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(12) United States Patent (10) Patent No.: US 6,340,686 B1 Furuya Et Al

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(12) United States Patent (10) Patent No.: US 6,340,686 B1 Furuya Et Al USOO6340686B1 (12) United States Patent (10) Patent No.: US 6,340,686 B1 Furuya et al. (45) Date of Patent: Jan. 22, 2002 (54) THIENOPYRIMIDINE COMPOUNDS, THEIR (57) ABSTRACT PRODUCTION AND USE A compound of the formula: (75) Inventors: Shuichi Furuya; Nobuhiro Suzuki; Nobuo Choh, all of Tsukuba; Yoshi Nara, Suita, all of (JP) 21 (73) Assignee: Takeda Chemical Industries, Ltd., + (R), Osaka (JP) (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 O U.S.C. 154(b) by 0 days. F (21) Appl. No.: 09/571,215 (22) Filed: May 16, 2000 Related U.S. Application Data F (63) Continuation of application No. 09/530,495, filed as appli- wherein R and R each is hydrogen, hydroxy, C, a cation No. PCT/JP00/01777 on Mar. 23, 2000. alkoxy, Calkoxy-carbonyl or C. alkyl which may be substituted; R is hydrogen, halogen, hydroxy or (30) Foreign Application Priority Data Calkoxy which may be Substituted; or adjacent two Mar. 24, 1999 (JP) ........................................... 11-O79371 R may form C, alkylenedioxy; R" is hydrogen or Jan. 25, 2000 (JP) ........................................... 12-018019 C, alkyl; R is C, alkyl which may be substituted or (51) Int. Cl." ..................... A61K 31/519; CO7D 495/06 a group OI.f theIne fIOrmula la: (52) U.S. Cl. ........................................ 514/258; 544/278 (58) Field of Search ........................... 514/258; 544/278 (56) References Cited R5 FOREIGN PATENT DOCUMENTS WO WO95/284.05 10/1995 wherein R is hydrogen or R' and R may form hetero WO WO 96/24597 8/1996 cycle; and n is 0–5, or a Salt thereof, has an excellent GnRH-antagonizing activity, and is useful for prevent Primary Examiner John M. Ford ing or treating SeX hormone-dependent diseases. (74) Attorney, Agent, or Firm Mark Chao; Elaine M. Ramesh 24 Claims, 1 Drawing Sheet U.S. Patent Jan. 22, 2002 US 6,340,686 B1 Fig. 1 LH Concentrations in Castrated Cynomolgus Monkey Plasma 350 3OO 250 % LH Conc. 200 150 OO 50 O -30 -20 - 10 0 1 0 20 30 40 50 Time (h) A control group A compound group 1 0 control group 2 O compound group 2 O compound group 3 *% ratios respective reference values immediately prior to administration US 6,340,686 B1 1 2 THIENOPYRIMIDINE COMPOUNDS, THEIR DISCLOSURE OF INVENTION PRODUCTION AND USE This application is a continuation of copending applica We, the present inventors, have studied various tion Ser. No. 09/530,495, filed Apr. 26, 2000. 5 compounds, and as a result, have found for the first time the following novel compound which has a Substituent, a group TECHNICAL FIELD of the formula: -NH-CO-NR'R' wherein each symbol is as defined below, on the para-position of the phenyl group The present invention relates to thieno2,3-dipyrimidine of the thieno 2,3-dpyrimidine skeleton, or a salt thereof compounds exhibiting gonadotropin releasing hormone hereinafter Sometimes referred to briefly as compound (I). (GnRH) antagonizing activity, their production and use. And we also have found out that compound (I) has an unexpected, excellent GnRH-antagonizing activity, based BACKGROUND ART upon the above Specific Substituent, and low toxicity and is 15 therefore Satisfactory as a medicine having GnRH Secretion of anterior pituitary hormones undergoes feed antagonizing activity, and developed the present invention back control by peripheral hormones Secreted from target organs of the respective hormones and by Secretion based on this finding. regulating hormones from the hypothalamus, which is the upper central organ of the anterior lobe of the pituitary (I) (hereinafter, these hormones are collectively called “hypo thalamic hormones' in this specification). At the present Stage for, hypothalamic hormones, the existence of nine kinds of hormones including, for example, thyrotropin releasing hormone (TRH), and gonadotropin releasing hor 25 mone GnRH, sometimes called LH-RH (luteinizing hor mone releasing hormone) has been confirmed. These hypo thalamic hormones are believed to show their actions via the receptors which are considered to exist in the anterior lobe of the pituitary, and efforts to find the receptor-gene expres Sion Specific to these hormones, including for humans, have been made. Accordingly, antagonists or agonists specifically and Selectively acting on these receptors should control the action of the hypothalamic hormone and the Secretion of anterior pituitary hormone. As a result, Such antagonists or 35 agonists are expected to be useful in preventing or treating anterior pituitary hormone diseases. wherein Known compounds possessing GnRH-antagonizing R" and R each represents a hydrogen atom, a hydroxy activity include GnRH-derived linear peptides (U.S. Pat. 40 group, a C- alkoxy group, a C- alkoxy-carbonyl Nos. 5,140,009 and 5,171,835), a cyclic hexapeptide deriva tive (JP-A-61-191698), a bicyclic peptide derivative group or a C- alkyl group which may be Substituted; Journal of Medicinal Chemistry, Vol. 36, pp. 3265–3273 R represents a hydrogen atom, a halogen atom, a (1993), and So forth. Non-peptide compounds possessing hydroxy group or a C- alkoxy group which may be GnRH-antagonizing activity include compounds described 45 Substituted; or in WO95/284.05 (JP-A-8-295693), WO 97/14697 (JP-A-9- adjacent two R may form, taken together, a C- alky 169767), WO 97/14682 (JP-A-9-169735) and WO 96/24597 lenedioxy group; (JP-A-9-169768), etc. R" represents a hydrogen atom or a C- alkyl group; Peptide compounds pose a large number of problems to be 50 resolved with respect to oral absorbability, dosage form, R represents a C- alkyl group which may be Substituted dose volume, drug Stability, Sustained action, metabolic or a group of the formula: stability etc. There is strong demand for an oral GnRH antagonist, especially one based on a non-peptide compound, that has excellent therapeutic effect on hormone 55 dependent cancers, e.g., prostatic cancer, endometriosis, precocious puberty etc., that does not show transient R5 hypophysial-gonadotropic action (acute action) and that has excellent bioavailability. 60 wherein R represents a hydrogen atom or R' and R may BRIEF DESCRIPTION OF DRAWINGS form, taken together, a heterocycle, and in represents an integer of 0 to 5. FIG. 1 shows the percent LH concentrations in test Accordingly, the present invention relates to: monkey plasma. In the figure, -A- represents control group 1, -d- represents control group-2, -A- represents compound 65 1 a compound (I); group-1, -O- represents compound group-2 and -O- repre 2 a compound of the above 1 or a salt thereof, which Sents compound group-3, respectively. is a compound of the formula: US 6,340,686 B1 4 10 a compound of the above 1 or a salt thereof, wherein R' is a hydroxy group, a methoxy group or a (Ia) Cs alkyl group; R is a hydrogen atom or a C- alkyl group; R" is a C- alkyl group; R is a benzyl group; and n is 0; 11 5-(N-benzyl-N-methylaminomethyl)-1-(2,6- difluorobenzyl)-6-4-(3-methoxyureido)phenyl-3- phenylthieno 2,3-dipyrimidine-2,4(1H,3H)-dione or a Salt thereof; 1O 12 a process for producing a compound of Claim 1 or a Salt thereof, which comprises reacting a compound of the formula: (II) 15 21 ---Rs), N S wherein R and Reach is a hydrogen atom, a hydroxy group, a C- alkoxy group or a C- alkyl group which O may be substituted; R is a hydrogen atom, a halogen atom or a C- alkoxy group; R' is a C- alkyl group; F and R is as defined above; 25 3 a compound of the above 1 or a salt thereof, wherein R" is a C- alkoxy group; 4 a compound of the above 3 or a salt thereof, wherein R is a hydrogen atom; 5 a compound of the above 1 or a salt thereof, wherein wherein each Symbol is as defined above, or a Salt R is a hydrogen atom; thereof hereinafter sometimes referred to briefly as 6 a compound of the above 1 or a Salt thereof, wherein compound (II) with carbonyldiimidazole or phosgene, Ris a group of the formula: followed by reacting with a compound of the formula: 35 (III) R1 NH R5 A. 40 wherein R is as defined above; wherein each Symbol is as defined above, or a Salt 7 a compound of the above 2 or a salt thereof, wherein thereof hereinafter sometimes referred to briefly as R" is a C- alkyl group and R is a hydrogen atom; compound (III)); 8 a compound of the above 1 or a salt thereof, wherein 45 13 a pharmaceutical composition which comprises a n is 1 or 2, compound of the above 1 or a salt thereof; 9 a compound of the above 1 or a salt thereof, wherein R" is (i) a hydroxy group, (ii) a C- alkoxy group, or 14 a pharmaceutical composition of the above 13 (iii) a C- alkyl group which may be Substituted by which is for antagonizing gonadotropin-releasing hor hydroxy or C. alkyl-carbonyloxy; R is a hydrogen 50 mone, atom, a C- alkyl group or a C- alkoxy-carbonyl 15 a pharmaceutical composition of the above 14 group; R is a hydrogen atom, a halogen atom, a which is for preventing or treating a SeX hormone hydroxy group or a C- alkoxy-C alkoxy group; or dependent disease; adjacent two R form, taken together, a C- alkylene 16 a method for antagonizing gonadotropin-releasing dioxy group; R is a hydrogen atom or a C- alkyl 55 hormone in a mammal in need thereof which comprises group; R is a C- alkoxy-C alkyl group or a group administering to Said mammal an effective amount of a compound of the above 1 or a salt thereof with a of the formula: pharmaceutically acceptable excipient, carrier or dilu ent, 60 17 use of a compound of the above 1 or a salt thereof for manufacturing a pharmaceutical composition for R5 antagonizing gonadotropin-releasing hormone, and SO forth.
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