 above.

Table 25

-88GB 290723 B6

pr. Ex. C. R ^JJ r35 R ³⁴ yield (% by weight) m.p. (° C) 1 methyl 2-methoxy methoxy 46 119-122 2 methyl 2-fluoro methoxy 97 128-131 3 phenyl 2-methoxy methoxy 95 97-102 4 phenyl 2-fluoro nitro 100 ALIGN! 140-143 5 phenyl 2-fluoro methoxy 97 152-156 6 phenyl 2-fluoro methoxy 100 ALIGN! 165-170 7 phenyl 2,4-difluoro methoxy 77 155-160 8 phenyl 2,6-difluoro methoxy 100 ALIGN! 160-162 9 phenyl 2-chloro-6-fluoro methoxy 98 150-155 10 phenyl 2-methylthio methoxy 76 152-158 11 benzyl 2-fluoro methoxy 89 128-134 12 benzyl 2,6-difluoro methoxy 100 ALIGN! 123-127 13 4-methoxyphenyl 2-fluoro methoxy 93 150-155 14 4-methoxyphenyl 2,6-difluoro methoxy 84 153-157 15 Dec cyclohexyl 2-fluoro methoxy 93 144-150 16 cyclohexyl 2,6-difluoro methoxy 97 145-150 17 phenyl 2,6-difluoro nitro 93 155-160 18 2-methoxyphenyl 2-fluoro methoxy 93 152-153 19 Dec 2-methoxyphenyl 2,6-difluoro methoxy 100 ALIGN! 148-150 20 May 3-methoxyphenyl 2-fluoro methoxy 92 155-158 21 3-methoxyphenyl 2,6-difluoro methoxy 91 160-163 22nd 2-chlorophenyl 2-fluoro methoxy 97 147-152 23 2-chlorophenyl 2,6-difluoro methoxy 98 150-155 24 3-chlorophenyl 2-fluoro methoxy 100 ALIGN! 148-153 25 3-chlorophenyl 2,6-difluoro methoxy 100 ALIGN! 152-157 26 4-chlorophenyl 2-fluoro methoxy 91 161-164 27 Mar: 4-chlorophenyl 2,6-difluoro methoxy 86 145-146

Working example 41

3-Cyanomethyl-4,7-dihydro-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -4-oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester

To a suspension of the compound produced in Working Example 7 (Compound No. 10) (0.80 g, 1.51 mmol) in dimethylsulfoxide (DMSO) was added sodium cyanide (0.084 g, 1.66 mmol) at room temperature. The reaction mixture was heated to 60 ° C and stirred for an additional 4 h. After cooling to room temperature, the reaction mixture was poured into water. The mixture was extracted with ethyl acetate (2 x 50 mL). The extract was washed with water and dried. The resulting solution was evaporated to dryness. A pale yellow oil (0.77 g) was obtained. This product was used in the following working example 42 without further purification.

Working example 42

4,7-Dihydro-3-ethoxycarbonylmethyl-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -4-oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester

To a solution of the compound produced in Working Example 41 (0.77 g) in anhydrous ethanol (250 mL) was carefully added dropwise concentrated sulfuric acid (50 drops) at room temperature. The reaction mixture was refluxed for 15 h, then neutralized under ice-cooling with an excess of aqueous sodium bicarbonate solution and then extracted with ethyl acetate (3 x 500 mL). The extract was washed with water and dried. Concentration under reduced pressure gave a brownish solid (0.72 g). This solid is chromatographed on silica gel. Crystals are obtained which are collected

Recrystallization from ethyl acetate / hexane. Colorless crystals (0.28 g, total yield 35%) were obtained. 129 DEG-201 DEG. For C ₂₈ H ₂₆ NO ₆ SF.0.7 H ₂ O calculated: 62.72% C, 5.02% H, 2.61% N, found: 62.57% C, 4.84% H, 2 53% N. 1 H NMR spectrum (300 MHz, CDCl ₃ , δ): 1.38 (3H, t, J = 7.2 Hz), 2.68 (3H, t, J = 7.2 Hz) 3.84 (3H, s), 4.04 (2H, s). 4.16 (2H, q, J = 7.2Hz), 4.37 (2H, q, J = 7.2Hz), 5.23 (2H, s), 6.92-7.42 (8H) m / z, 8.36 (1H, s). IR (KBr) 3430, 1727, 1611, 1502, 1255, 1183, 1033, 762 and 520 cm @ ^-1 .

Working example 43

4,7-Dihydro-7- (2-fluorobenzyl) -3-hydroxyethyl-2- (4-methoxyphenyl) -4-oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester

To a solution of the compound (0.21 g) produced in Working Example 42 in anhydrous tetrahydrofuran (THF) was added lithium aluminum hydride under ice-cooling. The reaction mixture was allowed to warm to room temperature, stirred for another 1h and poured into saturated aqueous ammonium chloride solution. Extract with ethyl acetate (3 x 100 mL). The extract was washed with a saturated aqueous ammonium chloride solution, dried and filtered. Concentration under reduced pressure gave a solid which was chromatographed on silica gel. An amorphous pale yellow compound (0.16 g, 66%) was obtained. 1 H NMR (300 MHz, CDCl 3, δ): 0.90 (3H, t, J = 7.2 Hz), 1.70 (1H, brs), 3.29 (2H, t, J = 6.0) Hz), 3.84 (3H, s), 4.20-4.23 (2H, m), 4.37 (2H, q, J = 7.2 Hz), 5.29 (2H, s), 6.93 to 7.34 (8H, m), 8.45 (1H, s). FAB-MS m / z 482 (MH) ^&lt; ^{+ &gt;} .

Working example 44

4,7-Dihydro-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -3- (N-methyl-N-benzylaminoethyl) -4-oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester acid

To a solution of the compound produced in Working Example 43 (0.08 g, 0.67 mmol) in methylene chloride (5 mL) was added an excess of phosphorus tribromide (0.5 mL) under ice-cooling. The reaction mixture was allowed to warm to room temperature, stirred for an additional 1 h, ethyl acetate (20 mL) was added, washed with water and dried. Concentration of the filtrate under reduced pressure gave a solid which was dissolved in dimethylformamide (DMF, 5 mL) to which was added excess diisopropylethylamine (100 mg) and N-benzylmethylamine (100 mg). The reaction mixture was stirred for an additional 1 h. Ethyl acetate (20 mL) was added, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and dried. Concentration of the dried solution under reduced pressure gives a solid which is chromatographed on silica gel. A pale yellow amorphous substance (0.005 g, 4 wt%) was obtained. 1 H NMR (300 MHz, CDCl ₃ , δ): 1.40 (3H, t, J = 7.2 Hz), 2.70 (3H, s), 3.30-3.60 (4H, m) 3.83 (3H, s), 4.06 (2H, s), 4.40 (2H, q, J = 7.2 Hz), 5.28 (2H, s), 6.56-7, 51 (13H, m), 8.54 (1 H, s). Mass Spectrum (FAB) m / z 585 (MH) ^&lt; ^{+ &gt;} .

Working example 45

5- (1-Acetoxyethyl) -4,7-dihydro-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -3-methyl-4-oxothieno [2,3-b] pyridine

To a solution of the compound prepared in Working Example 29 (0.55 g, 1.32 mmol) in pyridine (25 mL) was added glacial acetic acid (2.69 g, 26.3 mmol) under ice-cooling. The reaction mixture was allowed to warm to room temperature, stirred for an additional 24 h, concentrated under reduced pressure, and partitioned between ethyl acetate (50 mL) and 1N HCl (10 mL). The aqueous layer was extracted with ethyl acetate, the organic layer was washed with saturated aqueous sodium chloride solution and dried. Concentration of the dried solution under reduced pressure gives a solid which is chromatographed on silica gel. It is obtained

A light yellow solid (0.67 g) was recrystallized from ethyl acetate-hexane. Colorless needles (0.492 g, 81%) were obtained, mp 145-146 ° C. 1 H NMR (200 MHz, CDCl ₃ , δ): 1.56 (3H, d, J = 6.5 Hz), 2.07 (3H, s), 2.66 (3H, s), 3.04 (3H, s), 5.19 (2H, s), 6.13 (1H, q, J = 6.5 Hz), 6.94 (2H, d, J = 8.8 Hz), 7.10 to 7.50 (6H, m), 7.53 (1H, s).

Working example 46

5- (1-Acetoxyethyl) -4,7-dihydro-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxothieno [2,3-b] pyridine

To a solution of Compound 13 produced in Working Example 7 (0.15 g, 0.28 mmol) in dimethylformamide (DMF, 15 mL) at room temperature was added ethyldiisopropylamine (0.094 g, 0.34 mmol) and N-benzylmethylamine (0.041 g). , 0.34 mmol). The reaction mixture was stirred for 1 h, concentrated under reduced pressure, and the concentrate was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate (10 mL). The aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried. Concentration of the dried solution under reduced pressure gives a solid which is chromatographed on silica gel. A pale yellow solid (0.05 g) was obtained, which was recrystallized from ethyl acetate-diethyl ether. Colorless crystals (0.05 g, 29% by weight), mp 183-187 ° C are obtained. For C34H33N2O4SF.2 H ₂ O: calculated: 65.79% C 6.00% H 4.51% N Found: 63.69% C 5.55% H 5.02% N H NMR spectrum (500 MHz, CDCl ₃ , δ): 1.59 (3H, d, J = 6.9 Hz), 2.09 (3H, s), 2.88 (3H, d, J = 7.4 Hz) ), 3.88 (3H, s), 4.40 (1H, m), 4.5-4.7 (3H, m), 5.46 (2H, s), 6.16 (1H, m) 7.08 (2H, d, J = 7.2 Hz), 7.16 (1H, t, J = 9.5 Hz), 7.22 (1H, t, J = 7.6 Hz), 7 3 to 7.5 (6H, m), 7.97 (1H, s). FAB-MS m / z 585 (MH) ^&lt; ^{+ &gt;} .

Working example 47

Starting from the compound produced in Working Example 7, the compounds listed in Table 26 were prepared in substantially the same manner as described in Working Example 46 above.

Table 26

-91 CZ 290723 B6 rh. 47 RR ³⁶ R Yield mp

merge C. (% by weight) (° C) 1 4-nitrophenyl 2,6-difluorobenzyl benzoyl 83 197-199 2 4-nitrophenyl 2,6-difluorobenzyl isobutyryl 66 151-152 3 4-ethoxycarbonylphenyl 2,6-difluorobenzyl benzoyl 87 175-180 (.HCI) 169-171 (free) 4 4-butoxyphenyl 2-fluoro-benzyl ethoxycarbonyl 72 200-202

Working Example 48

4,7-Dihydro-7- (2-fluorobenzyl) -5- (1-hydroxyethyl) -2- (4-methoxyphenyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxothieno [2,3-b] pyridine

To a solution of the compound prepared in Working Example 46 (0.15 g, 0.28 mmol) in methanol (5 mL) was added aqueous potassium carbonate solution (prepared by dissolving 0.012 g of potassium carbonate in 1 mL of water). After stirring for 3 h, the reaction mixture was concentrated under reduced pressure. The concentrate was partitioned between ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (10 mL). The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with a saturated aqueous sodium chloride solution, dried and concentrated under reduced pressure. A solid (0.018 g, 77%) was obtained. 183 DEG-187 DEG. For C32H31N2O3SF.H2O calculated: 68.55% C, 5.93% H, 5.00% N, found: 68.69% C, 5.79% H, 4.92% N. 1 H NMR spectrum (500 MHz) CDCl3, .delta.: 1.56 (3H, d, J = 6.4 Hz), 2.16 (3H, s), 3.68 (2H, br), 3.86 (3H, s), 4 17 (2H, s), 4.7-4.9 (1H, brs), 4.97 (1H, q, J = 6.4z), 5.22 (2H, s), 6.95 ( 2H, d, J = 6.9 Hz), 7.1-7.3 (5H, m), 7.13-7.18 (3H, m), 7.37 (1H, m), 7.46 (1H, s), 7.74 (2H, d, J = 8.6Hz). Mass Spectrum (FAB) m / z 543 (MH) ^&lt; ^{+ &gt;} .

Working example 49

Starting from the compound produced in Working Example 27, the compounds listed in Table 27 were prepared in essentially the same manner as described above in Working Examples 23, 24 and 37.

Table 27

-92EN 290723 B6

pr. Ex. C. R ³² R ³⁶ yield (% by weight) m.p. (° C) 1 4-N'-methylureidophenyl 2-chloro-6-fluorobenzyl 63 199-200 2 4-N'-methylureidophenyl 2-chloro-6-fluorobenzyl 30 182-184 3 4-propionylaminomethyl 2-chloro-6-fluorobenzyl 46 172-173 4 4-N'-methylureidophenyl 2,6-difluorobenzyl 79 214-215 5 4-propionylaminophenyl 2,6-difluorobenzyl 100 ALIGN! 100-102 6 4-N'-methylthioureidophenyl 2,6-difluorobenzyl 74 215-217 7 4- (2-methoxypropionyl) 2,6-difluorobenzyl 62 110-112 8 4-butyrylaminophenyl 2-fluorobenzyl 48 203-204 9 4-valerylaminophenyl 2-fluorobenzyl 47 206-208 10 4-ethoxycarbonylaminophenyl 2-fluorobenzyl 40 amorphous 11 4-N'-methylthioureidophenyl 2-fluorobenzyl 59 204-205 12 4-N'-phenylureidophenyl 2-fluorobenzyl 48 205-207

Working example 50

4,7-Dihydro-7- (2,6-difluorobenzyl) -3- (N-methyl-N-benzylaminomethyl) -2- (4-nitrophenyl) -4-oxothieno [2,3-b] pyridine-5- (N (isopropyl) carboxamide

To a solution of isopropylamine (0.296 g, 5 mmol) in anhydrous methylene chloride (5 mL) was added dropwise a hexane solution of trimethylaluminum (15%, 2.41 mL, 5.0 mmol) at 0 ° C. The mixture was allowed to warm to room temperature and stirred for an additional 1 h. To this solution was added a solution of compound 2 produced in Working Example 26 (0.12 g, 0.25 mmol) in anhydrous methylene chloride under ice-cooling (about 0 ° C). (3 mL) in 30 min. The mixture was stirred for an additional 1 h at room temperature, chloroform (50 mL) was added and the mixture was washed with water. The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. Recrystallization from chloroform-ethyl acetate: ethyl ether gave colorless crystals (0.096 g, 70%), mp 200-202 ° C. 1 H NMR (500 MHz, CDCl ₃ , free amine δ): 1.30 (6H, d, J = 6.7 Hz), 2.15 (3H, s), 3.66 (2H, s), 4 18 (2H, s), 4.18-4.31 (1H, m), 5.32 (2H, s), 7.00 (2H, t, J = 7.26 Hz), 7.13-7 4.31 (1H, m), 5.32 (2H, s), 7.00 (2H, t, J = 7.26 Hz), 7.13-7.25 (5H, m), 7.42 (1H, t, J = 7.3Hz), 8.02 (2H, d, J = 8.9Hz), 8.26 (2H, d, J = 8.9Hz), 8.73 (1H) , s), 10.02 (1H, d, J = 9.1 Hz). IR (KBr): 2974, 1661, 1597, 1547, 1497, 1346, 1212, and 1035 cm @ ^-1 . Mass Spectrum (FAB) m / z 617 (MH) ^&lt; ^{+ &gt;} .

-93GB 290723 B6

Working example 51

Starting from the compounds prepared in Working Examples 26, 27, 37, 38 and 49, compounds 5 listed in Tables 28 and 29 were prepared in essentially the same manner as described in Working Example 50 above.

Table 28

pr. Ex. C. Ø ³³ Ø ³⁵ Ř ³⁷ yield (% by weight) m.p. (° C) 1 4-N'-methyl-2,6-difluorobenzyl ureidophenyl N-isopropyl- N-methylcarboxamide 76 133-135 (184-186 as.HCl) 2 4-N'-methyl-2,6-difluorobenzyl ureidophenyl N-methyl-O-methylhydroxamic acid 80 138-140 3 4-Propionyl-2,6-difluorobenzyl aminophenyl N, N-dimethyl carboxamide 55 110-112 4 4-Propionyl-2,6-difluorobenzyl aminophenyl pyrrolidinylamide 43 130-132 5 4-Propionyl-2,6-difluorobenzyl aminophenyl Ν ', Ν'-dimethyl amino-1,3-propyl carboxamide 46 90-92 6 4-Propionyl-2,6-difluorobenzyl aminophenyl N-methyl-N-butyl carboxamide 28 120-122 7 4-N'-methyl-2,6-difluorobenzyl ureidophenyl N-methyl-N-benzylcarboxamide 27 Mar: 135-137 (179-181 .HCI) 8 4-N'-methyl-2,6-difluorobenzyl ureidophenyl N-isopropylcarboxamide 55 148-150 9 4-nitro-2,6-difluorobenzyl aminophenyl 4-Methyl-O-methyl-hydroxamic acid 96 100-102 10 4-Propionyl-2,6-difluorobenzyl aminophenyl N-isopropylcarboxamide 56 144-146 11 4-Propionyl-2,6-difluorobenzyl aminophenyl N-butylcarboxamide 32 107-109 12 4-N'-methyl-2-chloro-6-fluoro-ureidophenyl benzyl N-isopropylcarboxamide 77 172-174 13 4-Propionyl-2-chloro-6-fluoro-aminophenyl benzyl N-isopropylcarboxamide 75 120-122 14 4-Propionyl-2-chloro-6-fluoro-aminophenyl benzyl N-butylcarboxamide 40 105-107 15 Dec 4-acetyl-2-fluorobenzyl aminophenyl N-isopropylcarboxamide 83 184-186

-94EN 290723 B6

Table 28 - continued

pr. Ex. C. Ř ³⁷ Ø ³⁵ R ³⁷ yield (% by weight) m.p. (° C) 16 4-propionyl- 2,6-difluorobenzyl N-methyl-O-me- 74 amorphous aminophenyl thylhydroxamic acid 17 4-N'-methyl- 2,6-difluorobenzyl N-methyl-N- 54 156-158 ureidophenyl - (2-pyridyl) carboxamido (.HCI) 18 4-propionyl- 2,6-difluorobenzyl N-methyl-N- 85 148-150 aminophenyl - (2-pyridyl) carboxamido (.HCI) 19 Dec 4-N'-methyl- 2,6-difluorobenzyl N-ethyl-N-benzyl 26 125-127 ureidophenyl carboxamide (.HCI)

Table 29

merge (% by weight) _____ (° C) methyl bromo 2,6-difluoro-N-methyl-O- 87 192-194 benzylmethylcarbohydroxamic acid

Working example 52

5-Benzoyl- (2,6-difluorobenzyl) -4,7-dihydro-7-3-methyl-2- (4-nitrophenyl) -4-oxothieno [2,3-b] pyridine

Compound 4 produced in Working Example 12 (3.93 g, 7.87 mmol) was dissolved in anhydrous tetrahydrofuran (THF) with gentle heating. To this solution was added dropwise a solution of phenylmagnesium bromide in THF (1M, 15.7 mL, 15.7 mmol) with cooling to 0 ° C over 10 minutes. The mixture was stirred for an additional 1 h. The reaction mixture was partitioned between ethyl acetate (300 mL) and water (50 mL). The aqueous layer was extracted again with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the concentrate was chromatographed on silica gel. Yellow crystals (3.00 g, 74%) were obtained, which were recrystallized from ethyl acetate-hexane, mp 114-116 ° C. For C ₂₈ H ₁₈ N ₂ O ₄ SF ₂ .0.7 H ₂ O calculated: 63.56% C, 3.70% H, 5.29% N, found: 63.83% C, 3.95% H, 5.08% N. 1 H NMR (500MHz, CDCl 3, δ): 2.68 (3H, s), 5.30 (2H, s), 7.02 (2H, t, J = 8.1) Hz), 7.43 (3H, t, J = 7.2 Hz), 7.52-7.63 (3H, m), 7.86 (2H, d, J = 7.5 Hz), 7, 99 (1H, s), 8.30 (2H, d, J = 8.7Hz). IR spectrum (KBr); 3422, 3068, 1665, 1615, 1491, 1473, 1346 and 853 cm ^1st Mass Spectrum (FAB) m / z 517 (MH) ^&lt; ^{+ &gt;} .

-95EN 290723 B6

Working example 53

Starting from the compounds produced in Working Example 51, the compounds listed in Table 30 were prepared in substantially the same manner as described above in Working Example 52.

Table 30

4-nitrophenyl isobutyryl compound C.

(% by weight) (° C) phenyl bromide

N-methyl N-benzylaminomethyl N-methyl N-benzylaminomethyl methyl

2,6-didifluorobenzyl

2,6-didifluorobenzyl

2,6-difluorobenzyl

236-238

(.HCl) isobutyryl benzoyl

204-205

229-230

Working Example 54

2- (4-Aminophenyl) -5-benzoyl-7- (2,6-difluorobenzyl) -4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -4-oxothieno [2,3-b] pyridine

To Compound 1 produced in Working Example 47 (0.30 g, 0.47 mmol) in ethanol (6 mL) was added one drop of concentrated hydrochloric acid to make the mixture homogeneous. To this solution was added dropwise iron powder (0.105 g, 2.0 mmol) and concentrated hydrochloric acid (0.39 mL, 4.7 mmol). After stirring at room temperature for 5 h, the reaction mixture was filtered through celite. A small amount of aqueous ammonia was added to the filtrate and the mixture was concentrated under reduced pressure. The concentrate was poured into ice water, neutralized with sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and chromatographed on silica gel. Crystallization from isopropyl ether gave yellow needles (0.24 g, 84%), mp 126-128 ° C. For compound C ₃₆ H 9 N ₃ O _{2 2} H ₂ O SF2.0,5 calculated: 68.93% C 5.04% H 6.70% N Found: 68.71% C, 5.18% H, 6.62% N. 1 H NMR (300 MHz, CDCl ₃ , δ): 2.13 (3H, s), 3.65 (2H, s), 3.87 (2H, brs), 4.14 (2H, s), 5 28 (2H, s), 6.74 (2H, d, J = 8.7Hz), 7.00 (2H, t, J = 7.8Hz), 7.16-7.24 (5H, m), 7.36-7.46 (3H, m), 7.53 (1H, t, J = 7.2 Hz), 7.62 (2H, d, J = 8.4 Hz), 89 (2H, d, J = 7.2Hz), 7.94 (1H, s). IR (KBr): 3358, 1607, 1495, 1473, and 1053 cm @ ^-1 . Mass Spectrum (FAB) m / z 606 (MH) ^&lt; ^{+ &gt;} .

-96GB 290723 B6

Working example 55

2- (4-Aminophenyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-5-isobutyryl-3- (N-methyl-N-benzylaminomethyl) -4-oxothieno [2,3-b] pyridine

To a solution of compound 2 produced in Working Example 47 (0.25 g, 0.415 mmol) in methanol (5 mL) was added dropwise iron powder (0.093 g, 1.66 mmol) and concentrated hydrochloric acid (0.8 mL) dropwise with cooling. . After stirring at room temperature for 1 h, the reaction mixture was filtered through celite. To the filtrate was added saturated aqueous sodium bicarbonate (10 mL), and the mixture was extracted with 3 x 30 mL of methylene chloride. The combined extract was washed with water, dried over magnesium sulfate, concentrated under reduced pressure and the residue chromatographed on silica gel. A pale yellow amorphous substance (0.203 g, 86%) was obtained. ¹ H NMR (300 MHz, CDCl ₃ , δ): 1.18 (6H, d), 2.11 (3H, s), 3.65 (2H, s), 3.85 (2H, brs), 4 17 (2H, s), 4.18 (1H, m), 5.25 (2H, s), 6.73 (2H, d), 6.95 (2H, t), 7.10-7, 26 (5H, m), 7.42 (1H, m), 7.58 (2H, d), 8.27 (1H, s).

Working Example 56

5-Benzoyl-7- (2,6-difluorobenzyl) -4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -2- (4-propionylaminophenyl) -4-oxothieno [2,3-b] pyridine

The compound produced in Working Example 54 (0.14 g, 0.23 mmol) was dissolved in anhydrous methylene chloride (2 mL). To this solution was added triethylamine (0.038 mL) under ice-cooling (0 ° C). After stirring for a while, propionyl chloride (0.021 mL, 0.243 mmol) was added to the mixture. The mixture was then stirred for an additional 40 minutes under ice-cooling (0 ° C). The reaction mixture was partitioned between methylene chloride (25 mL) and a very dilute aqueous potassium bicarbonate solution (1 mL). The aqueous layer was extracted again with methylene chloride (25 mL). The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-isopropyl ether. Yellow needles (0.10 g, 65%) were obtained, mp 226-228 ° C. For C 9 H ₃₃ N ₃ O ₃ SF _{3 2} .0,7 H ₂ O: calculated: 69.46% C 5.14% H 6.23% N Found: 69.60% C, 5.18% H, 6.04% N.

This compound was dissolved in ethyl acetate, to which was added a saturated solution of HCl in ether (equimolar to slight excess). Crystals are thus obtained. These crystals are recrystallized from isopropyl ether. Light yellow needles (0.095 g, 61%) were obtained, mp 218-220 ° C. For compound ₃ C 9 H ₃₃ N ₃ O ₃ SF ₂ .HC1.3,5 H ₂ O: calculated: 61.53% C 5.43% H 5.52% N Found: 61.83% C, 5 33% H, 5.30% N. 1 H NMR (300 MHz, DMSO-d ₆ , δ): 1.11 (3H, t, J = 7.2 Hz), 1.93 (3H, s) 2.35 (2H, q, J = 7.5Hz), 3.44 (2H, s), 4.00 (2H, s), 5.62 (2H, s), 7.11-7, 25 (6H, m), 7.43-7.72 (10H, m), 7.79 (2H, d, J = 7.5 Hz), 8.40 (1H, s), 10.03 (1H) , s). IR (KBr): 3422, 3068, 1603, 1502, 1473, and 1035 cm @ -1. Mass Spectrum (FAB) m / z 662 (MH) ^&lt; ^{+ &gt;} .

Working example 57

Starting from the compounds produced in Working Examples 54 and 55, the compounds listed in Table 31 were prepared in essentially the same manner as described above in Working Examples 56, 23, 24, 27 and 38.

-97GB 290723 B6

Table 31

pr. Ex. C. R ³² Ø ³⁵ X yield (% by weight) m.p. (° C) [m.p. .HC1] 1 4-N'-methylureidophenyl 2,6-difluorobenzyl benzoyl 68 238-240 [230-231] 2 4-propionylaminophenyl 2,6-difluorobenzyl isobutyryl 64 201-204 [207-214] Λ 4-N'-methylureidophenyl 2,6-difluorobenzyl isobutyryl 55 207-210 [222-226] 4 4-ethanesulfonamidophenyl 2,6-difluorobenzyl benzoyl 49 [185-187] 5 4-isobutyrylaminophenyl 2,6-difluorobenzyl benzoyl 79 [216-218] 6 4-N ', N'-dimethylureidophenyl 2,6-difluorobenzyl benzoyl 73 [180-183] Ί 4-N'-isopropylureidophenyl 2,6-difluorobenzyl benzoyl 65 245-247 H 8 4-pyrrolidinecarboxamidophenyl 2,6-difluorobenzyl benzoyl 65 [176-178] 9 4- (2,2,2-trifluoroethoxycarboxylaminophenyl) 2,6-difluorobenzyl benzoyl 70 [232-234] 10 4-isobutyrylaminophenyl 2,6-difluorobenzyl isobutyryl 73 [192-197]

Working Example 58

5-Benzoyl-7- (2,6-difluorobenzyl) -4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -2- (4-nitrophenyl) -4-oxothieno [2,3-b] pyridine

Compound 9 produced in Working Example 51 (1.91 g, 3.09 mmol) was dissolved in anhydrous tetrahydrofuran (THF, 30 mL) with heating. To this solution was added dropwise a solution of phenylmagnesium bromide in THF (1M, 6.18 mL, 6.2 mmol) under ice-cooling (0 ° C) over 10 minutes. The mixture was stirred for an additional 1 hour under ice-cooling. The reaction mixture was then partitioned between ethyl acetate (100 mL) and HCl (0.5 N, 100 mL). The organic layer was washed again with a saturated aqueous sodium chloride solution (100 mL), dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was chromatographed on silica gel. Yellow crystals (1.00 g, 51%) are obtained, which are recrystallized from isopropyl ether. Yellow needles are obtained, mp 197-199 ° C. For C ₃₆ H ₂₇ N ₃ O ₄ SF ₂ .0.7 H ₂ O calculated: 66.70% C, 4.42% H, 6.48% N, found: 66.59% C, 4.48% H, 6.42% N. 1 H NMR (300 MHz, CDCl ₃ , δ): 2.17 (3H, s), 3.61 (2H, s), 4.16

-98EN 290723 B6 (2H, s), 5.30 (2H, s), 7.03 (2H, t, J = 8.1 Hz), 7.19 to 7.25 (5H, m), 7.40 to 2H 7.47 (3H, m), 7.56 (1H, t, J = 7.5Hz), 7.88 (2H, d, J = 6.9Hz), 7.96 (1H, s), 8.10 (2H, d, J = 8.7Hz), 8.28 (2H, d, J = 8.7Hz). IR spectrum (KBr); 3430, 1663, 1611, 1518, 1473, 1348 and 853 cm ^-1 . Mass Spectrum (FAB) m / z 636 (MH) ^&lt; ^{+ &gt;} .

Working example 59

Starting from compounds 2, 9 and 16 produced in Working Example 51, the compounds listed in Table 32 were prepared in essentially the same manner as described in Working Example 58 above. This method is another way to produce the compounds described in Working Examples 56 and (57)

Table 32

isobutyryl (% w / w) (° C)

207-2:

N-methyl-N-benzyl aminomethyl

N-methyl-N-benzylaminomethyl

N-methyl-N-benzylaminomethyl

N-methyl-N-benzylaminomethyl dophenyl)

4-propionylaminophenyl

4- (N'-methylureidophenyl)

4-propionylaminophenyl

4- (N ' -methylurei 2,6-didifluorobenzyl)

2,6-didifluorobenzyl

2,6-didifluorobenzyl

2,6-didifluorobenzyl isobutyryl benzoyl benzoyl

222-226

218-220

230-232

Working example 60

6- (4-Aminophenyl) -2,4 (1H, 3H) -dioxo-1- (2-fluorobenzyl) -3-phenyl-5- (N-methyl-N-benzylaminomethyl) thieno [2,3-d] pyrimidine

Compound 4 produced in Working Example 40 (0.15 g, 0.247 mmol) was dissolved in ethanol (15 mL). To this solution was added 10% palladium on carbon (15 mg). The mixture was hydrogenated for 8 h at room temperature under atmospheric pressure under hydrogen. The reaction mixture was filtered under reduced pressure. The filtrate was concentrated under reduced pressure. The concentrate is chromatographed on silica gel. A yellow crystalline amorphous substance was obtained (0.046 g, 32% by weight). 1 H NMR spectrum (300 MHz, CDCl ₃ , δ): 2.05 (3H, s), 3.57 (2H, s), 3.81 (2H, brs), 3.89 (2H, s), 5.29 (2H, s), 6.69 (2H, d, J = 8.7 Hz), 7.05 to 7.56 (16H, m). Mass Spectrum (FAB) m / z 577 (MH) ^&lt; ^{+ &gt;} .

-99GB 290723 B6

Working example 61

6- (4-Acetylaminophenyl) -2,4 (1H, 3H) -dioxo-1- (2-fluorobenzyl) -5- (N-methyl-N-benzylaminomethyl) -3-phenylthieno [2,3-d] pyrimidine

The compound produced in Working Example 60 (0.63 g, 0.11 mmol) was dissolved in anhydrous pyridine (5 mL). Acetic anhydride (0.01 mL, 0.11 mmol) was added to the solution. The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The concentrate was partitioned between methylene chloride (30 mL) and saturated aqueous sodium chloride solution (10 mL). The aqueous layer was extracted again with methylene chloride (30 mL). The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was chromatographed on silica gel to give a colorless solid (0.01 g, 15%). 1 H NMR (300MHz, CDCl 3, δ): 2.06 (3H, s), 2.19 (3H, s), 3.57 (2H, s), 3.90 (2H, s), 5.30 (2H, s), 7.04-7.57 (16H, s), 7.70 (2H, d, J = 8.4 Hz).

Working example 62

4,7-Dihydro-7- (2-fluorobenzyl) -2- (4-hydroxyphenyl) -3-methyl-4-oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester

To a solution of Compound No. 3 produced in Working Example 65 (1.30 g, 2.70 mmol) in tetrahydrofuran (80 mL) was added 1M HCl in ether (81 mL, 81 mmol) under ice-cooling. After stirring at room temperature for 60 h, the reaction mixture was concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium chloride solution (50 mL). The aqueous layer was extracted again with ethyl acetate (50 mL). The combined organic layer was dried over magnesium sulfate and concentrated by distilling off the solvent under reduced pressure. The remaining solid was recrystallized from ethyl acetate-ethanol. Yellow needles (0.81 g, 69%) were obtained, mp 225-227 ° C. For C ₂₄ H ₂₀ NO ₄ SF · 0.1 H ₂ O calculated: C 65.62, H 4.63, N 3.19. Found: C 65.46, H 4.65, 3.33 1 H NMR spectrum (300 MHz, CDCl ₃ , δ): 1.30 (3H, t, J = 7.0 Hz), 4.24 (2H, q, J = 7.0 Hz), δ 52 (2H, s), 6.84 (2H, d, J = 8.4 Hz), 7.20 to 7.46 (6H, m), 8.65 (1H, s), 9.75 ( 1H, s). IR (KBr): 3856, 1711, 1611, 1589, 1510, 1493, and 1448 cm @ ^-1 . Mass Spectrum (FAB) m / z 438 (MH) ^&lt; ^{+ &gt;} .

Working example 63

4,7-Dihydro-7- (2-fluorobenzyl) -2- (4-hydroxyphenyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester acid

Compound No. 26 produced in Working Example 7 (0.026 g, 0.46 mmol), N-methylbenzylamine (0.072 mL, 0.56 mmol) and N-ethyldiisopropylamine (0.12 mL, 0.69 mmol) were used as starting material. ). In essentially the same manner as described above in Working Example 8, a yellow amorphous substance (0.24 g) was prepared. To a solution of this amorphous in ethanol (6 mL) was added 1 N HCl (4 mL, 4 mmol). The mixture was then stirred at room temperature for 2 h. 1N HCl (8 mL, 8 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 19 h. To the reaction mixture was added water containing sodium bicarbonate (1.01 g, 12.0 mmol), followed by extraction with ethyl acetate (3 x 30 mL). The combined organic layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The residue is chromatographed on silica gel. This gave a colorless oil (0.15 g, 58%). To a solution of this oil in ethanol (3 mL) was added a 1M solution of HCl in ether (0.35 mL, 0.35 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was recrystallized from ether. A white powder (0.116 g, total yield 41% by weight) was obtained as the hydrochloride, mp 231-235 ° C. For C32H29N2O SF.HC1.1,5 ₄ H ₂ O: calculated: 61.98% C 5.36% H 4.52% N Found: 61.99% C,

- 100GB 290723 B6

5.23% Η, 4.55% N. 1 H NMR (300 MHz, CDCl ₃ , δ): 1.39 (3H, t, J = 7.1 Hz), 2.53 (3H, brs), 4, 09 (2H, brs), 4.38 (2H, q, J = 7.1 Hz), 4.39 (2H, brs), 5.46 (2H, s), 7.05 (2H, d, J) = 8.5 Hz), 7.13-7.51 (11H, m), 8.57 (1H, s). IR (KBr): 3422, 2988, 1719, 1695, 1605, 1543, 1504, and 1458 cm @ ^-1 .

Working example 64

2- (4-Butoxyphenyl} -4,7-dihydro-7- (2-fluorobenzyl) -3-methyl-4-oxothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester

To a solution of the compound produced in Working Example 62 (0.30 g, 0.686 mmol) in DMF (10 mL) was added sodium hydride (30 mg, 0.75 mmol) under ice-cooling, then the mixture was stirred at room temperature for 1 h. to this solution was added butyl iodide (0.19 g, 1.03 mmol). The mixture was stirred at room temperature for 15 h. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium chloride solution (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The resulting solid residue was recrystallized from ethyl acetate-hexane. Colorless crystals (0.33 g, 97% by weight) are obtained, mp 119-121 ° C. For C ₂₈ H ₂₈ NO ₄ SF.0,2 H ₂ O Calculated: 67,64,71% C 5.76% H 2.82% N Found: 67.36% C, 5.69% H , 2.68% N. Mass spectrum (FAB) m / z 494 (MH) ^&lt; ^{+ &gt;} .

Working Example 65

When Compound No. 7 produced in Working Example 3 and Compound 3 produced in Working Example 53 were used as starting materials, the compounds listed in Table 33 were prepared in essentially the same manner as described in Working Example 19 above.

Table 33

188-190

2-fluorobenzyl compound C.

(wt.) [m.p. .HCI]

4- (4-nitrobenzyloxycarbonyl) phenyl 4-ethoxycarbonylphenyl 4-methoxymethoxyphenyl 4-ethoxycarbonylphenyl

2,6-difluorobenzyl 2-fluorobenzyl

2-methoxybenzyl ethoxycarbonyl benzoyl ethoxycarbonyl ethoxycarbonyl

221-223

112-113

171-172

- 101 GB 290723 B6

Working example 66

5-Benzoyl-7- (2,6-difluorobenzyl) -4,7-dihydro-2- (4-N-ethylaminocarboxyphenyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxothieno [2,3-b] pyridine

A solution of compound No. 3 produced in Working Example 47 (0.15 g, 0.226 mmol) in ethanol (3 mL) and THF (3 mL) was treated with 1N aqueous sodium hydroxide solution (1.2 mL, 1.2 mmol). ). A carboxylic acid derivative is obtained. To a solution of this carboxylic acid derivative in THF (5 mL) was added triethylamine (0.084 mL, 0.60 mmol) and isobutyl chloroformate under ice-cooling under a nitrogen atmosphere, and the mixture was stirred under ice-cooling for 1.5 hours at room temperature. rooms. To this solution was added dropwise a 70% (w / w) aqueous solution of ethylamine (0.16 mL, 2.48 mmol) under ice-cooling, the mixture was stirred for 30 minutes under ice-cooling and at room temperature for 2 hours. The reaction mixture was partitioned between saturated aqueous sodium chloride solution (50 mL) and ethyl acetate (50 mL), and the aqueous layer was extracted with ethyl acetate (50 mL). The organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was chromatographed on silica gel. A pale yellow amorphous solid was obtained (0.095 mg, 63%). To a solution of this amorphous compound in methylene chloride (4 mL) was added a 1M solution of HCl in ether (0.29 mL, 0.29 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for an additional 10 minutes. The reaction mixture was concentrated under reduced pressure. Crystallization of the residue from methylene chloride-ethyl acetate-ether gave a pale yellow powder (0.088 g, 56% overall yield) as the hydrochloride, mp 156-160 ° C. For C 9 H ₃₃ N ₃ O ₃ SF ₃ .HC1.1,8 ₂ H ₂ O: calculated: 64.11% C 5.19% H 5.75% N Found: 63.88% C 4, 90% H, 5.59% N. 1 HNMR spectrum (300 MHz, CDCl 3, free amine δ): 1.28 (3H, t, J = 7.2 Hz), 2.13 (3H, brs), 3 49-3.58 (2H, m), 3.62 (2H, brs), 4.16 (2H, brs), 5.30 (2H, s), 6.23 (1H, brs), 6, 99-7.05 (2H, m), 7.17-7.26 (5H, m), 7.39-7.58 (4H, m), 7.83-7.97 (7H, m). IR (KBr, hydrochloride): 3386, 3064, 1655, 1630, 1605, 1543, 1508, 1497, and 1473 cm ^-1 . Mass Spectrum (FAB) m / z 662 (MH) ^&lt; ^{+ &gt;} .

Working example 67

If compounds Nos. 3 and 4 produced in Working Example 47 were used as starting materials, the compounds listed in Table 34 were prepared in essentially the same manner as described in Working Example 66 above.

Table 34

-102GB 290723 B6

pr. Ex. C. F ...... R ^ R ³⁷ yield (% by weight) m.p. (° C) 1 N-methyl- 4-N, N-di- 2-fluoro- ethoxy- 80 110-113 N-benzyl- ethylamino benzyl carbonyl aminomethyl carboxyphenyl 2 N-methyl- 4-N-propyl 2,6-di- benzoyl 75 153-157 N-benzyl- aminocarboxy difluor- aminomethyl phenyl benzyl 3 N-methyl- 4-N-allylamino 2,6-di- benzoyl 69 152-156 N-benzyl- carboxyphenyl difluor- aminophenyl benzyl

Working Example 68

4,7-Dihydro-5-ethoxymethyl-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -3- (Nmethyl-N-benzylaminomethyl) -4-oxothieno [2,3-b] pyridine hydrochloride

To a solution of Compound No. 2 produced in Working Example 25 (0.23 g, 0.435 mmol) in anhydrous THF (5 mL) was added sodium hydride (19 mg, 0.475 mmol) under nitrogen atmosphere under ice-cooling. The mixture was then stirred at 0 ° C for 30 minutes. To this mixture was added ethyl iodide (0.038 mL, 0.475 mmol) and allowed to warm to room temperature. After stirring at room temperature for 2 h, ethyl iodide (0.038 mL, 0.475 mmol) was added and the mixture was stirred for 19 h. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was partitioned between ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL). The aqueous layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was chromatographed on silica gel. A white solid (0.09 g, 37%) was obtained. To a solution of this solid in methylene chloride was added a 1M solution of HCl in ether (0.2 mL, 0.2 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was recrystallized from methylene chloride-ethyl acetate-ether. There was thus obtained a white powder (0.058 g) as the hydrochloride, mp 200-204 ° C. For C 33 H 3 N _{3 2} O3SF2.HC1.0,5 H ₂ O: calculated: 65.82% C 5.86% H 4.65% N Found: 66.01% C, 5.67% H, 4 62% N. 1 H NMR (300 MHz, CDCl ₃ , δ): 1.28 (3H, t, J = 7.0 Hz), 2.15 (3H, brs), 2.86 (2H, brs) ), 3.68 (2H, q, J = 7.0 Hz), 3.86 (3H, s), 4.21 (2H, brs), 4.57 (2H, s), 5.31 (2H , brs), 7.00-7.69 (14H, m). Mass Spectrum (FAB) m / z 557 (MH) ^&lt; ^{+ &gt;} .

Working Example 69

5-Benzoyloxymethyl-4,7-dihydro-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -3- (Nmethyl-N-benzylaminomethyl) -4-oxothieno [2,3-b] pyridine hydrochloride

When compound 2 produced in Working Example 25 and benzyl chloride in place of ethyl iodide were used as starting materials, the title compound was prepared as a pale yellow crystalline powder (0.10 g, 79% by weight) in essentially the same manner as described in Working Example 68 above. .), m Mp 77-83 ° C.

-103GB 290723 B6

Working Example 70

4,7-Dihydro-5-ethylthiomethyl-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxothieno [2,3-b] pyridine hydrochloride

To a solution of Compound # 2 produced in Working Example 25 (0.15 g, 0.284 mmol) in anhydrous THF (5 mL) was added tributylphosphine (0.36 mg, 1.44 mmol) and diethyl disulfide (0.18 mL, 1 mL). , 46 mmol). The mixture was refluxed for 5 h. To this mixture was added tributylphosphine (0.27 mL, 2.88 mmol) and diethyl disulfide (0.36 mmol, 2.92 mmol) and the mixture was refluxed for 3 days. After cooling, the reaction mixture was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium chloride solution (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was chromatographed on silica gel. A white solid (0.124 g, 76%) was obtained. To a solution of this solid in methylene chloride (3 mL) was added a 1M solution of HCl in ether (0.45 mL, 0.45 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was recrystallized from methylene chloride-ethyl acetate-ether. There was thus obtained a white powder (0.09 g) as the hydrochloride, mp 213-217 ° C. For C33H33N2O2S2F.HCl.H2O calculated: 63.19% C, 5.78% H, 4.47% N, found: 63.21% C, 5.69% H, 4.59% N. 1 H NMR spectrum ( 300 MHz, CDCl ₃ , δ): 1.27 (3H, t, J = 7.4 Hz), 2.23 (3H, brs), 2.56 (2H, q, J = 7.4 Hz), 3.76 (2H, s), 3.79 (2H, br), 3.86 (3H, s), 4.25 (2H, brs), 5.25 (2H, s), 6.97 (2H , d, J = 8.6 Hz), 7.12 to 7.39 (10H, m), 7.71 (2H, brs). IR (KBr): 3480, 2966, 1609, 1520 and 1458 cm ^1st Mass Spectrum (FAB) m / z 573 (MH) ^&lt; ^{+ &gt;} .

Working example 71

7- (2,6-Difluorobenzyl) -4,7-dihydro-6-isobutyl-3- (N-methyl-N-benzylaminomethyl) -4-oxo-2- (4-propionylaminophenyl) thieno [2,3-b] ethyl ester hydrochloride Pyridine-5-carboxylic acid

To a mixture of Compound No. 5 produced in Working Example 49 (0.10 g, 0.159 mmol) and copper (I) iodide (0.095 g, 0.5 mmol) was added isobutylmagnesium bromide (0.5 mL, 1 mmol) under ice-cooling. To this mixture, anhydrous THF (20 mL) was added under ice-cooling, and the mixture was stirred for 1 h. The reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate, followed by distilling off the solvent under reduced pressure. The resulting brown oil (0.124 g) was dissolved in methylene chloride (5 mL) and dichlorodicyanquinone (0.0207 g, 0.091 mmol) was added. The mixture was stirred under ice-cooling for 2 h. The reaction mixture was partitioned between chloroform (50 mL) and water (30 mL). The aqueous layer was extracted with chloroform (50 mL). The organic layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure. A brown oil (0.02 g, 32% wt) was obtained. This oil was recrystallized from ethyl acetate-hexane. Dark brown crystals are obtained, mp 135-137 ° C. H, 4.91; N, 6.35. Found: C, 58.34; H, 5.01; N, 6.75. (300 MHz, CDCl ₃ , δ): 1.07 (6H, brs), 1.23 (3H, brs), 1.46 (3H, t, J = 6.3 Hz), 2.10 (1H, brs), 2.0 to 2.96 (7H, m), 4.30 to 4.53 (6H, m), 5.55 (2H, brs), 6.94 to 7.90 (12H, m) . IR (KBr): 3428, 2970, 2214, 1725, 1688, 1628, 1589, 1504, 1470, 1386, 1152, 1025, 789, 784 and 700 cm ^1st Mass Spectrum (FAB) m / z 686 (MH) ^&lt; ^{+ &gt;} .

-104GB 290723 B6

Working example 72

5-Cyano-1,7-dihydro-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -3-methyl-4-oxothieno [2,3-b] pyridine

A mixture of compound 6 prepared in Working Example 12 (0.435 g, 1.03 mmol) and phosphorus oxychloride (0.145 mL, 1.56 mmol) was refluxed for 1 h. After cooling, the reaction mixture was partitioned between chloroform and aqueous sodium bicarbonate. The aqueous layer was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was chromatographed on silica gel. Recrystallization from ethyl acetate-isopropyl ether gave pale yellow crystals (0.225 g, 70%), m.p. Mp 215-216 ° C.

Working example 73

5-Ethylsulfinylmethyl-4,7-dihydro-7- (2-fluorobenzyl) -2- (4-methoxyphenyl) -3 (N-methyl-N-benzylaminomethyl) -4-oxothieno [2,3-b] pyridine hydrochloride

To a solution of the compound produced in Working Example 71 (0.15 g, 0.26 mmol) in methylene chloride (4 mL) was added 1M HCl in ether (0.29 mL, 0.29 mmol) under ice-cooling, and the mixture was cooled Stir for 5 minutes. The mixture was concentrated under reduced pressure. A yellow amorphous solid is obtained. A solution of m-chloroperbenzoic acid (45 mg, 0.26 mmol) in methylene chloride (5 mL) was added dropwise over 10 minutes to an ice-cooled solution of this amorphous substance in methylene chloride (5 mL). After stirring at 0 ° C for 1.5 hours and stirring at room temperature for 1.5 hours, the reaction mixture was partitioned between chloroform and aqueous sodium bicarbonate. The aqueous layer was separated and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was chromatographed on silica gel. A light yellow syrup (60 mg, 38.9%) was obtained. To a solution of this material (50 mg, 0.085 mmol) in methylene chloride (4 mL), which was cooled with ice, was added a 1M solution of HCl in ether (0.13 mL, 0.13 mmol), and the mixture was stirred under ice cooling for 5 minutes. . The reaction mixture was concentrated under reduced pressure. The residue was recrystallized from ether. A yellow powder (37 mg, 53%) was obtained as the hydrochloride, m.p. Mp 216-219 ° C.

Working Example 74

6- (Aminophenyl) -2,4 (1H, 3H) -dioxo-1- (2,6-difluorobenzyl) -5- (N-methyl-N-benzylaminomethyl) -3-phenylthieno [2,3-d] pyrimidine

When Compound No. 17 produced in Working Example 40 was used as the starting material, essentially the same procedure as described in Working Example 60 above produced the title compound as a crystalline amorphous substance (65% yield). 1 H NMR spectrum (300 MHz, CDCl ₃ , δ): 2.05 (3H, s), 3.56 (2H, s), 3.81 (2H, brs), 3.88 (2H, s), 5.36 (2H, s), 6.71 (2H, d, J = 8.7 Hz), 6.91 (2H, t, J = 8.7 Hz), 7.21-7.53 (13H) , m).

-105GB 290723 B6

Working Example 75

If the compound produced in Working Example 60 is used as the starting material, the following compounds are produced in essentially the same manner as described in Working Example 61 above:

No 1: 2,4 (2H, 3H) -dioxo-1- (2-fluorobenzyl) -5- (N-methyl-N-benzylaminomethyl) 3-phenyl-6- (4-propionylaminophenyl) thieno hydrochloride [2, 3-d] pyrimidine (86% yield, mp 172-175 ° C),

No 2: 2,4 (2H, 3H) -dioxo-1- (2-fluorobenzyl) -6- (4-isobutyrylaminophenyl) -5- (N-methyl-N-benzylaminomethyl) -3-phenylthieno [2,3- d] pyrimidine (77% yield, mp 185-188 ° C);

No. 3: 2,4 (2H, 3H) -dioxo-1- (2-fluorobenzyl) -6- (4-methoxyacetylaminophenyl) -5- (N-methyl-N-benzylaminomethyl) -3-phenylthieno [2,3- d] pyrimidine (88% yield, mp 157-162 ° C).

Working example 76

When using the compound produced in Working Example 8 (100 mg), lactose (165 mg), corn starch (5 mg), polyvinyl alcohol (4 mg) and magnesium stearate (1 mg), a tablet is prepared in a conventional manner.

Working Example

The compound produced in Working Example 8 (5 g) was dissolved in distilled water for injection to give a total volume of 100 ml. This solution is sterile filtered through a 0.22 µm membrane filter (manufactured by Sumitomo Electric Industries, Ltd. or Zartolius, Inc), dispensed into sterilized vials of 2 ml, lyophilized by conventional means to give a lyophilized injectable solution containing 100 mg. compounds per vial.

Working Example

When compound 15 produced in Working Example 9 (100 mg), lactose (165 mg), corn starch (25 mg), polyvinyl alcohol (4 mg) and magnesium stearate (1 mg) were used, a tablet was prepared in a conventional manner.

Working example 79

Compound 15 produced in Working Example 9 (5 g) was dissolved in distilled water for injection to give a total volume of 100 ml. This solution is sterile filtered through a 0.22 µm membrane filter (manufactured by Sumitomo Electric Industries, Ltd. or Zartolius, Inc), dispensed into sterilized vials of 2 ml, lyophilized by conventional means to give a lyophilized injectable solution containing 100 mg. compounds per vial.

-106GB 290723 B6

Working example 80

When compound 3 produced in Working Example 21 (100 mg), lactose (165 mg), corn starch (25 ml), polyvinyl alcohol (4 mg) and magnesium stearate (1 mg) were used, a tablet was prepared in a conventional manner.

Working example 81

Compound 3 produced in Working Example 21 (5 g) was dissolved in distilled water for injection to give a total volume of 100 ml. This solution is sterile filtered through a 0.22 µm membrane filter (manufactured by Sumitomo Electric Industries, Ltd. or Zartolius, Inc), dispensed into sterilized vials of 2 ml, lyophilized by conventional means to give a lyophilized injectable solution containing 100 mg. compounds per vial.

Working example 82

When using the compound produced in Working Example 23 (100 mg), lactose (165 mg), corn starch (25 mg), polyvinyl alcohol (4 mg) and magnesium stearate (1 mg), a tablet is prepared in a conventional manner.

Working example 83

The compound produced in Working Example 23 (5 g) was dissolved in distilled water for injection to give a total volume of 100 ml. This solution is sterile filtered through a 0.22 µm membrane filter (manufactured by Sumitomo Electric Industries, Ltd. or Zartolius, Inc), dispensed into sterilized vials of 2 ml, lyophilized by conventional means to give a lyophilized injectable solution containing 100 mg. compounds per vial.

Working example 84

If the compound produced in Working Example 56 (100 mg), lactose (165 mg), corn starch (25 mg), polyvinyl alcohol (4 mg) and magnesium stearate (1 mg) were used, then a tablet was prepared in a conventional manner.

Working example 85

Dissolve the compound produced in Working Example 56 (5 g) in distilled water for injection to give a total volume of 100 ml. This solution is sterile filtered through a 0.22 µm membrane filter (manufactured by Sumitomo Electric Industries, Ltd. or Zartolius, Inc), dispensed into sterilized vials of 2 ml, lyophilized to give a lyophilized injectable preparation containing 100 mg of compound per ml. medicine bottle.

Working example 86

When compound 2 produced in Working Example 57 (100 mg), lactose (165 mg), corn starch (25 mg), polyvinyl alcohol (4 mg) and magnesium stearate (1 mg) were used, tablets were prepared conventionally.

- 107GB 290723 B6

Working example 87

Compound 2 produced in Working Example 57 (5 g) was dissolved in distilled water for injection to give a total volume of 100 ml. This solution is sterile filtered through a 0.22 µm membrane filter (manufactured by Sumitomo Electric Industries, Ltd. or Zartolius, Inc), dispensed into sterilized vials of 2 ml, lyophilized to give a lyophilized injectable preparation containing 100 mg of compound per ml. medicine bottle.

Working example 88

When compound 3 produced in Working Example 57 (100 mg), lactose (165 mg), corn starch (25 mg), polyvinyl alcohol (4 mg) and magnesium stearate (1 mg) were used, tablets were prepared conventionally.

Working example 89

Compound 3 produced in Working Example 57 (5 g) was dissolved in distilled water for injection to give a total volume of 100 ml. This solution is sterile filtered through a 0.22 µm membrane filter (manufactured by Sumitomo Electric Industries, Ltd. or Zartolius, Inc), dispensed into sterilized vials of 2 ml, lyophilized to give a lyophilized injectable preparation containing 100 mg of compound per ml. medicine bottle.

Working example 90

Compound 7 produced in Working Example 51 (5 g) was dissolved in distilled water for injection to give a total volume of 100 ml. This solution is sterile filtered through a 0.22 µm membrane filter (manufactured by Sumitomo Electric Industries, Ltd. or Zartolius, Inc), dispensed into sterilized vials of 2 ml, lyophilized to give a lyophilized injectable preparation containing 100 mg of compound per ml. medicine bottle.

Working example 91

Compound 8 produced in Working Example 51 (5 g) was dissolved in distilled water for injection to give a total volume of 100 ml. This solution is sterile filtered through a 0.22 µm membrane filter (manufactured by Sumitomo Electric Industries, Ltd. or Zartolius, Inc), dispensed into sterilized vials of 2 ml, lyophilized to give a lyophilized injectable preparation containing 100 mg of compound. for a medicine bottle.

Working example 92

1) the compound produced in Working Example 56 5g 2) lactose.Crystalline cellulose (granules) 330 g 3) D-mannitol 29 g 4) low-substituted hydroxypropylcellulose 20 g 5) talc 25 g 6) hydroxypropylcellulose 50 g 7) aspartame 3g 8) Potassium glycyrrhetinate 3g 9) hydroxypropyl methylcellulose 2910 30 g (10) titanium dioxide 3.5 g

-108GB 290723 B6

11) yellow iron oxide

(12) light orthosilicic anhydride

0.5 g g

Component 1, 3,4, 5, 7 and 8 are suspended or dissolved in purified water. The nuclear granules of component 2 are coated with a suspension or solution. Crude fine granules are prepared and coated with components 9 to 11. Coated fine granules are prepared and blended with component 12. 500 g of fine granules containing 1% by weight are obtained. of the compound produced in Working Example 56. 500 mg of the fine granules thus produced are packaged.

Test Example 1

Preparation of ¹²⁵ I-leuprorelin

Ten μΐ 3.10 ^-4 M aqueous solution of leuprorelin and 10 μΐ 0.01 mg / ml lactoperoxidase in 0 M HEPES buffer (pH 7.4) was loaded into a tube to which was added 10 μΐ [37 MBq solution ^{L2 :,} I in 0.1 M HEPES buffer (pH 7.4). Stir the mixture, add 10 μΐ 0.001% hydrogen peroxide and allow the reaction to proceed at room temperature for 20 minutes. Add 700 μΐ of a 0.05% (w / w) TFA solution to the reaction mixture to stop the reaction. The product was purified by reverse phase HPLC. The HPLC conditions are as follows. ¹²⁵ I-Leuprorelin elutes with a retention time of 26 to 27 minutes. Column: TSK gel ODS-80 ™ CTR (4.6 mm by 10 cm), eluent: solvent A (0.05% w / w TFA), solvent B (40% w / w) acetonitrile - 0.05% ( at 0 minutes: 100% solvent A, at 3 minutes: 100% solvent B, at 40 minutes: 100% solvent B, elution temperature: room temperature, flow: 1 ml / min.

Test Example 2

Preparation of the membrane fraction of rat anterior pituitary lobes containing GnRH receptors of Wister rats (8 weeks old, male) was killed. Pituitary anterior lobes were collected, washed with ice-cold homogenate buffer (25 mM Tris (tris (hydroxymethyl) aminomethane) HCl, 0.3 M sucrose, 1 mM EGTA (glycol etherdiamine tetraacetate), 0.25 mM PMSF (phenylmethylsulfonyl chloride), 10 µl / ml aprotinin, 1 µg / ml pepstatin, 20 µg / ml leupeptin, 100 µg / ml phosphoramidone and 0.03% sodium azide, pH 7.5). The pituitary gland suspended in 2 ml of homogenate buffer is homogenized with a Polytron homogenizer. Separation by centrifugation is carried out at 700 x g for 15 minutes. The supernatant is placed in an ultra-centrifuge tube and centrifuged at 100,000 x g for 1 h. A membrane fraction is obtained as a precipitate. This precipitate was suspended in 2 ml assay buffer (25 mM Tris-HCl, 1 mM EDTA (ethylenediaminetetraacetate), 0.1% (w / w) BSA (bovine serum albumin), 0.25 mM PMSF, 1 µg / ml pepstatin 20). pg / ml leupeptin, 100 pg / ml phosphoramidone, 0.03% (w / w) sodium azide, pH 7.5), then collected by centrifugation for 1 h at 100,000 x g. ml of assay buffer, dispensed into vials and stored at -80 ° C until use.

Test Example 3

Preparation of membrane fraction of CHO (Chinese hamster ovary) cells containing human GnRH receptors

CHO cells (10 ⁹ ) expressing human GnRH receptors were suspended in phosphate buffered saline supplemented with 5 mM EDTA (PBS-EDTA). The suspension is separated by centrifugation for 5 minutes at 100 x g. 10 ml of homogenate cell buffer (10 mM NaHCO ₃ , 5 mM EDTA, pH 7.5) is added to the cell pellet and the mixture is homogenized with a homogenizer.

-109GB 290723 B6

Polytron. Separation by centrifugation is carried out for 15 minutes at 400 x g. The supernatant is transferred to an ultra-centrifuge tube which is centrifuged for 1 hour at 100,000 x g. A precipitate of the membrane fraction was obtained. The precipitate is suspended in 2 ml assay buffer and the mixture centrifuged at 100,000 x g for 1 h. The membrane fraction isolated as a precipitate is resuspended in 20 ml assay buffer, the product is vialed and stored at -80 ° C until use.

Test Example 4

Determination of ¹²³ I-Leuprorelin Binding Inhibition

Membrane fractions of rat pituitary and CHO cells expressing human GnRH receptors prepared in Test Examples 2 and 3 are diluted with assay buffer to a concentration of 200 µg / ml and dispensed into tubes of 180 μΐ. When using the membrane fraction from the anterior pituitary front lobes, 2 μΐ 0.1 mM compound dissolved in 60% (w / w) DMSO (dimethylsulfoxide) and 10 μΐ 38 nM ¹²⁵ I-leuprorelin are added simultaneously. In the case where using membrane fraction of CHO cells expressing human GnRH receptors are added simultaneously 2 μΐ 2mM of the compound dissolved in 60% (wt.) Of DMSO (dimethyl sulfoxide) and 10 μΐ 38 nM ¹² 'I-leuprorelin. To determine the amount of maximum binding, prepare a reaction solution supplemented with 2 μΐ 60% (w / w) DMSO and 10 μΐ 38nM ^12: I-leuprorelin. A reaction solution supplemented with 2 μΐ 100μ reakci leuprorelin dissolved in 60% (w / w) DMSO and 10 μΐ 38nM ¹²⁵ I-leuprorelin is also prepared to determine the amount of non-specific binding.

When using the rat pituitary anterior membrane lobe fraction, the reaction is allowed to proceed for 90 minutes at 4 ° C, whereas when using a CHO cell membrane fraction expressing human GnRH receptors, the reaction is allowed to proceed for 60 minutes at 25 ° C . The reaction mixtures are optionally filtered by suction through a Whatman (GF-F) glass filter treated with polyethyleneimine. After filtration is complete, the radioactivity of ¹²⁵ I-leuprorelin remaining on the filter paper is measured by a γ-counter.

By calculating according to equation (TS-SB) / (TB-NSB) .100 (SB means radioactivity obtained when compound is added, TB means maximum binding radioactivity, NSB means non-specific binding activity), inhibition of binding (5) of each test compound is determined. In addition, inhibition is determined by varying the concentrations of test compounds. The 50% inhibiting test compound (TB-NSB) concentration (IC 50 value) was calculated by the Hill method. The results are shown in Table 32.

Table 32

Inhibition of ^l25 I-leuprorelin binding Inhibition IC50 binding value (%) (μΜ)

test compound rat (ΙμΜ) human (20 μΜ) rat human compound from work. Ex 67 13 compound from work. Ex 9 46 112 1 0.08 (Compound No. 14) compound from work. Ex 9 38 114 1.9 0.08 (Compound No. 15) compound from work. Ex 21 35 106 2 0.03 (Compound # 3) compound from work. Ex 23 107 0.01

-110GB 290723 B6

Test Example 5

Inhibition of LH / FSH secretion by primary cultured anterior lobe cells of rat hypohysis

The anterior pituitary lobes of 40 Wistar rats (8 weeks old, male) are placed in a petri dish containing buffer A (0.7 mM sodium dihydrogen phosphate, 137 mM sodium chloride, 5 mM potassium chloride, 25 mM HEPES, 50 µg ml gentamicin sulfate) and washed once with buffer. A, Then the front lobes are divided into four parts which are washed twice. A portion of the rat frontal lobes thus washed are placed in a conical flask closed with a stopper containing enzyme solution I (buffer A containing 0.4% by weight of collagenase, 0.4% by weight of BSA (bovine serum albumin), 10µg / ml deoxyribonuclease and 0.2 This mixture was incubated for 1 h at 37 ° C with shaking, after aspiration and pipetting, the tissue fragments were repeatedly dispersed and transferred to a centrifuge tube, which was then centrifuged for 6 minutes to remove the supernatant. enzyme solution II (enzyme solution A containing 10% by weight of pancreatin) was added and the mixture was incubated for 8 minutes at 37 [deg.] C. 2 ml of FCS (fetal calf serum) were added to the mixture and centrifuged again at 480 x g for 6 minutes. The supernatant is discarded and the residue is suspended in 10 ml of culture medium I (Dulbecco's modified Eagle's medium, i.e. DMEM, containing 10% FCS, 20 mM HEPES, 50 µl / ml penicillin G, 50 µg / ml streptomycin and 3.7 µl). g / 1 hydro The material collected during filtration is washed twice with 10 ml portions of culture medium I, followed by the addition of the cells to be suspended in culture medium I to a cell density of 5.10 &lt; 6 &gt; cells / ml. The cell suspension was distributed to each well of a 24-well plate of 1 ml, incubated for 3 days in a CO ₂ incubator at 37 ° C in an atmosphere of 5 wt. % CO ₂ - 95 wt. air. 2 ml of culture medium II (culture medium I without 10% FCS) is added, followed by incubation for 1 h. The culture medium is discarded. To each well of a 24-well plate add 800 μΐ of fresh culture medium II, then simultaneously add a 20μΜ solution (100 μΐ) of compound 15 produced in Working Example 9 dissolved in 0.2% (v / v) dimethylsulfoxide and 100 μΐ 5nM GnRH. Culture without compound is used as a control. After a 3 h incubation at 37 ° C, 500 μΐ of culture supernatant is collected and centrifuged at 1000 x g for 10 minutes to give a supernatant. The concentrations of LH and FSH in the supernatant were determined by radioimmunoassay (Amersham Inc).

By calculation according to the formula: 100- (LH or FSH concentration in the presence of compound) / (LH or FSH control culture concentration). 100, inhibition (%) of LH or FSH secretion for each compound is determined. Compound 15 inhibited LH secretion by 28 ± 9.0% (p <0.01, n = 3) and FSH secretion by 20 ± 10% (p <0.01, n = 3).

From the foregoing results, it can be seen that compound 15 produced in Working Example 9 has GnRH antagonist activity.

Test Example 6

Suppression of testosterone concentration in rat plasma

Compound 15 produced in Working Example 9 was dissolved in Diluent I (20 wt% propylene glycol with 80 wt% physiological saline). The solution was administered once subcutaneously to male SD rats (8 weeks of age, n = 5). The dose was 30 mg per kg body weight. Animals treated with the diluent alone are used as controls. Blood is taken from the jugular vein under anesthesia with ether 24 hours after administration. Ethylenediaminetetraacetate (EDTA) was immediately added to the blood to a final concentration of 3 mg / ml and aprotinin to a final concentration of 300,000 U / ml. The mixture is centrifuged for 15 minutes at 3000 x g. The plasma testosterone concentration is measured by radioimmunoassay.

-111 CZ 290723 B6

Testosterone suppression (%) by the test compound is determined according to the formula: 100- (testosterone plasma concentration in the test group) / (testosterone plasma concentration in the control group). 100 ALIGN!

Compound 15 produced in Working Example 9 showed a suppression of 38 ± 9.7% (p <0.05).

Test Example 7

Suppression of testosterone concentration in mouse plasma

The compound produced in Working Example 56 was dissolved in Diluent II (0.5 wt% methylcellulose dissolved in distilled water). This solution is administered orally once daily for 3 consecutive days to male ICR mice (10 weeks of age, n = 12). The dose was 30 mg per kg body weight. ICR mice treated with diluent alone (n = 15) were used as controls. Blood is taken from the jugular vein under anesthesia with ether 24 h after administration. Ethylenediamine tetraacetate (EDTA) was immediately added to the blood to a final concentration of 3 mg / ml and aprotinin to a final concentration of 300,000 U / ml. The mixture is centrifuged for 15 minutes at 3000 x g. The plasma testosterone concentration is measured by radioimmunoassay.

Testosterone suppression (%) by the test compound is determined according to the formula: 100- (testosterone plasma concentration in the test group) / (testosterone plasma concentration in the control group). 100 ALIGN!

The compound produced in Working Example 56 showed a suppression of 85 ± 9.7% (p <0.05).

The gonadotropin releasing hormone antagonist of the present invention is effective as a prophylactic or therapeutic agent for the prevention or treatment of several hormone-dependent diseases, for example sex hormone-dependent cancers (e.g., prostate cancer, pituitary adenoma, cervical cancer, breast cancer), hypertrophy prostate, uterine fibroid, endometriosis, premature puberty, amenorrhea syndrome, polycystic ovary syndrome and acne vulgaris, or as a birth control agent (eg, contraceptive), infertility treatment agent and menstruation control agent. Furthermore, in the field of agricultural animals, the GnRH antagonist of the present invention is effective as an estrous cycle regulating agent in animals, improving the quality of edible meat, to control animal growth, and also a spawning accelerator in fisheries.

Industrial Applicability: The GnRH antagonist composition of the present invention is effective as a prophylactic or therapeutic agent for the prevention or treatment of several hormone-dependent diseases, for example sex hormone-dependent cancers (e.g., prostate cancer, cervical cancer, breast cancer, pituitary adenoma), benign hypertrophy of the prostate, uterine fibroid, endometriosis, premature puberty, amenorrhea, premenstrual syndrome, polycystic ovary syndrome, and acne vulgaris; it is effective as an agent to control conception in both sexes (eg fertilization control and menstrual cycle control agent); it can be used as a contraceptive for both sexes, as an ovulation inducing agent in females, as an infertility treatment agent by using a feedback effect after stopping its administration; is useful as an estrogen cycle regulator in livestock, an edible meat quality enhancer or an animal growth regulating agent; is useful as a spawning agent in fisheries.

Claims (25)

PATENT CLAIMS A fused bicyclic thiophene derivative of the general formula I wherein: - R ¹¹ is hydrogen, C 1-4 alkyl, a group of formula Q- (CH 2) _p -, wherein p is 1 or 2 and Q is C 6-18 aryl, optionally substituted a) halogen, (b) nitro; (c) cyano; d) amino, e) carboxy, optionally substituted (1) C ^ alkyl, (2) C ₃ _6cykloalkylem, (3) C-uarylem, (4) C-uaryl-C ^ alkyl, (5) 5-membered cyclic group selected from the group consisting of 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or 5- (1,2,4-thiadiazolyl), 1, 3,4-thiadiazolyl, 4- or 5- (1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl and 1H- or 2H- (6) a 6-membered cyclic group selected from the group consisting of N-oxido-2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxido-2-, 4- or 5-pyrimidinyl, 2- or 3-thiomorpholinyl, 2- or 3-morpholinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, 2- or 3-piperazinyl , triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl and N-oxido-3- or 4-pyridazinyl, or (7) a 5-8 membered cyclic group or a fused ring thereof selected from benzofuryl benzothiazolyl, benzoxazolyl, tetrazolo [ 1,5-b] pyridazine yl, triazolo [4,5-b] pyridazinyl, benzoimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indosinyl, quinolizinyl, 1,8-naphthylisinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acryazinyl, phenanthinyl, phenanthinyl, phenanthinyl, phenanthinyl, phenanthinyl, phenanthinyl, phenothiazinyl and phenoxazinyl, f) C 1-6 alkylenedioxy; g) a group of the formula -AR ¹⁵ wherein A is a) chemical bond, b) _C2-alkylene, -113GB 290723 B6 (c) C 1-6 alkenylene, d) a group of the formula - (C 1 -C 6) NR ²⁴ in which c is 0 to 3 and R ²⁴ is hydrogen or C 1-6 alkyl, e) a group of the formula -CO-, f) a group of the formula -CONR ²² wherein R ²² is (1) hydrogen, (2) C ^ alkyl, (3) C-cycloalkyl, (4) ₄ C6_i aryl, (5) a 5-membered cyclic group selected from the group consisting of 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl , 3-, 4- or 5-pyrazolyl, 2-, 4-, or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or 5- (1,2, 4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or 5- (1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl and 1H- or 2H-tetrazolyl, (6) a 6-membered cyclic group selected from the group consisting of N-oxido-2- 3- or 4- pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxido-2-, 4- or 5-pyrimidinyl, 2- or 3-thiomorpholinyl, 2- or 3-morpholinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, 2- or 3-piperazinyl, triazinyl, oxotriazinyl, 3-or 4-pyridazinyl, pyrazinyl and N-oxido-3- or 4-pyridazinyl, (7) a 5-8 membered cyclic group or a fused ring thereof selected from benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzoimidazolyl, quinolyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8-naphthylisinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl and phenoxazinyl, or (8) a -SO _P - group in which p is 1 or 2, (g) 'θ ^- , h) - S- or (i) a group of the formula NR ²² S (O) _e - in which e is 0 to 2 and R ²² is as above; R ' ⁵ is C 1-6 alkyl, - R ¹² is i) hydrogen, ii) C ^ alkyl, iii) C ₆ -i4aryl, optionally substituted, iv) C / uaryl-C ^ alkyl, optionally substituted, or v) C3_i4cykloalkyl or C ₃ _ ₁₀ bicycloalkyl, optionally substituted , - R is a group of the formula -NR R, wherein R is (1) C] _ ₆ alkyl, optionally substituted, (2) C ₃ _ ₆ cycloalkyl, optionally substituted, (3) co-uaryl, optionally substituted, (4 ) optionally substituted 5-membered cyclic group selected from 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl 2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or 5- (1 (2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or 5- (1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl and 1H- or 2H-tetrazolyl, (5) an optionally substituted 6-membered cyclic group selected from the group consisting of N-oxido-2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxido-2-, 4- or 5-pyrimidinyl, 2- or 3-thiomorpholinyl, 2- or 3-morpholinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, 2- or 3-piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl and N-oxido-3- or 4 -pyridazinyl, or (6) an optionally substituted 5- to 8-membered cyclic group or a fused ring thereof selected from benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzoimidazolyl , quinolyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8-naphthylisinyl, purinyl, pteridinyl, - 114C 290723 B6 dibenzofuranyl, carbazolyl, acrydinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl and phenoxazinyl, and R ²³ , is hydrogen or optionally substituted C 1-4 alkyl, - R is optionally substituted ^with CE-aryl, wherein the substituents for the above Cj_6alkyl C ₃ i ₀ cycloalkyl, C ₃ _i ₀ bicycloalkyl, C ^ uaryl, -i4aryl _C6-C ^ alkyl, 5-membered cyclic group membered cyclic group and the 5-8 membered cyclic group or fused ring thereof are individually 1 to 6 substituents selected from the group consisting of a) C6- | ₄ aryl, optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, amino, mono- or di-C 1-6 alkylamino, C 1-6 alkoxy and halogen, b) a mono- or di-C 1-6 alkylamino group, c) C 1-6 acylamino, (d) hydroxyl; e) carboxyl, (f) nitro; g) C 1-6 alkoxy, h) C _M alkyl Ikarbonyloxyl, (i) halogen; and j) a group of the formula -NR ²² R ²³ wherein R ²² is (1) hydrogen, (2) C ₆ alkyl, (3) C ₃ _6cykloalkyl, (4) C ₆ _i4aryl, (5) a 5-membered cyclic group selected from file including 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or 5- (1,2, 4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or 5- (1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl and ΙΗ- or 2H-tetrazolyl, (6) a 6-membered cyclic group selected from the group consisting of N-oxido-2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxido-2-, 4- or 5-pyrimidinyl, 2- or 3-thiomorpholinyl, 2- or 3-morpholinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, 2- or 3-piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl and N-oxido-3- or 4-pyridazinyl, (7) a 5-8 membered cyclic group or a fused ring thereof selected from benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzoimidazolyl, quinolyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8-naphthylisinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acrydinyl, phenthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl and phenoxazinyl, or (8) a -SO _P - group wherein p is 1 or 2, and R ²³ is is hydrogen or Ci_6alkyl, wherein a group of the formula -NR ²² R ²³ is optionally substituted with 1-6 substituents selected from the group consisting of (1 ') C ^ alkyl), (2) C ₂ _6alkenyl, (3) C ₂ _ ₆ alkynyl , (4) C ^ cycloalkyl, (5) C ₅ _ ₇ cycloalkenyl, (6) C ₇ _naralkyl, (7 ') C6_i ₄ aryl, (8) C ^ alkoxy, (9') C6_i ₄ aryloxy (10 ') C 1-6 alkanoyl, (1') C 1-6 arylcarbonyl, (12 ') C _1-8 alkanoyloxy, (13') C 1-6 arylcarbonyloxy, (14 ') carboxyl, (15') C 1-6 alkoxycarbonyl, (16 ') carbamoyl, (17 ') N-mono-C 1-4 alkylcarbamoyl, (18') N, N-di-C 1-4 alkylcarbamoyl, (19 ') cyclic aminocarbonyl selected from the group consisting of 1-aziridinylcarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl and morpholinocarbonyl, (20 ') halogen, (21') mono- to trihalo-C 1-6 alkyl, (22 ') oxo, (23') amidino, (24 ') imino (25 ') amino, (26') mono- or di-C 1-6 alkylamino, - 115GB 290723 B6 (27 ') a 3 to 6-membered cyclic amino group containing, in addition to a carbon atom and one nitrogen atom, 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, (28') C 1-4 alkanoylamino, (29 ') benzamido, (30 ') carbamoylamino, (31') N-C 1-4 alkylcarbamoylamino, (32 ') N N-di-C 1-4 alkylcarbamoylamino, (33') C _1-3 alkylenedioxy, (34 ') -B (OH) ₂ , (35') ) hydroxyl, (36 ') epoxy, (37') nitro, (38 ') cyano, (39') mercapto, (40 ') sulfo, (4Γ) sulfino, (42') phosphono, (43 ') sulfamoyl, (44 ') C 1-6 alkylsulfamoyl, (45') di-C _1-6 alkylsulfamoyl, (46 ') C 1-6 alkylthio, (47') phenylthio, (48 ') C 1-6 alkylsulfinyl, (49') phenylsulfinyl, ( 50 ') C 1-6 alkylsulfonyl and (51') phenylsulfonyl, ar is 0 to 3, or salts thereof. 2. A compound according to claim 1 of the formula I wherein R ¹¹ is a group of the formula Q- (CH2) p-, wherein p is 1 or 2 and Q is C ₄ _i ₆ aryl, optionally substituted a) halogen, (b) nitro, (c) cyano, d) amino, e) carboxyl, optionally substituted with (1) C 1-4 alkyl, (2) C 1-4 cycloalkyl, (3) C 1-4 aryl, (4) C 1-4 aryl-C 1-4 alkyl, (5) a 5-membered cyclic group selected from 2; - or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or 5- (1,2,4-thiadiazolyl), 1, 3,4-thiadiazolyl, 4- or 5- (1,2,3-thiadiazolyl), 1,25-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl and 1H- or 2H-tetrazolyl, (6) a 6-membered cyclic group selected from the group including N-oxido-2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxido-2-, 4- or 5-pyrimidinyl, 2- or 3-thiomorpholinyl, 2- or 3 -morpholinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, 2- or 3-piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl , pyrazinyl and N-oxido-3- or 4-pyridazinyl, or (7) a 5-8 membered cyclic group or a fused ring thereof selected from benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [ 4,5bjpyridazinyl, benzoimidazolyl, quinolyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8-naphthylisinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acrydinyl, phenathridinyl, chroma nyl, benzoxazinyl, phenazinyl, phenothiazinyl and phenoxazinyl, f) C 1-6 alkylenedioxy; g) a group of the formula -AR ¹⁵ wherein A is a) chemical bond, b) C 1-4 alkylene, c) C2-6 alkenylene, d) a group of the formula - (CH ₂ ) _c NR ²⁴ wherein c is 0 to 3 and R ²⁴ is hydrogen or C 1-4 alkyl, -116GB 290723 B6 e) -CO- group, f) a group of the formula -CONR ²² , wherein R ²² is (1) hydrogen, (2) C ₁₆ alkyl, (3) C 6 -cycloalkyl, (4) C 6 -aryl, (5) a 5-membered cyclic group selected from the group consisting of 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl , 3-, 4- or 5-pyrazolyl, 2-, 4-, or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or 5- (1,2, 4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or 5- (1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl and ΙΗ- or 2H-tetrazolyl, (6) a 6-membered cyclic group selected from the group consisting of N-oxido-2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxido-2-, 4- or 5-pyrimidinyl, 2- or 3-thiomorpholinyl, 2- or 3-morpholinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, 2- or 3-piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl and N-oxido-3- or 4-pyridazinyl, (7) a 5-8 membered cyclic group or a fused ring thereof selected from benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzoimidazolyl, quinolyl, isoquinolinyl, quinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8-naphthylisinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acrydinyl, phenthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl and phenoxazinyl, or (8) a -SO _P - group wherein p is 1 to 2 g) -o- h) - S- or i) a group of the formula -NR ²² S (O) e, wherein e is 0 to 2, R ²² is as defined above, R ¹⁵ is C 1-6 alkyl, and the other substituents are as in claim 1. A compound according to claim 1, wherein Q in R ¹¹ is C 1-4 aryl optionally substituted by halogen, and the other substituents are as in claim 1. 4. A compound according to claim 1 of the formula I wherein R ¹³ is a mono-C6-i4aryl Ci_6alkylaminoskupina optionally substituted with 1-5 substituents selected from the group consisting of a) C 6-14 aryl, optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, amino, mono- or C 1-6 alkylamino, C 1-6 alkoxy and halogen, b) a mono- or di-C 1-6 alkylamino group, c) C 1-4 acylamino, (d) hydroxyl; e) carboxyl, (f) nitro; g) C 1-6 alkoxy, h) C 1-4 alkylcarbonyloxy, (i) halogen; and j) a group of the formula -NR ²² R ²³ wherein R ²² is (1) hydrogen, (2) Ci_6alkyl, (3) C ₃ _ ₆ cycloalkyl, (4) C ₆ _i4aryl, 5-membered cyclic group selected from the group consisting of 2 - or 3-thienyl, -117GB 290723 B6 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 2- or 5- (1,2,4-thiadiazolyl), 1,3,4 -thiadiazolyl, 4- or 5- (1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl and 1H or 2H-tetrazolyl, (6) a 6-membered cyclic group selected from the group consisting of N-oxido-2,3-or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxido -2-, 4- or 5-pyrimidinyl, 2- or 3-thiomorpholinyl, 2- or 3-morpholinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, 2- or 3-piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl and N-oxido-3 or 4-pyridazinyl, (7) a 5-8 membered cyclic group or a fused ring thereof, selected from benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzoimidazolyl, quinolyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8-naphthylisinyl, purinyl, pteridinyl, dibenzofuranyl carbazolyl, acrydinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl and phenoxazinyl, or (8) a group of the formula -SO _P - wherein p is 1-2 and R ² 'is hydrogen or C 1-6 alkyl, wherein the group of the formula -R ²² R ²³ is optionally substituted with 1 to 6 substituents selected from the group consisting of jícího (1 ') C-alkyl, (2) C ₂ _6alkenyl, (3') C ^ alkynyl, (4 ') C écykloalkyl, (5) C ₅ _ ₇ cycloalkenyl, (6) C ₇ _ _N aralkyl, (7) C ₆ _ ₁₄ aryl, (8) C ^ alkoxy, (9 ') C6_i4aryloxyl, (10) C] _ ₆ alkanoyl, (11') a C6-i4arylkarbonyl, (12 ') Ci_6alkanoyloxyl (13 ') C 6-14 arylcarbonyloxy, (14') carboxyl, (15 ') C _1-6 alkoxycarbonyl, (16') carbamoyl, (17 ') N-mono-C 1-4 alkylcarbamoyl, (18') N, N-di _{C] Jt} alkylcarbamoyl, (19 ') a cyclic aminocarbonyl selected from the group consisting of 1-aziridinylcarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl and morpholinocarbonyl, (20 ') halogen, (2') mono- to trihalo-C 1-6 alkyl, (22 ') oxo, (23') amidino, (24 ') imino, (25') (26 ') mono- or di-C 1-6 amino; ₄ alkylamino, (27 ') a 3 to 6-membered cyclic amino group containing, in addition to a carbon atom and one nitrogen atom, 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, (28') C _1-6 alkanoylamino, (29 ') benzamido, (30 ') carbamoylamino, (3') N-C 1-4 alkylcarbamoylamino, (32 ') N, N-di-C 1-4 alkylcarbamoylamino, (33') C _1-3 alkylenedioxy, (34 ') -B (OH) ₂ , (35 ') hydroxyl, (36') epoxy, (37 ') nitro, (38') cyano, (39 ') mercapto, (40') sulfo, (4Γ) sulfo, (42 ') phosphono, (43') ') sulfamoyl, (44') C _1-6 alkylsulfamoyl, (45 ') di-C _1-6 alkylsulfamoyl, (46') C 1-6 alkylthio, (47 ') phenylthio, (48') C | ₆ alkylsulfinyl, (49 ') phenylsulfinyl, (50') C _1-6 alkylsulfonyl and (51 ') phenylsulfonyl, and the other substituents are as in claim 1. 5. A compound according to claim 1, wherein R &lt; ¹³ &gt; is benzylamino optionally substituted with 1 to 6 substituents selected from the group consisting of a) C 6-14 aryl which is optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, amino, mono- or C 1 -C 6 alkylamino, C 1-4 alkoxy and halogen, b) a mono- or di-C 1-6 alkylamino group, c) C 1-4 acylamino, (d) hydroxyl; e) carboxyl, (f) nitro; (g) C 1-6 alkoxy, -118GB 290723 B6 h) C 1-6 alkylcarbonyloxy, (i) halogen; and j) a group of the formula -NR ²² R ²³ wherein R ²² is (1) hydrogen, (2) C ^ alkyl, (3) C ₃ _6cykloalkyl, (4) a C _ ₁₄ aryl, (5) a 5-membered cyclic group selected from a file comprising 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 2- or 5- (1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or 5 - (1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl and 1H or 2H-tetrazolyl, (6) a 6-membered cyclic group selected from the group consisting of: including N-oxido-2, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxido-2-, 4- or 5-pyrimidinyl, 2- or 3-thiomorpholinyl, 2- or 3- morpholinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, 2- or 3-piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, (7) a 5-8 membered cyclic group, or a fused ring thereof, selected from benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4, 5-b] pyridazines 1, benzoimidazolyl, quinolyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8-naphthylisinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acrydinyl, phenanthridinyl, chromanyl, benzoxazinyl, chromanyl, benzoxazinyl, chromoxyl, benzoxazinyl, chromanyl, benzoxazinyl, 8) a group of formula -SO 2 -, wherein p is 1 or 2, and R ²³ is hydrogen or C 1-6 alkyl, wherein the group of formula -R ²² R ²³ is optionally substituted with 1 to 6 substituents selected from (1 ') ) C ^ alkyl, (2) C-alkenyl, (3) C-alkynyl, (4) C ₃ _6cykloalkyl, (5) C ₅ _ ₇ cycloalkenyl, (6) C ₇ _naralkyl (7 ' ) -i ₄ C ₆ aryl, (8 ') C ^ alkoxy, (9') ₄ C6_i aryloxy, (10 ') Ci_6alkanoyl, (11') C6_i ₄ arylcarbonyl, (12) C ^ alkanoyloxy, (13 ') C6_i ₄ arylkarbonyloxyl, (14 ') carboxy, (15') Ci_6alkoxykarbonyl (16 ') carbamoyl, (17') _{N-mono-C] 4} alkylcarbamoyl, (18 '), Ν, Ν-di-C ^ alkylcarbamoyl, ( 19 ') cyclic aminocarbonyl selected from the group consisting of 1-aziridinylcarbonyl, 1-azet idinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl and morpholinocarbonyl, (20 ') halogen, (2') mono- to trihalo-C 1-6 alkyl, (22 ') oxo, (23') amidino, (24 ') imino, (25 ') amino, (26') mono- or di-C 1-6 alkylamino, (27 ') 3- to 6-membered cyclic amino having 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, (28 ') C 1-4 alkanoylamino, (29') benzamido, (30 ') carbamoylamino, (31') NC | ₄ alkylkarbamoylaminoskupina, (32 ') of N, N-di-C | ₄ alkylkarbamoylaminoskupina, (33) C ₁ _ ₃ alkylenedioxy, (34 ") -B (OH) _2, (35 ') hydroxy, (36") epoxy, (37') nitro, (38 ') cyano, (39 ') mercapto, (40') sulfo, (41 ') sulfino, (42') phosphono, (43 ') sulfamoyl, (44') C 1-6 alkylsulfamoyl, (45 ') di-C 1-6 alkylsulfamoyl, (46') C 1-6 alkylthio, (47 ') phenylthio, (48') C 1-6 alkylsulfinyl, (49 ') phenylsulfinyl, (50') C 1-4 alkylsulfonyl and (51 ') phenylsulfonyl, and the other substituents are as in claim 1. 6. A compound according to claim 1 of the formula I wherein R ¹⁴ is phenyl optionally substituted with 1-6 substituents selected from the group consisting of a) C _1-4 aryl which is optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, amino, mono- or C _1-6 alkylamino, C 1-6 alkoxy and halogen, b) a mono- or di-C 1-6 alkylamino group, c) C1-4 acylamino, (d) hydroxyl; -119GB 290723 B6 e) carboxyl, (f) nitro; (g) C1-6alkoxy, h) C _1-6 alkylcarbonyloxy, (i) halogen; and j) a group of the formula -NR ²² R ²³ wherein R ²² is (1) hydrogen, (2) C] _6alkyl, (3) C ₃ _6cykloalkyl, (4) -CO-aryl and _4, (5) a 5-membered cyclic group selected from 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 2- or 5- (1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or 5- (1,2 (3) thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl and 1H or 2H-tetrazolyl; (6) a 6-membered cyclic group selected from the group consisting of N-oxido- 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxido-2-, 4- or 5-pyrimidinyl, 2- or 3-thiomorpholinyl, 2- or 3-morpholinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, 2- or 3-piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl and N-oxido-3- or 4-pyridazinyl, (7) 5-8 membered cyclic or a fused ring group selected from benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzoimidazolyl, quinolyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8-naphthylisinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acrydinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl and phenoxazinyl, or (8) a group of the formula -SO 2 - wherein p is 1 or 2 and R ²³ is hydrogen or Ci_6alkyl, wherein the group of formula -R ²² R @ ³ is optionally substituted with 1-6 substituents selected from the group consisting of (Γ) Ci_6alkyl, (2) C ₂ _6alkenyl, (3 ') C ₂ _6alkinyl , (4) C ₃ _6cykloalkyl, (5) C ₅ _ ₇ cycloalkenyl, (6 ') C7_naralkyl, (7') C6_i ₄ aryl, (8 ') C | _ ₆ alkoxy, (9 ') C ₆ aryloxy _i _4, (10) C | ₆ alkanoyl, (11 ') C 1-4 ₄ arylcarbonyl, (12 ') C _1-6 alkanoyloxy, (13') C 6-18 arylcarbonyloxy, (14 ') carboxyl, (15') C _1-6 alkoxycarbonyl, (16 ') carbamoyl, (17') N-mono-C _1-4 alkylcarbamoyl, ( 18 ') N, N-di-C 1-6 alkylcarbamoyl, (19') cyclic aminocarbonyl selected from the group consisting of 1-aziridinylcarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl and morpholinocarbonyl, (20 ') halogen, (2Γ) mono- to trihalo-C 1-4 alkyl, (22 ') oxo, (23') amidino, (24 ') imino, (25') amino, (26 ') mono- or di-C 1-4 alkylamino, ( 27 ') a 3 to 6 membered cyclic amino group containing, in addition to a carbon and one nitrogen atom, 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, (28') C _1-6 alkanoylamino, (29 ') benzamido, (30') carbamoylamino, (3 ') N-C 1-4 alkylcarbamoylamino, (32') N, N-di-C 1-4 alkylcarbamoylamino, (33 ') C 1-4 alkylenedioxy, (34') -B (OH) ₂ , (35 ') hydroxyl, (36 ') epoxys (37 ') nitro, (38') cyano, (39 ') mercapto, (40') sulfo, (4Γ) sulfino, (42 ') phosphono, (43') sulfamoyl, (44 ') C 1-6 alkylsulfamoyl, ( 45 ') di-C 1-6 alkylsulfamoyl, (46') C 1-6 alkylthio, (47 ') phenylthio, (48') C 1-6 alkylsulfinyl, (49 ') phenylsulfonyl, (50') C 1-6 alkylsulfonyl and (51 ') phenylsulfonyl, and other substituents are as in claim 1. 7. Compounds according to claim 1 of the formula I wherein R ¹² is i) C ₆ alkyl, ii) aryl C6_i ₄ iii) ₄ C6_i aryl-Ci_6alkyl or C iv) ₃ _ ₁₀ cycloalkyl or C ₃ _iobicykloalkyl, wherein the substituents ii) to iv) are optionally substituted with 1 to 6 substituents selected from the group consisting of a) ₄ C6_i aryl, optionally substituted with 1-4 substituents selected from the group consisting of hydroxyl, amino, mono- or di-C $ alkylamino Ci_6alkoxyl and halogen, - 120GB 290723 B6 b) a mono- or di-C 1-6 alkylamino group, c) C 1-4 acylamino, (d) hydroxyl; e) carboxyl, (f) nitro; (g) C 6-6 alkoxy, h) C 1-6 alkylcarbonyloxy, (i) halogen; and j) a group of the formula -NR ²² R ²³ wherein R ²² is (1) hydrogen, (2) C ^ alkyl, (3) C ₃ _6cykloalkyl, (4) C ^ uaryl, (5) a 5-membered cyclic group selected from 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or 5- (1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or 5- (1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2, 3-triazolyl, 1,2,4-triazolyl and 1H- or 2H-tetrazolyl, (6) a 6-membered cyclic group selected from the group consisting of N-oxido-2-, 4- or 4-pyridyl, 2-, 4- or 5 -pyrimidinyl, N-oxido-2-, 4- or 5-pyrimidinyl, 2- or 3-thiomorpholinyl, 2- or 3-morpholinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, 2- or 3-piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl and N-oxido-3- or 4-pyridazinyl, (7) a 5-8 membered cyclic group or a fused ring thereof selected from benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzoimidazolyl, quinolyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8-naphthylisinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acrydinyl, phenthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl and phenoxazinyl, or (8) the -SO _P group in which p is 1 or 2, and R ²³ is hydrogen or C 1-6 alkyl, wherein the group -NR ²² R ²³ is optionally substituted with 1 to 6 substituents selected from the group consisting of (() C 1-6 alkyl, (2 ') C ₂ . ₆ alkenyl, (3) C ₂ _6alkinyl, (4) C ₃ _6cykloalkyl, (5) C ₅ _7cykloalkenyl, (6 ') C naralkyl, (7) C ₆ _i ₄ aryl, (8) C | _6alkoxyl, (9) C ₆ _ ₁₄ aryloxy (10 ') Ci_6alkanoyl, (11) C ^ uarylkarbonyl, (12') C ₈ alkanoyloxy, (13) C ^ | ₄ arylkarbonyloxyl, (14 ') carboxy, (15') Ci_6alkoxykarbonyl (16 ') carbamoyl, (17') N-mono-C _M alkylcarbamoyl, (18 ') of N, N-di-Ci_4alkylkarbamoyl, (19') a cyclic aminocarbonyl selected from the group consisting of 1-aziridinylcarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl and morpholinocarbonyl, (20 ') halogen, (21') mono- to trihalo-C 1-4 alkyl, (22 ') oxo, (23 ') amidino, (24') imino, (25 ') amino, (26') mono- or di-C 1-6 alkylamino, (27 ') 3- to 6-membered cyclic amino group containing, in addition to carbon and one nitrogen, 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, (28 ') C 1-6 alkanoylamino, (29') benzamido, (30 ') carbamoylamino, (31') N-C 1-4 alkylcarbamoylamino, (32 ') N, N- di-C 1-4 alkylcarbamoylamino, (33 ') C _1-3 alkylenedioxy, (34') -B (OH) ₂ , (35 ') hydroxyl, (36') epoxy, (37 ') nitro, (38') cyano, (3 ') 9 ') mercapto, (40') sulfo, (41 ') sulfino, (42') phosphono, (43 ') sulfamoyl, (44') C 1-6 alkylsulfamoyl, (45 ') di-C 1-6 alkylsulfamoyl, (46') C 1-6 alkylthio, ( 47 ') phenylthio, (48') C 1-6 alkylsulfinyl, (49 ') phenylsulfinyl, (50') C 1-6 alkylsulfonyl and (51 ') phenylsulfonyl, and the other substituents are as in claim 1. - 121 GB 290723 B6 5. A compound according to claim 1 which is 5-benzylaminomethyl-1- (2-chloro-6-fluorobenzyl) 2,4 (1H, 3H) -dioxo-6- (4-methoxyphenyl) -3-phenylthieno [2,3- d] pyrimidine or a salt thereof. A process for the preparation of derivatives according to claim 7, characterized in that the thiophene derivative of the general formula (II) in which: R ¹¹ is a group of the formula Q- (CH 2) _p - wherein Q is as in claim 1 and _p is 1 or 2, R ¹² is i) C ^ alkyl, ii) a C-uaryl, iii) a C-uaryl -C ₆ alkyl, or iv) C3_i ₀ cycloalkyl or C ₃ _i ₀ bicycloalkyl, wherein all substituents i) to iv) are optionally substituted by 1 to 6 substituents selected from the group consisting of a) C 6-18 aryl, optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, amino, mono- or di-C 1-6 alkylamino, C 1-6 alkoxy and halogen, b) a mono- or di-C _1-6 alkylamino group, c) C1-4 acylamino, (d) hydroxyl; e) carboxyl, (f) nitro; (g) C 1-6 alkoxy, h) C 1-6 alkylcarbonyloxy, (i) halogen; and j) a group of the formula -NR ²² R ²³ , wherein R ²² is (1) hydrogen, (2) C 1-6 alkyl, (3) C ₃₆ cycloalkyl, (4) C 6-18 aryl, (5) 5-membered cyclic group selected from a file comprising 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or 5- (1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or 5- (1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2, 3-triazolyl, 1,2,4-triazolyl and 1H- or 2H-tetrazolyl, (6) a 6-membered cyclic group selected from the group consisting of N-oxido-2-, 4- or 4-pyridyl, 2-, 4- or 5 -pyrimidinyl, N-oxido-2-, 4- or 5-pyrimidinyl, 2- or 3-thiomorpholinyl, 2- or 3-morpholinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1 , 4-thiazinyl, 1,3-thiazinyl, 2- or 3-piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl and N-oxido-3- or 4-pyridazinyl, (7) 5-8 membered cyclic group or a fused ring thereof selected from benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzoimidazolyl, quinolyl, isoquinolinyl, -122CZ 290723 B6 cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8-naphthylisinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acrydinyl, phenthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenoxiazinyl, phenothiazinyl, phenxiazinyl, phenothiazinyl, SO _P - in which p is 1 or 2, and R ^2? is hydrogen or Ci_6alkyl, wherein a group of the formula -NR ²² R ²³ is optionally substituted with 1-6 substituents selected from the group consisting of (1 ') C ^ alkyl, (2') C2 ^ alkenyl, (3) C ₂ _6alkinyl ( 4) C ₃ -6cykloalkyl, (5) C ₅ _7cykloalkenyl, (6) C ₇ _naralkyl, (7 ') C -i4aryl, (8) C | _ ₆ alkoxy, (9') C ₆ _i4aryloxyl, (10) C ^ alkanoyl, (1Γ) C ^ uarylkarbonyl, (12 ') C ₈ alkanoyloxy, (13) C ₆ _i4arylkarbonyloxyl, (14') carboxy, (15) C] _éalkoxykarbonyl, (16 ') carbamoyl (17 ') N-mono-C 1-4 alkylcarbamoyl, (18') N, N-di-C 1-4 alkylcarbamoyl, (19 ') cyclic aminocarbonyl selected from the group consisting of 1-aziridinylcarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl , N-methylpiperazinylcarbonyl and morpholinocarbonyl, (20 ') halogen, (21') mono- to trihalo-C 1-6 alkyl, (22 ') oxo, (23') amidino, (24 ') imino, (25') amino (26 ') a mono- or di-C 1-6 alkylamino group, (27') a 3- to 6-membered cyclic amino group containing k other than carbon and one nitrogen atom, 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, (28 ') C 1-6 alkanoylamino, (29') benzamido, (30 ') carbamoylamino, (31') N-C 1-4 alkylcarbamoylamino, ( 32 ') N, N-di-C 1-4 alkylcarbamoylamino, (33') C _1-3 alkylenedioxy, (34 ') -B (OH) ₂ , (35') hydroxyl, (36 ') epoxy, (37') nitro, (38 ') ') cyano, (39') mercapto, (40 ') sulfo, (4Γ) sulfino, (42') phosphono, (43 ') sulfamoyl, (44') C 1-6 alkylsulfamoyl, (45 ') di-C 1-6 alkylsulfamoyl, ( 46) C ^ alkylthio, (47 ") phenylthio, (48) C _b6 alkylsulfinyl, (49") phenylsulfinyl, (50) _{C) 6} alkylsulfonyl and (51 ") phenylsulfonyl, R ¹⁴ and r are as in claim 1 a X is a leaving group, or a salt thereof, reacts with a compound of the formula R &lt; ¹ &gt; H, wherein R ¹³ is as in claim 1, or a salt thereof. 10. A gonadotropin-releasing hormone antagonist pharmaceutical composition comprising as an active ingredient at least one derivative according to claim 1, or a salt thereof, in association with a carrier, excipient or diluent. Pharmaceutical composition for the prevention or treatment of sex hormone-dependent diseases, characterized in that it contains, as an active ingredient, in an effective amount at least one derivative according to claim 1, or a salt thereof, in association with a carrier, excipient or diluent. Pharmaceutical composition for the prevention or treatment of sex hormone-dependent cancer, benign prostatic hypertrophy or uterine fibroid, comprising as an active ingredient at least one derivative according to claim 1, or a salt thereof, in association with a carrier, excipient or diluent. A pharmaceutical composition for the prevention or treatment of sex hormone-dependent cancers selected from the group consisting of prostate cancer, uterine cancer, breast cancer and mucosal adenoma, characterized in that it contains at least one derivative according to claim 1, or an effective amount thereof, a salt, in association with a carrier, excipient or diluent. 14. A pharmaceutical composition for the prevention or treatment of sex hormone-dependent diseases selected from the group consisting of prostatauxi, endometriosis, uterine fibroid and premature puberty, comprising as an active ingredient in an effective amount At least one derivative according to claim 1, or a salt thereof, in association with a carrier, excipient or diluent. Pharmaceutical composition for controlling pregnancy, characterized in that it contains, as an active ingredient, in an effective amount at least one derivative according to claim 1, or a salt thereof, in association with a carrier, excipient or diluent. A pharmaceutical composition for controlling the menstrual cycle, characterized in that it contains as an active ingredient in an effective amount at least one derivative according to claim 1, or a salt thereof, in association with a carrier, excipient or diluent. A pharmaceutical composition for contraception, characterized in that it contains, as an active ingredient, in an effective amount at least one derivative according to claim 1, or a salt thereof, in association with a carrier, excipient or diluent. Use of the derivatives according to claim 1, or salts thereof, for the manufacture of a pharmaceutical composition for antagonizing gonadotropin releasing hormone in a mammal suffering from gonadotropin releasing hormone production disorders. Use of the derivatives according to claim 1, or salts thereof, for the manufacture of a pharmaceutical composition for the treatment of sex hormone dependent diseases. Use of the derivatives according to claim 1, or salts thereof, for the manufacture of a pharmaceutical composition for the treatment of sex hormone dependent cancer, benign prostatic hypertrophy or uterine fibroid. Use of the derivatives according to claim 1, or salts thereof, for the manufacture of a pharmaceutical composition for the treatment of sex hormone dependent cancer selected from the group consisting of prostate cancer, uterine cancer, breast cancer and mucosal adenoma. Use of the derivatives according to claim 1, or salts thereof, for the manufacture of a pharmaceutical composition for the treatment of sex hormone dependent diseases selected from the group consisting of prostatauxi, endometriosis, uterine fibroid and premature puberty. Use of the derivatives according to claim 1, or salts thereof, for the manufacture of a pharmaceutical composition antagonizing the gonadotropin releasing hormone for controlling pregnancy in mammals. Use of the derivatives according to claim 1, or salts thereof, for the manufacture of a pharmaceutical composition antagonizing gonadotropin releasing hormone for controlling the menstrual cycle in mammals. Use of the derivatives according to claim 1, or salts thereof, for the manufacture of a pharmaceutical composition antagonizing gonadotropin releasing hormone for contraception in mammals.