NZ332206A - 2,4-Dioxo-thieno[2,3-d]pyrimidine derivatives useful as gonadotropin releasing hormone antagonists - Google Patents
2,4-Dioxo-thieno[2,3-d]pyrimidine derivatives useful as gonadotropin releasing hormone antagonistsInfo
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Abstract
A 2,4-dioxo-thieno[2,3-d]pyrimidine derivative or a salt thereof has the formula (I) wherein: R11 is H, alkyl or Q-(CH2)p-; Q is optionally substituted aryl; p is 1 to 3; R12 is H, alkyl or optionally substituted aryl, aralkyl or cycloalkyl; R13 is an optionally substituted amino; R14 is an optionally substituted aryl and r is 0-3. A pharmaceutical composition thereof is useful for treating or preventing a sex hormone dependent cancer, benign prostatic hypertrophy or myoma of the uterus.
Description
- 1a -
DESCRIPTION
BICYCLIC THIOPENE DERIVATIVES AND USE AS GONADOTROPIN RELEASING HORMONE ANTAGONISTS
Technical Field The present invention relates to a pharmaceutical composition for antagonizing a gonadotropin-releasing hormone (GnRH) containing a condensed-bycyclic compound 10, consisting of a homo or hetero 5 to 7-membered ring group and a homo or hetero 5 to 7-membered ring group. The present invention also relates to novel condensed-ring thiophene derivatives and salts thereof. The present invention further relates to methods for 15 manufacturing the novel condensed-ring thiophene derivatives and the salts thereof.
Related compounds, compositions and uses are described and claimed in New Zealand patent application No. 283813, from which this application has been divided.
Background Art
2 0 Secretion of anterior pituitary hormone undergoes the.control by peripheral hormone secreted from target organs for the respective hormones and by secretion-accelerating or -inhibiting hormone from hypothalamus, which is the upper central organ of anterior lobe of 25 pituitary (in this specification, these hormones are collectively called "hypothalamic hormone"). At the present stage, as hypothalamic hormones, nine kinds of hormones including, for example, thyrotropin releasing hormone (TRH) or gonadotropin releasing hormone {GnRH: 30 sometimes called as LH-RH (luteinizing hormone releasing hormone)} are confirmed their existence (c£. Seirigaku 2, compiled by M. Iriku and K Toyama, published by Bunkohdo, p610-618, 19 86).. These hypothalamic hormones are assumed to show their actions 35 via the receptor which is considered to exist in the anterior lobe of pituitary.(cf. ibid), and observatinal studies of receptor genes specific to these hormones,
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including cases of human, have been developed (Receptor Kiso To Rinsho, compiled by H. Imura, et al. , published by Asakura Shoten, p297-3Q4, 1993). Accordingly, antagonists or agonists specifically and selectively 5 acting on these receptors control the action of hypothalamic hormone and controlling the secretion of anterior pituitary hormone. As the results,they are expected to be useful for prophylactic and therapeutic agents of anterior pituitary hormone dependent 10 diseases.
Leuprorelin acetate [Fujino et al., Biological and Biophysical Research Communications, Vol.60, 00.406-413, 1974); Oliver, R.T.D. et al., British Journal of Cancers, Vol.59, p.82 3, 19 89; and Toguchi et al., 15 Journal of International Medical Research, Vol.18, pp. 35-41 ]■,' which is a highly potent derivative of gonadotropic hormone-releasing hormone, one of the hypothalamic hormones, (hereinafter sometimes abbreviated as GnRH) [Schally A. V. et at., Journal of 20 Biological Chemistry, Vol. 246, pp.7230-7236, 1971; and Burgus, R. et al., Proceeding of Natural Academic Science, USA, Vol.69, pp278-282, 1972], by administration of multiple doses, lowers release.production of gonadotropic hormone in 25 pituitary, causing lowering of reactivity on gonadotropic hormone is spermary,and ovary to suppress secretion of testosterone and estrogen. Leuprorelin acetate has, therefore, been known to show antitumor activity on such hormone-dependent cancers as 30 exemplified by prostate cancer, and has been widely used in the clinical field. Leuprorelin acetate has been widely used clinically also as a therapeutic agent of e.g. endometriosis and precocious puberty. The high antitumor activity of leuprorelin acetate is assumed to 35 be due to its high resistance, as compared with natural GnRH, against protease,and to high affinity to
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GnRH receptor causing desensitization of GnRH due to decrease in number of receptors. However, as leuprorelin acetate is an ultra-agonist on GnRH receptor, it has been known that, immediately after the first administration, a transient aggravation accompanied with the rise of serum testosterone concentration due to pituitary-gonadotropic action (acute action) is observed. Circumstances being such as above, GnRH-antagonistic drugs which are expected to have substantially the same therapeutic effects as described above but not to cause the above-mentioned transient pituitary-gonadotropic action (acute action) have been desired. As compounds having such GnRH antagonistic activity, a number of compounds including, for example, derivatives of GnRH such as straight-chain peptides, (USP 5140009, 5171835), cyclic hexapeptide derivatives [JPA S61 (1986)-19169-8 ] or bicyclie peptide derivatives [Journal of medicinal chemistry, Vol.36, pp.3265-3273, 1993]. These compounds are, however, all peptides, which leave many.problems including., for example, dosage forms, stability of drugs, durability of actions and stability on metabolism. For solving these problems, orally administrable GnRH antagonistic drugs, especially non-peptide ones, are strongly desired. At the present -stage, however, no report on non-peptide GnRH antagonistic drugs has been made.
The object of the invention lies in providing novel compounds having excellent gonadotropic hormone releasing hormone antagonistic activity as well as excellent gonadotropic hormone releasing hormone antagonistic agents, or in at least providing a useful alternative.
Disclosure of Invention
The present invention provides novel condensed-ring thiophene derivatives and salts
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thereof. The present invention further provides methods for manufacturing the novel condensed-ring thiophene derivatives and the salts thereof.
More specifically, the present invention provides: (1) a compound of the formula (II):
0
formula:
Q-(CH2)p-
in which Q is aryl which may be substituted by a)
halogen, b) nitro, c) cyano, d) amino, e) an on-t-■? onally substituted carboxyl, f) lower alkylenedioxy or g) a group of the formula: -A-R15 in which A is a chemical bond or a spacer group, R15 is alkyl, an optionally substituted cycloalkyl or an optionally substituted heterocyclic group; p is an integer of 1 to 3;
R12 is hydrogen, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted cycloalkyl; R13 is an optionally substituted amino,;
R14 is an optionally substituted aryl;
r■is 0 to 3 ,
or a salt thereof,
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-
9 0 If & |
(21' a compound according to (1) , wherein R11 is a group of the formula:
Q-(CH2)p-
wherein p is an integer of 1 to 3; Q is aryl which may be substituted by a) halogen, b) .nitro, c) cyano, d) amino, e) an optionally substituted carboxyl, f) lower alkylenedioxy or g) a group of the formula -A-R15 in which A is a chemical bond or a spacer group, R15 is alkyl,
<3) a compound according to (1) , wherein Q is aryl which may be substituted by halogen,
(4) a compound according to (1) , wherein R13 is optionally substituted mono-aralkylamino,
(5j a compound according to (1) , wherein R13 is
1 C
iJ optionally substituted benzylamino,
(6) a compound according to (-j) , wherein R14 is optionally substituted phenyl,
, (7) a compound which is 5-benzylaminomethyl-l-(2-chloro-6-fluorobenzyl}-2,4(1H,3H)-dioxo-6-(4-methoxyphenyl)-3-phenylthieno[2,3-d]pyrimidine or its salt,
(8) a method for producing a compound of (2) , which comprises reacting a compound of the formula (IV):
X-(Cfl2)r
(IV)
wherein Ru is a group of the formula:
Q-(CHz)p-
in which Q is aryl which may be substituted by a)
halogen, b) nitro, c) cyamo, d) amino, e) an optionally substituted carboxyl, f) lower alkylenedioxy or g) a group of the formula: -A- R15 in which A is a chemical intellectual property i office of n.z.
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D rr r in r n
bond or a spacer group, R15 is alkyl; p is an integer of 1 to 3; R12' is alkyl, optionally substituted aryl, optionally substituted ararkyl or optionally substituted cycloalkyl;
R14 and r are the same meaning as defined in claim 1; X is a leaving group; or a salt thereof, with a compound of the formula:
r13h
.wherein R^ is the same meaning as defined in (1) , or a salt thereof,
(9) A pharmaceutical composition which comprises a compound or a salt thereof according to (1),
(10) Use of a composition according to (9) in the preparation of a medicament for preventing or treating a sex hormone dependent disease,
(11) Use of a composition according to (9) in the preparation of a medicament for preventing or treating a sex hormone dependent cancer, benign prostatic hypertrophy or myoma of the uterus,
(12) Use of a composition according to (9) in the preparation of a medicament for preventing or treating prostatic cancer, uterus cancer, breast cancer or pituitary adenoma,
(13) Use of a composition according to (9) in the preparation of a medicament for preventing or treating prostatauxe, endometriosis, myoma uteri or precocious puberty,
(14) A. pregnancy controlling composition, which comprises a compound or a salt thereof according to (1), and a carrier, excipient or diluent,
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(15) A menstrual cycle controlling composition, which comprises a compound or a salt thereof according to (1), and a carrier, excipient or diluent,
(16) Use of a composition according to (14) in the preparation of a medicament for contraception.
As the aryl shown by Ru or in the optionally substituted aryl shown by R12 and R14, mention is made of, for example, mono cyclic- or condensed polycyclic-aromatic hydrocarbon residues. Preferable example of them includes C6_14 aryl such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like. Among these, phenyl, 1-naphthyl and 2-naphthyl are more preferable. • '
The number of substituent is one or more, preferably one to three.- Examples of the substituents include, Cw alkyl (e.g. methyl, ethyl, propyl), C2.^ alkenyl (e.g. vinyl, allyl, 2-buetnyl) , C3.4 alkynyl (e.g. propargyl, 2-butynyl), C3.7 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), aryl (e.g. phenyl, naphthyl), 5- to 9-membered aromatic heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (e.g. furyl, thienyl, pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl), 5- to 9-membered nonaromatic heterocyclic group having 1 to 4 hetero atoms selected intellectual property office of n.z.
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from a nitrogen atom, an oxygen atom and a sulfur atom (e.g. oxiranyl, azetidinyl, oxethanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazynyl) , C7.10 aralkyl (e.g. benzyl, phenethyl), amino, N-monosubstituted amino (e.g. N-C^g alkyl amino such as methylamino, ethylamino, propylamino), N,N-
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aisubstituted amino [e.g. N,N-di(C1.fi alkyl) amino such as dimethylamino, diethylamino], amidino, acyl (e.g. Ci.g alkyl-carbonyl such as. acetyl, propionyl, butyryl; C6_u aryl-carbonyl such as benzoyl; C7_12 aralkyloxy-5 carbonyl such as benzyloxycarbonyl), carbamoyl, N-
monosubstituted carbamoyl [e.g. N-(C1_S) alkyl)carbamoyl such as methylcarbamoyl, ethylcarbamoyl,
ethylcarbamoyl, propylcarbamoyl], N,N-disustituted carbamoyl [e.g. N,N-di(Cx_6 alkyl)carbamoyl such as 10 dimethylcarbamoyl, diethylcarbamoyl], sulfamoyl, N-
monosubstituted sulfamoyl [e.g. N-(C1_6 alkyl) sulfamoyl such as methylsulfamoyl, ethylsulfamoyl, propylsulfamoyl], N,N-disubstituted sulfamoyl [e.g. N,N-di(C^6 alkyl)sulfamoyl such as dimethylsulfamoyl, 15 diethylsulfamoyl], carboxyl, C]_3 alkoxy-carbonyl (e.g.
methoxycarbonyl, ethoxycarbonyl), hydroxyl, alkoxy
(e.g. methoxy, ethoxy, propoxy) which may have a substituent (e.g. alkyl, halogen, alkylthio,
hydroxyl), C2_4 alkenyloxy (e.g. vinyloxy, allyloxy) , 2 0 cycloalkyloxy (e.g. C3_7 cycloalkyloxy such as cyclopropyloxy, cyclobutyloxy) , aralkyloxy (e.g. C7.10 aralkyloxy such as benzyloxy), aryloxy (e.g. phenyloxy, naphthyloxy) , mercapto, Ci_3 alkylthio (e.g. methylthio, ethylthio, propylthio), aralkylthio (e.g. C7_10
2 5 aralkylthio such as benzylthio), arylthio (e.g.
phenylthio, naphthylthio), C]_3 alkylenedioxy (e.g. methylenedioxy, ethylenedioxy, propylenedioxy), sulfo, cyano, azide, nitro, nitrosohalogen *fulorine, chlorine, bromine iodine), and the like.
3 0 As the aralkyl in the optionally substituted aralkyl shown by R12, mention is made of, for example, aryl-alkyl. The aryl is of the same meaning as defined above. Examples of the alkyl include cl_6 alkyl such as methyl, ethyl, propyl, butyl, pentyl, hexyl. The 35 substituents are of the same meaning as defined in the intellectual property office of n.z.
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12
substituents which the above aryl, shown by R , may have.
As the cycloalkyl in the optionally substituted
11 12
cycloalkyl shown by R and R , mention is made of, for example, C3.10 cycloalkyl and C3_10 bicycloalkyl. The preferable examples of them include cyclolprolyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, bicyclo[2,2,ljheptyl, bicyclo[2,2,2]octyl, bicyclo[3,2,l]octyl, bicyclo[3,2,1]nonyl, bicyclo[4,2,IJnonyl, bicyclo[4,3,1]decyl. Among these, cyclopentyl and cyclohexyl are more preferable. The substituents are of the same meaning as definede in the substituents which aryl, shown by R12, may have.
As the heterocyclic group in the optionally substituted heterocyclic group shown by Ru, mention is made of, for example, 5- to 13-membered aromatic heterocyclic group having one to four hetero atom(s) sedected from an oxygen atom, a sulfur atom and a nitrogen atom; or saturated or unsaturated non-aromatic heterocyclic group.
Examples of the aromatic heterocyclic group include an aromatic 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, triazinyl), an aromatic-condensed-ring . heterocyclic group {e.g. benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indoryl, isoindoryl, lH-indazolyl, benzoimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, 1,2-binzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,
naphthylidinyl, purinyl, pteridinyl, carbazolyl, a-
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carbolinyl, {3-carbolinyl, y-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl,
phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo[l,2-b]pyridazinyl, pyrazolo[l,5-a]pyridyl, imidazof1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-bjpyridazinyl, imidazo[1,2-a]pyridazinyl, 1,2-4-tiazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-bjpyridazinyl}.
Examples of the non-aromatic heterocyclic group include oxylanyl, azetizinyl, oxethanyl, thiethanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl.
The heterocyclic group may have one or more substituents, preferably one to three substituents. The substituents are of the same meaning as defined in the optionally substituted aryl shown by R12.
As the substituents in the optionally substituted carboxyl group shown by Q, mention is made of, for example, alkyl, cycloalkyl, aryl, aralkyl, a heterocyclic group. Examples of alkyl include alkyl such as methyl, ethyl, propyl, isopropyl, butyl, t-■ butyl, pentyl and hexyl. These are of the same meaning as defined above.
As the lower alkylenedioxy shown by Q, mention is made of, for example, C^g alkylenedioxy (e.g. methylenedioxy, ethylenedioxy, propylenedioxy, 2,2-dimethylmetylenedioxy).
As the lower alkyl shown by R11, mention is made of, for example, .C^.. alkyl (e . g.. methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl).
As the optionally substituted amino group shown by
13
R , mention is made of, for example, a group of the formula: -NR2Z'R23' wherein R22' is an optionally substituted aryl, an optionally substituted'
heterocyclic group;.
R23' is hydrogen, an optionally substituted al
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The optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heterocyclic group are of the same meaning as defined above.
As the spacer group shown by the symbol "A",
mention is made of, fro example, alkylene (e.g.
methylene, ethylene), cz_6 (e.g. vinylene,
butadienylene) ; a group of the formula: - (CH2)cNR24-in which c is 0 to 3, R24 is hydrogen, alkyl (e.g-.
methyl, ethyl, butyl); a group of the formula: -CO-; a group of the formula: -CONR22- in which R22 is of the same meaning as defined above; -0-; -S-; a group of the formula: -NR22S(0)e- in which e is 0 to 2, R22 is of the same meaning as defined above.
Ru is preferably a group of the formula:
-(CH2)pQ'
wherein p is an integer of 1 to 3;
Q' is aryl which may be substituted by halogen, nitro,
cyano, amino, an optionally substituted carboxyl group,
lower alkylenedioxy or a group of the formula-: -A-R15 in which R15 is a lower alkyl group, A is .of the same meaning as defined above.
The aryl which may be substituted by halogen,
nitro, cyano, amino, the optionally substituted carboxyl group, lower alkylenedioxy or the group of the formula: -A-R16, shown by Q', are the of the same meaning as defined above. The lower alkyl group is of the same meaning as defined above.
Q' is preferably an aryl which may be substituted by halogen (fluorine, chlorine, bromine, nitrogen).
13
R is preferably an optionally substituted monoaralkylamino. The optionally substituted aralkyl in the optionally substituted monoaralkylamino is of the same meaning as defined above. The aralkyl is preferably benzyl.
R14 is "preferably optionally substituted phenyl which is of the same meaning as defined above.
INTELLECTUAL PROPERTY OFFICE OF N.Z.
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The compound (II) and its salts can be produced easily by per se known methods, as exemplified by the following production methods 1 and 2.
[Production Method 1]
In accordance with the method disclosed by K. Gewald, E. Schinke and H. Battcher, Chem. Ber., 9.9., 94-100 (1966), an adequate ketone or aldehyde having an active methylene (i) was allowed to react with a cyanoacetic acid ester derivative and sulfur to convert into a 2-aminothiophene derivative (ii). More specifically, in the case of using ketone (R1 #H),. it is subjected to heating under reflux together with a cyanoacetic acid ester derivative, in the presence of acetic acid and ammonium acetate, in a proper solvent such as toluene to give an alkylidene cyanoacetic acid ester'derivative, which is then heated in an adequate solvent, for example, ethanol in the presence of sulfur and a base to afford a 2-aminothiophene derivative (ii) . And, in the" case of using aldehyde (R1,=H) , it is heated in a proper solvent, for example, dimethylformamide, in the presence of a cyanoacetic acid ester derivative, sulfur and a base to give a 2-aminothiophene derivative (ii).. The compound (ii) thus obtained is heated, in accordance with the method disclosed by Kuwata et al. [cf. German Patent 2,435,025], with diethyl ethoxymethylenemalonate to give an adduct (iii). The adduct is stirred in a intellectual property office of n.z.
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-Insolvent, which, does not give undesirable effect on the reaction, (s-g- alcohols such as ethanol and methanol), in the presence of a base (e.g. alkali metal hydroxide such as potassium hydroxide and sodium hydroxide) at 5 temperatures ranging from about 10 to 70°C to give carboxylic acid (iv). Then, the carboxylic acid (iv) thus obtained was subjected to ring-closure by heating in polyphosphoric acid ester (PPE) to give a thieno[2,3-b]pyridine derivative (v). The compound (v) 10 is stirred in a solvent, which does not give undesirable effect on the reaction, (e.g. amides such as dimethylformamide and dimethylacetamide), in the presence of a halogenated aralkyl derivative and a base (e.g. an organic base such as pyridine and-15 triethylamine) at temperatures ranging from about 10 to 100°C to give a 4,7-dihydro-4-oxothieno[2,3-b]pyridine-5-carboxylic acid ester derivative shown by the formula (la). Then, the compound (la) is stirred together with N-bromosuccinimide (NBS) in a solvent, which does not 20 give undesirable effect on the reaction, (e.g.
halogenated hydrocarbons such as carbon tetrachloride and chloroform) in the presence of a, a.'-azobisisobutyronitrile, at temperatures ranging from about 30 to 100°C to give a compound (lb ). The 25 compound (lb ) is•stirred together with various amines in a solvent, which does not give.undesirable effect on the reaction, (e.g. amides such as dimethylformamide and dimethylacetamide, nitrile .such as acetonitrile and alcohols such as ethanol) in the presence of a base at temperatures ranging from about 10 to 100°C to produce the compound (I ). The production method 1 described, above is shown in Scheme 1:
-
4 <■>
■ > -\ ^ k!)
Scheme 1
r1'
(i)
1)NCC1I2C02R' NIUOAc AcOlI
2)S HNE12 (Rl* Till)
-taUCOiR'
S NEta (R1' =10
EtG COjEt :o2Et
R'\ \CQ2R'
R2
.COzEt il COzEt
(iii)
KO It—E ton r1' ,co2n
S' i
R2^\ (iv)
■C01E t
N^Y
COjEt
(la)
MBS
AIBN etc.
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wherein R is hydrogen or an alkyl group, R' is an alkyl group, X is a leaving group, Xa is halogen, and
2 4 5 7 3 9
R,R,R,R/R,R/m and n are of the same meanina as defined in the above.
The alkyl group shown by R1' and R' is of the same meaning as defined above.
As the leaving group shown by X, mention is made of, for example, a group which is potentially substituted by a nucleophilic reagent such as a 10 hydrocarbon residue having a hetero atom (e.g. an ■ oxygen atom, a sulfur atom, a nitrogen atom) being negatively charged. The preferable examples of the " leaving group include halogen (e.g. iodine, bromine chlorine), alkanoyloxy (e.g. acetoxy) , a.lkylsulf onyloxy 15 (e-g- methanesulfonyloxy), alkyl-arylsulfonyloxy (e.g. p-toluenesulfonyloxy).
The halogen shown by Xa is fluorine, iodine, chlorine, iodine. Among these, bromine is more preferable.
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[Production Method 2]
Starting from the 2-aminothiophene derivative (ii), the urea derivative (II) was produced by, for example, the following method A or B.
1. Method A: The 2-aminothiophene derivative (ii) produced by the method described in Production Method 1 or a salt thereof is allowed to react with an isocyanate derivative. The isocyanate derivative is exemplified by derivatives represented by the formula, R12-NCO (wherein R12 is of the same meaning as defined above). The reaction of the compound (ii) or a salt thereof with the isocyanate derivative is conducted in an solvent which does not adversely affect on the reaction (e.g. tetrahydrofuran,. pyridine, dioxane, benzene, dichloromethane, 1,2-dichloroethane, toluene,, xylene) at temperatures ranging from about 15 to about 130°C. The isocyanate derivative is employed in an amount of about 1 to 5 equivalents, preferably about 1.1 to 2.5 equivalents, relative to 1 equivalent of the compound (ii). The reaction time ranges from several hours to several days, preferably from about 15 minutes to about two days.
2. Method B: Amine [e.g. a compound represented by the
12 12
formula R -NH2 (wherein R is of the same meaning as defined above)] is subjected to addition reaction to an isocyanate derivative produced by allowing a 2-aminothiophene derivative (ii) or a salt thereof to react with phosgene or an equivalent compound thereof [e.g. diphosgene such as bis(trichloromethyl)carbonate, triphosgene such as trichlormethylchloroformate] . The reaction of the compound (ii) or a salt thereof with phosgene or an equivalent compound thereof is conducted in a solvent which does not affect adversely on the reaction (e.g. dioxane, tetrahydrofuran, benzene,
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toluene, xylene, 1,2-dichloroethane, chloroform) at temperatures ranging from about 40 to 120°C. Phosgene or an equivalent compound thereof is employed in an -amount ranging from about 0.5 to 2 equivalents, 5 preferably from about 0.9 to 1.1 equivalent). The reaction time ranges from several minutes to several days, preferably from about 15 minutes to about two days. The addition reaction of amine is conducted in a solvent which does not affect adversely on the reaction 10 (e-g- pyridine, tetrahydrofuran, dioxane, benzene,
dichloromethane, 1,2-dichloroethane, toluene, xylene) at temperatures ranging from about 15 to 130°C- Amine ^ is employed in an amount ranging from about 1 to 5 equivalents, preferably from about 1.1 to 3 15 equivalents. The reaction time ranges from several minutes to several days, preferably from about 15 minutes to about two days.
The compound (XV) or a salt thereof thus produced is processed with a base to cause ring-closure reaction 20 to thereby produce a thieno [2,3-d] pyrimidine derivative (XVI). The ring-closure reaction is conducted in a solvent which does not affect adversely on the reaction. The solvent is exemplified by ■ alcohols such as methanol, ethanol or propanol, and 25 ethers such as dioxane or tetrahydrofuran. ^ As the base, use is made of, for example, an alkali metal alkoxide such as sodium methylate, sodium ethylate or sodium isopropoxide, and an alkali metal hydride such-as sodium hydride.
3 0 The amount of the base to be employed ranges from
1 to 5 equivalents, preferably from about 1.5 to 3 equivalents, relative to 1 equivalent of the compound (XV).
The reaction temperature ranges from about 10°C to 35 the boiling point of the solvent then employed,
preferably from about 25°C to the boiling point of the office of n.z.
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solvent then employed.
The reaction time ranges from several minutes to several days, preferably from about 10 minutes to two days .
The compound (XVI) and a -halogenated aralkyl derivative are stirred, in the presence of a base (e.g. an organic base such as pyridine or triethylamine), in a solvent which does not affect adversely on the reaction (e.g. amides such as dimethylformamide or dimethylacetamide), at about 10 to 100°C, to produce a 2,4-dioxothieno[2,3-d]pyrimidine derivative (Ila). Subsequently, the said compound (Ila) is stirred together with N-bromosuccinimide (NBS) in a solvent which does not affect adversely on the reaction (e.g. halogenated hydrocarbons such as carbon tetrachloride or chloroform), in the presence of a, a'-azobisisobutyronitrile, to thereby produce the compound (lib). Further, the said compound is stirred together with various amines, in the presence of a base, in a solvent which does not affect adversely on the reaction (e.g. amides such as dimethylformamide or dimethylacetamide, nitriles such as acetonitrile, alcohols such as ethanol), at temperatures ranging from about 10 to 100°C, to thereby produce the compound (II). When necessary,the said compound is made into a corresponding salt with a suitable acid (e.g. hydrochloric acid or oxalic acid).
The foregoing Production Method 2 is shown by Scheme 2:
Scheme 2
wherein each symbol is of the same meaning as defined above.
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As salts of the compounds of this invention obtained thus above, physiologically acceptable acid addition salts are preferable. Examples of such salts include those with an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid) or those with an organic acid (e.g.
formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, bezenesulfonic acid, and p-toluenesulfonic acid).
Further, when the compound (I) of this invention has an acid group such as -COOH, the compound(I) may form a salt with an inorganic base (e.g. an alkali metal•or alkaline earth metal such as sodium, potassium, calcium and magnesium; ammonia) or an organic base (e.g. trimethylamine, triethylamine, pyridine, picolin, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine and ,N,N'-dibenzylethylenediamine) .
Especially preferable examples of the compounds or their salts of this invention include 5-benzylmethylaminomethyl-1-(2-chloro-6-fluorobenzyl)-2,4(1H,3H)-dioxo-6-(4-methoxyphenyl)-3-phenylthieno[2,3-d]pyrimidine or its salts.
The compounds or salts thereof of the present invention produced thus above can be isolated and purified by a conventional separating means such as recrystallization, distillation and chromatography. In the case where the compound (II) is produced in the free form, it can be converted to a salt thereof by a per se conventional means or a method analogous thereto. On the contrary, when it is obtained in the form of a salt, it can be converted to its free form or to any other salt.
INTELLECTUAL PROPERTY OFFICE OF N.Z.
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In the case where the compound or a salt thereof of the present invention is an optically active compound, it can be separated into d-compound and 1-compound by means of a conventional optical resolution Since the compounds of this invention have a GnRH antagonistic activity and low in toxicity, they can be safely used for the therapy of male hormone or female hormone dependent diseases as well as the therapy of
(T')
diseases caused by excess secretion of these hormones, in warm-blooded animals (e.g. human, monkey, cow,
horse, dog, cat, rabbit, rat and mouse), suppressing the secretion of gonadotropic hormone by the action of 5 GnRH receptor antagonistic action. More specifically, the compounds of this invention are effective as a prophylactic or therapeutic agent for the prevention or treatment of several hormone dependent diseases, for example, a sex hormone dependent cancer (e.g. prostate 10 cancer, cancer of the uterine cervix, breast cancer,
pituitary adenoma), benign prostatic hypertrophy, myoma of the uterus, endometriosis, precocious puberty, amenorrhea, premenstrual syndrome, polycystic ovary syndrome and acne vulgaris. And, the compounds of this 15 invention are also effective as a fertility controlling agent in both sexes (e.g. pregnancy controlling agents and menstrual cycle controlling agents). The compounds of this invention can be further used as a contraceptive of male or female and, as an ovulation-20 inducing agent of female. The compound of this invention can be used as an infertility treating agent by using a rebound effect owing to a stoppage of administration thereof. Further, the compounds of this invention are useful as modulating estrous cycles in 25 animals in the field of animal husbandry, and as an agent for improving the quality of edible meat or promoting the growth of animals. Besides, the compounds of this invention are useful as an agent of spawning promotion in fish. While the compounds of 30 this invention can be used singly, they can also effectively be used by administering in combination with a steroidal or non-steroidal antiandrogenic agent. The compound of this invention can be used for the suppressing a passing ascent of testosterone 35 concentration in plasma, the ascent which occurs in administration of GnRH super antagonist such as
/r
INTELLECTUAL PROPERTY OFFICE OF N.Z.
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(followed by page 23)
leuprorelin acetate. The compound of this invention can effectively be used by administering in combination with a chemoterapeutic agent for cancer. In treatment of prostate cancer, examples of the chemoterapeutic 5 agent include Ifosfamide, UFT, Adriamycin, Peplomycin, Cisplatin and the like. In treatment of breast cancer, examples of the chemoterpeutic agent include Cyclophohamide, 5-FU-, UFT, Methotrexate, Adriamycin, Mitomycin C, Mitoxantrone and the like.
When the compound of this invention is employed,
in the field of animal husbandry or fisheries, as prophylactic and therapeutic agents of the above-' mentioned diseases,,is can be administered orally or non-orally in accordance with per se known means. It 15 is mixed with a pharmaceutically acceptable carrier and usually administered orally as a solid preparation such as tablet, capsule, granule or powder, or non-orally as intravenous, subcutaneous or intramuscular injection, or as suppository or sublingually administrable tablet. 20 Further, it is.sublingually, subcutaneously or intramuscularly administered as a prolonged release formulation such as sublingually administrable tablets, or microcapsules. The daily dose varies with the degree of affliction; age, sex, body weight and difference of sensitivity of the subject to be administered; the time and intervals of administration, properties, dosage forms and kinds of the medicinal preparation; and kinds of the effective components, and it ranges usually, though not specifically limited, 3 0 from about 0.01 to 10 mg, preferably from about 0.02 to 2 mg, more preferably from about 0.01 to 1 mg, relative to 1 kg body weight of warm-blooded animals, which is administered usually once daily or by 2 to 4 divided dosages. The daily dose when used in the field of 35 animal husbandry or fishery varies with the conditions analogous to those mentioned above, it ranges, relative
INTELLECTUAL PROPERTY OFFICE OF N.Z.
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- 24
to 1 kg body weight of the subject animal or fish, from about 0.001 to 5 mg, preferably from about 0.002 to 2 mg, once or 2 to 3 divided dosages.
As the above-mentioned pharmaceutically acceptable 5 carriers, conventional various organic or inorganic carriers are used, and they are incorporated as excipients, lubricants, binders and disintegrants in solid compositions; and as solvents, solubilisers, suspending agents, isotonizing agents, buffering agents 10 and pain-easing agents in liquid compositions. And, depending on necessity, further additives such as preservatives, anti-oxidants, coloring agents and sweeteners can also be used.
Preferable examples of the above-mentioned 15 excipients include lactose, sugar, D-mannito, starch, crystalline cellulose and more volatile silicon dioxide. Preferable examples of above-mentioned lubricants include magnesium stearate, calcium stearate, talc and colloid silica. Preferable examples 2 0 of the above-mentioned binders include crystalline cellulose, sugar, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxymethyl cellulose and polyvinyl pyrrolidone. Preferable examples of the above-mentioned disintegrants include starch, carboxymethyl 25 cellulose, carboxymethyl cellulose calcium, cross, carmelose sodium, cross carmelose sodium and carboxymethyl starch sodium. Preferable examples of the above-mentioned solvents include water for injection, alcohol, propylene glycol, macrogol, sesame 30 oil and corn oil. Preferable examples of the above-mentioned solubilizers include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, tris-aminomethane, cholesterol, triethanolamine, sodium carbonate and sodium citrate. Preferable examples of 35 the above-mentioned suspending agents include surfactants such as stearyl triethanolamine, sodium
- 25 - ■*& ^
€ T ^
iC
lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzetoniura chloride and monostearic glyceryl ester; and hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, 5 sodium carboxymethyl cellulose, methyl cellulose,
hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose. Preferable examples of the above-mentioned isotonizing agents include sodium chloride, glycerin and D-mannitol. Preferable examples 10 of the above-mentioned buffering agents include buffer solutions such as phosphate, acetate, carbonate and citrate. Preferable examples of the above-mentioned ) pain-easing agents include benzyl alcohol. Preferable examples of the above-mentioned preservatives include 15 para-hydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alc.ohol, dehydroacetic acid and sorbic acid. Preferable examples of the above-mentioned anti-oxidants include sulfite and ascorbic acid.
2 0 To the compound of this invention, are added, for example, a suspending agent, a solubilizer, a stabilizer, an isotonizing agent and a preservative, then the mixture is 'formulated, in accordance with a per se known method, into an intravenous, subcutaneous or intramuscular injection. These injections can be processed into lyophilized preparations, when necessary, by a per se known method.
Examples of the above-mentioned pharmaceutical composition are oral agents (e.g. diluted powders, 30 granules, capsules and tablets), injections, dropping injections, external agents (e.g. transnasal preparations, percutaneous preparations, etc.), ointments (e.g. rectal ointment, vaginal.ointment, etc.) and the like.
Such pharmaceutical compositions can be manufactured by a per se known method commonly used in
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26
SS 2p
preparing pharmaceutical compositions.
The compound of the present invention or a salt thereof can be made into injections either in a form of an aqueous injection together with dispersing agents [e.g. Tween 80 (Atlas Powder, U.S.A.), HCO 80 (Nikko Chemicals, Japan), polyethylene glycol, carboxymethylcellulose, sodium alginate, etc.], preservatives, (e.g. methyl paraben, propyl paraben, benzyl alcohol, etc.), isotonizing agents (e.g. sodium chloride, mannitol, sorbitol, glucose, etc.) and the like or in a form of an oily injection by dissolving, suspending or emulsifying in plant oil (e.g. olive oil, sesame oil, cotton seed 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 molded by compressing, for example, with fillers (e.g. lactose, sucrose, starch, etc.), disintegrating agents ('e.g. starch, calcium carbonate, etc.), binders (e.g. starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or lubricants (e.g. talc, magnesium stearate, polyethylene glycol 6000, etc.) and the like. If necessary, the composition is coated by a per se known method with an object of masking the taste, enteric coating or long-acting. Examples of the coating agent therefore are hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, po.lyoxyethylene glycol, Tween 80, pluronic F 68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (a copolymer of methacrylic acid with acrylic acid; manufactured by Rohm, Germany), red oxide of iron and the like. Subcoating layer may be pri
enteric coating and the core according to per se known method.
In preparing an external composition, the compound of the present invention or a salt thereof as it is or a salt thereof is subjected to a per se known method to give a solid, semisolid or liquid agent for external use. For example, the solid preparation is manufactured as follows. Thus, the compound of the present invention as it is or after adding/mixing fillers (e.g. glycol, mannitol, starch,
microcrystalline cullulose, etc.), thickeners (e.g. natural gums, cellulose derivatives, acrylic acid polymers, etc.) and the like thereto/therewith is made into a powdery composition. With respect to the liquid composition, an oily or aqueous suspension is manufactured by the manner nearly the same as in the case of the injection. In the case of a semisolid composition, the preferred one is an aqueous or oily gel or an ointment. Each of them may be compounded with a pH adjusting agent (e.g. carbonic acid, phosphoric acid, .citric acid, hydrochloric acid, sodium hydroxide, etc.), an antiseptic agent (e.g. p-hydroxybenzoates, chlorobutanol, benzalkonium chloride, etc.) and the like.
In the manufacture of an ointment for example, the compound of the present invention or a salt thereof can be made into an oily or an aqueous solid, semisolid or liquid ointment. Examples of the oily base material applicable in the above-mentioned composition are glycerides of higher fatty acids [e.g. cacao butter, Witepsols (manufactured by Dynamite-Nobel), etc.], medium fatty acids [e.g. Miglyols (manufactured by Dynamite-Nobel), etc.] and plant oil (e.g. sesame oil, soybean oil, cotton seed oil, etc.) and the like. Examples of the aqueous base material are polyethylene glycols and propylene glycol and those of the base
INTELLECTUAL PROPERTY OFFICE OF N.Z.
2 3 APR 2001
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**£ ^ ^ " ■ v v/
material for aqueous gel are natural gums, cellulose derivatives, vinyl polymers, acrylic acid polymers,
etc.
Best Mode for Carrying Out of the Invention By way of the following Reference Examples,
Working Examples and Test Examples, the present invention will be described more specifically, but they are not intended to limit the scope of this invention thereto.
XH-NMR spectra were taken with the Varian GEMINI 2 00 (200 MHz) type spectrometer, JEOL LAMBDA300 (300MHz) type spectrometer or the Brucker AM 500 (5 00 MHz) type spectrometer, employing tetramethylsilane as the internal standard. All delta values were expressed in ppm.
The symbols used in the present specification have the following meanings:
s: singlet, d: doublet, t: triplet, dt: double triplet, m: multiplet, br: broad Reference Example 1
2-Amino-5-phenylthiophene-3-carboxylic acid ethyl ester
To a mixture of ethyl cyanoacetate (6.1 g, 50 iranol), sulfur (1.61 g, 50 mmol) triethylamine (3.5 ml,
mmol) and dimethylformamide (10 ml) was added dropwise, with stirring at 45°C, phenylacetaldehyde (50% diethylphthalate solution; 12.05 g, 50 mmol) for 20 minutes. The mixture was stirred for 9 hours at 45 °C, and the reaction mixture was concentrated. The resulting residue was extracted.with ethylacetate. The extract was washed with an aqueous sodium chloride solution, which was then dried (MgSO^), followed by distilling off the solvent under reduced pressure. The residue was chromatographed on silica gel, followed by crystallization from ether-hexane to give slightly yellow plates (5.55 g, 45%), m.p.124.5-125.5°C (value in literature reference 123-124°C).
Elemental Analysis for C13H13N02S:
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C(%) H(%) N(%)
Calcd.: 63.13 ; 5.30 ; 5.66 Found : 62.99 ; 5.05 ; 5.63 1H-NMR (200MHz, CDC13) S: 1.37(3H,t,J=7.1Hz), 4.30(2H,d,J=7.1Hz), 5.97(2H,br), 7.17-7.46(6H,m).
IR(KBr): 3448, 3320, 1667 , 1590, 1549 cm"1.
Reference Example 2
2-Amino-4-methyl-5-(4-methoxyphenyl)thiophene-3-carboxylic acid ethyl ester
A mixture of 4-methoxyphenylacetone (16.5 g, 0.10 mol), ethyl cyanoacetate (12.2 g, 0.10 mol), ammonium acetate (1.55 g, 20 mmol), acetic acid (4.6 ml, 80 mmol) and benzene (20 ml) was heated for 2 4 hours under reflux, while removing water produced in the reaction mixture using a Dean and Stark apparatus. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane and an aqueous sodium hydrogencarbonate solution. The organic layer was washed with an aqueous sodium chloride solution, which was then dried (MgS04), followed by distilling of the solvent under reduced pressure. To an ethanol (30 ml) solution of the residue were added sulfur (3.21 g, 0.10 mol) and diethylamine (10.4 ml, 0.10. mol). The mixture was stirred at 50-60°C for 2h and then concentrated, and the concentrate was extracted with ethyl acetate. The extract was washed with an aqueous sodium chloride solution and dried (MgS04) , followed by distilling off the solvent-under reduced pressure. The residue was chromatographed on silica gel, which was the crystallized from ether-hexane to give a pale yellow plates (11.5 g, 40%), m.p.79-80°C.
Elemental Analysis for Ci5H17N03S:
C(%) H(%) N(%) S(%)
Calcd.: 61.83 ; 5.88 ; 4.81 ; 11.01
Found : 61.81 ; 5.75 ; 4.74 ; 10.82
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H-NMR (200MHz, CDC13) 5: 1.37(3H,t,J=7.1Hz),
2.28(3H,s), 3.83(3H,s), 4.31(2H,q,J=7.1Hz), 6 . 05(2H,brs), 6.91(2H,d,J=8.8Hz), 7.27(2H,d,J=8.8Hz). IR(KBr): 3426, 3328, 1651, 1586, 1550, 1505, 1485 cm"1. FAB-MS m/z: 291 (M+)
Reference Example 3
Employing various acetone derivatives in place of 4-methoxyphenylacetone, compounds shown in Table 1 were produced in accordance with substantially the same manner as described in Reference Example 2.
Table 1
>20
^CGGCjHs
>■21.
-NHj
R.Ex. 3
R20
R21
Yield m. p.
Cpd.No.
(%)
(°C)
1
methyl phenyl
40
64-65
2
methyl
2-methoxypheny1
12
70-71
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received
JJ?9
Reference Example 4
2-Amino-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylic acid ethyl ester
In substantially the same procedure as described in Reference Example 1, using 4-nitrophenylacetone (35.0 g, 195 mmol) in place of 4-methoxyphenyl acetone, ethyl cyanoacetate (23 g, 19.5 mmol), ammonium acetate (3.1 g, 40 mmol), acetic acid (9.1 ml, 159 mmol),
sulfur (5.0 g, 16 0 mmol) and diethylamine (16.0 ml, 160 mmol), the titled compound was produced as colorless crystals (22.2 g, 52%). m.p.168-170°C (recrystallized from ether-hexane).
Elemental Analysis for C1AHuN20AS:
C(%) H(%) N(%)
Calcd.: 54.89 ; 4.61 ; 9.14 Found : 54.83 ; 4.90 ; 9.09 1H-NMR (200MHz, CDC13) S: 1.39(3H,t,J=7.1Hz),
2.4 0(3H,s), 4.34(2H,q,J=7.1Hz) , 6.27(2H,brs), 7.48(2H,d,J=8.7Hz), 8.23(2H,d,J=8.7Hz).
IR (KBr): 3446, 3324, 1667, 1580, 1545, 1506, 1491, 1475, 1410, 1332 cm"1.
Reference Example 5
2,4(1H,3H)-Dioxo-5-methyl-6-(4-methoxyphenyl)-thieno[2,3-d]pyrimidin-3-acetic acid ethyl ester
To a solution of the compound produced in Reference Example 1 (5.00 g, 17.20 mmol) was added ethyl isocyanatoacetate (2.90 ml, 25.80 mmol). The mixture was stirred for 6 hours at 45°C, followed by concentration under reduced pressure. 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 ■ for 2 4 hoiars at room temperature, to which was added 2N
INTELLECTUAL PROPERTY OFFICE OF N.Z.
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HCl (18 ml, 36 mmol). Ethanol was distilled off under reduced pressure, and the residue was subjected to filtration, which was washed with water-ethanol and dried under reduced pressure, followed by recrystallization from ethanol to give white needles (5.70 g, 89%). m.p.164-165°C.
Elemental Analysis for ClsHiaN205S:
C(%) H(%) N(%)
Calcd.: 57.74 ; 4.85 ; 7.48 Found : 57.78 ; 5.03 ; 7.45 ^-NMR (200MHz, CDC13) 5: 1.30(3H,t,J=7.2Hz),
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=8.8Hz), 10.58(lH,s). IR (KBr): 2914, 1742, 1713, 1655, 1605, 1568, 1528, 149 9 cm"1.
Reference Example 6
Employing, as starting materials, the compounds produced in Reference Examples 2, 3 and 4, compounds set forth in Table 2 were produced, in accordance with the method described in Reference Example 5.
Table 2
R . Ex. 6 Cpd.No.
33
R
R34
Yield (%)
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
benzyl methoxy
92
241-242
INTELLECTUAL PROPERTY OFFICE OF N.Z.
2 3 APR 2001
R.Ex. 6 Cpd.No.
r33
R34
Yield
(%)
m.p.
(°C)
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
2-chlorophenyl methoxy
95
285-286
11
3-chlorophenyl methoxy
97
>300
12
4-chlorophenyl methoxy
95
>300
Reference Example 7
2, 4 (1H,3H)-Dioxo-6-(4-nitrophenyl)-5-
methylthieno[2,3-d]pyrimidin-3-acetic acid ethyl ester To the compound 1 produced in Reference Example 6 (2.20 g, 6.39 mmol) was added conc. sulfuric acid (12 ml). To the mixture was added dropwise, under ice-cooling, a solution of sodium nitrate (550 mg, 6.47 mmol) in conc. sulfuric acid, followed by stirring for one hour under ice-cooling. The reaction mixture was poured into ice-water, which was extracted with ethyl acetate. The extract was washed with an aqueous sodium chloride solution and dried (MgS04) , followed by distilling off the solvent under reduced pressure. The residue was chromatographed on silica gel to give a yellowish solid (1.30 g, 52%), which was then recrystallized from ethyl acetate - hexane to yellow crystals, m.p.277-280°C.
Elemental Analysis for C17H15N306S . 0 . 4H20:
C(%) H(%) N(%)
Calcd.: 51.48 ; 4.01 ; 10.59 Found : 51.64; 3.79; 10.61 lH-NMR (200MHz, CDC13) S: 1. 33 ( 3H, t, J=7 . 2Hz ) ,
2 . 56 ( 3-H, s ) , 4.28(2H,q, J=7 ,2Hz) , 4.79(2H,s), 7.57(2H,d,J=8.8Hz), 8.30(2H,d,J=8.8Hz), 10.30(lH,s). IR (KBr) : 1748, 1719, 1663, 1522, 1460 cm"1.
intellectual property
OFFICE OF N.Z.
2 3 APR 2001 R F n F 1V F I)
Reference Example 8
2 ,4 (1H,3H)-Dioxo-l-(2-fluorobenzyl)-6-(4-nitrophenyl)-5-methylthieno[2,3-d]pyrimidin-3-acetic acid ethyl ester
To a solution of the compound produced in
Reference Example 7 (70 0 mg, 1.8 0 mmol) in dimethylformamide (10 ml) were added potassium carbonate (372 mg, 2.70 mmol), potassium iodide (299 mg, 1.80 mmol) and 2-fluorobenzyl chloride (0.43 ml, 3.60 mmol). The mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated, and the concentrate was partitioned between ethyl acetate and an aqueous sodium chloride solution. The aqueous layer was extracted with ethyl acetate. The combined.extract was washed with an aqueous sodium chloride solution, which was then dried (MgS04) , followed by distilling off the solvent under reduced pressure. The residue was chromatographed on silica gel to give a white powder (500 mg, 5 6%), m.p.155-158°C.
Elemental Analysis for C24H20N3O6SF . 0 . 5H20 :
C(%) H(%) N(%)
Calcd. : 56.91 4.18 ; - 8.30 Found : 56.74 ; 3.84 ; 8.25 rH-NMR (200MHz, CDC13) Ss 1.32(3H,t,J=7.2Hz),
3.84(3H,s), 4.27(2H,q,J=7.2Hz), 4.84(2H,s), 5.30(2H,s), 7.06-7.33(4H,m), 7.54(2H,d,J=8.9Hz),
7.27(2H,d,J=8.9Hz).
IR (KBrj : 1748, .1711, 1673, 1.520, 1491 cm"1.
Reference Example 9
Starting from the compounds produced in Reference Example 6, compounds set forth in Table 3 were produced in accordance with the method described in Reference Example 8.
INTELLECTUAL PROPERTY OFFICE OF N.Z.
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Table 3
- 35
'2201
1 /-v-R"
ch2-(J
Ref.Ex. 9 Cpd.No.
R33
. R3S
R34
Yield {7.)
m.p.
C°C)
1
ethyl acetate
2-fiuoro methoxy
87
127-128
2
methyl
2-rnethoxy methoxy
92
174-175
3
methyl
2-fluoro methoxy
97
179-180
4
phenyl
2-methoxy methoxy
93
240-241
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
9
phenyl
2,4-
difluoro methoxy
73
227-228
phenyl
2,6-
difluoro methoxy
87
291-292
11
phenyl
2-chloro, 6-fluoro methoxy
91
287-288
12
phenyl
2-methyl-thio methoxy
■ 81
239-240
13
benzyl
2-fluoro methoxy
• 86
124-126
14
benzyl
2,6-
difluoro methoxy
82
161-163
4-methoxy-phenyl
2-fluoro methoxy
87
270-272
16
4-methoxyphenyl
2,6-
difluoro methoxy. "
83
>300
17
cyclohexyl
2-fluoro me thoxy
79
172-173
18
cyclohexyl
2,6-
difluoro methoxy
73
207-208
19
phenyl
2,6-
difluoro nitro
93
280-282
2-methoxy-phenyl
2-fluoro methoxy
84
195-198
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received
- 36
■' < 0 ^
Ref.Ex. 9 C.nri . Nn .
R33
R35-
R34
Yield m m.p.
C°C1
21
2-methoxy-phenyl
2,6-
difluoro methoxy
86
205-208
22
3-me thoxy-phenyl
2-fluoro methoxy
89
241-242
23
3-methoxyphenyl
2,6-
difluoro methoxy
85
253-255
24
2-chloro-phenyl
2-fluara methoxy
91
220-221
2-chloro-phenyl
2,6-
difluoro methoxy
83
178-182
26
3-chloro-phenyl
2-fluoro methoxy
90
247-248
27
3-chloro-phenyl
2,6-
difluoro methoxy
93
278-279
28
4-chlara-phenyl
2-fluoro methoxy
79
269-270
29
4-chloro-phenyl
2, 6-
aifluoro methoxy
91
>300
Reference Example 10
-Bromomethyl-2,4(1H,3H)-dioxo-1-(2-fluorobenzyl)-6-(4-nitrophenyl)thieno[2,3-d]pyrimidin-3-acetic acid ethyl ester
A mixture of the compound produced in Reference Example 8 (0.300 g, 0.603 mmol), N-bromosuccinimide (0.107 g, 0.603 mmol), a,a'-azobisisobutyronitrile (10 mg, 0.60 mmol) and carbon tetrachloride (15 ml) was refluxed for 2 hours. Upon cooling resulting insolubles were filtered off from the reaction mixture. The filtrate was diluted with chloroform. The organic layer was washed with an aqueous sodium chloride solution and dried (MgSO*,) , then the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to give colorless needles (0.284 g, 82%), m.p.165-167°C.
Elemental Analysis for C24H19N3OsSBrF:
Calcd, Found
C(%) 50.01 49 . 87
H ( % ) 3.32 3.27
N( %
7 . 29 7.23
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LH-NMR (200MHz, CDC13) 5: 1. 31 ( 3H, t, J=7 . 1Hz ) , 4.26(2H,q,J=7.1Hz), 4.78(2H,s), 4.86(2H,s), 5.30(2H,s), 7.07-7. 37(4H,m), 7.75(2H,d,J=8.8Hz),
8.33(2H,d,J=8.8Hz).
IR (KBr): 1713 , 1673, 1524, 1477 cm"1.
Reference Example 11
Starting from the compounds produced in Reference Example 9, compounds set forth in Table 4 were produced in accordance with the method described in Reference Example 10.
Table 4
0
Br-CIf
2\
3 3
I- —Ai35
Ref.Ex. 11 Cpd.No.
R33
R35
R34
Yield
U)
m.p.
(°C)
1
ethyl acetate
2-fluoro methoxy
70
.2-153
2
methyl
2-methoxy methoxy
63
173-176
3
methyl
2-fluoro methoxy
82
175-177
4
phenyl
2-methoxy methoxy
93
240-241
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
phenyl
2,6-
difluoro methoxy
87
250-252
11
phenyl
2-chloro, 6-fluoro methoxy
86
255-257
12
phenyl
2-methyl-thio methoxy
90
212-214
13
benzyl
2-fluoro methoxy
83
132-134
Intellectual property office of n.z.
2 3 APR 2001
received
- 38
-■ f) ./a
: •/ tni
Ref.Ex. 11
C.pd . Nn .
R33
R35
R34
Yield
(7.\
m.p.
f°r.)
14
benzyl
2,6- ' difluoro methoxy
89
154-155
4-methoxy phenyl
2-fluoro methoxy
88
226-228
16
4-methoxy phenyl
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
phenyl
2,6-
difluoro nitro
94
228-229
2-methoxy-phenyl
2-fluoro methoxy
77
180-181
21
2-methoxy-phenyl
2,6-
difluoro methoxy
79
212-214
22
3-methoxyphenyl
2-fluoro methoxy
82
234-235
23
3-methoxyphenyl
2,6-
difluoro methoxy
88
255-256
24
2-chloro-phenyl
2-fluoro methoxy
85
175-178
2-chloro-phenyl
2,6-
difluoro methoxy
88
191-193
26
3-chloro-phenyl
2-fluoro methoxy
81
243-246
27
3-chloro-phenyl
2,6-
difluoro me thoxy
92
270-273
28
4-chloro-phenyl
2-fluoro methoxy
84
■ 271-274
29
4-chloro-phenyl
2,6-
difluoro methoxy
78
265-268 .
Reference Example 12
-Benzylmethylaminomethyl-2 ,4 (1H., 3H) -dioxo-1- (2-f luorobenzyl) -6-nitrophenyl) thieno [ 2 , 3-djpyrimidin-3-acetic acid ethyl ester hydrochloride
To a solution of the compound produced in Reference Example 10 ^0.270 g, 0.47 mmol) in dimethylformamide (10 ml) were added, under ice-cooling, ethyl diisopropylamine (0.12 ml, 0.710 mmol) and benzylmethyl amine (0.07 ml, 0.56 mmol).. The mixture was stirred for 20 hours at room temperature.
INTELLECTUAL PROPERTY OFFICE OF N.Z.
2 3 APR 2001
received
The reaction mixture was concentrated, and the concentrate was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was extracted with ethyl acetate. Organic layers were combined and dried (MgS04) , then the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel to give a colorless oil (0.297 g, 100%). To a solution of this oil in ethyl acetate was added, under ice-cooling, IN ethereal hydrochloric acid. The mixture was stirred for 10 minutes at the same temperature. The reaction mixture was concentrated under reduced pressure,, and the concentrate was crystallized from ethyl acetate -ether to give the corresponding hydrochloride (0.084 g) as white crystals.
m.p.[hydrochloride] 120-128°C Elemental Analysis for C32H29N4O6SF.HCl.H2O:
C(%) H(%) N(%)
Calcd.: 57.27 ? 4.81? 8.35 Found : 57.23 ; 4.55 ; 8.42 ^-NMR (200MHz, CDC13) [free amine] S:
1.31(3H,t,J=7.1Hz), 2.16(3H,s), 3.61(2H,s), 3.97(2H,s), 4.27(2H,q,J=7.1Hz), 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, 1493 cm"1. Working Example 1
-Benzylmethylaminomethyl-2,4(1H,3H)-dioxo-l-(2-fluorobenzyl)-6-(4-methoxyphenyl)-3-phenylthieno[2,3— d]pyrimidine hydrochloride
To a solution of the compound 15 produced in Reference Example 11 (0.150 g,. 0.3,10 mmol) in dimethylformamide (10 ml), with ice-cooling, were added ethyldiisopropylamine (0.08 ml, 0.460 mmol) and methylbenzylamine (0.05 ml, 0.370 mmol). After stirring for 2 hours at room temperature, the reaction
INTELLECTUAL PROPERTY OFFICE OF N.Z.
2 3 APR 2001
received
- 40
f 9 <9
mixture was concentrated. The residue, was partitioned between ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was 5 dried (MgSO4) . The solvent was distilled off under reduced pressure, and the residue was chromatographed on silica gel to give a colourless oil (0.159 g, 97%). To the solution of this oil in ethyl acetate (4 ml) was added, with ice-cooling, an IN solution of hydrogen 10 chloride in ether (0.3 ml). After stirring for 10
minutes under ice-cooling, the reaction mixture was concentrated with reduced pressure. The residue was crystallized from ethyl acetate-ether to give a titled hydrochloride (0.144 g) as white crystals. 15 m.p. [hydrochloride] 140-143°C
Elemental Analysis for C35H30N3O3SF-HC1 *H20:
C(%) H(%) N(%)
Calcd.: 65 . 05 ; 5 .14 ; 6.50 Found : 65.14 ; 5.03; 6.37 20 ^-NMR (200MHz, CDCl3) [free amine] S: 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=8.8Hz), 7 . 05-7.60( 14H,m),
7.66(2H,d,J=8.8Hz)
IR(KBr) [hydrochloride]: 1711, 1665, 1543, 1477 cm"1. 25 Working Example 2
Starting from the compounds produced in Reference Example 11, compounds set forth in Table 5 were produced in accordance with the method described in Working Example 1.
intellectual property office of n.z.
2 3 APR 2001 RECEIVED
W.Ex.2 Cpd.No.
R33
R35
R3A
Yield (I)
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
97-105
4
phenyl
2-fluoro
■ nitro
100
140-143 .
phenyl
3-fluoro methoxy
97
152-156
6
phehy1
4-fluoro methoxy
100
165-170
7
phenyl
2,4-
difluoro methoxy
77
155-160
8
phenyl
2,6-
difluoro methoxy
100
160-162
9
phenyl
2-chloro, 6-fluoro methoxy
98
150-155
phenyl
2-methy1-thio methoxy
76
152-158
11
benzyl
2-fluoro methoxy
89
128-134
12
benzyl
2,6-
difluoro methoxy
100
123-127
13
4-methoxy phenyl
2-fluoro methoxy
93
150-155
14
4-me thoxy phenyl
2,6-
difluoro methoxy
84
153-157
. 15
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-methoxy-phenyl
2-fluoro methoxy
93
- 152-153
19
2-methoxy-phenyl
2, 6-
difluoro methoxy
100
148-150
3-methoxyphenyl
2-fluoro methoxy.
92
155-158
rTNtiaECTUALPKOPERT^
1 OFFICE OF N.Z.
, 1 2 3 APR 2001
1 RECEIVED
W.Ex.2 npd.Nn.
R33
R"35 .
R34
Yield
(7.)
m.p.
(°C.)
21
3-methoxyphenyl
2,6-
difluoro methoxy
91
160-163
22
2-chloro-phenyl
2-fluoro me thoxy
97
147-152
23
2-chloro-phenyl
2,6-
difluoro methoxy
98
150-155
24
3-chloro-phenyl
2-fluoro methoxy
100
148-153
3-chloro-phenyl
2,6-
difluoro methoxy
100
152-157
26
4-chloro-phenyl
2-fluoro methoxy
91 '
161-164
27
4-chloro-phenyl
2,6-
difluoro methoxy
86
145-146
Working Example 3
6- ( 4 -Aminophenyl)-2,4(1H,3H)-dioxo-1-(2-fluorobenzyl)-3-phenyl-5-(N-methyl-N-benzylaminomethyl)thieno[2 , 3-d]pyrimidine
s
43 -
The compound 4 produced in Working Example 2 (0.15 g, 0.247 mmol) was dissolved in ethanol (15 ml), to which was added 10% palladium-carbon (15 mg). The mixture was hydrbgenized for 8 hours at room temperature under atmospheric pressure in an atmosphere of hydrogen. The reaction mixture was filtrated with celite, and the filtrate was concentrated under reduced pressure. The concentrate was chromatographed on silica gel to give a yellow crystalline amorphous ( 0 .046 g, 32%) .
*H-NMR (300MHz, CDCl3) S: 2.05(3H,s), 3.5 7(2H,s), 3.81(2H>br s), 3.89(2H,s), 5.29(2H,s), 6.69(2H,d,J=8.7Hz), 7.05-7.56(16H,m).
FAB-Mass m/z 577(MH)+
Working Example 4
6-(4-Acetylaminophenyl)-2,4(1H,3H)-dioxo-1-(2- -
f. luorobenzyl)-5-(N-methyl-N-benzylaminomethyl)-3-phenylthieno[2,3-d]pyrimidine
The compound produced in Working Example 3 (0.63
g, 0.11 mmol) was dissolved in anhydrous pyridine (5 ml), to which was added acetic anhydride (0.01 ml, 0.11 mmol). The mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The concentrate was partitioned between methylene chloride (30 ml) and a ' saturated aqueous sodium chloride solution (10 ml). The aqueous layer was again extracted with methylene chloride (30 ml). The combined organic layer was dried over magnesium sulfate, which was concentrated, under reduced pressure. The concentrate was chromatographed on silica gel to give a colorless solid (0.01 g, 15%). ^-NMR (300MHz, CDC13) S: 2.06(3H,s), 2.19(3H,s),
3.57(2H,s), 3.90(2H,s), 5.30(2H,5), 7.04-7.57(16H,s), 7.70(2H,d,J=8.4Hz).
9 o &PR 2001
rEXE
J
44
Working Example 5
6-(Aminophenyl)-2,4(1H,3H)-dioxo-1-(2,6-
difluorobenzyl)-5-(N-methyl-N-benzylaminomethyl) -3-
phenylthieno[2,3-d]pyrimidine
Employing the compound No. 17 produced in Working Example 2, as the starting material, in accordance with substantially the same procedure as described in Working Example 3, the title compound was produced as a crystalline amorphous (yield 65%).
:H-NMR (300MHz, CDC13) 6: 2.05(3H,s), 3.56(2H,s), 3.81(2H,br s), 3.88(2H,s), 5.36(2H,s), 6.71(2H,d,J=8.7Hz), 6.91(2H,t,J=8.7Hz), 7.21-7.53(13H,m).
Working Example 6
Employing the compound produced in Working Example 3, as the starting material, in accordance with substantially the same procedure as described in Working Example 4, the following compounds were produced.
No. 1: 2,4(2H,3H)-Dioxo-1-(2-fluorobenzyl)-5-(N-methyl-N-benzylaminomethyl)-3-phenyl-6-(4-propionylaminophenyl)thieno[2,3-d]pyrimidine hydrochloride (yield: 86%, m.p. 172-175°C) No. 2: 2,4(2H,3H)-Dioxo-l-(2-fluorobenzyl)-6-(4-isobutyrylaminophenyl)-5-(N-methyl-N-benzylaminomethyl )-3-phenylthieno[2,3-d]pyrimidine hydrochloride (yield: 77%, m.p. 185-188°C)
intellectual property office of n.z.
2 3 APR 2001
received
No, 3: 2,4(2H,3H)-Dioxo-1-(2-fluorobenzyl)-6-(4-methoxyacetylaminophenyl)-5-(N-methyl-N-benzylaminomethyl )-3-phenylthieno[2,3-d]pyrimidine hydrochloride (yield: 88%, m.p. 157-162°C)
Working Example 7
Using 3-benzylaminomethyl-4,7-dihydro-7-(2-methoxybenzyl)-3-(4-methoxyphenyl)-4-oxothienyl[2,3-b]pyridine-5-carboxylic acid ethyl ester hydrochloride (100 mg), lactose (165 mg), corn starch (5 mg),
polyvinyl alcohol (4 mg) and magnesium stearate (1 mg), a tablet was prepared by a conventional method.
The gonadotropin-releasing hormone antagonistic agent of the present invention is effective as a prophylactic or therapeutic agent for the prevention or treatment of several hormone dependent diseases, for example, a sex hormone dependent cancer (e.g. prostatic cancer^ pituitary adenoma , . cancer of the uterine cervix, breast cancer), prostatic hypertrophy, myoma of the uterus, endometriosis, precocious puberty, amenorrhea syndrome., polycystic ovary syndrome ana. acne vulgaris-, or as a fertility controlling agent (e.g. a contraceptive agent) infertility treating agent, a menstruation controlling agent. Further, in the field of animal husbandry,, the gona.olotropin-releasing hormone antagonistic agent of the present invention is effective as agents of. controlling oestrus in animals, improving the quality of edible meat, growth regulation of animals, and also a spawning-accelerating agent in the field of fisheries.
INTELLECTUAL PROPERTY OFFICE OF N.Z.
2 3 APR 2001
received
Claims (19)
1. A compound of the formula: wherein R11 is hydrogen, lower alkyl, group of the formula: Q-(CH2)p- in which Q is aryl which may be substituted by a) halogen, b) nitro, c) cyano, d) amino, e) an optionally substituted carboxyl, f) lower alkylenedioxy or g) a group of- the formula: -A-R10 in which A is a chemical bond or a spacer group, R15 is alkyl, an optionally substituted cycloalkyl or an optionally substituted heterocyclic group; p is an integer of T to 3; R.12 is hydrogen, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted cycloalkyl; R13 is an optionally r r substituted amino R14 is an optionally substituted aryl; r is 0 to 3, or a salt thereof.
2. A compound according to .claim 1, wherein Ru is a group of the formula:
Q-(CH2) p - wherein p is an integer of 1 to 3; Q is aryl which may be substituted by a) halogen, b) nitro, c) cyano, d) amino, e) an optionally substituted carboxyl, f) lower alkylenedioxy or g) a group of the formula -A-R15 in which A is a chemical bond or a spacer group, R15 is alkyl.
' INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 3 APR 2001 received 10 15 20 2 5 30 ~ 47 ~ * ^ ^ ' V .77;< <£ (1 ■#;3. A compound according to claim 1, wherein Q is aryl which may be substituted by halogen.;• 13 •;4. A compound according to claim 1, wherein R is optionally substituted mono-aralkylamino.;13;
5. A compound according to claim 1, wherein R is optionally substituted benzyl amino.;* 4
6. A compound according to claim 1, wherein R~ is optionally substituted phenyl.
7. . A compound which is 5-benzylaminomethyl-l-(2-chloro-6-fluorobenzyl)-2,4(1H,3K)-dioxo-S-(4-methoxyphenyl)-3-pheny!thieno[2,3-d]pyrimidine or its salt.
8. A method for producing a compound of claim 2, which comprises reacting a compound of the formula: 0 •R12' J?11' wherein RU is a group of the formula: Q-(CHz)p- in which Q is aryl which may be substituted by a) halogen, b) nitro, c) cyano, d) amino, e) an optionally substituted carboxyl, f> lower alkylenedioxy or g) a group of the formula: -A-R15 in which A is a chemical bond or a spacer group, R15 is alkyl; p is an integer of 1 to 3; 12' R is alkyl, optionally substituted aryl, optionally substituted ararkyl or optionally substituted cycloalkyl; INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 3 APR 2001 received - 48 - 4 'f ^ : J-aJ ^j) ® y '(j) R14 and r are the same meaning as defined in claim 1; X is a leaving group, or a salt thereof, with a compound of the formula: R13H wherein R13 is the same meaning as defined in claim 1, or a salt thereof.
9. A pharmaceutical composition which comprises a compound or a salt thereof according to claim 1.
10. Use of a composition according to claim 9 in the preparation of a medicament for preventing or treating a sex hormone dependent disease.
11. Use of a composition according to claim 9 in the preparation of a medicament for preventing or treating a sex hormone dependent cancer, benign prostatic hypertrophy or myoma of the uterus.
12. Use of a composition according to claim 9 in the preparation of a medicament for preventing or treating prostatic cancer, uterus cancer, breast cancer or pituitary adenoma.
13. Use of a composition according to claim 9 in the preparation of a medicament for preventing or treating prostatauxe, endometriosis, myoma uteri or precocious puberty.
14. A pregnancy controlling composition, which comprises a compound or a salt thereof according to claim 1, and a carrier, excipient or diluent.
15. A menstrual cycle controlling composition, which comprises a compound or a salt thereof according to claim 1, and a carrier, excipient or diluent.- INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 3 APR 2001 received
16. Use of a composition according to claim 14 in the preparation of a medicament for contraception.
17. A compound as claimed in claim 1 as specifically set forth herein.
18. A process for the preparation of a compound as claimed in claim 1 substantially as herein described with reference to the Examples.
19. A composition containing a compound as claimed in claim 1 substantially as herein described. TAKEDA CHEMICAL INDUSTRIES, LTD., intellectual property office of n.z. 2 3 APR 2001 received END
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP8073294 | 1994-04-19 | ||
JP19554194 | 1994-08-19 | ||
JP27101094 | 1994-11-04 | ||
JP2071795 | 1995-02-08 | ||
JP4015195 | 1995-02-28 | ||
NZ283813A NZ283813A (en) | 1994-04-19 | 1995-04-14 | 4-oxo-thieno[2,3-b]pyridine derivatives and medicaments |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ332206A true NZ332206A (en) | 2001-06-29 |
Family
ID=27548936
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NZ332206A NZ332206A (en) | 1994-04-19 | 1995-04-14 | 2,4-Dioxo-thieno[2,3-d]pyrimidine derivatives useful as gonadotropin releasing hormone antagonists |
Country Status (1)
Country | Link |
---|---|
NZ (1) | NZ332206A (en) |
-
1995
- 1995-04-14 NZ NZ332206A patent/NZ332206A/en unknown
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