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WO2005032527A2 - Benzo (4, 5) thieno (2, 3-d) pyrimidin-4-ones and their use in therapy - Google Patents

Benzo (4, 5) thieno (2, 3-d) pyrimidin-4-ones and their use in therapy Download PDF

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Publication number
WO2005032527A2
WO2005032527A2 PCT/EP2004/006230 EP2004006230W WO2005032527A2 WO 2005032527 A2 WO2005032527 A2 WO 2005032527A2 EP 2004006230 W EP2004006230 W EP 2004006230W WO 2005032527 A2 WO2005032527 A2 WO 2005032527A2
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alkyl
group
compound
benzo
optionally substituted
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WO2005032527A3 (en
WO2005032527B1 (en
Inventor
Leena HIRVELÄ
Nina Johansson
Pasi Koskimies
Olli Taneli PENTIKÄINEN
Tommi NYRÖNEN
Tiina Annamaria Salminen
Mark Stuart Johnson
Pekka Lehtovuori
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Abbott Healthcare Products BV
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Solvay Pharmaceuticals BV
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Priority to CA002527617A priority Critical patent/CA2527617A1/en
Priority to AT04803089T priority patent/ATE479437T1/en
Priority to JP2006515869A priority patent/JP4605800B2/en
Priority to MXPA05012745A priority patent/MXPA05012745A/en
Priority to PL04803089T priority patent/PL1635839T3/en
Priority to EP04803089A priority patent/EP1635839B1/en
Priority to DE602004028934T priority patent/DE602004028934D1/en
Priority to AU2004277311A priority patent/AU2004277311B8/en
Priority to DK04803089.4T priority patent/DK1635839T3/en
Application filed by Solvay Pharmaceuticals BV filed Critical Solvay Pharmaceuticals BV
Priority to BRPI0411295-4A priority patent/BRPI0411295A/en
Priority to SI200431535T priority patent/SI1635839T1/en
Publication of WO2005032527A2 publication Critical patent/WO2005032527A2/en
Publication of WO2005032527A3 publication Critical patent/WO2005032527A3/en
Publication of WO2005032527B1 publication Critical patent/WO2005032527B1/en
Priority to IL172316A priority patent/IL172316A0/en
Anticipated expiration legal-status Critical
Priority to NO20060123A priority patent/NO20060123L/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61P5/00—Drugs for disorders of the endocrine system
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    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones

Definitions

  • the present invention relates to novel thiophenepyrimidinone derivatives which represent inhibitory compounds of the 17 ⁇ -hydroxysteroid dehydrogenase enzymes, preferably of the 17 ⁇ - hydroxysteroid dehydrogenase type 1 (17 ⁇ -HSD1), type 2 (17 ⁇ -HSD2) or type 3 (17 ⁇ -HSD3) enzyme, to their salts, to pharmaceutical preparations containing these compounds and to processes for the preparation of these compounds.
  • the invention concerns the therapeutic use of said thiophenepyrimidinone derivatives, particularly their use in the treatment or prevention of steroid hormone dependent diseases or disorders, such as steroid hormone dependent diseases or disorders requiring the inhibition of 17 ⁇ -hydroxysteroid dehydrogenase enzymes, in particular 17 ⁇ -HSD type I enzymes, and/or requiring the modulation of the endogenous 17 ⁇ -estradiol and/or testosterone concentration.
  • steroid hormone dependent diseases or disorders such as steroid hormone dependent diseases or disorders requiring the inhibition of 17 ⁇ -hydroxysteroid dehydrogenase enzymes, in particular 17 ⁇ -HSD type I enzymes, and/or requiring the modulation of the endogenous 17 ⁇ -estradiol and/or testosterone concentration.
  • 17 ⁇ -HSDs Mammalian 17 ⁇ -Hydroxysteroid dehydrogenases
  • NAD(H) or NADP(H) dependent enzymes which catalyze - besides other reactions - the final steps in male and female sex hormone biosynthesis.
  • These enzymes convert inactive 17-keto-steroids into their active 17 ⁇ -hydroxy-forms or catalyze the oxidation of the 17 ⁇ -hydroxy-forms into the 17-keto- steroids. Because both estrogens and androgens have the highest affinity for their receptors in the 17 ⁇ -hydroxy form, 17 ⁇ -HSD enzymes play an essential role in the tissue-selective regulation of the activity of sex steroid hormones.
  • 17 ⁇ -HSD enzyme family 10 human members of the 17 ⁇ -HSD enzyme family have been described (types 1-5, 7, 8, 10, 11 and 12).
  • the human 17 ⁇ -HSD family members share less than 30% similarity in their primary structure.
  • the 17 ⁇ -HSDs are expressed in distinct, though in some cases, overlapping patterns.
  • the different types of 17 ⁇ -HSDs also differ in their substrate and cofactor specificities.
  • the 17 ⁇ -HSDs catalyze the reaction in a unidirec- tional way: types 1, 3, 5 and 7 use NADP(H) as a cofactor and catalyze the reductive reaction (activation), while types 2, 4, 8 and 10 catalyze the oxidative reaction (inactivation) using NAD(H) as a cofactor.
  • 17 ⁇ -HSDs Due to their essential role in the tissue-selective regulation of the activity of sex steroid hormones 17 ⁇ -HSDs can be involved in the occurrence and development of estrogen-sensitive pathologies (f. ex. breast, ovarian, uterine and endometrium cancers etc.) and androgen- sensitive pathologies (f. ex. prostate cancer, benign prostatic hyperplasia, acne, hirsutism, etc). Furthermore, many types of 17 ⁇ -HSD have been shown to be involved in the pathogenesis of particular human disorders.
  • 17 ⁇ -HSD3 is known to be involved in the development of pseudohermaphroditism
  • the 17 ⁇ -HSD8 plays a role in polycystic kidney disease
  • the 17 ⁇ -HSD4 is related to the occurrence of bifunctional enzyme deficiency. Therefore treatment of sex steroid-sensitive diseases by administration of specific inhibitors of the 17 ⁇ -HSDs enzymes have been suggested, optionally in combination with potent and specific antiestrogens and antiandrogens [Labrie F et al. (1997) Steroids, 62:148-58].
  • each type of 17 ⁇ -HSD has a selective substrate affinity, directional
  • the selectivity of drug action could be achieved by targeting a particular 17 ⁇ -HSD isozyme.
  • individual modulation of the particular 17 ⁇ -HSDs it is possible to influence or even control the local and paracrine concentration of estrogens and androgens in different target tissues.
  • the best characterized member of the 17 ⁇ -HSD family is the type 1 17 ⁇ -HSD [EC 1.1.1.62].
  • This enzyme could be crystallized in different states of functionality (e.g. with and without ligand and/or co-factor).
  • the 17 ⁇ -HSD1 catalyzes in vitro the reduction as well as the oxidation between estrone (E1) and estradiol (E2). However, under physiological in vivo conditions the enzyme only catalyzes the reductive reaction from the estrone (E1) to the estradiol (E2).
  • the 17 ⁇ -HSD1 was found to be expressed in a variety of hormone-dependent tissues, e.g. placenta, mammary gland tissue or uterus and endometrium tissue, respectively.
  • Estradiol itself is, especially in comparison to the significantly less active estrone, a very potent hormone, which regulates the expression of a variety of genes by binding to the nuclear estrogen receptor and plays an essential role in the proliferation and differentiation of the target cell.
  • Physiological as well as pathological cell proliferations can be estradiol dependent.
  • breast cancer cells are stimulated by a locally raised estradiol concentration.
  • the occur- rence or course of benign pathologies such as endometriosis, uterine leiomyomas (fibroids or myomas), adenomyosis, menorrhagia, metrorrhagia and dysmenorrhea is dependent from the existence of significantly high estradiol levels.
  • Endometriosis is a well-known gynaecological disorder that affects 10 to 15% of women in the reproductive age. It is a benign disease defined as the presence of viable endometrial gland and stroma cells outside the uterine cavity. It is most frequently found in the pelvic area. In women developing endometriosis, the endometrial cells entering the peritoneal cavity by retrograde menstruation (the most likely mechanism) have the capacity to adhere to and invade the peritoneal lining, and are then able to implant and grow. The implants respond to steroid hormones of the menstrual cycle in a similar way as the endometrium in the uterus.
  • the infiltrating lesions and the blood from these lesions which are unable to leave the body cause inflammation of the surrounding tissue.
  • the most common symptoms of endometriosis are dysmenor- rhoea, dyspareunia and (chronic) abdominal pain. The occurrence of these symptoms is not related to the extent of the lesions.
  • Some women with severe endometriosis are asymptomatic, while women with mild endometriosis may have severe pain. Endometriosis is found in up to 50% of the women with infertility. However, currently no causal relation has been proven between mild endometriosis and infertility. Moderate to severe endometriosis can cause tubal damage and adhesions leading to infertility.
  • Uterine leiomyomas fibroids or myomas
  • benign clonal tumours arise from smooth muscle cells of the human uterus. They are clinically apparent in up to 25% of women and are the single, most common indication for hysterectomy. They cause significant morbidity, including prolonged and heavy menstrual bleeding, pelvic pressure and pain, urinary problems, and, in rare cases, reproductive dysfunction. The pathophysiology of myomas is not well understood.
  • Myomas are found submucosaliy (beneath the endometrium), intramurally (within the myo- metrium) and subserosally (projecting out of the serosal compartment of the uterus), but mostly are mixed forms of these 3 different types.
  • the presence of estrogen receptors in leiomyoma cells has been studied by Tamaya et al. [Tamaya et al. (1985) Acta Obstet Gynecol Scand., 64:307-9]. They have shown that the ratios of estrogen receptor compared to progesterone and androgen receptor levels were higher in leiomyomas than in the corresponding normal myo- metrium. Surgery has long been the main treatment for myomas.
  • medical therapies that have been proposed to treat myomas include administration of a variety of steroids such as the androgenic steroids danazol or gestrinone, GnRH agonists and progestogens, whereby the administration is often associated a variety of serious side-effects.
  • the reversible or even irreversible inhibitors of the 17 ⁇ -HSD1 should have no or only pure antagonistic binding activities to the estradiol receptor, in particular to the estrogen receptor ⁇ subtype, since agonistic binding of the estrogen receptor would lead to activation and therefore - by regulation of a variety of genes - to the proliferation and differentiation of the target cell.
  • antagonists of the estrogen receptor so called anti-estrogens, bind competitively to the specific receptor protein thus preventing access of endogenous estrogens to their specific binding site.
  • a selective 17 ⁇ -HSD1 inhibitor may be useful for the prevention of the aforementioned hormone- dependent cancers, especially breast cancer.
  • 17 ⁇ -HSD3 A further well characterized member of the 17 ⁇ -HSD family is the 17 ⁇ -HSD type 3 en- zyme (17 ⁇ -HSD3).
  • the 17 ⁇ -HSD3 has a distinct feature compared to other 17HSDs: it is found to be expressed almost exclusively the testis, whereas the other isoenzymes are expressed more widely in several tissues.
  • 17 ⁇ -HSD3 has a crucial role in androgen biosynthesis. It converts 4-androstene-3,17-one (A) to testosterone (T).
  • A 4-androstene-3,17-one
  • T testosterone
  • the biological significance of the 17 ⁇ - HSD3 is of undeniable physiological importance.
  • These diseases include but are not limited to benign prostatic hyperplasia, prostatitis, acne, seborrhea, hirsutism, androgenic alopecia, precocious puberty, adrenal hyperplasia, and polycystic ovarian syndrome. Furthermore, considering the fact that 17 ⁇ -HSD3 is found mainly in the testis, the development of potent inhibitors could be of interest for blocking spermatogenesis and as an anti-fertility agent for males.
  • 17 ⁇ -HSD type 2 (designated 17 ⁇ -HSD type 2 or 17 ⁇ -HSD2) was cloned by expression cloning, and found to be equally active using androgens and estrogens as substrates for oxidation [Andersson S. (1995) J. Steroid Biochem. Molec. Biol., 55:533-534].
  • the recombinant 17 ⁇ -HSD2 converts the highly active 17 ⁇ -hydroxysteroids such as estradiol (E2), testosterone (T), and dehydrotestosterone (DHT) to their inactive keto forms.
  • E2 estradiol
  • T testosterone
  • DHT dehydrotestosterone
  • the 17 ⁇ -HSD2 can, to a lesser extent, also convert 20 ⁇ -hydroxyprogesterone (20 ⁇ P) to progesterone (P).
  • This modulation of steroid levels may be employed for a wide variety of indications, including the following: for the prevention and treatment of osteoporosis, for the treatment of ovarian cancer, for the treatment of breast cancer, for the treatment of endometrial cancer, for the treatment of endometriosis, for the treatment of prostate cancer and/or for the treatment of androgen-dependent hair-loss.
  • Manhas et al describe the synthesis and antiin- flammatory activity of some substituted thienopyrimidinones [Manhas MS et al. (1972) J Med Chem. 15(1): 106-7].
  • Gadad et al. describe the synthesis and antihyperlipaemic activity of some 2-aminomethyl-3-aryl-5,6,7,8-tetrahydrobenzo(b) / 5,6-dimethylthieno (2,3-d)-pyrimidin-4-ones [Gadad AK et al. (1996) Arzneistoffforschung. 46(10):981-5].
  • thiophenepyrimidinone derivatives of the present invention would be valuable in therapy, especially in the treatment or prevention of steroid hormone dependent diseases or disorders, such as steroid hormone dependent- diseases or disorders requiring the inhibition of 17 ⁇ -hydroxysteroid dehydrogenase (HSD) enzymes.
  • HSD 17 ⁇ -hydroxysteroid dehydrogenase
  • compounds of formula (I) represent potent inhibitors of the 17 ⁇ -HSD1 , 17 ⁇ -HSD3 and/or 17 ⁇ - HSD2 enzyme and possess valuable pharmacological properties for the treatment and/or pro- phylaxis of malignant steroid dependent diseases or disorders such as breast cancer, prostate carcinoma, ovarian cancer, uterine cancer, endometrial cancer and endometrial hyperplasia, but also for the treatment and/or prophylaxis of benign steroid d ependent diseases or disorders such as endometriosis, uterine fibroids, uterine leiomyoma, adenomyosis, dysmenorrhea, rnenorrhagia, metrorrhagia, prostadynia, benign prostatic hyperplasia, prostatitis, acne, sebor- rhea, hirsutism, androgenic alopecia, precocious puberty, adrenal hyperplasia, polycys
  • estrogen-dependent diseases which may be treated and/or prevented with an effective amount of a compound of the invention are multiple sclerosis, rheumatoid arthritis, Alzheimer's disease, colon cancer, tissue wounds, skin wrinkles and cataracts.
  • compounds of formula (I) may be useful for the prevention and treatment of osteoporosis, and for blocking spermatogenesis and as an anti-fertility agent for males.
  • the present invention relates to the use of a compound having the structural formula (I)
  • X is S, SO or S0 2
  • R1 and R2 are individually selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloheteroalkyl, substituted cyclohet- eroalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyclo- heteroalkyl-alkyl, substituted cycloheteroalkyl-alkyl, or R2 itself may be independently selected from acyl, carboxyl, or amido, whereby R1 and R2 cannot be simultaneously unsubstituted alkyl,
  • hydrocarbon chain -C(R3)-C(R4)-C(R5)-C(R6)- of the six-membered ring is saturated or contains one or two double bonds between the carbon atoms;
  • R3 and R4 are individually selected from the group consisting of hydrogen, oxo, halogen or dihalogen, acyl, alkyl, substituted alkyl, hydroxyl, carboxyl, amido, amino, nitrile, thio, alkoxy, acyloxy, aryloxy, alkylthio and arylthio;
  • R5 represents hydrogen
  • R6 is hydrogen or halogen, for the manufacture of a medicament for the treatment and/or prevention of a steroid hormone dependent disease or disorder, preferably for a steroid hormone dependent disease or disorder requiring the inhibition of a 17 ⁇ -hydroxysteroid dehydrogenase (17 ⁇ -HSD) enzyme, most preferably requiring the inhibition of the 17 ⁇ -HSD type 1 , 17 ⁇ -HSD type 2 or 17 ⁇ -HSD type 3 en- zyrne.
  • a steroid hormone dependent disease or disorder preferably for a steroid hormone dependent disease or disorder requiring the inhibition of a 17 ⁇ -hydroxysteroid dehydrogenase (17 ⁇ -HSD) enzyme, most preferably requiring the inhibition of the 17 ⁇ -HSD type 1 , 17 ⁇ -HSD type 2 or 17 ⁇ -HSD type 3 en- zyrne.
  • the invention concerns a compound of formula (I)
  • X is S, SO or S0 2
  • R1 and R2 are individually selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloheteroalkyl, substituted cyclohet- eroalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyclo- heteroalkyl-alkyl, substituted cycloheteroalkyl-alkyl, or R2 itself may be independently selected from acyl, carboxyl, or amido, whereby R1 and R2 cannot be simultaneously unsubstituted alkyl, and whereby R2 has to be different from methyl if all substituents R3, R5 and R6 simultaneously represent hydrogen and R4 represents hydrogen or methyl;
  • R3 and R4 are individually selected from the group consisting of hydrogen, oxo, halogen or dihalogen, acyl, alkyl, substituted alkyl, hydroxyl, carboxyl, amido, amino, nitrile, thio, alkoxy, acyloxy, aryloxy, alkylthio and arylthio;
  • R5 represents hydrogen
  • R6 is hydrogen or halogen
  • the hydrocarbon chain -C(R3)-C(R4)-C(R5)-C(R6)- of the six-membered ring is saturated or contains one or two double bonds between the carbon atoms; whereby the six-membered ring comprising the hydrocarbon chain -C(R3)-C(R4)-C(R5)-C(R6)- has to be an aromatic ring if all the substituents R3, R4, R5 and R6 are simultaneously hydrogen;
  • the invention concerns a novel compound of formula (I)
  • X is S, SO or S0 2
  • R1 and R2 are individually selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloheteroalkyl, substituted cyclohet- eroalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyclo- heteroalkyl-alkyl, substituted cycloheteroalkyl-alkyl, or R2 itself may be independently selected from acyl, carboxyl, or amido, whereby R1 and R2 cannot be simultaneously unsubstituted alkyl, and whereby R2 has to be different from methyl if all substituents R3, R5 and R6 simultan eously represent hydrogen and R4 represents hydrogen or methyl;
  • R3 and R4 are individually selected from the group consisting of hydrogen, oxo, halogen or dihalogen, acyl, alkyl, substituted alkyl, hydroxyl, carboxyl, amido, amino, nitrile, thio, alkoxy, acyloxy, aryloxy, alkylthio and arylthio;
  • R5 represents hydrogen
  • R6 is hydrogen or halogen
  • the hydrocarbon chain -C(R3)-C(R4)-C(R5)-C(R6)- of the six-membered ring is saturated or contains one or two double bonds between the carbon atoms; whereby the six membered ring comprising the hydrocarbon chain -C(R3)-C(R4)-C(R5)-C(R6)- has to be an aromatic ring if all the substituents R3, R4, R5 and R6 are simultaneously hydrogen;
  • the invention concerns a pharmaceutical composition
  • a pharmaceutical composition comprising as active agent a compound of formula (I) as defined herein, for which no use in therapy earlier has been disclosed, and at least a pharmaceutically acceptable carrier.
  • the invention concerns the use of a compound of formula (I) as defined herein for the treatment or prevention of a steroid hormone dependent disease or disorder.
  • a steroid hormone dependent disease or disorder is a disease or disorder requiring the inhibition of a 17 ⁇ -hydroxysteroid dehydrogenase enzyme, preferably of the 17 ⁇ -HSD type 1, 17 ⁇ -HSD type 2 or 17 ⁇ -HSD type 3.
  • compound shall here be understood to cover any and all isomers (e. g., enantiomers, stereoisomers, diastereomers, rotomers, and tautomers ), racemates or any mixture of isomers, prodrugs, and any pharmaceutically acceptable salt of said compound. Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.
  • substituted means that the specified group or moiety bears one or more substituents. Where any group may carry multiple substituents and a variety of possible substituents is provided, the substituents are independently selected and need not be the same.
  • unsubstituted means that the specified group bears no substituents.
  • the compounds of the present invention may contain asymmetric centers on the molecule, depending upon the nature of the various substituents. In certain instances, asymmetry may also be present due to restricted rotation about the central bond adjoining the two aromatic rings of the specified compounds. It is intended that all isomers (including enantiomers and diastereomers), either by nature of asymmetric centers or by restricted rotation as described above, as separated, pure or partially purified isomers or racemic mixtures thereof, be included within the ambit of the instant invention.
  • halogen refers to fluorine (F, Fluoro-), bromine (Br, Bromo-), chlorine (CI, Chloro), and iodine (J, lodo-) atoms. Preferred in the context of the present invention are Br, CI and F.
  • dihalogen trihalogen
  • perhalogen refer to two, three and four substituents, respectively, each individually selected from the group consisting of fluorine, bromine, chlorine, and iodine atoms.
  • hydroxyl refers to the group -OH
  • thiol refers to the group -SH
  • sulfamoyl refers to the group -S0 2 -NH 2
  • nitro refers to the group -N0 2
  • nitrile or “cyano” refers to the group -CN
  • the carbon content of various hydrocarbon containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix -C j defines the number of carbon atoms present from the integer "i" to the integer "j" inclusive.
  • C r C 4 -alkyl refers to alkyl of 1-4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl and isomeric forms thereof.
  • alkyl stands for a hydrocarbon radical which may be linear, cyclic or branched, with single or multiple branching, whereby the alkyl group comprises 1 to 12 carbon atoms.
  • alkyl stands for a linear or branched (with single or multiple branching) alkyl chain of 1 to 8 carbon atoms, exemplified by the term (C-pCsJalkyl, more preferably of 1 to 4 carbon atoms exemplified by the term (C
  • (C ⁇ -C 8 )alkyl is further exemplified by such groups as methyl; ethyl; n-propyl; isopropyl; n-butyl; sec-butyl; isobutyl; tert-butyl; n-pentyl; isopentyl; neopentyl; tert-pentyl; 2- or 3-methylpentyl; n-hexyl; isohexyl, and the like.
  • the alkyl group may be partially unsaturated, forming such groups as, for example, propenyl (allyl), methyl-propenyl, butenyl, pentenyl, pentinyl, hexenyl, octadienyl, and the like.
  • alkyl further comprises cycloalkyl groups, preferably cyclo(C 3 -C 8 )alkyl which refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and isomeric forms thereof such as methylcyclopropyl; 2- or 3-methylcyclobutyl; 2-, or 3-methylcyclopentyl, and the like.
  • the cycloalkyl group may also be partly unsaturated, forming such groups as, for example, cyclohexenyl, cyclopentenyl, cyclooctadienyl, and the like.
  • alkyl comprises a cycloalkyl-alkyl group comprising 4 to 12 carbon atoms, preferably "cyclo(C 3 -C 8 )alkyl- (CrC 4 )alkyl” which refers to a alkyl group of 1 to 4 carbon atoms as described above substi- tuted with a cyclo(C 3 -C 8 )alkyl group as described above, forming such groups as for example cyclopropylnnethyl, cyclohexylmethyl, cyclopentylethyl or cyclohexenylethyl.
  • substituted alkyl refers to alkyl as just described and substituted by up to five, more preferably by up to three, most preferably by one or two substituents independently se- lected from the group consisting of halogen, hydroxyl, thiol, nitro, nitrile, alkoxy, aryloxy, acyloxy, amino, amido, acylamino, alkylthio, arylthio, acyl, carboxyl, sulfamoyl, sulfonamide, and alkylsulfonyl , as defined herein. These groups may be attached to any carbon atom of the alkyl moiety.
  • substituted alkyl refers to substituted C-i-C/ t -alkyl.
  • Halogenated alkyl, halogenated alkoxy and halogenated alkylthio are substituents in which the alkyl moieties (preferably (C ⁇ -C 6 )alkyl, more preferably (C ⁇ -C 4 )alkyl, and most preferably methyl) are substituted either partially or in full with halogens, generally with chlorine and/or fluorine.
  • Preferred examples of such substituents are trifluoromethyl, trifluoromethoxy, trifluoromethylthio, dichloromethyl, pentafluoroethyl, dichloropropyl, fluoromethyl and difluoro- methyl.
  • alkoxy refers to a group -OR, where R may be alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl or substituted heteroarylalkyl as defined herein, wherein the alkyl chain may be optionally further substituted as defined herein.
  • alkoxy refers to - 0-(Ci-C 4 )alkyl (or (CrC )alkoxy), with the (C C 4 )alkyl group as defined above, or to -0-(C C 4 )alkyl-phenyl, preferably benzoxy or phenethyloxy, optionally substituted in the aryl group with up to five independently selected substituents, in particular hydroxyl, halogen, (C-
  • aryloxy refers to a group -OAr, where Ar may be aryl, substituted aryl, heteroaryl or substituted heteroaryl as defined herein.
  • Ar represents aryl as defined herein, which is optionally substituted in the aryl group with up to five independently selected substituents, in particular hydroxyl, halogen, (C ⁇ -C 4 )-alkyl, (C ⁇ -C )-alkoxy, halogenated (C C 4 )- alkyl, or halogenated (C C 4 )-alkoxy; the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents.
  • aryloxy refers to phenoxy, optionally substituted as defined above.
  • acyloxy refers to a group -O-CO-R, where R may be alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl as defined herein, wherein the alkyl chain may be optionally further substituted as defined herein.
  • alkylacyloxy represents a preferred selection of the term “acyloxy” and refers to the group -0-CO-C ⁇ -C 12 -alkyl, preferably to -0-CO-C ⁇ -C 8 -alkyl, and most preferably to -O- CO-C r C 4 -alkyl.
  • arylacyloxy represents a preferred selection of the term “acyloxy” and refers to the group —O-CO-Ar, wherein Ar represents aryl as defined herein, preferably phenyl, which is optionally substituted in the aryl group with up to five independently selected substit uents, in particular hydroxyl, halogen, (C- ⁇ -C )-aIkyl, (CrC 4 )-alkoxy, halogenated (CrC 4 )-alkyl, or halogenated (C ⁇ -C 4 )-alkoxy; the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents
  • heteroaryl-acyloxy represents a preferred selection of the term “acyloxy” and refers to the group -O-CO-HetAr, wherein HetAr represents heteroaryl as defined herein, preferably thienyl, furyl or pyridinyl.
  • carbonyl represents a preferred selection of the term “acyl” and refers to the group -CHO.
  • arylacyl represents a preferred selection of the term “acyl” and refers to the group -CO-Ar, wherein Ar represents aryl as defined herein, preferably phenyl, which is optionally substituted in the aryl group as defined herein.
  • heteroarylacyl represents a preferred selection of the term “acyl” and refers to the group -CO-HetAr, wherein HetAr represents heteroaryl as defined herein, preferably thienyl, furyl or pyridinyl.
  • alkylthio (“alkylsulfanyl”) and “alkylsulfonyl” refers to a group -SR and - respectively, where R may be alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl or substituted heteroarylalkyl, as defined herein.
  • Ar represents aryl, which is optionally substituted in the aryl group with independently selected substituents as defined herein, in particular hydroxyl, halogen, (C 1 -C 4 )-alkyl, (C C ⁇ -alkoxy, halogenated (C C 4 )-alkyl, or halogenated (C C 4 )-alkoxy, the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents.
  • arylthio refers to phenylsulfanyl, optionally substituted as defined above.
  • amino refers to the group -NRR', where R and R' may independently be hydrogen, alkyl (optionally substituted in the alkyl chain with up to five independently selected substituents as defined herein, in particular hydroxyl, halogen or (C ⁇ -C )-alkoxy), aryl or aryl- (C ⁇ -C 4 )-alkyl (both optionally substituted in the aryl group with up to five independently selected substituents as defined herein, in particular hydroxyl, halogen, (C C 4 )-alkyl, (CrC ⁇ -alkoxy, halogenated (CrC ⁇ -alkyl, or halogenated (C C 4 )-alkoxy, the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents), heteroaryl or heteroaryl-(C 1 -C 4 )-alkyl (both optionally substituted in the heteroaryl group with up to three independently selected substituents), ary
  • alkylamino represents a preferred selection of the term “amino” and refers to the group -NRR', where R and R' may independently be hydrogen or (CrC 4 )alkyl.
  • acylamino refers to the group -NR-CO-R', where R and R' may independently be hydrogen, alkyl (optionally substituted in the alkyl chain with up to five independently se- lected substituents as defined herein, in particular hydroxyl, halogen or (C ⁇ -C 4 )-alkoxy), aryl or aryl-(CrC 4 )-alkyI (both optionally substituted in the aryl group with independently selected substituents as defined herein, in particular hydroxyl, halogen, (CrC 4 )-alkyl, (C C 4 )-alkoxy, halogenated (C ⁇ -C 4 )-alkyl, or halogenated (CrC )-aIkoxy, the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents), heteroaryl or heteroaryl-(C ⁇ -C 4 )-alkyl (both optionally substituted in the hetero
  • carbonylamino represents a preferred selection of the term “acylamino” and refers to the group -NR-CO-CH 2 -R', where R and R' may be independently selected from hydrogen or (d-C 4 )alkyl.
  • sulfonamide refers to the group -S0 2 -NRR', wherein R and R' may independently be selected from hydrogen or (C 1 -C 4 )alkyl.
  • aryl refers to an aromatic carbocyclic group comprising 6 to 14, more preferably 6 to 10, carbon atoms and having at least one aromatic ring or multiple condensed rings in which at least one ring is aromatic.
  • aryl is phenyl, naphthyl, indanyl, indenyl, fluo- renyl, 1,2,3,4-tetrahydro-naphthalen-1-yl or even biphenyl.
  • heteroaryl refers to an aromatic carbocyclic group of having a single 4 to 8 membered ring or multiple condensed rings comprising 6 to 14, more preferably 6 to 10, ring atoms and containing at least one heteroatom, such as N, O or S, within at least one ring, the number of N atoms being 0-3 and the number of O and S atoms each being 0-1; in which group at least one heterocyclic ring is aromatic.
  • Examples of such groups include pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, benzoimidazolyl, 1 ,3-dihydro-benzoimidazolyl, benzofuran, benzo[b]thiophene and the like.
  • heteroaryl is quinolinyl, furyl, benzoimidazolyl, pyridinyl, thienyl, indolyl, benzo[b]thiophene, pyridinyl, imidazolyl, pyrazolyl or thiazolyl.
  • the aryl and the heteroaryl group may optionally be substituted by substituents independently selected from the group consisting of halogen, hydroxyl, (C ⁇ -C 6 )alkoxy, (C 1 -C 6 )alkyl, halogenated (C ⁇ -C 6 )alkyl, halogenated (C ⁇ -C 6 )alkoxy, oxo, thiol, nitro, nitrile, sulfamoyl, sulfonamide, carboxyl, aryloxy or arylalkyloxy (both optionally substituted in the aryl moiety with independently selected substituents as defined herein), (G
  • the heteroaryl group may further be optionally substituted with an aryl or an aryloxy group, which aryl group may be optionally substituted in the aryl moiety with substituents, especially hydroxyl, halogen, (C 1 -C 6 )alkoxy, (C C ⁇ )alkyl, halogenated (C ⁇ -C 6 )alkyl or halogenated (C
  • the aryl group may further be optionally substituted with a heteroaryl group.
  • Substituted aryl is preferably substituted by substituents selected from the group consisting of (C C ⁇ )alkoxy, preferably methoxy, hydroxyl, (C ⁇ -C )alkyl, halogen, halogenated (C C 4 )alkyl, pre ferably halogenated methyl, most preferably trifluoromethyl, halogenated (C C 6 )alkoxy, and sulfonamide, the number of said substituents being up to five for halogen, and up to four, preferably up to three, for any combination of said other substituents.
  • substituents selected from the group consisting of (C C ⁇ )alkoxy, preferably methoxy, hydroxyl, (C ⁇ -C )alkyl, halogen, halogenated (C C 4 )alkyl, pre ferably halogenated methyl, most preferably trifluoromethyl, halogenated (C C 6 )alkoxy, and sulfonamide
  • the aryl may be further substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly unsaturated cyclic 5, 6, 7, or 8 membered ring system, optionally containing up to three heteroatoms, such as N, O or S, the number of N atoms being 0-3 and the number of O and S atoms each being 0-2.
  • the two groups which are attached to adjacent carbon atoms are combined into a saturated cyclic 5 or 6 membered ring system, optionally containing up to three heteroatoms, such as N or O, the number of N atoms being 0-3 and the number of O atoms each being 0-2.
  • This cyclic ring system may optionally be further substituted by an oxo group.
  • Preferred examples of such a substituted aryl groups are benzo[1 ,3]dioxol, 2,3-dihydrobenzofuran, 3H-isobenzofuran-1-one and 1,3-dihydro- benzoimidazol-2-one.
  • Substituted heteroaryl is preferably substituted by up to three, preferably up to two sub- stituents selected from the group consisting of halogen, (CrC 4 )-alkoxy, (C C )-alkyl, preferably methyl, (d-C 4 )-alkyl-carboxyl, preferably carboxylmethylester, halogenated (C ⁇ -C 4 )-alkyl, preferably halogenated methyl, halogenated (C C 4 )-alkoxy, phenoxy (optionally substituted with up to three, preferably one halogen), benzyloxy, benzyl or phenyl.
  • sub- stituents selected from the group consisting of halogen, (CrC 4 )-alkoxy, (C C )-alkyl, preferably methyl, (d-C 4 )-alkyl-carboxyl, preferably carboxylmethylester, halogenated (C ⁇ -
  • cycloheteroalkyl refers to a four- to eight-membered heterocyclic ring containing at least one heteroatom, such as N, O or S, the number of N atoms being 0-3 and the number of O and S atoms each being 0-1, which system may be saturated, partly unsaturated or hydroaromatic, and which ring can be part of a multiple condensed ring-system in which some rings may be aromatic.
  • cycloheteroalkyls examples include pyrrolidinyl, tetrahydrofur l, tetrahydrothiophenyl, tetrahydropyridinyl, dioxolyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperid- inyl, morpholinyl, thiornorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, thiazepanyl, dihydro-1H-pyrrolyl, 1 , 3-dihydro-benzoimidazolyl and the like.
  • cycloheteroalkyl groups are pyrrolidinyl, morpholinyl, tetrahydrofuryl, piperidinyl or dioxolyl.
  • the cycloheteroalkyl group may optionally be substituted by up to three substituents, independently selected from the group consisting of oxo, alkyl, aryl or aryl-(C C 4 )-alkyl (both optionally substituted in the aryl group with independently selected substituents as defined herein), hydroxyl, (CrC 6 )alkoxy, halogenated (C C 6 )alkyl, halogenated (C- ⁇ -C 6 )alkoxy, carboxyl- (C ⁇ -C 6 )alkyl, thiol, nitrile, sulfamoyl, sulfonamide, carboxyl, aryloxy or arylalkyloxy (both option- ally substituted in the aryl moiety with
  • cycloheteroalkyl may be attached to any carbon atom of the cycloheteroalkyl moiety.
  • Substituted cycloheteroalkyl is preferably substituted with oxo, (C ⁇ -C )alkyl, preferably methyl, phenyl and/or (d-C 4 )alkylphenyl, in particular benzyl.
  • arylalkyl refers to an alkyl group substituted with up to three independently selected aryl groups; preferably the term “arylalkyl” refers to "aryKd-C ⁇ -alkyl” or diaryl-(C C 4 )- alkyl, whereby the aryl is an aryl group as defined above.
  • Arylalkyl is preferably benzyl (-CH2- Phenyl) or phenethyl (-CH 2 -CH 2 -Phenyl).
  • substituted arylalkyl refers to an arylalkyl group as defined above, wherein the aryl group is substituted as defined above.
  • heteroarylalkyl refers to an alkyl group substituted with up to three independently selected heteroaryl groups; preferably the term “heteroarylalkyl” refers to "heteroaryl-(C C )-alkyl", whereby the heteroaryl is a heteroaryl group as defined above.
  • substituted heteroarylalkyl refers to a heteroarylalkyl group as defined above, wherein the heteroaryl group is substituted as defined above.
  • cycloheteroalkyl-alkyl refers to an alkyl group substituted with up to three independently selected cycloheteroalkyl groups; preferably the term “cycloheteroalkyl-alkyl” refers to "cycloheteroalkyl -(C ⁇ -C )-alkyl", whereby the cycloheteroalkyl is a cycloheteroalkyl group as defined above.
  • "cycloheteroalkyl-alkyl” is morpholinylethyl, morpholinylpropyl, piperidinylethyl, tetrahydrofurylmethyl or pyrrolidinylpropyl.
  • substituted cycloheteroalkyl-alkyl refers to a cycloheteroalkyl-alkyl group as defined above, wherein the cycloheteroalkyl-alkyl group is substituted as defined above.
  • substituted cycloheteroalkyl-alkyl is dimethyl-[1 ,3]-dioxolylmethyl or 2-oxo-pyrrolidinyl- propyl.
  • pro-drug represents derivatives of the compounds of the in- vention that are drug precursors which, following administration to a patient, release the drug in vivo via a chemical or physiological process.
  • pro-drugs are derivatives of the compounds of the invention in which functional groups carry additional substituents which may be cleaved under physiological conditions in vivo and thereby releasing the active principle of the compound (e. g., a pro-drug on being brought to a physiological pH or through an enzyme action is converted to the desired drug form).
  • pharmaceutically acceptable salts refers to salt forms that are pharmacologi- cally acceptable and substantially non-toxic to the subject being administered the compounds of the invention.
  • Pharmaceutically acceptable salts of compounds of formula I include conventional and stoichiometrical acid-addition salts or base-addition salts formed from suitable non-toxic organic or inorganic acids or inorganic bases. Acid addition salts, for example, from compounds of formula I with a basic nitrogen atom are formed preferably with organic or inorganic acids. Suitable inorganic acids are, for example, halogenic acids such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • Suitable organic acids are, for example, carboxylic, phosphonic, or sulfonic acids, for example acetic acid, propionic acid, glycolic acid, lactic acid, hydroxybutyric acid, malic acid, malenic acid, malonic acid , salicylic acid, fumaric acid, succinic acid, adipic acid, tartaric acid, citric acid, glutaric acid, 2- or 3-glycerophosphoric acid and other mineral and carboxylic acids well known to those skilled in the art.
  • the salts are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce a salt in the conventional manner.
  • Compounds containing acidic substituents may also form salts with inorganic or organic bases.
  • suitable bases for salt formation include, but are not limited to, inorganic bases such as alkali or alkaline earth-metal (e.g., sodium, potassium, lithium, calcium, or magnesium) hydroxides, and those derived from ammonium hydroxides (e.g., a quaternary ammonium hydroxide such as tetramethylammonium hydroxide).
  • inorganic bases such as alkali or alkaline earth-metal (e.g., sodium, potassium, lithium, calcium, or magnesium) hydroxides, and those derived from ammonium hydroxides (e.g., a quaternary ammonium hydroxide such as tetramethylammonium hydroxide).
  • salts formed with pharmaceutical acceptable amines such as ammonia, alkyl amines, hydroxyal- kylamines, N-methylglucamine, benzylamines, piperidines, and pyrrolidines and the like.
  • Certain compounds will be acidic in nature, e.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • an effective amount means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e. g., provide a positive clinical response).
  • the effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician.
  • R1 and R2 may be individually selected from the group consisting of -C ⁇ -C, 2 -alkyl, which alkyl can be linear, cyclic, branched or partially unsaturated, and which can be optionally substituted with up to three substituents individually selected from the group consisting of hydroxyl, CrC ⁇ -alkoxy, thiol, CrC 12 -alkylthio, aryloxy, aryla- cyl, -CO-OR, -O-CO-R, heteroaryl-acyloxy, and -N(R) 2 ; whereby said aryl group is phenyl or naphthyl, and can be optionally substituted with up to three halogen; whereby said heteroaryl group is thienyl, furyl or pyridinyl aryl and aryl-CrC 12 -alkyl, which aryl is selected from the group consisting of phenyl, biphenyl, naphthyl, indanyl
  • R2 itself may be independently selected from -CO-R, -CO-O-R, or -CO-N(R) 2 ;
  • R3 and R4 are individually selected from the group consisting of hydrogen, oxo, thio, halogen or dihalogen, -CO-R, preferably CHO, -CO-O-R, nitrile, -CO-N(R) 2 , -O-CO-R, -O-R, -S-R, -N(R) 2 , -C
  • R represents hydrogen, Crd-alkyl, phenyl-C ⁇ -C 4 -alkyl or phenyl, optionally substituted in the phenyl moiety with up to three substituents selected from the group consisting of halogen, hydroxyl, and d-C 4 -alkoxy, preferably methoxy.
  • At least one of the substituents R3 to R6 shall be different from hydrogen, particularly in case the six-membered ring comprising the hydrocarbon chain -C(R3)-C(R4)-C(R5)-C(R6)- is not an aromatic ring.
  • Especially preferable compounds are those where the six-membered ring comprising the hydrocarbon chain -C(R3)-C(R4)-C(R5)-C(R6)- is an aromatic ring.
  • Particularly preferable compounds of formula (I) are those where R2 is selected from the group consisting of
  • -CrC 8 -alkyl which alkyl can be linear, cyclic, branched or partially unsaturated, and which can be optionally substituted with up to three substituents individually selected from the group consisting of hydroxyl, dCs-alkoxy, thiol, d-C 8 -alkylthio, aryloxy, -CO-O- C r C 8 -alkyl, and -O-CO-R'; whereby said aryl group is phenyl or naphthyl, and can be optionally substituted with up to three halogen; aryl and aryl-CrC 8 -alkyl, which aryl is selected from the group consisting of phenyl, biphenyl, naphthyl, indanyl, indenyl and fluorenyl, whereby the aryl moiety can be optionally substituted with up to five substituents individually selected from the group consisting of halogen, hydroxyl, d-
  • R' represents hydrogen or d-d-alkyl
  • R7 is hydrogen, halogen, hydroxyl or C C 4 -alkoxy, preferably methoxy
  • R8 is hydrogen, C C 4 -alkoxy, preferably methoxy, hydroxyl, nitrile, halogen, or halogenated C C 4 -alkyl, preferably trifluormethyl
  • R9 is hydrogen, d-d-alkoxy, preferably methoxy, hydroxyl, nitrile, halogen, or N,N-di-d-C 4 - alkyl-sulphonamide
  • R10 is hydrogen, C C -alkoxy, preferably methoxy, hydroxyl, nitrile, halogen, or halogenated d-d-alkyl, preferably trifluormethyl
  • R11 is hydrogen, halogen, hydroxyl or d-C -alkoxy, preferably methoxy
  • alkyl can be linear, cyclic, branched or partially unsaturated
  • -d-d-alkyl substituted with one or two substituents selected from the group consisting of -CO-O-R"; -O-R"; -O-Ar, whereby Ar is phenyl optionally substituted with halogen; -O-CO-R", phenyl or biphenyl, optionally substituted in the phenyl moiety with up to three d-C 4 - alkoxy, preferably methoxy, groups; -CO-O-R", -CO-R", preferably -CHO -naphthyl,
  • heteroaryl which can be selected from the group consisting of thienyl, furyl, pyridinyl, ben- zothienyl, and pyrazoloyl, whereby the heteroaryl group can be optionally substituted by one or two substitu- ents individually selected from the group consisting of halogen, d-C -alkyl, halogenated d-d-alkyl, preferably trifluormethyl, phenyl and phenoxy, whereby the phenyl group can be optionally substituted with up to three halogen;
  • R" represents hydrogen or d-d-alkyl, preferably methyl or ethyl.
  • R2 is selected from the group consisting of a residue of formula (II)
  • R7 is hydrogen, bromo, chloro, or fluoro
  • R8 is hydrogen, d-C 4 -alkoxy, preferably methoxy, or hydroxyl
  • R9 is hydrogen, d-C 4 -alkoxy, preferably methoxy, or hydroxyl
  • R10 is hydrogen, C C -alkoxy, preferably methoxy, or hydroxyl
  • R11 is hydrogen
  • -d-d-alkyl which alkyl can be linear, cyclic, or branched; optionally substituted with an -O- CO-(d-C 4 )-alkyl or -CO-0-(C C 4 )-alkyl group; and -heteroaryl which can be selected from the group consisting of thienyl, furyl, pyridinyl, ben- zothienyl, and pyrazoloyl.
  • R2 is methoxyphenyl, trimethoxyphenyl, 2- bromo-3,4,5-trimethoxyphenyl, 2-chloro-3,4,5-trimethoxyphenyl, thienyl, or propyl.
  • Particularly preferable compounds of formula (I) are those where R1 is selected from the group consisting of
  • alkyl can be linear, cyclic, branched or partially unsaturated, and which can be optionally substituted with up to three substituents individually selected from the group consisting of hydroxyl, C ⁇ -C 8 -alkoxy, thiol, -NH 2 , C ⁇ -C 8 -alkylthio, aryloxy, arylacyl, -CO-0-d-C 8 -alkyl, Ci-d-alkylacyloxy, heteroaryl-acyloxy, and d-C 8 - alkylamino; whereby said aryl group is phenyl or naphthyl, and can be optionally substituted with up to three halogen; whereby said heteroaryl group is thienyl, furyl or pyridinyl, aryl and aryl-d-d-alkyl, which aryl moiety is selected from the group consisting of phenyl, biphenyl, naphthyl
  • alkyl can be linear, cyclic or branched
  • aryl and aryl-C C 4 -alkyl which aryl moiety is selected from the group consisting of phenyl, indanyl, and fluorenyl, wherein the alkyl moiety can be optionally substituted with a hydroxyl group; and wherein the aryl moiety can be optionally substituted with up to three substituents individually selected from the group consisting of halogen, -O-R"; -S0 2 -R", -S0 2 -N(R") 2 , or which aryl may be optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated cyclic 5 or 6 membered ring
  • Ar represent phenyl, optionally substituted with halogen or methoxy
  • HetAr represents thienyl, furyl, pyridinyl
  • R" represents hydrogen or C 1 -C 4 -aIkyl, preferably methyl or ethyl.
  • R1 is selected from the group consisting of
  • alkyl can be linear, cyclic or branched, -d-C 4 -alkyl, substituted with one or two substituents independently selected from the group consisting of C C 4 -alkoxy, hydroxyl, and -O-CO-HetAr, phenyl-d-d-alkyl, wherein the aryl moiety can be optionally substituted with up to three substituents individually selected from the group consisting of halogen, d-d-alkoxy, and hydroxyl, heteroaryl-d-d-alkyl, which heteroaryl moiety is selected from the group consisting of pyrimid- inyl, furyl, pyridinyl, and thienyl, whereby the heteroaryl group can be optionally substituted with one or two su b- stituents individually selected from the group consisting of halogen, d-d-alkoxy, and hydroxyl, and cycloheteroal
  • R1 substituents are those where R1 is selected from the group consisting of isobutyl, 3-methylbutyl, benzyl, phenethyl, tetrahydrofurylmethyl, furylmethyl, 5-bromo-furan-2- ylmethyl, 5-bromo-2-methoxybenzyl, thiophene-2-carboxylic acid ethyl ester, and methoxyethyl.
  • Particularly preferable compounds of formula (I) are those, where in R3 is selected from the group consisting of hydrogen, oxo, -O-R', -O-Ar, -O-CO-R', halogen, thio, -S-R', and -S-Ar, wherein R' represents hydrogen or C C 8 -alkyl, Ar represents phenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy or methoxy.
  • R3 is selected from the group consisting of hydrogen, oxo, -O-R", -O-Ar, -O-CO-R", halogen, thio, -S-R", and -S-Ar; wherein R" represents hydrogen or d-d-alkyl, preferably methyl or ethyl, and Ar represent phenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy or methoxy.
  • R3 substituents are those where R3 is selected from the group consisting of hydrogen, hydroxyl, oxo, chloro, bromo, phenoxy, phenylthio, C C 4 -alkoxy, C ⁇ -C 4 -alkylthio, and -O-CO-d-d-alkyl.
  • R3 substituents are those where R3 is selected from the group consisting of hydrogen, hydroxyl, oxo, -0-CO-CH 3 , and -S-ethyl.
  • Particularly preferable compounds of formula (I) are those, where in R4 is selected from the group consisting of hydrogen, C ⁇ -C 8 -alkyl, optionally substituted with hydroxyl; -CO-R', -CO-O- R', halogen and dihalogen, wherein R' represents hydrogen or d-d-alkyl.
  • Most preferable compounds of formula (I) are those, where R4 is selected from the group consisting of hydrogen, d-d-alkyl, optionally substituted with hydroxyl; -CO-R", -CO-O-R", halogen and dihalogen wherein R" represents hydrogen or C C 4 -alkyl, preferably methyl or ethyl.
  • R4 is different from d-C 4 -alkyl, in case R1 is benzyl.
  • R4 substituents are those where R4 is selected from the group consisting of hydrogen, halogen, carbonyl, and -CO-CrC -alkyl.
  • R4 substituents are those where R4 is selected from the group consisting of hydrogen, bromo and carbonyl.
  • Preferred compounds of formula (I) are further those wherein R6 is hydrogen or halogen, pref- erably bromo.
  • Preferred compounds of formula (I) are further those wherein X represents S.
  • Especially preferable compounds of formula (I) are the compounds of formula (I)
  • X is S, SO or S0 2 ;
  • R1 is selected from the group consisting of:
  • alkyl can be linear, cyclic or branched
  • -d-d-alkyl substituted with one or two substituents independently selected from the group consisting of d-d-alkoxy, hydroxyl, and -O-CO-HetAr, phenyl-d-C 4 -alkyl, wherein the aryl moiety can be optionally substituted with up to three substituents individually selected from the group consisting of halogen, C ⁇ -C 4 -alkoxy, and hydroxyl, heteroaryl-d-C -alkyl, which heteroaryl moiety is selected from the group consisting of pyrimid- inyl, furyl, pyridinyl, and thienyl, whereby the heteroaryl group can be optionally substituted with one or two su bstituents individually selected from the group consisting of halogen, d-d-alkoxy, and hydroxyl, and cycloheteroalkyl-C ⁇ -C 4 -alkyl, which cycloheteroalkyl moiety is
  • R2 is selected from the group consisting of i) a residue of formula (II)
  • R7 is hydrogen, bromo, chloro, orfluoro
  • R8 is hydrogen, d-d-alkoxy, preferably methoxy, or hydroxyl
  • R9 is hydrogen, C 1 -C 4 -alkoxy, preferably methoxy, or hydroxyl
  • R10 is hydrogen, d-C 4 -alkoxy, preferably methoxy, or hydroxyl
  • R11 is hydrogen
  • alkyl can be linear, cyclic, or branched; optionally substituted with an -O- CO-(C C 4 )-alkyl or -CO-0-(C C 4 )-alkyl group ; -heteroaryl which can be selected from the group consisting of thienyl, furyl, pyridinyl, ben- zothienyl, and pyrazoloyl;
  • R3 is selected from the group consisting of hydrogen, oxo, hydroxyl, C ⁇ -C 4 -alkoxy, -O-CO-d- C 4 -a!kyl, and d-d-alkylthio;
  • R4 is selected from the group consisting of hydrogen, halogen, carbonyl, -CO-d-C 4 -alkyl, and
  • R6 is hydrogen or bromo.
  • a particularly preferred subgroup of the aforementioned group are compounds, wherein R1 is selected from the group consisting of isobutyl, 3-methylbutyl, benzyl, tetrahydrofurylmethyl, furylmethyl, 5-bromo-furan-2-ylmethyl, 5-bromo-2-methoxybenzyl, thiophene-2- carboxylic acid ethyl ester, and methoxyethyl;
  • R2 is selected from the group consisting of methoxyphenyl, trimethoxyphenyl, 2-bromo-3,4,5- trimethoxyphenyl, 2-chloro-3,4,5-trimethoxyphenyl, thienyl, and propyl;
  • R3 is selected from the group consisting of hydroxyl, oxo, -0-CO-CH 3 , and -S-ethyl;
  • R4 is selected from the group consisting of hydrogen, bromo and carbonyl
  • R6 is hydrogen or bromo.
  • the present invention comprises compounds, wherein
  • R1 is linear, cyclic or branched -C 3 -C 8 -alkyl
  • R2 is trimethoxyphenyl, 2-bromo-3,4,5-trimethoxyphenyl, or 2-chloro-3,4,5-trimethoxyphenyl,
  • R3 is hydrogen or hydroxyl
  • R4 is hydrogen
  • R6 is hydrogen or bromo
  • the six-membered ring comprising the hydrocarbon chain -C(R3)-C(R4)-C(R5)-C(R6)- is an aromatic ring.
  • the invention relates to a compound selected from the group con- sisting of exemplary compounds
  • the invention also relates to pharmaceutical compositions comprising one or more of the compounds of the invention for which no use in therapy has been disclosed earlier, or their salts or pro-drugs, as active agent and at lease one pharmaceutically acceptable carrier.
  • the invention relates to the use of an effective amount of a novel compound as defined herein for the treatment or prevention of a steroid hormone dependent disease or disorder in a mammal, in particular a human.
  • a steroid hormone dependent dis- ease or disorder is an estradiol or testosterone dependent disease or disorder.
  • the invention relates to the use of an effective amount of a novel compound as defined within the present invention for the treatment or prevention of a steroid hormone dependent disease or disorder in a mammal, whereby the steroid hormone dependent disease or disorder requires the inhibition of a 17 ⁇ -hydroxysteroid dehydrogenase (HSD) enzyme, preferably the human 17 ⁇ -hydroxy steroid dehydrogenase (HSD) enzyme type 1 , type 2 or type 3.
  • HSD 17 ⁇ -hydroxysteroid dehydrogenase
  • HSD human 17 ⁇ -hydroxy steroid dehydrogenase
  • the steroid hormone dependent dis- ease or disorder to be treated and/or prevented requires the lowering of the endogenous 17 ⁇ - estradiol or testosterone concentration in a generalized and/or tissue specific manner.
  • the invention also relates to a method of treating a mammal such as a human having a condition related to 17 ⁇ -hydroxysteroid dehydrogenase (HSD) type 1, type 2 or type 3 activity, comprising administering to the mammal an amount of a compound of this invention, or a salt or a prodrug thereof, which amount is effective to treat the condition.
  • a mammal such as a human having a condition related to 17 ⁇ -hydroxysteroid dehydrogenase (HSD) type 1, type 2 or type 3 activity
  • HSD 17 ⁇ -hydroxysteroid dehydrogenase
  • the conditions to be treated and/or prevented in the context of the present invention include but are not limited to breast cancer, prostate carcinoma, ovarian cancer, uterine cancer, endometrial cancer, endometrial hyperplasia, endometriosis, uterine fibroids, uterine leio- myoma, adenomyosis, dysmenorrhea, menorrhagia, metrorrhagia, prostadynia, benign prostatic hyperplasia, prostatitis, acne, seborrhea, hirsutisrn, androgenic alopecia, precocious puberty, adrenal hyperplasia, polycystic ovarian syndrome,and urinary dysfunction.
  • a further condition to be treated and/or prevented in the context of the present invention includes osteoporosis.
  • estrogen-dependent diseases which may be treated and/or prevented with an ef- fective amount of a compound of the invention are multiple sclerosis, rheumatoid arthritis, Alzheimer's disease, colon cancer, tissue wounds, skin wrinkles and cataracts.
  • the invention relates to use of an effective amount of a compound of the invention for the treatment or prevention of one of the aforementioned disease or disorders in a mammal whereby the mammal is a human, preferably a female and most preferably a pre- or peri-menopausal female in the case of gynaecological disorders.
  • compounds of formula (I) may be useful for blocking spermatogenesis and as an anti-fertility agent for males.
  • the disclosed compounds are also useful as diagnostic agents (e.g. in diagnostic kits or for use in clinical laboratories) for screening for the presence or absence of 17 ⁇ -hydroxysteroid dehydrogenase (HSD) type 1 , type 2 and/or type 3 activity.
  • HSD 17 ⁇ -hydroxysteroid dehydrogenase
  • the methods of the present invention can be incorporated in the form of a variety of embodiments, only a few of which are disclosed herein. It will be apparent for the expert skilled in the field that other embodiments ex ist and do not depart from the spirit of the invention. Thus, the described embodiments are illustrative and should not be construed as restrictive.
  • the method of the invention is primarily intended for treatment in a mammal, preferably in humans and other primates, of steroid hormone dependent diseases or disorders, in particular estradiol dependent diseases or disorders, wherein the steroid hormone dependent disease or disorder preferably requires the inhibition of a 17 ⁇ -hydroxysteroid dehydrogenase (HSD) enzyme, preferably the type 1 17 ⁇ -hydroxysteroid dehydrogenase (HSD) enzyme [EC 1.1.1.62].
  • HSD 17 ⁇ -hydroxysteroid dehydrogenase
  • HSD type 1 17 ⁇ -hydroxysteroid dehydrogenase
  • the compounds may be administered orally, dermally, parenterally, by injection, by pulmonal or nasal delivery, or sublingually, rectally or vaginally in dosage unit formulations.
  • administered by injection includes intravenous, intraarticular, intramuscular (e.g. by depot injection where the active compounds are released slowly into the blood from the depot and carried from there to the target organs), intraperitoneal, intradermal, subcutaneous, and intrathecal injections, as well as use of infusion techniques.
  • Dermal administration may include topical application or transdermal administration.
  • One or more compounds may be present in association with one or more non-toxic pharmaceutically acceptable auxiliaries such as excipients, adjuvants (e.g.
  • buffers such as, but not limited to, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styl, sulfate, styl, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene, styrene,
  • the pharmaceutical composition may be formulated for example as immediate release, sustained release, pulsatile release, two or more step release, depot or other kind of release formulations.
  • auxiliaries as well as further suitable diluents, flavorings, sweetening agents, coloring agents etc. may be used, depending on the intended mode of administration as well as particular characteristics of the active compound to be used, such as solubility, bioavailability etc.
  • Suitable auxiliaries and further ingredients may be such as recommended for pharmacy, cosmetics and related fields and which preferably are listed in the European Pharmacopoeia, FDA approved or cited in the "GRAS" list (FDA List of food additives that are 'generally recognized as safe' (GRAS)).
  • One mode of application of the compounds of general formula (I) or of pharmaceutical compositions comprising one or more of said compounds is oral application, e. g., by tablets, pills, dragees, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixiers, solid emulsions, solid dispersions or dispersible powders.
  • the compounds suitable for the purposes of the present invention as defined above can be admixed with commonly known and used adjuvants and excipients such as for example, gum arabic, talcum, starch, sugars (such as, e. g., mannitose, methyl cellulose, lactose), gelatin, surface-active agents, magnesium stearate, aqueous or non-aqueous solvents, paraffin derivatives, cross-linking agents, dispersants, emulsifiers, lubricants, conserving agents, flavoring agents (e. g., ethereal oils), solubility enhancers (e.
  • adjuvants and excipients such as for example, gum arabic, talcum, starch, sugars (such as, e. g., mannitose, methyl cellulose, lactose), gelatin, surface-active agents, magnesium stearate, aqueous or non-aqueous solvents, paraffin derivatives, cross-
  • the active ingredients may also be dispersed in a microparticle, e. g. a nanoparticulate, composition.
  • the active agents can be dissolved or suspended in a physiologically acceptable diluent, such as, e. g., water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers.
  • a physiologically acceptable diluent such as, e. g., water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers.
  • oils for example and without limitation, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil may be used.
  • the active agent can be in the form of an aqueous, lipid, oily or other kind of solution or suspension or even administered in the form of liposomes or nano-suspensions.
  • Transdermal application can be accomplished by suitable patches, as generally known in the art, specifically designed for the transdermal delivery of active agents, optionally in the presence of specific permeability enhancers. Furthermore, also emulsions, ointments, pastes, creams or gels may be used for transdermal delivery.
  • intravaginal devices e. g. vaginal rings
  • IUS intrauterine systems
  • the compounds may also be administered in the form of suppositories.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug.
  • a depot implant comprising an inert carrier material, such as biologically degradable polymers or synthetic silicones such as e. g. silicone rubber.
  • an inert carrier material such as biologically degradable polymers or synthetic silicones such as e. g. silicone rubber.
  • Such implants are designed to release the active agent in a controlled manner over an extended period of time (e. g., 3 to 5 years).
  • the actually required dosages of the agents of this invention for any given patient will depend upon a variety of factors, including, but not limited to the activity of the specific compound employed, the particular HSD type 1 , type 2 or type 3 related condition being treated, the particular composition formulated, the mode of administration, time and duration of administration, route of administration and the particular site being treated, and furthermore the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, rate of excretion, drug combinations, and the severity of the condition undergoing therapy.
  • an exemplary daily dose generally employed ill be from about 0.01 ⁇ g/kg to about 100 mg/kg of total body weight, whereby courses of treatment may be repeated at appropriate time intervals.
  • Administration of pro-drugs may be dosed at weight levels that are chemically equivalent to the weight levels of the fully active compounds.
  • the daily dosage for parenteral administration will generally be from about O.01 ⁇ g/kg to about 100 mg/kg of total body weight.
  • a daily rectal dosage regimen will generally be from about 0.01 ⁇ g/kg to about 200 mg/kg of total body weight.
  • a daily vaginal dosage regimen will generally be from about 0.01 ⁇ g/kg to about 100 mg/kg of total body weight.
  • the daily topical dosage regimen will generally be from about 0.1 ⁇ g to about 100 mg administered between one to four times daily.
  • the transdermal concentration will generally be that required to maintain a daily dose of from 0.01 ⁇ g/kg to 100 mg/kg of total body weight.
  • the compounds of the present invention may be prepared by use of known chemical reactions and procedures. Nevertheless, the following general preparative methods are presented to aid the reader in synthesizing the 17- ⁇ -Hydroxysteroid Dehydrogenase inhibitors with specific details provided below in the experimental section to illustrate working examples.
  • ⁇ /-substituted amides b can be prepared by variety of synthetic methods.
  • the treatment of acyl halides with primary amines is a general procedure for the preparation of amides.
  • Oxidation of compound c was performed by using oxidant like PCC (pyridinium chloro- chromate) affording 4,8-dione of the formula d.
  • Carbonyl compound d was formylated in the Vilsmeier reaction using phosphorous oxychloride in DlvlF affording chloroaldehydes of the formula e (Ref. Koeller, S., Lellouche, J.-P., Tetrahedron L.ett. 1999, 40, 7043.
  • Chloroaldehyde e was treated with alkyl and aryl alcohols or thiols in the presence of base to form compound of the formula f.
  • Aldehydes can be reduced to primary alcohols, i.&. compound of the formula g, by a number of reducing agents (e.g. LiAIH 4 and NaBH 4 ).
  • aromatic compounds of the formula j and k can be prepared by dehydrobromination of bromide derivatives of the formula h and i.
  • a catalyst e.g. ben- zoylperoxide afforded several different bromides which were isolated and identified.
  • a catalyst e.g. ben- zoylperoxide afforded several different bromides which were isolated and identified.
  • 3,4,5-trimethoxyphenyl group in the R2-position was monobrominated as well as ⁇ -bromo- and ⁇ , ⁇ -dibromo carbonyl derivatives were produced.
  • the aromatization was achieved by the use of microwaves. In microwave dielectric heating the temperature increase is uniform throughout the sample (Ref. Lidstroem, P. et al.
  • cleavage of ethers can be achieved by numerous reagents e.g. different acidic reagents or Lewis acids.
  • Methoxymethyl derivative I was easily demethylated by using boron tribromide according to the Scheme 3.
  • Alcohol m was acetylated to compound n by using a general procedure (AcOH, pyridine).
  • Carbonyl compounds of the formula c can be ⁇ -hydroxy lated or ⁇ -carbonylated according to the reaction route of Scheme 4.
  • Alternative route is, for example, the alkaline hydrolysis of ⁇ -bromo carbonyl compound affords ⁇ -hydroxy ketones of the formula o and ⁇ -diketones of the formula P
  • the compound No. 27 (1.0 g, 2.94 mmol) was dissolved in dichloromethane (30 ml), cooled with ice-bath and BBr 3 (2.9 ml, 2.94 mmol) was added. Stirring was continued at room temperature for five hours. Water (1 ml) was added and the solvent was evaporated. 10% NaOH-solution (10 ml) was added and stirred well for 10 min. The solution was acidified by HCI-addition. The product was extracted with EtOAc and organic phase was washed with brine. The crude prod- uct was recrystallized from ethanol.
  • the compound No. 28 (200 mg, 0.61 mmol) was dissolved in a solution of acetic acid anhydride (2 ml) and pyridine (1 ml) and stirred for an hour at room temperature. Water (5 ml) was added and the solid precipitate was isolated. The yield of the acetylated product was 213 mg (95%).
  • the compound No. 1 (100 mg, 0.22 mmol) was dissolved in dichloromethane.
  • BBr 3 (1M - solution, 220 ⁇ l, 0.22 mmol) was added.
  • the reaction mixture was stirred at room temperature and boron tribromide was added several times (portion-wise 100 ⁇ l) until the reaction was completed.
  • the reaction mixture was washed with water. Water phase was extracted with ethyl acetate and organic phase was washed with brine.
  • the crude product was purified by crystallization from CH 2 CI 2 .
  • the compound No. 25 (250 mg, 0.81 mmol) was dissolved in dichloromethane (10 ml) and benzoyl peroxide (1-2 mg) was added. The reaction mixture was refluxed and bromine (85 ⁇ l, 1.61 mmol, 200 mol-%) was added. Refluxing was continued until the reaction was compleated. The reaction mixture was washed with water (10 ml). The organic phase was evaporated and the precipitate was purified by flash chromatography. The compound No. 45 was isolated as a by-product. NMR (CDCI 3 ): 2.28 (s, 3H), 2.57-2.78 (m, 2H), 3.08-3.17 (m, 2H), 4.70 (m, 1H), 7.20-7.30 (5H). MS (TOF, ES+) m/z 411/413 (M + Na).
  • the compound No. 2 (2.0 g, 4. mmol, 100 mol-%) and benzoylperoxide (99 mg, 0.4 mmol, 10 mmol%) were dissolved in dichloromethane (40 ml). While the reaction mixture was refluxing bromine (440 ⁇ l, 8.4 mmol, 200 mol-%) in dichloromethane (16 ml) was added. Trie reaction was completed in 3.5 hours. The cooled reaction mixture was washed with water (40 ml). The organic phase was evaporated. The crude product was purified by chromatography using dichloromethane-EtOAc as an eluent. The compounds No. 47, 48 and 49 were isolated as byproducts.
  • the compound No. 47 (0.6 g, 1.0 mmol), NaOAc (1.66 g, 20.2 mmol) was dissolved in acetic acid (4 ml) in a microwave vial. The reaction mixture was heated with microwaves at 180 °C for an hour. Water (20 ml) was added to the reaction mixture and the product was extracted with EtOAc (5 x 30 ml). The crude product was purified by flash chromatography. The compounds No. 50, 51 and 52 were isolated as by-products.
  • the compound No. 46 (157 mg, 0.28 mmol) was dissolved in pyridine (4 ml). Powdered NaOH (23 mg, 0.56 mmol) dissolved in water (1 ml) was added to the reaction mixture. Stirring was continued at room temperature for 1.5 hours and the reaction mixture was poured into 1% HCI (10 ml) and the product was extracted with EtOAc (3 x 10 ml). The organic phase was washed with 5% NaHC03-solution (3 x 10 ml), water (3 x 10 ml) and brine (3 x 10 ml). The crude product was purified by flash chromatography.
  • amide thiophene-2-carboxylic acid 2-[(thiophene-2-carbonyl)-amino]-ethyl ester as one starting material.
  • the amide thio- phene-2-carboxylic acid 2-[(thiophene-2-carbonyl)-amino]-ethyl ester was prepared as usually using thiophene carbonyl chloride and ethanolamine as starting materials.
  • amide thiophene-2-carboxylic acid 2-(2-methoxy-ethyl)-amide was prepared as usually using thiophene carbonyl chloride and 2- methoxyethylamine as starting materials.
  • the compound No.135 (50 mg) was dissolved in a mixture of dichloromethane and methanol (v/v 1:1 , 2ml) and warmed at 40 °C for two days. The solvent was evaporated. The crude product was purified by chromatography using toluene-EtOAc (9:1) as an eluent.
  • the compound No. 135 (50 mg, 0.1 mmol) and K2C03 (25 mg) were stirred in ethanol for two hours. The solvent was evaporated. The precipitate was dissolved in dichloromethane and washed with water.
  • the LC-MS system consists of 2 Perkin Elmer series 200 micro-pumps.
  • the pumps are connected to each other by a 50 ⁇ tee mixer.
  • the mixer is connected to the Gilson 215 autosampler.
  • the LC methode consists of the following steps:
  • the auto sampler has a 2 ⁇ l injection loop.
  • the auto sampler is connected to a Varian Polaris C18 A 30*4.6 mm column with 3 ⁇ m particles.
  • the column is thermo stated in a Perkin Elmer series 200 column oven at 40°C.
  • the column is connected to an Applied Biosystems ABI 785 UV meter with a 2.7 ⁇ l flowcel.
  • the wavelength is set to 254 nm.
  • the UVmeter is connected to a Sciex API 150EX mass spectrometer having the following parameters (Scanrange: 150-900 Amu, Polarity: positive, Scan mode: profile, Resolution Q1: UNIT, Step size: 0.10 amu, Time per scan: 0.500 sec, NEB: 10, CUR: 10, IS: 5200, TEM: 325, DF: 30, FP: 225, EP: 10).
  • the light scattering detector is connected to the Sciex API 150.
  • the light scattering detector is a Sedere Sedex 55 operating at 50°C and 3 bar N 2 pressure.
  • the complete systems is controlled by a Dell optiplex GX400 computer operating under Windows NT.

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Abstract

This invention relates to novel thiophenepyrimidinone derivatives and their use in therapy, especially for use in the treatment and/or prevention of a steroid hormone de­pendent diseases or disorder, such as steroid hormone dependent diseases or disorders requiring inhibition of 17ß-hydroxysteroid dehydrogenase enzymes.

Description

Solvay Pharmaceuticals B.\Λ
NOVEL COMPOUNDS AND THEIR USE IN THERAPY
FIELD OF THE INVENTION
The present invention relates to novel thiophenepyrimidinone derivatives which represent inhibitory compounds of the 17β-hydroxysteroid dehydrogenase enzymes, preferably of the 17β- hydroxysteroid dehydrogenase type 1 (17β-HSD1), type 2 (17β-HSD2) or type 3 (17β-HSD3) enzyme, to their salts, to pharmaceutical preparations containing these compounds and to processes for the preparation of these compounds. Furthermore, the invention concerns the therapeutic use of said thiophenepyrimidinone derivatives, particularly their use in the treatment or prevention of steroid hormone dependent diseases or disorders, such as steroid hormone dependent diseases or disorders requiring the inhibition of 17β-hydroxysteroid dehydrogenase enzymes, in particular 17β-HSD type I enzymes, and/or requiring the modulation of the endogenous 17β-estradiol and/or testosterone concentration. BACKGROUND OF THE INVENTION
The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
Mammalian 17β-Hydroxysteroid dehydrogenases (17β-HSDs) are NAD(H) or NADP(H) dependent enzymes which catalyze - besides other reactions - the final steps in male and female sex hormone biosynthesis. These enzymes convert inactive 17-keto-steroids into their active 17β-hydroxy-forms or catalyze the oxidation of the 17β-hydroxy-forms into the 17-keto- steroids. Because both estrogens and androgens have the highest affinity for their receptors in the 17β-hydroxy form, 17β-HSD enzymes play an essential role in the tissue-selective regulation of the activity of sex steroid hormones.
At present, 10 human members of the 17β-HSD enzyme family have been described (types 1-5, 7, 8, 10, 11 and 12). The human 17β-HSD family members share less than 30% similarity in their primary structure. The 17β-HSDs are expressed in distinct, though in some cases, overlapping patterns. The different types of 17β-HSDs also differ in their substrate and cofactor specificities. In intact cells in culture, the 17β-HSDs catalyze the reaction in a unidirec- tional way: types 1, 3, 5 and 7 use NADP(H) as a cofactor and catalyze the reductive reaction (activation), while types 2, 4, 8 and 10 catalyze the oxidative reaction (inactivation) using NAD(H) as a cofactor. [see e.g. Labrie et al. (2000) Trends Endocrinol Metab., 11:421-7]. Due to their essential role in the tissue-selective regulation of the activity of sex steroid hormones 17β-HSDs can be involved in the occurrence and development of estrogen-sensitive pathologies (f. ex. breast, ovarian, uterine and endometrium cancers etc.) and androgen- sensitive pathologies (f. ex. prostate cancer, benign prostatic hyperplasia, acne, hirsutism, etc). Furthermore, many types of 17β-HSD have been shown to be involved in the pathogenesis of particular human disorders. For example, 17β-HSD3 is known to be involved in the development of pseudohermaphroditism, the 17β-HSD8 plays a role in polycystic kidney disease and the 17β-HSD4 is related to the occurrence of bifunctional enzyme deficiency. Therefore treatment of sex steroid-sensitive diseases by administration of specific inhibitors of the 17β-HSDs enzymes have been suggested, optionally in combination with potent and specific antiestrogens and antiandrogens [Labrie F et al. (1997) Steroids, 62:148-58].
Due to the fact that each type of 17β-HSD has a selective substrate affinity, directional
(reductive or oxidative) activity in intact cells, and a particular tissue distribution, the selectivity of drug action could be achieved by targeting a particular 17β-HSD isozyme. By individual modulation of the particular 17β-HSDs it is possible to influence or even control the local and paracrine concentration of estrogens and androgens in different target tissues.
The best characterized member of the 17β-HSD family is the type 1 17β-HSD [EC 1.1.1.62]. This enzyme could be crystallized in different states of functionality (e.g. with and without ligand and/or co-factor). The 17β-HSD1 catalyzes in vitro the reduction as well as the oxidation between estrone (E1) and estradiol (E2). However, under physiological in vivo conditions the enzyme only catalyzes the reductive reaction from the estrone (E1) to the estradiol (E2). The 17β-HSD1 was found to be expressed in a variety of hormone-dependent tissues, e.g. placenta, mammary gland tissue or uterus and endometrium tissue, respectively. Estradiol itself is, especially in comparison to the significantly less active estrone, a very potent hormone, which regulates the expression of a variety of genes by binding to the nuclear estrogen receptor and plays an essential role in the proliferation and differentiation of the target cell. Physiological as well as pathological cell proliferations can be estradiol dependent. Especially many breast cancer cells are stimulated by a locally raised estradiol concentration. Furthermore, the occur- rence or course of benign pathologies such as endometriosis, uterine leiomyomas (fibroids or myomas), adenomyosis, menorrhagia, metrorrhagia and dysmenorrhea is dependent from the existence of significantly high estradiol levels. Endometriosis is a well-known gynaecological disorder that affects 10 to 15% of women in the reproductive age. It is a benign disease defined as the presence of viable endometrial gland and stroma cells outside the uterine cavity. It is most frequently found in the pelvic area. In women developing endometriosis, the endometrial cells entering the peritoneal cavity by retrograde menstruation (the most likely mechanism) have the capacity to adhere to and invade the peritoneal lining, and are then able to implant and grow. The implants respond to steroid hormones of the menstrual cycle in a similar way as the endometrium in the uterus. The infiltrating lesions and the blood from these lesions which are unable to leave the body cause inflammation of the surrounding tissue. The most common symptoms of endometriosis are dysmenor- rhoea, dyspareunia and (chronic) abdominal pain. The occurrence of these symptoms is not related to the extent of the lesions. Some women with severe endometriosis are asymptomatic, while women with mild endometriosis may have severe pain. Endometriosis is found in up to 50% of the women with infertility. However, currently no causal relation has been proven between mild endometriosis and infertility. Moderate to severe endometriosis can cause tubal damage and adhesions leading to infertility. The aims of treatment of endometriosis are pain relief, resolution of the endometriotic tissue and restoration of fertility (if desired). The two common treatments are surgery or anti-inflammatory and/or hormonal therapy or a combination thereof. Uterine leiomyomas (fibroids or myomas), benign clonal tumours, arise from smooth muscle cells of the human uterus. They are clinically apparent in up to 25% of women and are the single, most common indication for hysterectomy. They cause significant morbidity, including prolonged and heavy menstrual bleeding, pelvic pressure and pain, urinary problems, and, in rare cases, reproductive dysfunction. The pathophysiology of myomas is not well understood. Myomas are found submucosaliy (beneath the endometrium), intramurally (within the myo- metrium) and subserosally (projecting out of the serosal compartment of the uterus), but mostly are mixed forms of these 3 different types. The presence of estrogen receptors in leiomyoma cells has been studied by Tamaya et al. [Tamaya et al. (1985) Acta Obstet Gynecol Scand., 64:307-9]. They have shown that the ratios of estrogen receptor compared to progesterone and androgen receptor levels were higher in leiomyomas than in the corresponding normal myo- metrium. Surgery has long been the main treatment for myomas. Furthermore, medical therapies that have been proposed to treat myomas include administration of a variety of steroids such as the androgenic steroids danazol or gestrinone, GnRH agonists and progestogens, whereby the administration is often associated a variety of serious side-effects.
Everything that has been said above in relation to the treatment of uterine leiomyomas and endometriosis equally applies to other benign gynaecological disorders, notably adenomy- osis, functional menorrhagia and metrorrhagia. These benign gynaecological disorders are all estrogen sensitive and are treated in a comparable way as described herein before in relation to uterine leiomyomas and endometriosis. The available pharmaceutical treatments, however, suffer from the same major drawbacks, i.e. they have to be discontinued once the side-effects become more serious than the symptoms to be treated and symptoms reappear after discontinuation of the therapy.
Since the aforementioned malign and benign pathologies are all 17β-estradiol dependent, a reduction of the endogenous 17β-estradiol concentration in the respective tissue will result in an impaired or reduced proliferation of 17β-estradiol cells in said tissues. Therefore, it may be concluded that selective inhibitors of the 17β-HSD1 enzyme are well suited for their use to impair endogenous productions of estrogens, in particular of 17β-estradioI, in myomas, endo- metriotic, adenomyotic and endometrial tissue. The application of a compound acting as selective inhibitor on the 17β-HSD1 which preferentially catalyzes the reductive reaction will result in a lowered intracellular estradiol-concentration since the reductive conversion of the estrone into the active estradiol is reduced or suppressed. Therefore, reversible or even irreversible inhibi- tors of the 17β-HSD1 may play a significant role in the prophylaxis and/or treatment of steroid- hormone, in particular 17β-estradiol, dependent disorders or diseases. Furthermore, the reversible or even irreversible inhibitors of the 17β-HSD1 should have no or only pure antagonistic binding activities to the estradiol receptor, in particular to the estrogen receptor α subtype, since agonistic binding of the estrogen receptor would lead to activation and therefore - by regulation of a variety of genes - to the proliferation and differentiation of the target cell. In contrast, antagonists of the estrogen receptor, so called anti-estrogens, bind competitively to the specific receptor protein thus preventing access of endogenous estrogens to their specific binding site. At present it is described in the literature that several malignant disease as breast cancer, prostate carcinoma, ovarian cancer, uterine cancer, endometrial cancer and endometrial hyper- plasia may be treated by the administration of a selective 17β-HSD1 inhibitor. Furthermore, a selective 17β-HSD1 inhibitor may be useful for the prevention of the aforementioned hormone- dependent cancers, especially breast cancer.
Several reversible or irreversible inhibitors of the 17β-HSD1 enzyme of steroidal and even non-steroidal origin are already known from the literature. The characteristics of these inhibitory molecules, which mainly have a substrate or cofactor-like core structure, have been reported in the literature [reviewed in: Poirier D. (2003) Curr Med Chem. 10:453-77].
A further well characterized member of the 17β-HSD family is the 17β-HSD type 3 en- zyme (17β-HSD3). The 17β-HSD3 has a distinct feature compared to other 17HSDs: it is found to be expressed almost exclusively the testis, whereas the other isoenzymes are expressed more widely in several tissues. 17β-HSD3 has a crucial role in androgen biosynthesis. It converts 4-androstene-3,17-one (A) to testosterone (T). The biological significance of the 17β- HSD3 is of undeniable physiological importance. Mutations in the gene for 17β-HSD3 have found to lead to decreased T formation in the fetal testis and consequently to a human intersex disorder termed male pseudohermaphroditism [Geissler WM et al. (1994) Nat Genet., 7:34-9]. With regard to the indication prostate cancer, the primary cancer ceils mostly retain their responsiveness to androgens in their regulation of proliferation, differentiation, and programmed cell death for some period. At present, androgen deprivation is the only effective systemic hormonal therapy available for prostate cancer. The development of selective inhibitors against 17β-HSD3 is a new therapeutic approach for the treatment of androgen dependent disease [Labrie et al. (2000) Trends Endocrinol Metab., 11 :421-7]. Furthermore, Oefelein et al. reported that the depot GnRH analogue fails, in nearly 20% of cases, to achieve castrate levels of T in men [Oefelein MG & Cornum R (2000) J Urol.; 164:726-9]. In order to improve the response rate to endocrine therapy for men with prostate cancer it may be important to selectively inhibit testicular 17β-HSD3 activity. Besides prostate cancer, many other androgen-sensitive diseases, i.e. diseases whose onset or progress is aided by androgenic activity, may be treated by selectively inhibiting 17β-HSD3 activity. These diseases include but are not limited to benign prostatic hyperplasia, prostatitis, acne, seborrhea, hirsutism, androgenic alopecia, precocious puberty, adrenal hyperplasia, and polycystic ovarian syndrome. Furthermore, considering the fact that 17β-HSD3 is found mainly in the testis, the development of potent inhibitors could be of interest for blocking spermatogenesis and as an anti-fertility agent for males.
Several reversible or irreversible inhibitors of the 17β-HSD3 enzymes of steroidal and even non-steroidal origin are already known from the literature. The characteristics of these inhibitory molecules have been reported in the literature [reviewed in: Poirier D. (2003) Curr Med Chem. 10:453-77]. For example, US patent No. 6,541 ,463 discloses androsterone derived inhibitors for 17β-HSD3. These derivatives have been synthesised by parallel solid- and liquid- phase chemistry and some of these compounds showed 2 to 18-fold higher inhibition activity than that of the natural substrate of the enzyme, A-dione, used itself as a inhibitor. Furthermore, the international patent application WO 01/42181 discloses benzyl-tetralins, the chemical struc- ture of which is related to that of the phytoestrogen biochanin, as 17β-HSD3 inhibitors. Furthermore, international patent applications WO 98/32724, WO 98/30556 and WO 99/12540 disclose tetralone, benzopyrane and benzofuranone derivatives, which have a 17β-HSD inhibitory activity, for the treatment of hormone sensitive diseases. Microsomal 17β-hydroxysteroid dehydrogenase of human endometrium and placenta
(designated 17β-HSD type 2 or 17β-HSD2) was cloned by expression cloning, and found to be equally active using androgens and estrogens as substrates for oxidation [Andersson S. (1995) J. Steroid Biochem. Molec. Biol., 55:533-534]. The recombinant 17β-HSD2 converts the highly active 17β-hydroxysteroids such as estradiol (E2), testosterone (T), and dehydrotestosterone (DHT) to their inactive keto forms. In addition, the 17β-HSD2 can, to a lesser extent, also convert 20β-hydroxyprogesterone (20βP) to progesterone (P). The broad tissue distribution together with the predominant oxidative activity of 17β-HSD2 suggest that the enzyme may play an essential role in the inactivation of highly active 17β-hydroxysteroids, resulting in diminished sex hormone action in target tissues. Dong and colleagues showed significant 17β- HSD 2 activity in cultured human osteoblasts and osteoblast-like osteosarcoma cells MG63 and TE85, but not in SaOS-2 [Dong Y et al. (1998) J. Bone Min. Res., 13:1539-1546]. The potential for interconversion of E1 to E2, T to A, and DHT to A by bone cells could therefore represent important mechanism for the local regulation of intracellular ligand supply for the estrogen and androgen receptors in the osteoblasts and other steroid sensitive cells. This modulation of steroid levels may be employed for a wide variety of indications, including the following: for the prevention and treatment of osteoporosis, for the treatment of ovarian cancer, for the treatment of breast cancer, for the treatment of endometrial cancer, for the treatment of endometriosis, for the treatment of prostate cancer and/or for the treatment of androgen-dependent hair-loss.
Several reversible or irreversible inhibitors of the 17β-HSD2 enzymes of steroidal and even non-steroidal origin are already known from the literature. The characteristics of these inhibitory molecules have been reported in the literature [reviewed in: Poirier D. (2003) Curr Med Chem. 10:453-77]. In addition, the international patent application WO 02/26706 discloses
17β-HSD2 inhibitors of non-steroidal origin.
Some thienopyrimidinones derivatives that are described as being useful in therapy have already been disclosed in the literature: The Japanese patent publication JP48042271B (Yoshi- tomi Pharmaceutical industries Ltd.) disclose compounds useful as central nervous depressants and anti -inflammatory agents. The US patent No. 5,597,823 (Abbott Laboratories, Inc.) d escribes adrenergic antagonist useful in the treatment of benign prostate hyperplasia. The Japanese patent application JP62132884 ( Mitsubishi Chem. Ind. Ltd.) discloses Benzylthieno- pyrimidinones useful as cardiovascular agents. Manhas et al describe the synthesis and antiin- flammatory activity of some substituted thienopyrimidinones [Manhas MS et al. (1972) J Med Chem. 15(1): 106-7]. Gadad et al. describe the synthesis and antihyperlipaemic activity of some 2-aminomethyl-3-aryl-5,6,7,8-tetrahydrobenzo(b) / 5,6-dimethylthieno (2,3-d)-pyrimidin-4-ones [Gadad AK et al. (1996) Arzneimittelforschung. 46(10):981-5]. Manjunath et al. describe the synthesis and evaluation of 2-chloromethyl-3-N-substituted arylthieno(2,3-d)pyrimidin-4-ones and derivatives for central nervous system depressant activity [ Manjunath KS et al. (1997) Arzneimittelforschung. 47(9): 1005-8]. Furthermore, several other Thienopyrimidinones derivatives have been described but were not related to any medical use so far. For example, the compounds (3-Benzyl-7-tert-butyl-
4-0X0-3,4,5,6,7, 8-hexahydro-benzo[4,5]thieno[2,3-d]pyrimidin-2-yl)-acetic acid methyl ester
(CAS reg. no 423749-31-9) and 2,3-Dibenzyl-7-tert-butyl-5,6,7,8-tetrahydro-3H- benzo[4,5]thieno[2,3-d]pyrimidin-4-one (CAS reg. no 372974-51-1) are commercially available.
However, according to the inventors' knowledge none of the already known compounds described above has been described as useful in the treatment and/or prevention of a steroid hormone dependent disease or disorder, particularly a steroid hormone dependent disease or disorder requiring the inhibition of the 17β-hydroxysteroid dehydrogenase (17HSD) type 1, type
2 or type 3 enzyme.
There is a need for the development of compounds that are selectively inhibiting the 17β- HSD1, 17β-HSD3 and/or 17β-HSD2 enzyme, while desirably failing to inhibit substantially other members of the 17β-HSD protein family, or other catalysts of sex steroid degradation or activation. In particular, it is an aim of the present invention to develop selective inhibitors of the 17β- HSD1 enzyme, whereby in addition the compounds have no or only pure antagonistic binding affinities to the estrogen receptor (both subtypes α and β). SUMMARY OF THE INVENTION
Therefore, it is an object of the present invention to develop novel inhibitors of the 17β- HSD1 and 17β-HSD2 enzyme, which have valuable pharmacological properties and which are suited for the treatment of estrogen dependent diseases and disorders. It is a further object of the present invention to develop novel inhibitors of the 17β-HSD3 enzyme, which have valuable pharmacological properties and which are suited for the treatment of androgen dependent diseases and disorders.
It has now been found that the thiophenepyrimidinone derivatives of the present invention would be valuable in therapy, especially in the treatment or prevention of steroid hormone dependent diseases or disorders, such as steroid hormone dependent- diseases or disorders requiring the inhibition of 17β-hydroxysteroid dehydrogenase (HSD) enzymes. In particular, compounds of formula (I) represent potent inhibitors of the 17β-HSD1 , 17β-HSD3 and/or 17β- HSD2 enzyme and possess valuable pharmacological properties for the treatment and/or pro- phylaxis of malignant steroid dependent diseases or disorders such as breast cancer, prostate carcinoma, ovarian cancer, uterine cancer, endometrial cancer and endometrial hyperplasia, but also for the treatment and/or prophylaxis of benign steroid d ependent diseases or disorders such as endometriosis, uterine fibroids, uterine leiomyoma, adenomyosis, dysmenorrhea, rnenorrhagia, metrorrhagia, prostadynia, benign prostatic hyperplasia, prostatitis, acne, sebor- rhea, hirsutism, androgenic alopecia, precocious puberty, adrenal hyperplasia, polycystic ovarian syndrome, or urinary dysfunction. Further estrogen-dependent diseases which may be treated and/or prevented with an effective amount of a compound of the invention are multiple sclerosis, rheumatoid arthritis, Alzheimer's disease, colon cancer, tissue wounds, skin wrinkles and cataracts. Furthermore, compounds of formula (I) may be useful for the prevention and treatment of osteoporosis, and for blocking spermatogenesis and as an anti-fertility agent for males.
Accordingly, the present invention relates to the use of a compound having the structural formula (I)
Figure imgf000009_0001
wherein
X is S, SO or S02
R1 and R2 are individually selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloheteroalkyl, substituted cyclohet- eroalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyclo- heteroalkyl-alkyl, substituted cycloheteroalkyl-alkyl, or R2 itself may be independently selected from acyl, carboxyl, or amido, whereby R1 and R2 cannot be simultaneously unsubstituted alkyl,
the hydrocarbon chain -C(R3)-C(R4)-C(R5)-C(R6)- of the six-membered ring is saturated or contains one or two double bonds between the carbon atoms;
R3 and R4 are individually selected from the group consisting of hydrogen, oxo, halogen or dihalogen, acyl, alkyl, substituted alkyl, hydroxyl, carboxyl, amido, amino, nitrile, thio, alkoxy, acyloxy, aryloxy, alkylthio and arylthio;
R5 represents hydrogen, and
R6 is hydrogen or halogen, for the manufacture of a medicament for the treatment and/or prevention of a steroid hormone dependent disease or disorder, preferably for a steroid hormone dependent disease or disorder requiring the inhibition of a 17β-hydroxysteroid dehydrogenase (17β-HSD) enzyme, most preferably requiring the inhibition of the 17β-HSD type 1 , 17β-HSD type 2 or 17β-HSD type 3 en- zyrne.
According to another aspect, the invention concerns a compound of formula (I)
Figure imgf000010_0001
wherein
X is S, SO or S02
R1 and R2 are individually selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloheteroalkyl, substituted cyclohet- eroalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyclo- heteroalkyl-alkyl, substituted cycloheteroalkyl-alkyl, or R2 itself may be independently selected from acyl, carboxyl, or amido, whereby R1 and R2 cannot be simultaneously unsubstituted alkyl, and whereby R2 has to be different from methyl if all substituents R3, R5 and R6 simultaneously represent hydrogen and R4 represents hydrogen or methyl;
R3 and R4 are individually selected from the group consisting of hydrogen, oxo, halogen or dihalogen, acyl, alkyl, substituted alkyl, hydroxyl, carboxyl, amido, amino, nitrile, thio, alkoxy, acyloxy, aryloxy, alkylthio and arylthio;
R5 represents hydrogen,
R6 is hydrogen or halogen, and
the hydrocarbon chain -C(R3)-C(R4)-C(R5)-C(R6)- of the six-membered ring is saturated or contains one or two double bonds between the carbon atoms; whereby the six-membered ring comprising the hydrocarbon chain -C(R3)-C(R4)-C(R5)-C(R6)- has to be an aromatic ring if all the substituents R3, R4, R5 and R6 are simultaneously hydrogen;
for use in therapy.
According to a third aspect, the invention concerns a novel compound of formula (I)
Figure imgf000011_0001
wherein
X is S, SO or S02
R1 and R2 are individually selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloheteroalkyl, substituted cyclohet- eroalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyclo- heteroalkyl-alkyl, substituted cycloheteroalkyl-alkyl, or R2 itself may be independently selected from acyl, carboxyl, or amido, whereby R1 and R2 cannot be simultaneously unsubstituted alkyl, and whereby R2 has to be different from methyl if all substituents R3, R5 and R6 simultan eously represent hydrogen and R4 represents hydrogen or methyl;
R3 and R4 are individually selected from the group consisting of hydrogen, oxo, halogen or dihalogen, acyl, alkyl, substituted alkyl, hydroxyl, carboxyl, amido, amino, nitrile, thio, alkoxy, acyloxy, aryloxy, alkylthio and arylthio;
R5 represents hydrogen,
R6 is hydrogen or halogen, and
the hydrocarbon chain -C(R3)-C(R4)-C(R5)-C(R6)- of the six-membered ring is saturated or contains one or two double bonds between the carbon atoms; whereby the six membered ring comprising the hydrocarbon chain -C(R3)-C(R4)-C(R5)-C(R6)- has to be an aromatic ring if all the substituents R3, R4, R5 and R6 are simultaneously hydrogen;
under the proviso that said compound is not (3-Benzyl-7-tert-butyl-4-oxo-3,4,5,6,7,8-hexahydro- benzo[4,5]thieno[2,3-d]pyrimidin-2-yl)-acetic acid methyl ester or 2,3-Dibenzyl-7-tert- butyI-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one.
According to a fourth aspect, the invention concerns a pharmaceutical composition comprising as active agent a compound of formula (I) as defined herein, for which no use in therapy earlier has been disclosed, and at least a pharmaceutically acceptable carrier.
According to a fifth aspect, the invention concerns the use of a compound of formula (I) as defined herein for the treatment or prevention of a steroid hormone dependent disease or disorder. Preferably, the steroid hormone dependent disease or disorder is a disease or disorder requiring the inhibition of a 17β-hydroxysteroid dehydrogenase enzyme, preferably of the 17β-HSD type 1, 17β-HSD type 2 or 17β-HSD type 3.
DETAILED DESCRIPTION OF THE INVENTION
Definitions:
The following terms are used to describe various constituents of the chemical composition useful in this invention. The terms are defined as follows:
As used herein, the terms "comprising" and "including" are used herein in their open, non- limiting sense.
The word "compound" shall here be understood to cover any and all isomers (e. g., enantiomers, stereoisomers, diastereomers, rotomers, and tautomers ), racemates or any mixture of isomers, prodrugs, and any pharmaceutically acceptable salt of said compound. Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.
The term "substituted" means that the specified group or moiety bears one or more substituents. Where any group may carry multiple substituents and a variety of possible substituents is provided, the substituents are independently selected and need not be the same. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents. Any asymmetric carbon atoms may be present in the (R)-, (S)- or (R.S)-configuration, preferably in the (R)- or (S)-configuration, whichever is most active. Substituents at a double bond or a ring may be present in cis- (.=Z-) or trans (=E-) form.
The compounds of the present invention may contain asymmetric centers on the molecule, depending upon the nature of the various substituents. In certain instances, asymmetry may also be present due to restricted rotation about the central bond adjoining the two aromatic rings of the specified compounds. It is intended that all isomers (including enantiomers and diastereomers), either by nature of asymmetric centers or by restricted rotation as described above, as separated, pure or partially purified isomers or racemic mixtures thereof, be included within the ambit of the instant invention.
The term "halogen" refers to fluorine (F, Fluoro-), bromine (Br, Bromo-), chlorine (CI, Chloro), and iodine (J, lodo-) atoms. Preferred in the context of the present invention are Br, CI and F. The terms "dihalogen", "trihalogen" and "perhalogen" refer to two, three and four substituents, respectively, each individually selected from the group consisting of fluorine, bromine, chlorine, and iodine atoms.
The term "hydroxyl" refers to the group -OH
The term "oxo" refers to the group =0 The term "thio" refers to the group =S
The term "thiol" refers to the group -SH
The term "sulfonyl" refers to the group -S(0)1-2-
The term "sulfamoyl" refers to the group -S02-NH2
The term "nitro" refers to the group -N02 The term "nitrile" or "cyano" refers to the group -CN
For the purpose of the present invention, the carbon content of various hydrocarbon containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix -Cj defines the number of carbon atoms present from the integer "i" to the integer "j" inclusive. Thus CrC4-alkyl refers to alkyl of 1-4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl and isomeric forms thereof.
The term "alkyl" stands for a hydrocarbon radical which may be linear, cyclic or branched, with single or multiple branching, whereby the alkyl group comprises 1 to 12 carbon atoms. In one embodiment, the term "alkyl" stands for a linear or branched (with single or multiple branching) alkyl chain of 1 to 8 carbon atoms, exemplified by the term (C-pCsJalkyl, more preferably of 1 to 4 carbon atoms exemplified by the term (C|-C4)alkyl. The term (Cι-C8)alkyl is further exemplified by such groups as methyl; ethyl; n-propyl; isopropyl; n-butyl; sec-butyl; isobutyl; tert-butyl; n-pentyl; isopentyl; neopentyl; tert-pentyl; 2- or 3-methylpentyl; n-hexyl; isohexyl, and the like. The alkyl group may be partially unsaturated, forming such groups as, for example, propenyl (allyl), methyl-propenyl, butenyl, pentenyl, pentinyl, hexenyl, octadienyl, and the like. The term "alkyl" further comprises cycloalkyl groups, preferably cyclo(C3-C8)alkyl which refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and isomeric forms thereof such as methylcyclopropyl; 2- or 3-methylcyclobutyl; 2-, or 3-methylcyclopentyl, and the like. The cycloalkyl group may also be partly unsaturated, forming such groups as, for example, cyclohexenyl, cyclopentenyl, cyclooctadienyl, and the like. Furthermore, the term "alkyl" comprises a cycloalkyl-alkyl group comprising 4 to 12 carbon atoms, preferably "cyclo(C3-C8)alkyl- (CrC4)alkyl" which refers to a alkyl group of 1 to 4 carbon atoms as described above substi- tuted with a cyclo(C3-C8)alkyl group as described above, forming such groups as for example cyclopropylnnethyl, cyclohexylmethyl, cyclopentylethyl or cyclohexenylethyl.
The term "substituted alkyl" refers to alkyl as just described and substituted by up to five, more preferably by up to three, most preferably by one or two substituents independently se- lected from the group consisting of halogen, hydroxyl, thiol, nitro, nitrile, alkoxy, aryloxy, acyloxy, amino, amido, acylamino, alkylthio, arylthio, acyl, carboxyl, sulfamoyl, sulfonamide, and alkylsulfonyl , as defined herein. These groups may be attached to any carbon atom of the alkyl moiety. Substituted alkyl is preferably substituted with hydroxyl, halogen, Cι-C4-alkoxy, arylacyl, preferably phenylacyl, phenoxy, benzyloxy, C1-C4-aIkylthio, an alkylamino group -NR"2, a carboxyl group -(C=0)-OR", an alkylacyloxy group -O-CO-R, or a heteroaryl acyloxy group - O-CO-HetAr, wherein R" represents hydrogen or C1-C4-alkyl. Preferably substituted alkyl refers to substituted C-i-C/t-alkyl.
Halogenated alkyl, halogenated alkoxy and halogenated alkylthio are substituents in which the alkyl moieties (preferably (Cι-C6)alkyl, more preferably (Cι-C4)alkyl, and most preferably methyl) are substituted either partially or in full with halogens, generally with chlorine and/or fluorine. Preferred examples of such substituents are trifluoromethyl, trifluoromethoxy, trifluoromethylthio, dichloromethyl, pentafluoroethyl, dichloropropyl, fluoromethyl and difluoro- methyl.
The term "alkoxy" refers to a group -OR, where R may be alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl or substituted heteroarylalkyl as defined herein, wherein the alkyl chain may be optionally further substituted as defined herein. Preferably, the term "alkoxy" refers to - 0-(Ci-C4)alkyl (or (CrC )alkoxy), with the (C C4)alkyl group as defined above, or to -0-(C C4)alkyl-phenyl, preferably benzoxy or phenethyloxy, optionally substituted in the aryl group with up to five independently selected substituents, in particular hydroxyl, halogen, (C-|-C )-alkyl, (C C4)-alkoxy, halogenated (Cι-C4)-alkyl, or halogenated (C C4)-alkoxy; the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents.
The term "aryloxy" refers to a group -OAr, where Ar may be aryl, substituted aryl, heteroaryl or substituted heteroaryl as defined herein. Preferably, Ar represents aryl as defined herein, which is optionally substituted in the aryl group with up to five independently selected substituents, in particular hydroxyl, halogen, (Cι-C4)-alkyl, (Cι-C )-alkoxy, halogenated (C C4)- alkyl, or halogenated (C C4)-alkoxy; the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents. Preferably, aryloxy refers to phenoxy, optionally substituted as defined above. The term "acyloxy" refers to a group -O-CO-R, where R may be alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl as defined herein, wherein the alkyl chain may be optionally further substituted as defined herein. The term "alkylacyloxy" represents a preferred selection of the term "acyloxy" and refers to the group -0-CO-Cι-C12-alkyl, preferably to -0-CO-Cι-C8-alkyl, and most preferably to -O- CO-CrC4-alkyl.
The term "arylacyloxy" represents a preferred selection of the term "acyloxy" and refers to the group —O-CO-Ar, wherein Ar represents aryl as defined herein, preferably phenyl, which is optionally substituted in the aryl group with up to five independently selected substit uents, in particular hydroxyl, halogen, (C-ι-C )-aIkyl, (CrC4)-alkoxy, halogenated (CrC4)-alkyl, or halogenated (Cι-C4)-alkoxy; the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents
The term "heteroaryl-acyloxy" represents a preferred selection of the term "acyloxy" and refers to the group -O-CO-HetAr, wherein HetAr represents heteroaryl as defined herein, preferably thienyl, furyl or pyridinyl. The term "acyl" refers to a group -(C=0)-R, where R may be hydrogen, alkyl, aryl or aryl-
(Cι-C4)-aIkyl (both optionally substituted in the aryl group with independently selected substituents as defined herein), heteroaryl or heteroaryl-(C1-C4)-alkyl (both optionally substituted in the heteroaryl group with up to three independently selected substituents as defined herein), as defined herein. Preferably, the term "acyl" refers to a group -(C=0)-R\ where R' represents hydrogen, (Cι-C4)alkyl, phenyl, or phenyl-(C C4)alkyl, preferably benzyl.
The term "carbonyl" represents a preferred selection of the term "acyl" and refers to the group -CHO. The term "alkylacyl" represents a preferred selection of the term "acyl" and refers to a group -(C=0)-alkyl, preferably -(C=0)-(C C4)alkyl. The term "arylacyl" represents a preferred selection of the term "acyl" and refers to the group -CO-Ar, wherein Ar represents aryl as defined herein, preferably phenyl, which is optionally substituted in the aryl group as defined herein. The term "heteroarylacyl" represents a preferred selection of the term "acyl" and refers to the group -CO-HetAr, wherein HetAr represents heteroaryl as defined herein, preferably thienyl, furyl or pyridinyl.
The term "carboxyl" refers to a group -(C=0)-OR, where R may be hydrogen, alkyl, sub- stituted alkyl, aryl or aryl-(Cι-C4)-alkyl (both optionally substituted in the aryl group with independently selected substituents as defined herein), heteroaryl or heteroaryl-(Cι-C4)-alkyl (both optionally substituted in the heteroaryl group with independently selected substituents as defined herein), as defined herein. Preferably, the term "carboxyl" refers to a group -(C=0)-OR', where R' represents hydrogen, (Cι-C4)alkyl, phenyl, or (CrC4)alkyl-phenyl, preferably benzyl; whereby the phenyl moiety may be optionally substituted with substituents independently selected from the group consisting of hydroxyl, halogen, (Cι-C4)alkoxy, (C C4)-alkyl, halogenated (Cι-C )alkyl and halogenated (Cι-C4)alkoxy, the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents. The term "alkylcarboxyl" represents a preferred selection of the term "carboxyl" and refers to a group -(C=0)-OR, where R is hydrogen or Cι-C4 alkyl.
The terms " alkylthio" ("alkylsulfanyl") and "alkylsulfonyl" refers to a group -SR and - respectively, where R may be alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl or substituted heteroarylalkyl, as defined herein. Preferably, the term "alkylthio" ("alkylsulfanyl") refers to a group -SR'and the term "alkylsulfonyl" refers to a group -S(0)n=ι-2- R', respectively , where R' represents (C C4)alkyl, or (Cι-C4)alkyl-phenyl, preferably benzyl; optionally substituted in the alkyl chain with up to threee substituents as defined herein, preferably hydroxyl, (C C4)-alkoxy or halogen.
The term "arylthio" ("arylsulfanyl") and "arylsulfonyl" refers to a group -S-Ar and -S(0)n=1. 2-Ar, respectively, where Ar represents aryl, substituted aryl, heteroaryl or substituted heteroaryl, as defined herein. Preferably Ar represents aryl, which is optionally substituted in the aryl group with independently selected substituents as defined herein, in particular hydroxyl, halogen, (C1-C4)-alkyl, (C C^-alkoxy, halogenated (C C4)-alkyl, or halogenated (C C4)-alkoxy, the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents. Preferably, arylthio refers to phenylsulfanyl, optionally substituted as defined above. The term "amino" refers to the group -NRR', where R and R' may independently be hydrogen, alkyl (optionally substituted in the alkyl chain with up to five independently selected substituents as defined herein, in particular hydroxyl, halogen or (Cι-C )-alkoxy), aryl or aryl- (Cι-C4)-alkyl (both optionally substituted in the aryl group with up to five independently selected substituents as defined herein, in particular hydroxyl, halogen, (C C4)-alkyl, (CrC^-alkoxy, halogenated (CrC^-alkyl, or halogenated (C C4)-alkoxy, the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents), heteroaryl or heteroaryl-(C1-C4)-alkyl (both optionally substituted in the heteroaryl group with up to three independently selected substituents as defined herein), as defined herein.
The term "alkylamino" represents a preferred selection of the term "amino" and refers to the group -NRR', where R and R' may independently be hydrogen or (CrC4)alkyl.
The term "amido" refers to the group -(C=0)-NRR', where R and R' may independently be hydrogen, alkyl (optionally substituted in the alkyl chain with up to five independently selected substituents as defined herein, in particular hydroxyl, halogen or (C-ι-C4)-alkoxy), aryl or aryl-(Cι-C4)-alkyl (both optionally substituted in the aryl group with independently selected substituents as defined herein, in particular hydroxyl, halogen, (C-ι-C4)-alkyl, (CrC4)-alkoxy, halogenated (Cι-C4)-alkyl, or halogenated (C1-C4)-alkoxy, the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents), heteroaryl or heteroaryHCi-Q -alkyl (both optionally substituted in the heteroaryl group with up to three independently selected substituents as defined herein), as defined herein.
The term "alkylamido" represents a preferred selection of the term "amido" and refers to the group -(C=0)— NRR', where R and R' may be independently selected from hydrogen or (Cr C4)alkyl.
The term "acylamino" refers to the group -NR-CO-R', where R and R' may independently be hydrogen, alkyl (optionally substituted in the alkyl chain with up to five independently se- lected substituents as defined herein, in particular hydroxyl, halogen or (Cι-C4)-alkoxy), aryl or aryl-(CrC4)-alkyI (both optionally substituted in the aryl group with independently selected substituents as defined herein, in particular hydroxyl, halogen, (CrC4)-alkyl, (C C4)-alkoxy, halogenated (Cι-C4)-alkyl, or halogenated (CrC )-aIkoxy, the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents), heteroaryl or heteroaryl-(Cι-C4)-alkyl (both optionally substituted in the heteroaryl group with up to three independently selected substituents as defined herein), as defined herein. The term "carbonylamino" represents a preferred selection of the term "acylamino" and refers to the group -NR-CO-CH2-R', where R and R' may be independently selected from hydrogen or (d-C4)alkyl. The term "sulfonamide" refers to the group -S02-NRR', wherein R and R' may independently be selected from hydrogen or (C1-C4)alkyl.
The term "aryl" refers to an aromatic carbocyclic group comprising 6 to 14, more preferably 6 to 10, carbon atoms and having at least one aromatic ring or multiple condensed rings in which at least one ring is aromatic. Preferably, aryl is phenyl, naphthyl, indanyl, indenyl, fluo- renyl, 1,2,3,4-tetrahydro-naphthalen-1-yl or even biphenyl.
The term "heteroaryl" refers to an aromatic carbocyclic group of having a single 4 to 8 membered ring or multiple condensed rings comprising 6 to 14, more preferably 6 to 10, ring atoms and containing at least one heteroatom, such as N, O or S, within at least one ring, the number of N atoms being 0-3 and the number of O and S atoms each being 0-1; in which group at least one heterocyclic ring is aromatic. Examples of such groups include pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, benzoimidazolyl, 1 ,3-dihydro-benzoimidazolyl, benzofuran, benzo[b]thiophene and the like. Preferably, heteroaryl is quinolinyl, furyl, benzoimidazolyl, pyridinyl, thienyl, indolyl, benzo[b]thiophene, pyridinyl, imidazolyl, pyrazolyl or thiazolyl. The aryl and the heteroaryl group may optionally be substituted by substituents independently selected from the group consisting of halogen, hydroxyl, (Cι-C6)alkoxy, (C1-C6)alkyl, halogenated (Cι-C6)alkyl, halogenated (Cι-C6)alkoxy, oxo, thiol, nitro, nitrile, sulfamoyl, sulfonamide, carboxyl, aryloxy or arylalkyloxy (both optionally substituted in the aryl moiety with independently selected substituents as defined herein), (G|-C6)alkylthio, arylthio or arylalkylthio (both optionally substituted in the aryl moiety with independently selected substituents as defined herein), amino, amido, acyl, and acylamino, as defined herein, the number of said sub- stituents being up to five for halogen, and up to three for any combination of said other substituents. The heteroaryl group may further be optionally substituted with an aryl or an aryloxy group, which aryl group may be optionally substituted in the aryl moiety with substituents, especially hydroxyl, halogen, (C1-C6)alkoxy, (C Cβ)alkyl, halogenated (Cι-C6)alkyl or halogenated (C|-C6)alkoxy, the number of said substituents being up to five for halogen, and up to three for any combination of said other substituents. The aryl group may further be optionally substituted with a heteroaryl group. Substituted aryl is preferably substituted by substituents selected from the group consisting of (C Cβ)alkoxy, preferably methoxy, hydroxyl, (C ι-C )alkyl, halogen, halogenated (C C4)alkyl, pre ferably halogenated methyl, most preferably trifluoromethyl, halogenated (C C6)alkoxy, and sulfonamide, the number of said substituents being up to five for halogen, and up to four, preferably up to three, for any combination of said other substituents. Preferably substituted aryl is substituted phenyl.
The aryl may be further substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated or partly unsaturated cyclic 5, 6, 7, or 8 membered ring system, optionally containing up to three heteroatoms, such as N, O or S, the number of N atoms being 0-3 and the number of O and S atoms each being 0-2. Preferably, the two groups which are attached to adjacent carbon atoms, are combined into a saturated cyclic 5 or 6 membered ring system, optionally containing up to three heteroatoms, such as N or O, the number of N atoms being 0-3 and the number of O atoms each being 0-2. This cyclic ring system may optionally be further substituted by an oxo group. Preferred examples of such a substituted aryl groups are benzo[1 ,3]dioxol, 2,3-dihydrobenzofuran, 3H-isobenzofuran-1-one and 1,3-dihydro- benzoimidazol-2-one.
Substituted heteroaryl is preferably substituted by up to three, preferably up to two sub- stituents selected from the group consisting of halogen, (CrC4)-alkoxy, (C C )-alkyl, preferably methyl, (d-C4)-alkyl-carboxyl, preferably carboxylmethylester, halogenated (Cι-C4)-alkyl, preferably halogenated methyl, halogenated (C C4)-alkoxy, phenoxy (optionally substituted with up to three, preferably one halogen), benzyloxy, benzyl or phenyl. The term "cycloheteroalkyl" refers to a four- to eight-membered heterocyclic ring containing at least one heteroatom, such as N, O or S, the number of N atoms being 0-3 and the number of O and S atoms each being 0-1, which system may be saturated, partly unsaturated or hydroaromatic, and which ring can be part of a multiple condensed ring-system in which some rings may be aromatic. Examples of such cycloheteroalkyls include pyrrolidinyl, tetrahydrofur l, tetrahydrothiophenyl, tetrahydropyridinyl, dioxolyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperid- inyl, morpholinyl, thiornorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, thiazepanyl, dihydro-1H-pyrrolyl, 1 , 3-dihydro-benzoimidazolyl and the like. Preferred examples of such cycloheteroalkyl groups are pyrrolidinyl, morpholinyl, tetrahydrofuryl, piperidinyl or dioxolyl. The cycloheteroalkyl group may optionally be substituted by up to three substituents, independently selected from the group consisting of oxo, alkyl, aryl or aryl-(C C4)-alkyl (both optionally substituted in the aryl group with independently selected substituents as defined herein), hydroxyl, (CrC6)alkoxy, halogenated (C C6)alkyl, halogenated (C-ι-C6)alkoxy, carboxyl- (Cι-C6)alkyl, thiol, nitrile, sulfamoyl, sulfonamide, carboxyl, aryloxy or arylalkyloxy (both option- ally substituted in the aryl moiety with independently selected substituents as defined herein), (Cι-Ce)alkylthio, arylthio or arylalkylthio (both optionally substituted in the aryl moiety with independently selected substituents as defined herein), amino, amido, acyl, and acylamino, as defined herein. These groups may be attached to any carbon atom of the cycloheteroalkyl moiety. Substituted cycloheteroalkyl is preferably substituted with oxo, (Cι-C )alkyl, preferably methyl, phenyl and/or (d-C4)alkylphenyl, in particular benzyl.
The term "arylalkyl" refers to an alkyl group substituted with up to three independently selected aryl groups; preferably the term "arylalkyl" refers to "aryKd-C^-alkyl" or diaryl-(C C4)- alkyl, whereby the aryl is an aryl group as defined above. Arylalkyl is preferably benzyl (-CH2- Phenyl) or phenethyl (-CH2-CH2-Phenyl).
The term "substituted arylalkyl" refers to an arylalkyl group as defined above, wherein the aryl group is substituted as defined above.
The term "heteroarylalkyl" refers to an alkyl group substituted with up to three independently selected heteroaryl groups; preferably the term "heteroarylalkyl" refers to "heteroaryl-(C C )-alkyl", whereby the heteroaryl is a heteroaryl group as defined above. The term "substituted heteroarylalkyl" refers to a heteroarylalkyl group as defined above, wherein the heteroaryl group is substituted as defined above.
The term "cycloheteroalkyl-alkyl" refers to an alkyl group substituted with up to three independently selected cycloheteroalkyl groups; preferably the term "cycloheteroalkyl-alkyl" refers to "cycloheteroalkyl -(Cι-C )-alkyl", whereby the cycloheteroalkyl is a cycloheteroalkyl group as defined above. Preferably, "cycloheteroalkyl-alkyl" is morpholinylethyl, morpholinylpropyl, piperidinylethyl, tetrahydrofurylmethyl or pyrrolidinylpropyl.
The term "substituted cycloheteroalkyl-alkyl" refers to a cycloheteroalkyl-alkyl group as defined above, wherein the cycloheteroalkyl-alkyl group is substituted as defined above. Preferably, "substituted cycloheteroalkyl-alkyl" is dimethyl-[1 ,3]-dioxolylmethyl or 2-oxo-pyrrolidinyl- propyl.
The term "pro-drug" as used herein, represents derivatives of the compounds of the in- vention that are drug precursors which, following administration to a patient, release the drug in vivo via a chemical or physiological process. In particular, pro-drugs are derivatives of the compounds of the invention in which functional groups carry additional substituents which may be cleaved under physiological conditions in vivo and thereby releasing the active principle of the compound (e. g., a pro-drug on being brought to a physiological pH or through an enzyme action is converted to the desired drug form).
The term "pharmaceutically acceptable salts" refers to salt forms that are pharmacologi- cally acceptable and substantially non-toxic to the subject being administered the compounds of the invention. Pharmaceutically acceptable salts of compounds of formula I include conventional and stoichiometrical acid-addition salts or base-addition salts formed from suitable non-toxic organic or inorganic acids or inorganic bases. Acid addition salts, for example, from compounds of formula I with a basic nitrogen atom are formed preferably with organic or inorganic acids. Suitable inorganic acids are, for example, halogenic acids such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, or sulfonic acids, for example acetic acid, propionic acid, glycolic acid, lactic acid, hydroxybutyric acid, malic acid, malenic acid, malonic acid , salicylic acid, fumaric acid, succinic acid, adipic acid, tartaric acid, citric acid, glutaric acid, 2- or 3-glycerophosphoric acid and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce a salt in the conventional manner. Compounds containing acidic substituents may also form salts with inorganic or organic bases. Examples of suitable bases for salt formation include, but are not limited to, inorganic bases such as alkali or alkaline earth-metal (e.g., sodium, potassium, lithium, calcium, or magnesium) hydroxides, and those derived from ammonium hydroxides (e.g., a quaternary ammonium hydroxide such as tetramethylammonium hydroxide). Also contemplated are salts formed with pharmaceutical acceptable amines such as ammonia, alkyl amines, hydroxyal- kylamines, N-methylglucamine, benzylamines, piperidines, and pyrrolidines and the like. Certain compounds will be acidic in nature, e. g. those compounds which possess a carboxyl or pheno- lie hydroxyl group. Salts of phenols can be made by heating acidic compounds with any of the above mentioned bases according to procedures well known to those skilled in the art.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The phrase "effective amount" as used herein, means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e. g., provide a positive clinical response). The effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician. Preferred Embodiments
According to a preferred embodiment of the present invention, the substituents R1 to R4 are defined as follows:
R1 and R2 may be individually selected from the group consisting of -Cι-C,2-alkyl, which alkyl can be linear, cyclic, branched or partially unsaturated, and which can be optionally substituted with up to three substituents individually selected from the group consisting of hydroxyl, CrC^-alkoxy, thiol, CrC12-alkylthio, aryloxy, aryla- cyl, -CO-OR, -O-CO-R, heteroaryl-acyloxy, and -N(R)2; whereby said aryl group is phenyl or naphthyl, and can be optionally substituted with up to three halogen; whereby said heteroaryl group is thienyl, furyl or pyridinyl aryl and aryl-CrC12-alkyl, which aryl is selected from the group consisting of phenyl, biphenyl, naphthyl, indanyl, indenyl and fluorenyl, whereby the alkyl moiety can be optionally substituted with one or two hydroxyl groups, and whereby the aryl moiety can be optionally substituted with up to five substituents individually selected from the group consisting of halogen, hydroxyl, C C12- alkoxy, nitro, nitrile, dd-alkyl, halogenated d-C^-alkyl, -S02-N(R)2, and CrC12-alkylsulphonyl; or which aryl may be optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated cyclic 5, 6 or 7 membered ring system, optionally containing up to three heteroatoms, such as N or O, the number of N atoms being 0-3 and the number of O atoms each being 0-2, whereby the cyclic ring system may optionally be further substituted by an oxo group; heteroaryl and heteroaryl-Ci-d2-alkyl, which heteroaryl is selected from the group consisting of pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, benzoimidazolyl, 1 ,3- dihydro-benzoimidazolyl, benzofuran, and benzo[b]thiophene, whereby the heteroaryl group can be optionally substituted with up to three substituents individually selected from the group consisting of halogen, d-d- alkyl, halogenated Cι-C8-alkyl, -CO-OR, aryl or aryloxy, whereby the aryl group is selected from phenyl or naphthyl and can be optionally substituted with up to three halogen atoms; cycloheteroalkyl and cycloheteroalkyl-C C8-alkyl, which cycloheteroalkyl moiety is selected from the group consisting of piperidinyl, pyrrolidinyl, tetrahydrofuryl, dioxolyl, morpholinyl, tetrahydrothiophenyl, tetrahydropyridinyl, azetidinyl, thiazolidinyl, oxazolidinyl, thiomor- pholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, thiazepanyl, dihydro-1H-pyrrolyl, and 1 ,3-dihydro-benzoimidazolyl, whereby the cycloheteroalkyl moiety can be optionally substituted with up to two substituents individually selected from the group consisting of oxo, C-ι-C12-alkyl, hydroxyl,
Figure imgf000024_0001
and aryl-Cι-C12-alkyl;
or R2 itself may be independently selected from -CO-R, -CO-O-R, or -CO-N(R)2;
R3 and R4 are individually selected from the group consisting of hydrogen, oxo, thio, halogen or dihalogen, -CO-R, preferably CHO, -CO-O-R, nitrile, -CO-N(R)2, -O-CO-R, -O-R, -S-R, -N(R)2, -C|-Ci2-alkyl, which alkyl can be linear, cyclic, branched or partially unsaturated, and which alkyl can be optionally substituted with up to three substituents individually selected from the group consisting of hydroxyl, Crd-alkoxy, thiol, and -N(R)2;
wherein R represents hydrogen, Crd-alkyl, phenyl-Cι-C4-alkyl or phenyl, optionally substituted in the phenyl moiety with up to three substituents selected from the group consisting of halogen, hydroxyl, and d-C4-alkoxy, preferably methoxy.
According to a preferable embodiment, at least one of the substituents R3 to R6 shall be different from hydrogen, particularly in case the six-membered ring comprising the hydrocarbon chain -C(R3)-C(R4)-C(R5)-C(R6)- is not an aromatic ring.
Especially preferable compounds are those where the six-membered ring comprising the hydrocarbon chain -C(R3)-C(R4)-C(R5)-C(R6)- is an aromatic ring.
Particularly preferable compounds of formula (I) are those where R2 is selected from the group consisting of
-CrC8-alkyl, which alkyl can be linear, cyclic, branched or partially unsaturated, and which can be optionally substituted with up to three substituents individually selected from the group consisting of hydroxyl, dCs-alkoxy, thiol, d-C8-alkylthio, aryloxy, -CO-O- CrC8-alkyl, and -O-CO-R'; whereby said aryl group is phenyl or naphthyl, and can be optionally substituted with up to three halogen; aryl and aryl-CrC8-alkyl, which aryl is selected from the group consisting of phenyl, biphenyl, naphthyl, indanyl, indenyl and fluorenyl, whereby the aryl moiety can be optionally substituted with up to five substituents individually selected from the group consisting of halogen, hydroxyl, d-C8-alkoxy, nitro, nitrile, halogenated CrC8-alkyl, -S02-N(R')2, heteroaryl and heteroaryl-C C8-alkyl, which is selected from the group consisting of pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, benzoimidazolyl, 1 ,3-dihydro- benzoimidazolyl, benzofuran , and benzo[b]thiophene, whereby the heteroaryl group can be optionally substituted with up to three substituents individually selected from the group consisting of halogen, d-d-alky!, halogenated d-Ca-alkyl, aryl or aryloxy, whereby the aryl group is selected from phenyl or naphthyl and can be optionally substituted with up to three halogen atoms; -CO-R',
-CO-N(R')2, and -CO-O-R';
wherein R' represents hydrogen or d-d-alkyl.
Most preferable compounds of formula (I) are those where R2 is i) a residue of formula (II)
Figure imgf000025_0001
wherein R7 is hydrogen, halogen, hydroxyl or C C4-alkoxy, preferably methoxy,
R8 is hydrogen, C C4-alkoxy, preferably methoxy, hydroxyl, nitrile, halogen, or halogenated C C4-alkyl, preferably trifluormethyl, R9 is hydrogen, d-d-alkoxy, preferably methoxy, hydroxyl, nitrile, halogen, or N,N-di-d-C4- alkyl-sulphonamide R10 is hydrogen, C C -alkoxy, preferably methoxy, hydroxyl, nitrile, halogen, or halogenated d-d-alkyl, preferably trifluormethyl R11 is hydrogen, halogen, hydroxyl or d-C -alkoxy, preferably methoxy
or ii) -d-d-alkyl, which alkyl can be linear, cyclic, branched or partially unsaturated;
-d-d-alkyl, substituted with one or two substituents selected from the group consisting of -CO-O-R"; -O-R"; -O-Ar, whereby Ar is phenyl optionally substituted with halogen; -O-CO-R", phenyl or biphenyl, optionally substituted in the phenyl moiety with up to three d-C4- alkoxy, preferably methoxy, groups; -CO-O-R", -CO-R", preferably -CHO -naphthyl,
-heteroaryl which can be selected from the group consisting of thienyl, furyl, pyridinyl, ben- zothienyl, and pyrazoloyl, whereby the heteroaryl group can be optionally substituted by one or two substitu- ents individually selected from the group consisting of halogen, d-C -alkyl, halogenated d-d-alkyl, preferably trifluormethyl, phenyl and phenoxy, whereby the phenyl group can be optionally substituted with up to three halogen;
wherein R" represents hydrogen or d-d-alkyl, preferably methyl or ethyl.
Preferred R2 substituents are those where R2 is selected from the group consisting of a residue of formula (II)
Figure imgf000026_0001
wherein R7 is hydrogen, bromo, chloro, or fluoro, R8 is hydrogen, d-C4-alkoxy, preferably methoxy, or hydroxyl, R9 is hydrogen, d-C4-alkoxy, preferably methoxy, or hydroxyl, R10 is hydrogen, C C -alkoxy, preferably methoxy, or hydroxyl, R11 is hydrogen;
-d-d-alkyl, which alkyl can be linear, cyclic, or branched; optionally substituted with an -O- CO-(d-C4)-alkyl or -CO-0-(C C4)-alkyl group; and -heteroaryl which can be selected from the group consisting of thienyl, furyl, pyridinyl, ben- zothienyl, and pyrazoloyl.
Mostly preferred R2 substituents are those where R2 is methoxyphenyl, trimethoxyphenyl, 2- bromo-3,4,5-trimethoxyphenyl, 2-chloro-3,4,5-trimethoxyphenyl, thienyl, or propyl. Particularly preferable compounds of formula (I) are those where R1 is selected from the group consisting of
-d-d-alkyl, which alkyl can be linear, cyclic, branched or partially unsaturated, and which can be optionally substituted with up to three substituents individually selected from the group consisting of hydroxyl, Cι-C8-alkoxy, thiol, -NH2, Cι-C8-alkylthio, aryloxy, arylacyl, -CO-0-d-C8-alkyl, Ci-d-alkylacyloxy, heteroaryl-acyloxy, and d-C8- alkylamino; whereby said aryl group is phenyl or naphthyl, and can be optionally substituted with up to three halogen; whereby said heteroaryl group is thienyl, furyl or pyridinyl, aryl and aryl-d-d-alkyl, which aryl moiety is selected from the group consisting of phenyl, biphenyl, naphthyl, indanyl, indenyl, and fluorenyl, wherein the alkyl moiety can be optionally substituted with one or two hydroxyl groups, and wherein the aryl moiety can be optionally substituted with up to five substituents individually selected from the group consisting of halogen, hydroxyl, d-d-alkoxy, Ci-d-alkylsulphonyl, -S02-N(C1-C8-alkyl)2, Cι-C8-alkyl, halogenated d-C8-alkyl; or which aryl may be optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated cyclic 5 or 6 membered ring system, optionally containing up to three heteroatoms, such as N or O, the number of N atoms being 0-3 and the number of O atoms each being 0-2, whereby the cyclic ring system may optionally be further substituted by an oxo group; heteroaryl and heteroaryl-d-Cβ-alk l, which heteroaryl moiety is selected from the group con- sisting of quinolinyl, thiazolyl, pyrimidinyl, furyl, pyridinyl, thienyl, pyrrolyl, imidazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyrazinyl, indolyl, isoquinolinyl, benzoimidazolyl, 1 ,3-dihydro-benzoimidazolyl, benzofuran, and benzo[b]thiophene, whereby the heteroaryl group can be optionally substituted with up to three substituents individually selected from the group consisting of halogen, C C8-alkyl, and -CO-O- Cι-C8-alkyl; cycloheteroalkyl and cycloheteroalkyl-d-d-alkyl, which cycloheteroalkyl moiety is selected from the group consisting of piperidinyl, pyrrolidinyl, tetrahydrofuryl, dioxolyl, morpholinyl, tetrahydrothiophenyl, tetrahydropyridinyl, azetidinyl, thiazolidinyl, oxazolidinyl, thiomor- pholinyl, piperazinyl, azepan l, diazepanyl, oxazepanyl, thiazepanyl, dihydro-1H-pyrrolyl, and 1,3-dihydro-benzoimidazolyl, whereby the cycloheteroalkyl moiety can be optionally substituted with up to two substituents individually selected from the group consisting of oxo, d-d-alkyl, hydroxyl, d-d-alkoxy and aryl~d-C8-alkyl. Most preferable compounds of formula (I) are those where R1 is selected from the group consisting of
-d-C8-aIkyl, which alkyl can be linear, cyclic or branched,
-d-C4-aIkyl, substituted with one or two substituents independently selected from the group consisting of -O-R"; -O-Ar, -O-CO-HetAr, -CO-Ar, -CO-O-R", and -N(R")2, aryl and aryl-C C4-alkyl, which aryl moiety is selected from the group consisting of phenyl, indanyl, and fluorenyl, wherein the alkyl moiety can be optionally substituted with a hydroxyl group; and wherein the aryl moiety can be optionally substituted with up to three substituents individually selected from the group consisting of halogen, -O-R"; -S02-R", -S02-N(R")2, or which aryl may be optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated cyclic 5 or 6 membered ring system, optionally containing up to two O atoms, whereby the cyclic ring system may optionally be further substituted by an oxo group; heteroaryl and heteroaryl-d-d-alkyl, which heteroaryl moiety is selected from the group consisting of quinolinyl, thiazolyl, pyrimidinyl, furyl, pyridinyl, pyrazinyl, and thienyl, whereby the heteroaryl group can be optionally substituted with one or two su b- stituents individually selected from the group consisting of halogen, -d-d-alkyl, and -CO-O-R"; cycloheteroalkyl and cycloheteroalkyl-d-C -alkyl, which cycloheteroalkyl moiety is selected from the group consisting of piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuryl, and dioxolyl, whereby the cycloheteroalkyl moiety can be optionally substituted with up to two substituents individually selected from the group consisting of oxo, d-C -aIkyl, preferably methyl, and -d-d-alkyl-Ar, preferably benzyl or phenethyl. wherein Ar represent phenyl, optionally substituted with halogen or methoxy, HetAr represents thienyl, furyl, pyridinyl, and R" represents hydrogen or C1-C4-aIkyl, preferably methyl or ethyl.
Preferred R1 substituents are those where R1 is selected from the group consisting of
-d-C8-alkyl, which alkyl can be linear, cyclic or branched, -d-C4-alkyl, substituted with one or two substituents independently selected from the group consisting of C C4-alkoxy, hydroxyl, and -O-CO-HetAr, phenyl-d-d-alkyl, wherein the aryl moiety can be optionally substituted with up to three substituents individually selected from the group consisting of halogen, d-d-alkoxy, and hydroxyl, heteroaryl-d-d-alkyl, which heteroaryl moiety is selected from the group consisting of pyrimid- inyl, furyl, pyridinyl, and thienyl, whereby the heteroaryl group can be optionally substituted with one or two su b- stituents individually selected from the group consisting of halogen, d-d-alkoxy, and hydroxyl, and cycloheteroalkyl-d-C -alkyl, which cycloheteroalkyl moiety is selected from the group consisting of tetrahydrofuryl, piperidinyl, morpholinyl, and pyrrolidinyl,
Mostly preferred R1 substituents are those where R1 is selected from the group consisting of isobutyl, 3-methylbutyl, benzyl, phenethyl, tetrahydrofurylmethyl, furylmethyl, 5-bromo-furan-2- ylmethyl, 5-bromo-2-methoxybenzyl, thiophene-2-carboxylic acid ethyl ester, and methoxyethyl.
Particularly preferable compounds of formula (I) are those, where in R3 is selected from the group consisting of hydrogen, oxo, -O-R', -O-Ar, -O-CO-R', halogen, thio, -S-R', and -S-Ar, wherein R' represents hydrogen or C C8-alkyl, Ar represents phenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy or methoxy.
Most preferable compounds of formula (I) are those, where R3 is selected from the group consisting of hydrogen, oxo, -O-R", -O-Ar, -O-CO-R", halogen, thio, -S-R", and -S-Ar; wherein R" represents hydrogen or d-d-alkyl, preferably methyl or ethyl, and Ar represent phenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy or methoxy.
Preferred R3 substituents are those where R3 is selected from the group consisting of hydrogen, hydroxyl, oxo, chloro, bromo, phenoxy, phenylthio, C C4-alkoxy, Cι-C4-alkylthio, and -O-CO-d-d-alkyl.
Mostly preferred R3 substituents are those where R3 is selected from the group consisting of hydrogen, hydroxyl, oxo, -0-CO-CH3, and -S-ethyl.
Particularly preferable compounds of formula (I) are those, where in R4 is selected from the group consisting of hydrogen, Cι-C8-alkyl, optionally substituted with hydroxyl; -CO-R', -CO-O- R', halogen and dihalogen, wherein R' represents hydrogen or d-d-alkyl. Most preferable compounds of formula (I) are those, where R4 is selected from the group consisting of hydrogen, d-d-alkyl, optionally substituted with hydroxyl; -CO-R", -CO-O-R", halogen and dihalogen wherein R" represents hydrogen or C C4-alkyl, preferably methyl or ethyl.
Preferably, R4 is different from d-C4-alkyl, in case R1 is benzyl.
Preferred R4 substituents are those where R4 is selected from the group consisting of hydrogen, halogen, carbonyl, and -CO-CrC -alkyl.
Mostly preferred R4 substituents are those where R4 is selected from the group consisting of hydrogen, bromo and carbonyl.
Preferred compounds of formula (I) are further those wherein R6 is hydrogen or halogen, pref- erably bromo.
Preferred compounds of formula (I) are further those wherein X represents S.
Especially preferable compounds of formula (I) are the compounds of formula (I)
Figure imgf000030_0001
wherein
X is S, SO or S02;
R1 is selected from the group consisting of:
-C3-C8-alkyl, which alkyl can be linear, cyclic or branched,
-d-d-alkyl, substituted with one or two substituents independently selected from the group consisting of d-d-alkoxy, hydroxyl, and -O-CO-HetAr, phenyl-d-C4-alkyl, wherein the aryl moiety can be optionally substituted with up to three substituents individually selected from the group consisting of halogen, Cι-C4-alkoxy, and hydroxyl, heteroaryl-d-C -alkyl, which heteroaryl moiety is selected from the group consisting of pyrimid- inyl, furyl, pyridinyl, and thienyl, whereby the heteroaryl group can be optionally substituted with one or two su bstituents individually selected from the group consisting of halogen, d-d-alkoxy, and hydroxyl, and cycloheteroalkyl-Cι-C4-alkyl, which cycloheteroalkyl moiety is selected from the group consisting of tetrahydrofuryl, piperidinyl, morpholinyl, and pyrrolidinyl;
R2 is selected from the group consisting of i) a residue of formula (II)
Figure imgf000031_0001
wherein
R7 is hydrogen, bromo, chloro, orfluoro, R8 is hydrogen, d-d-alkoxy, preferably methoxy, or hydroxyl, R9 is hydrogen, C1-C4-alkoxy, preferably methoxy, or hydroxyl, R10 is hydrogen, d-C4-alkoxy, preferably methoxy, or hydroxyl, R11 is hydrogen,
and ii) -d-d-alkyl, which alkyl can be linear, cyclic, or branched; optionally substituted with an -O- CO-(C C4)-alkyl or -CO-0-(C C4)-alkyl group ; -heteroaryl which can be selected from the group consisting of thienyl, furyl, pyridinyl, ben- zothienyl, and pyrazoloyl;
R3 is selected from the group consisting of hydrogen, oxo, hydroxyl, Cι-C4-alkoxy, -O-CO-d- C4-a!kyl, and d-d-alkylthio;
R4 is selected from the group consisting of hydrogen, halogen, carbonyl, -CO-d-C4-alkyl, and
R6 is hydrogen or bromo.
A particularly preferred subgroup of the aforementioned group are compounds, wherein R1 is selected from the group consisting of isobutyl, 3-methylbutyl, benzyl, tetrahydrofurylmethyl, furylmethyl, 5-bromo-furan-2-ylmethyl, 5-bromo-2-methoxybenzyl, thiophene-2- carboxylic acid ethyl ester, and methoxyethyl;
R2 is selected from the group consisting of methoxyphenyl, trimethoxyphenyl, 2-bromo-3,4,5- trimethoxyphenyl, 2-chloro-3,4,5-trimethoxyphenyl, thienyl, and propyl;
R3 is selected from the group consisting of hydroxyl, oxo, -0-CO-CH3, and -S-ethyl;
R4 is selected from the group consisting of hydrogen, bromo and carbonyl; and
R6 is hydrogen or bromo.
In a further preferable subgroup the present invention comprises compounds, wherein
R1 is linear, cyclic or branched -C3-C8-alkyl,
R2 is trimethoxyphenyl, 2-bromo-3,4,5-trimethoxyphenyl, or 2-chloro-3,4,5-trimethoxyphenyl,
R3 is hydrogen or hydroxyl,
R4 is hydrogen, R6 is hydrogen or bromo, and wherein the six-membered ring comprising the hydrocarbon chain -C(R3)-C(R4)-C(R5)-C(R6)- is an aromatic ring.
The following compounds and their use, respectively, are especially preferred in the context of the present invention:
No. 1 3-Benzyl-2-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
No. 2 3-Benzyl-6,7-dihydro-2-(3,4,5-trimethoxyphenyl)-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione No. 3 3-Benzyl-8-chloro-4-oxo-2-(3,4,5-trimethoxyphenyl)-3,4,5,6-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidine-7-carbaldehyde
No. 4 3-Benzyl-4-oxo-8-phenoxy-2-(3,4,5-trimethoxyphenyl)-3,4,5,6-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidine-7-carbaldehyde
No. 5 3-Benzyl-4-oxo-8-phenoxy-2-(3,4,5-trimethoxyphenyl)-3,4-dihydro-benzo[4,5]thieno[2,3- d]pyrimidine-7-carbaldehyde
No. 6 3-Benzyl-8-ethylsulfanyl-4-oxo-2-(3,4,5-trimethoxyphenyl)-3,4,5,6-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidine-7-carbaldehyde
No. 7 3-Benzyl-8-ethoxy-4-oxo-2-(3,4,5-trirnethoxyphenyl)-3,4,5,6-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidine-7-carbaldehyde No. 8 3-Benzyl-4-oxo-8-phenylsulfanyI-2-(3,4,5-trimethoxyphenyl)-3,4,5,6-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidine-7-carbaldehyde
No. 9 3-Benzyl-4-oxo-8-phenylsulfanyl-2-(3,4,5-trimethoxyphenyl)-3,4-dihydro- benzo[4,5]thieno[2,3-d]pyrimidine-7-carbaldehyde No. 10 3-Phenyl-2-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
No. 11 3-Phenyl-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione No. 12 3-Benzyl-2-(p-methoxyphenyl)-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-
4-one
No. 13 3-Benzyl-2-(p-methoxyphenyl)-6J-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-
4,8-dione
No. 14 8-Chloro-2-(p-methoxyphenyl)-4-oxo-3-phenyl-3,4,5,6-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine-7-carbaldehyde
No. 15 3-Benzyl-2-(p-methoxyphenyl)-4-oxo-3,4,5,6-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine-7-carboxylic acid ethyl ester
No. 16 3-Benzyl-8-ethylsulfanyl-2-(p-methoxyphenyl)-4-oxo-3,4,5,6-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidine-7-carbaldehyde No. 17 3-Benzyl-2-(p-methoxyphenyl)-4-oxo-3,4-dihydro-benzo[4,5]thieno[2,3-d]pyrimidine-7- carbaldehyde
No. 18 3-Benzyl-8-ethylsulfanyl-2-(p-methoxyphenyl)-4-oxo-3,4-dihydro-benzo[4,5]thieno[2,3- d]pyrimidine-7-carbaldehyde
No. 19 3-Benzyl-8-ethylsulfanyl-7-hydroxymeth l-2-(p-methoxyphenyl)-3,4-dihydro-3H- benzo[4,5]thieno[2,3-d]pyrimidin-4-one
No. 20 3-Benzyl-7-hydroxymethyl-2-(p-methoxyphenyl)-8-phenoxy-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
No. 21 3-Benzyl-7-methyl-2-(p-methoxyphenyl)-8-phenoxy-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one No. 22 3-Phenyl-2-(p-methoxyphenyl)-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-
4-one
No. 23 3-Phenyl-2-(p-methoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidin-4,8- dione
No. 24 2-Methyl-3-phenyl-5,6J,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one No. 25 2-Methyl-3-phenyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
No. 26 2-(acetic acid methyl ester)-3-benzyl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
No. 27 3-Benzyl-2-methoxymethyl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4- one No. 28 3-Benzyl-2-hydroxymethyl-5,6J,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
No. 29 Acetic acid 3-benzyl-4-oxo-3,4,5,6,7,8-hexahydro-benzo[4,5]thieno[2,3-d]pyrimidin-2- ylmethyl ester
No. 30 Acetic acid 3-benzyl-4,8-dioxo-3,4,5,6,7,8-hexahydro-benzo[4,5]thieno[2,3-d]pyrimidin-
2-ylmethyl ester No. 31 3-Benzyl-2-methoxymethyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8- dione
No. 32 3-Benzyl-4,8-dioxo-3,4,5,6,7,8-hexahydro-benzo[4,5]thieno[2,3-d]pyrimidine-2- carboxylic acid methyl ester No. 33 3-Benzyl-4,9,9-trioxo-4,5,6,7,8,9-hexahydro-3H-9Iambda*6*-benzo[4,5]thieno[2,3- d]pyrimidine-2-carbaldehyde
No. 34 3-Benzyl-8-chloro-2-methoxymethyl-4-oxo-3,4,5,6-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine-7-carba!dehyde
No. 36 2-Methoxymethyl-3-phenyl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one No. 37 2-Methoxymethyl-3-phenyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidin-4,8- dione
No. 38 2-Hydroxymethyl-3-phenyl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
No. 39 Acetic acid 4-oxo-3-phenyl-3,4,5,6,7,8-hexahydro-benzo[4,5]thieno[2,3-d]pyrimidin-2- ylmethyl ester No. 40 4-Oxo-3-phenyl-3,4,5,6,7,8-hexahydro-benzo[4,5]thieno[2,3-d]pyrimidine-2-carboxylic acid ethyl ester
No. 41 3-Benzyl-2-(3,4,5-trihydroxyphenyl)-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
No. 42 3-Phenyl-2-(3,5-dihydroxy-4-methoxyphenyl)-5,6,7,8-tetrahydro-3H- benzo[4,5]thieno[2,3-d]pyrimidin-4-one
No. 43 3-Phenyl-2-(3,4,5-trihydroxyphenyl)-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
No. 44 7-Bromo-2-methyl-3-phenyl-6J-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8- dione No. 45 7,7-Dibromo-2-methyl-3-phenyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-
4,8-dione
No. 46 3-benzyl-7-bromo-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
No. 47 3-benzyl-7-bromo-2-(2-bromo-3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
No. 48 3-benzyl-7,7-dibromo-2-(2-bromo-3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
No. 49 3-Benzyl-2-(2-bromo-3,4,5-trimethoxyphenyl)-8-hydroxy-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one No. 50 Acetic acid 3-benzyl-2-(2-bromo-3,4,5-trimethoxyphenyl)-4-oxo-3,4-dihydro- benzo[4,5]thieno[2,3-d]pyrimidin-8-yl ester
No. 51 3-benzyl-2-(2-bromo-3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
No. 52 3-benzyl-7-bromo-2-(2-bromo-3,4,5-trimethoxyphenyl)-8-hydroxy-3H- benzo[4,5]thieno[2,3-d]pyrimidin-4-one No. 53 3-Benzyl-8-hydroxy-2-(3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4- one
No. 54 Acetic acid 3-benzyl-2-(3,4,5-trimethoxyphenyl)-4-oxo-3,4-dihydro-benzo[4,5]thieno[2,3- d]pyrimidin-8-yl ester No. 55 3-benzyl-7-bromo-9-oxo-2-(3,4,5-trimethoxyphenyl)-5,6,7,9-tetrahydro-3H-9lambda*4*- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
No. 56 3-Benzyl-2-phenyl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
No. 57 3-Benzyl-2-phenyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
No. 58 3-Benzyl-7-bromo-2-phenyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8- dione
No. 59 3-Benzyl-7,7-dibromo-2-phenyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-
4,8-dione
No. 60 3-Benzyl-8-hydroxy-2-phenyl-3H-benzo[4,5]thieno[2,3-d]pyrimidine-4-one
No. 61 3-Benzyl-2-thiophen-2-yl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one No. 62 3-Benzyl-2-thiophen-2-yl-6J-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8- dione
No. 63 3-Benzyl-2-thiophen-2-yl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8- dione
No. 64 3-Benzyl-2-(5-bromo-thiophen-2-yl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
No. 65 3-Benzyl-7-bromo-2-(5-bromothiophen-2-yl)-6J-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
No. 66 3-Benzyl-7,7-dibromo-2-(5-bromothiophen-2-yl)-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione No. 67 3-Benzyl-8-hydroxy-2-thiophen-2-yl-3H-benzo[4,5]thieno[2,3-d]pyrimidine-4-one
No. 68 3-Benzyl-2-(5-bromothiophen-2-yl)-8-hydroxy-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4- one
No. 69 Thiophene-2-carboxylic acid 2-(4-oxo-2-thiohen-2-yl-5,6,7,8-tetrahydro-4H- benzo[4,5]thieno[2,3-d]pyrimidin-3-yl)-ethyl ester No. 70 Thiophene-2-carboxylic acid 2-(4,8-dioxo-2-thiohen-2-yl-5,6,7,8-tetrahydro-4H- benzo[4,5]thieno[2,3-d]pyrimidin-3-yl)-ethyl ester
No. 71 Thiophene-2-carboxylic acid 2-(7-bromo-4,8-dioxo-2-thiohen-2-yl-5,6,7,8-tetrahydro-4H- benzo[4,5]thieno[2,3-d]pyrimidin-3-yl)-ethyl ester
No. 72 Thiophene-2-carboxylic acid 2-(7,7-dibromo-4,8-dioxo-2-thiohen-2-yl-5,6,7,8-tetrahydro- 4H-benzo[4,5]thieno[2,3-d]pyrimidin-3-yl)-ethyl ester
No. 73 Thiophene-2-carboxylic acid 2-(8-hydroxy-4-oxo-2-thiohen-2-yl-4H- benzo[4,5]thieno[2,3-d]pyrimidin-3-yl)-ethyl ester
No. 74 3-(2-Methoxyethyl)-2-thiophen-2-yl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one No. 75 3-(2-Methoxyethyl)-2-thiophen-2-yl-6J-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
No. 76 7-Bromo-3-(2-methoxyethyl)-2-thiophen-2-yl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione No. 77 3-Benzyl-2-thiophen-2-yl-5,6J,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
No. 78 3-Benzyl-2-(m-methoxyphenyl)-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-
4-one
No. 79 3-Benzyl-2-(m-methoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-
4,8-dione No. 80 3-Benzyl-7-bromo-2-(m-methoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
No. 81 3-Benzyl-7,7-dibromo-2-(m-methoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
No. 82 3-Benzyl-7,7-dibromo-2-(5-bromo-3-methoxyphenyl)-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
No. 83 3-Benzyl-8-hydroxy-2-(/T7-methoxyphenyl)- 3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
No. 84 Acetic acid 3-benzyl-84-oxo-2-(m-methoxyphenyl)-3,4-dihydro-benzo[4,5]thieno[2,3- d]pyrimidin-8-yl ester
No. 85 3-Butyl-2-(3,4,5-trimethoxyphenyl)-5,6J,8-tetrahydro-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
No. 86 3-Butyl-2-(3,4,5-trimethoxyphenyl)-6J-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
No. 87 7-Bromo-3-butyl-2-(3,4,5-trimethoxyphenyI)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione No. 88 3-Butyl-7,7-dibromo-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
No. 89 3-Butyl-8-hydroxy-2-(3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
No. 90 7-Bromo-3-butyI-8-hydroxy-2-(3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one No. 91 3-Benzyl-8-methoxy-2-(2-bromo-3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
No. 92 3-Benzyl-7-bromo-8-hydroxy-2-phenyl-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
No. 93 Acetic acid 3-benzyl-7-bromo-4-oxo-2-phenyl-3,4-dihydro-benzo[4,5]thieno[2,3- d]pyrimidin-8-yl ester No. 94 3-(2-Methoxybenzyl)-2-propyl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4- one
No. 95 3-(2-Methoxybenzyl)-2-propyI-6J-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8- dione No. 96 7-Bromo-3-(2-methoxybenzyl)-2-propyl-6J-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
No. 97 7,7-Dibromo-3-(5-bromo-2-methoxybenzyl)-2-propyl-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione No. 98 3-Benzyl-3-(5-bromo-2-methoxybenzyl)-8-hydroxy-2-propyl-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
No. 99 Acetic acid 3-benzyl-3-(5-bromo-2-methoxybenzyl)-4-oxo-2-propyl-3,4-dihydro- benzo[4 , 5]th ieno[2 , 3-d]pyrimidin-8-yl ester
No. 100 3-(5-Bromo-2-hydroxybenzyl)-8-hydroxy-2-propyl-3H-benzo[4,5]thieno[2,3-d]pyrimidin- 4-one
No. 101 3-Furan-2-ylmethyl-2-propyl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4- one
No. 102 3-Furan-2-ylmethyl-2-propyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8- dione No. 103 7-Bromo-3-(5-bromofuran-2-ylmethyl)-2-propyl-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
No. 104 7,7-Dibromo-3-(5-bromofuran-2-ylmethyl)-2-propyl-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
No. 105 3-(5-Bromofuran-2-ylmethyl)-8-hydroxy-2-propyl-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4- one
No. 106 Acetic acid 3-(5-bromofuran-2-ylmethyl)-4-oxo-2-propyl-3,4-dihydro- benzo[4,5]thieno[2,3-d]pyrimidin-8-yl ester
No. 107 7-Bromo-3-(5-bromofuran-2-ylmethyl)-8-hydroxy-2-propyl-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one No. 108 3-(2-Methoxyethyl)-2-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydro-3H- benzo[4,5]thieno[2,3-d]pyrimidin-4-one
No. 109 3-(2-Methoxyethyl)-2-(3,4,5-trimethoxyphenyl)-6, 7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
No. 110 7,7-Dibromo-2-(2-bromo-3,4,5-trimethoxyphenyl)-3-(2-methoxyethyl)-6,7-dihydro- 3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
No. 111 7-Bromo-2-(2-bromo-3,4,5-trimethoxyphenyl)-3-(2-methoxyethyl)-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
No. 112 2-(2-Bromo-3,4,5-trimethoxyphenyl)-8-hydroxy-3-(2-methoxyethyl)-3H- benzo[4,5]thieno[2,3-d]pyrimidin-4-one No. 1 3 3-lsobutyl-2-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
No. 114 3-lsobutyl-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione No. 115 7-Bromo-3-isobutyl-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
No. 116 7-Bromo-2-(2-bromo-3,4,5-trimethoxyphenyl)-3-isobutyl-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione No. 117 8-Hydroxy-3-isobutyl-2-(2-bromo-3,4,5-trirnethoxyphenyl)-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
No. 118 Acetic acid 2-(2-bromo-3,4,5-trimethoxyphenyl)-3-isobutyl-4-oxo-3,4-dihydro- benzo[4,5]-thieno[2,3-d]pyrimidin-8-yl ester
No. 119 3-Furan-2-yImethyl-2-(3,4,5-trimethoxylphenyl)-5,6,7,8-tetrahydro-3H- benzo[4,5]thieno[2,3-d]pyrimidin-4-one
No. 120 3-Furan-2-ylmethyl-2-(3,4,5-trimethoxylphenyl)-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
No. 121 7-Bromo-3-(5-bromofuran-2-ylmethyl)-2-(2-bromo-3,4,5-trimethoxylphenyl)-6,7-dihydro-
3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione No. 122 3-(5-Bromofuran-2-ylmethyl)-8-hydroxy-2-(3,4,5-trimethoxyphenyl)-3H- benzo[4,5]thieno[2,3-d]pyrimidin-4-one
No. 123 3-Benzyl-7-chloro-2-(2-chloro-3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
No. 124 3-Benzyl-2-(2-chloro-3,4,5-trimethoxyphenyl)-8-hydroxy-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
No. 125 3-(2-Methylbutyl)-2-(3,4,5-trimethoxyphenyl)-5,6J,8-tetrahydro-3H- benzo[4,5]thieno[2,3-d]pyrimidin-4-one
No. 126 3-(2-MethylbutyI)-2-(3,4,5-trimethoxyphenyl)-6J-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione No. 127 7-Bromo-3-(2-methylbutyl)-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
No. 128 7,7-Dibromo-2-(2-bromo-3,4,5-trimethoxyphenyl)-3-(2-methylbutyl)-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
No. 129 8-Hydroxy-3-(2-methylbutyl)-2-(3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
No. 130 3-(Tetrahydrofuran-2-ylmethyl)-2-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydro-3H- benzo[4,5]thieno[2,3-d]pyrimidin-4-one
No. 131 3-(Tetrahydro-furan-2-ylmethyl)-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione No. 132 7-Bromo-2-(2-bromo-3,4,5-trimethoxyphenyl)-3-(tetrahydrofuran-2-ylmethyl)-6,7- dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
No. 133 2-(2-Bromo-3,4,5-trimethoxyphenyl)-8-hydroxy-3-(tetrahydrofuran-2-ylmethyl)-3H- benzo[4,5]thieno[2,3-d]pyrimidin-4-one
No. 134 3-Butyl-2-thiophen-2-yl-6J-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione No. 135 5-Bromo-3-isobutyl-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
No. 136 3-lsobutyl-8-methoxy-2-(3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4- one No. 137 3-Benzyl-5-bromo-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
No. 138 3-Benzyl-8-methoxy-2-(3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4- one
No. 139 7-Chloro-2-(2-chloro-3,4,5-trimethoxyphenyl)-3-(tetrahydrofuran-2-ylmethyl)-6,7- dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
No. 140 2-(2-Chloro-3,4,5-trimethoxyphenyl)-8-hydroxy-3-(tetrahydrofuran-2-ylmethyl)-3H- benzo[4,5]thieno[2,3-d]pyrimidin-4-one
No. 141 7-Chloro-2-(2-chloro-3,4,5-trimethoxyphenyl)-3-(2-methylbutyl)-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione No. 142 7,7-Dichloro-2-(2-chloro-3,4,5-trimethoxyphenyl)-3-(2-methylbutyl)-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
No. 143 2-(2-Chloro-3,4,5-trimethoxyphenyl)-8-hydroxy-3-(2-methylbutyl)-3H- benzo[4,5]thieno[2,3-d]pyrimidin-4-one
No. 144 3-Pyridin-3-ylmethyl-2-(3,4,5-trimethylphenyl)-5,6,7,8-tetrahydro-3H- benzo[4,5]thieno[2,3-d]pyrimidin-4-one
No. 145 3-Benzyl-8-hydroxy-2-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydro-3H- benzo[4,5]thieno[2,3-d]pyrimidin-4-one
No. 146 3-Benzyl-7-bromo-2-p-methoxyphenyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione No. 147 3-Benzyl-7,7-dibromo-2-p-methoxyphenyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
No. 148 7-Bromo-8-hydroxy-3-(2-methoxyethyl)-2-thiophen-2-yl-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
No. 149 7-Bromo-8-hydroxy-3-(2-hydroxyethyl)-2-thiophen-2-yl-3H-benzo[4,5]thieno[2,3-d] pyrimidin-4-one
No. 150 3-Benzyl-8-chloro-2-(2-chloro-3,4,5-trimethoxyphenyl)-4-oxo-3,4-dihydro-benzo[4,5] thieno[2,3-d]pyrimidine-7-carbaldehyde
No. 151 8-Hydroxy-3-isobutyl-2-(3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4- one No. 618 3-Benzo[1,3]dioxol-5-yImethyl-8-hydroxy-2-(2-methoxy-phenyl)-3H-benzo[4,5] thieno[2, 3-d]pyrimidin-4-one
No. 633 3-Butyl-8-hydroxy-2-(2-methoxy-phenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
No. 637 3-Butyl-2-(2,4-difluoro-phenyl)-8-hydroxy-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one No. 674 2-(3,4-Dimethoxy-benzyl)-8-hydroxy-3-(2-pyrϊdin-2-yl-ethyl)-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
In a preferred embodiment, the invention relates to a compound selected from the group con- sisting of exemplary compounds
No. 16 3-Benzyl-8-ethylsulfanyl-2-(p-methoxyphenyl)-4-oxo-3,4,5,6-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidine-7-carbaldehyde
No. 17 3-Benzyl-2-(p-methoxyphenyl)-4-oxo-3,4-dihydro-benzo[4,5]thieno[2,3-d]pyrimidine-7- carbaldehyde No. 18 3-Benzyl-8-ethylsulfanyl-2-(p-methoxyphenyl)-4-oxo-3,4-dihydro-benzo[4,5]thieno[2,3- d]pyrimidine-7-carbaldehyde
No. 67 3-Benzyl-8-hydroxy-2-thiophen-2-yl-3H-benzo[4, 5]thieno[2,3-d]pyrimidine-4-one
No. 73 Thiophene-2-carboxylic acid 2-(8-hydroxy-4-oxo-2-thiohen-2-yl-4H- benzo[4,5]thieno[2,3-d]pyrimidin-3-yl)-ethyl ester No. 89 3-Butyl-8-hydroxy-2-(3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
No. 98 3-Benzyl-3-(5-bromo-2-methoxybenzyl)-8-hydrωcy-2-propyl-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
No. 99 Acetic acid 3-benzyl-3-(5-bromo-2-methoxybenzyl)-4-oxo-2-propyl-3,4-dihydro- benzo[4,5]thieno[2,3-d]pyrimidin-8-yl ester No. 105 3-(5-Bromofuran-2-ylmethyl)-8-hydroxy-2-propyl-3H-benzo[4,5]thieno[2,3-d]pyrimidin-
4-one
No. 106 Acetic acid 3-(5-bromofuran-2-ylmethyl)-4-oxo-2-propyl-3,4-dihydro- benzo[4,5]thieno[2,3-d]pyrimidin-8-yl ester
No. 117 8-Hydroxy-3-isobutyl-2-(2-bromo-3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
No. 124 3-Benzyl-2-(2-chloro-3,4,5-trimethoxyphenyl)-8-hydroxy-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
No. 127 7-Bromo-3-(2-methylbutyl)-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione No. 129 8-Hydroxy-3-(2-methylbutyl)-2-(3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
No. 135 5-Bromo-3-isobutyl-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
No. 140 2-(2-Chloro-3,4,5-trimethoxyphenyl)-8-hydroxy-3-(tetrahydrofuran-2-ylmethyl)-3H- benzo[4,5]thieno[2,3-d]pyrimidin-4-one
No. 143 2-(2-Chloro-3,4,5-trimethoxyphenyl)-8-hydroxy-3-(2-methylbutyl)-3H- benzo[4,5]thieno[2,3-d]pyrimidin-4-one
No. 148 7-Bromo-8-hydroxy-3-(2-methoxyethyl)-2-thiophen-2-yl-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one No. 633 3-Butyl-8-hydroxy-2-(2-methoxy-phenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one No. 637 3-Butyl-2-(2,4-difluoro-phenyl)-8-hydroxy-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one or a physiologically acceptable salt thereof. Pharmaceutically acceptable salts of the compounds of the invention as well as com- monly used pro-drugs and active metabolites of these compounds are also within the scope of the invention.
The invention also relates to pharmaceutical compositions comprising one or more of the compounds of the invention for which no use in therapy has been disclosed earlier, or their salts or pro-drugs, as active agent and at lease one pharmaceutically acceptable carrier.
Furthermore, the invention relates to the use of an effective amount of a novel compound as defined herein for the treatment or prevention of a steroid hormone dependent disease or disorder in a mammal, in particular a human. Preferably the steroid hormone dependent dis- ease or disorder is an estradiol or testosterone dependent disease or disorder.
In a preferred embodiment, the invention relates to the use of an effective amount of a novel compound as defined within the present invention for the treatment or prevention of a steroid hormone dependent disease or disorder in a mammal, whereby the steroid hormone dependent disease or disorder requires the inhibition of a 17β-hydroxysteroid dehydrogenase (HSD) enzyme, preferably the human 17β-hydroxy steroid dehydrogenase (HSD) enzyme type 1 , type 2 or type 3.
In a further preferred embodiment of the invention the steroid hormone dependent dis- ease or disorder to be treated and/or prevented requires the lowering of the endogenous 17β- estradiol or testosterone concentration in a generalized and/or tissue specific manner.
The invention also relates to a method of treating a mammal such as a human having a condition related to 17β-hydroxysteroid dehydrogenase (HSD) type 1, type 2 or type 3 activity, comprising administering to the mammal an amount of a compound of this invention, or a salt or a prodrug thereof, which amount is effective to treat the condition. Administration of compounds of this invention in combination with other pharmaceuticals used in treatment of the listed conditions is contemplated. The conditions to be treated and/or prevented in the context of the present invention include but are not limited to breast cancer, prostate carcinoma, ovarian cancer, uterine cancer, endometrial cancer, endometrial hyperplasia, endometriosis, uterine fibroids, uterine leio- myoma, adenomyosis, dysmenorrhea, menorrhagia, metrorrhagia, prostadynia, benign prostatic hyperplasia, prostatitis, acne, seborrhea, hirsutisrn, androgenic alopecia, precocious puberty, adrenal hyperplasia, polycystic ovarian syndrome,and urinary dysfunction. A further condition to be treated and/or prevented in the context of the present invention includes osteoporosis.
Further estrogen-dependent diseases which may be treated and/or prevented with an ef- fective amount of a compound of the invention are multiple sclerosis, rheumatoid arthritis, Alzheimer's disease, colon cancer, tissue wounds, skin wrinkles and cataracts.
In a preferred embodiment the invention relates to use of an effective amount of a compound of the invention for the treatment or prevention of one of the aforementioned disease or disorders in a mammal whereby the mammal is a human, preferably a female and most preferably a pre- or peri-menopausal female in the case of gynaecological disorders.
Furthermore, compounds of formula (I) may be useful for blocking spermatogenesis and as an anti-fertility agent for males.
The disclosed compounds are also useful as diagnostic agents (e.g. in diagnostic kits or for use in clinical laboratories) for screening for the presence or absence of 17β-hydroxysteroid dehydrogenase (HSD) type 1 , type 2 and/or type 3 activity. It will be appreciated that the methods of the present invention can be incorporated in the form of a variety of embodiments, only a few of which are disclosed herein. It will be apparent for the expert skilled in the field that other embodiments ex ist and do not depart from the spirit of the invention. Thus, the described embodiments are illustrative and should not be construed as restrictive.
Administration forms
The method of the invention is primarily intended for treatment in a mammal, preferably in humans and other primates, of steroid hormone dependent diseases or disorders, in particular estradiol dependent diseases or disorders, wherein the steroid hormone dependent disease or disorder preferably requires the inhibition of a 17β-hydroxysteroid dehydrogenase (HSD) enzyme, preferably the type 1 17β-hydroxysteroid dehydrogenase (HSD) enzyme [EC 1.1.1.62].
The compounds may be administered orally, dermally, parenterally, by injection, by pulmonal or nasal delivery, or sublingually, rectally or vaginally in dosage unit formulations. The term "administered by injection" includes intravenous, intraarticular, intramuscular (e.g. by depot injection where the active compounds are released slowly into the blood from the depot and carried from there to the target organs), intraperitoneal, intradermal, subcutaneous, and intrathecal injections, as well as use of infusion techniques. Dermal administration may include topical application or transdermal administration. One or more compounds may be present in association with one or more non-toxic pharmaceutically acceptable auxiliaries such as excipients, adjuvants (e.g. buffers), carriers, inert solid diluents, suspensing agents, preservatives, fillers, stabilizers, anti-oxidants, food additives, bioavailability enhancers, coating materials, granulating and disintegrating agents, binding agents etc., and, if desired, other active ingredients.
The pharmaceutical composition may be formulated for example as immediate release, sustained release, pulsatile release, two or more step release, depot or other kind of release formulations.
The manufacture of the pharmaceutical compositions according to the invention may be performed according to methods known in the art and will be explained in further detail below. Commonly known and used pharmaceutically acceptable auxiliaries as well as further suitable diluents, flavorings, sweetening agents, coloring agents etc. may be used, depending on the intended mode of administration as well as particular characteristics of the active compound to be used, such as solubility, bioavailability etc. Suitable auxiliaries and further ingredients may be such as recommended for pharmacy, cosmetics and related fields and which preferably are listed in the European Pharmacopoeia, FDA approved or cited in the "GRAS" list (FDA List of food additives that are 'generally recognized as safe' (GRAS)).
One mode of application of the compounds of general formula (I) or of pharmaceutical compositions comprising one or more of said compounds is oral application, e. g., by tablets, pills, dragees, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixiers, solid emulsions, solid dispersions or dispersible powders. For the preparation of pharmaceutical compositions for oral administration, the compounds suitable for the purposes of the present invention as defined above can be admixed with commonly known and used adjuvants and excipients such as for example, gum arabic, talcum, starch, sugars (such as, e. g., mannitose, methyl cellulose, lactose), gelatin, surface-active agents, magnesium stearate, aqueous or non-aqueous solvents, paraffin derivatives, cross-linking agents, dispersants, emulsifiers, lubricants, conserving agents, flavoring agents (e. g., ethereal oils), solubility enhancers (e. g., benzyl benzoate or benzyl alcohol) or bioavailability enhancers (e.g. Gelucire™). In the pharmaceutical composition, the active ingredients may also be dispersed in a microparticle, e. g. a nanoparticulate, composition.
For parenteral administration, the active agents can be dissolved or suspended in a physiologically acceptable diluent, such as, e. g., water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers. As oils for example and without limitation, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil may be used. More generally spoken, for parenteral administration the active agent can be in the form of an aqueous, lipid, oily or other kind of solution or suspension or even administered in the form of liposomes or nano-suspensions.
Transdermal application can be accomplished by suitable patches, as generally known in the art, specifically designed for the transdermal delivery of active agents, optionally in the presence of specific permeability enhancers. Furthermore, also emulsions, ointments, pastes, creams or gels may be used for transdermal delivery.
Another suitable mode of administration is via intravaginal devices (e. g. vaginal rings) or intrauterine systems (IUS) containing reservoirs for controlled release of active agents over extended periods of time. For rectal or vaginal administration of the drug the compounds may also be administered in the form of suppositories. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug.
Another mode of application is by implantation of a depot implant comprising an inert carrier material, such as biologically degradable polymers or synthetic silicones such as e. g. silicone rubber. Such implants are designed to release the active agent in a controlled manner over an extended period of time (e. g., 3 to 5 years).
It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics.
The actually required dosages of the agents of this invention for any given patient will depend upon a variety of factors, including, but not limited to the activity of the specific compound employed, the particular HSD type 1 , type 2 or type 3 related condition being treated, the particular composition formulated, the mode of administration, time and duration of administration, route of administration and the particular site being treated, and furthermore the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, rate of excretion, drug combinations, and the severity of the condition undergoing therapy.
It will be further appreciated by one skilled in the art that the optimal course of treatment, i.e., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests. Optimal dosages for a given set of conditions may be ascertained by those skilled in the art using conventional dosage-determination tests in view of the experimental data for a given compound. For oral administration, an exemplary daily dose generally employed ill be from about 0.01 μg/kg to about 100 mg/kg of total body weight, whereby courses of treatment may be repeated at appropriate time intervals. Administration of pro-drugs may be dosed at weight levels that are chemically equivalent to the weight levels of the fully active compounds. The daily dosage for parenteral administration will generally be from about O.01 μg/kg to about 100 mg/kg of total body weight. A daily rectal dosage regimen will generally be from about 0.01 μg/kg to about 200 mg/kg of total body weight. A daily vaginal dosage regimen will generally be from about 0.01 μg/kg to about 100 mg/kg of total body weight. The daily topical dosage regimen will generally be from about 0.1 μg to about 100 mg administered between one to four times daily. The transdermal concentration will generally be that required to maintain a daily dose of from 0.01 μg/kg to 100 mg/kg of total body weight.
Abbreviations and Acronyms
As employed herein, the following terms have the indicated meanings. 20βP 20β-hydroxyprogesterone A 4-androstene-3,17-one Ac Acetyl AcOH acetic acid HSD hydroxysteroid dehydrogenase DHT dehydrotestosterone DMF N,N-dimethylformamide E1 estron E2 estradiol ER estrogen receptor EtOAc ethyl acetate GnRH Gonadotropin Releasing Hormone MS mass spectrometry NAD(P)[H] nicotinamide-adenine-dinucleotide (phosphate) [reduced NAD(P)] NMR nuclear magnetic resonance P progesterone PCC pyridinium chlorochromate T testosterone TBAB Tetrabutylammonium Bromide THF tetrahydrofuran TOF ime-of-f light' General Preparative Methods
The compounds of the present invention may be prepared by use of known chemical reactions and procedures. Nevertheless, the following general preparative methods are presented to aid the reader in synthesizing the 17-β-Hydroxysteroid Dehydrogenase inhibitors with specific details provided below in the experimental section to illustrate working examples.
All variable groups of these methods are as described in the generic description if they are not specifically defined below.
It is recognized that compounds of the invention with each claimed optional functional group may not be prepared by each of the below-listed methods. Within the scope of each method, optional substituents may appear on reagents or intermediates which may act as protecting or otherwise non-participating groups. Utilizing methods well known to those skilled in the art, these groups are introduced and/or removed during the course of the synthetic schemes which provide the compounds of the present invention.
Flow Diagrams
The compounds according to this invention can be prepared as shown in Schemes 1 to 4.
Scheme 1. General route to thienopyrimidinones.
Figure imgf000046_0001
Synthesis of thienopyrimidinones is presented in Scheme 1. Thienopyrimidinones of the formula c can be synthesized starting from commercially available ethyl 2-amino-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate a in a reaction with suitable amides b in the presence of phosphorous oxychloride to give compound of the formula c. (Ref. Kapustina, M.V., Kharizomenova, I A, Shvedov, V.I., Chem. Heterocycl. Cornpd. (Engl. Trans.) 1991 , 425.). The appropriate Λ/-substituted amides b can be prepared by variety of synthetic methods. The treatment of acyl halides with primary amines is a general procedure for the preparation of amides. Oxidation of compound c was performed by using oxidant like PCC (pyridinium chloro- chromate) affording 4,8-dione of the formula d. Carbonyl compound d was formylated in the Vilsmeier reaction using phosphorous oxychloride in DlvlF affording chloroaldehydes of the formula e (Ref. Koeller, S., Lellouche, J.-P., Tetrahedron L.ett. 1999, 40, 7043. and Kapustina, M.V, Nikolaeva, I.S., Kharizomenova, I. A., Shvedov, V.I., Pushkina, T.V., Fomina, A. N., Pharm. Chem. J. 1992, 789.) Chloroaldehyde e was treated with alkyl and aryl alcohols or thiols in the presence of base to form compound of the formula f.
Aldehydes can be reduced to primary alcohols, i.&. compound of the formula g, by a number of reducing agents (e.g. LiAIH4 and NaBH4).
Scheme 2. Aromatization
bromination
Figure imgf000047_0001
dehydrobromiπation
Figure imgf000047_0002
According to the reaction route of the Scheme 2 aromatic compounds of the formula j and k can be prepared by dehydrobromination of bromide derivatives of the formula h and i. The bromination of carbonyl compound of the formula c by using bromine and a catalyst e.g. ben- zoylperoxide afforded several different bromides which were isolated and identified. Generally 3,4,5-trimethoxyphenyl group in the R2-position was monobrominated as well as α-bromo- and α,α-dibromo carbonyl derivatives were produced. The aromatization was achieved by the use of microwaves. In microwave dielectric heating the temperature increase is uniform throughout the sample (Ref. Lidstroem, P. et al. Tetrahedron 2001 , 57, 9225). In addition, the temperature increase considerably above the conventional boiling point of the solvent used is rapidly achieved. Microwave chemistry is generally suitable for various chemical reactions having several benefits like decrease of the reaction time, increase of yield and purity. A bromide of the formula h or i in the presence of sodium acetate in acetic acid was heated by the use of microwaves at 180 °C. Both the phenol of the formula j as well as the acetylated compound of the formula k could be obtained. Scheme 3. Demethylation and acetylation
Figure imgf000048_0001
The cleavage of ethers can be achieved by numerous reagents e.g. different acidic reagents or Lewis acids. Methoxymethyl derivative I was easily demethylated by using boron tribromide according to the Scheme 3. Alcohol m was acetylated to compound n by using a general procedure (AcOH, pyridine).
Scheme 4.
Figure imgf000048_0002
A number of methods are available to prepare α-hydroxy carbonyls and α-diketones. Carbonyl compounds of the formula c can be α-hydroxy lated or α-carbonylated according to the reaction route of Scheme 4. Alternative route is, for example, the alkaline hydrolysis of α-bromo carbonyl compound affords α-hydroxy ketones of the formula o and α-diketones of the formula P
The invention will be illuminated by the following non-restrictive Experimental Section. EXPERIMENTAL SECTION
The general procedure for preparation of amides (yields 60-99% depending on the amide). Reference example: Preparation of Λ/-benzyl-3,4,5-trimethoxybenzamide
3,4,5-Trimethoxybenzoyl chloride (5.0 g, 21.7 mmol) was dissolved in dichloromethane (50 ml). The reaction mixture was cooled with an ice-bath and benzylamine (4.74 ml, 43.4 mmol) was added slowly. The solid material was removed by filteration. The filtrate was poured into 30 ml of water. The organic phase was washed several times with water. The crude product was recrystallized from /-propanol.
Examples In order to more fully illustrate the nature of the invention and the manner of practicing the same, the following examples are presented, but they should not be taken as limiting.
Compound No. 1.
Preparation of 3-benzyl-2-(3,4,5-trimethoxyphenyl)-5,6J,8-tetrahydro-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
Figure imgf000049_0001
Commercially available ethyl 2-amino-4,5,6,7-tetrahydrobenzo(b)-thiophene-3-carboxylate (6.0 g, 26.6 mmol, 100 mol-%) and Λ/-benzyl-3,4,5-trimethoxybenzamide (10.4 g, 34.6 mmol, 130 mol-%) were dissolved in dry 1 ,2-dichloroethane. The reaction mixture was cooled with an ice- salt-bath and POCI3 (1.7 ml, 24.6 mmol, 130 mol-%) was added. The reaction mixture was refluxed for 24 hours. During refluxing POCI3 (340 μl) was added twice. The reaction mixture was poured into ice-water and after neutralization with sodium acetate the product was extracted into dichloromethane. The organic phases combined were washed with sodium bicar- bonate sat. (3 x 50 ml) and dried with MgS0 . The yield after recrystallization from /-propanol was 8.3 g (yield 68%).
NMR: 1.89 (br s, 4H), 2.82 (br s, 2H), 3.09 (br s, 2H), 3.59 (s, 6H), 3.84 (s, 3H), 5.23 (s, 2H), 6.48 (s, 2H), 7.02 (m, 2H), 7.22-7.31 (m, 3H). MS (TOF, ES+) m/z 463 (M + 1)
Compound No. 2
3-Benzyl-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8- dione
Figure imgf000050_0001
3-Benzyl-2-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4- one (Compound No.1) (8.2 g, 17.7 mmol) dissolved in dry dichloromethane (30 ml) was added quickly to a mixture of PCC (19.2 g, 89.0 mmol, 500 mol-%) in dichloromethane (200 ml). During refluxing PCC was added several times until the reaction was completed. The reaction mixture was filtered through Celite with dichloromethane. The crude product was purified by flash chromatography. The yield of the compound No. 2 was 4.1 g (48%).
NMR: 2.28 (m, 2H), 2.72 (m, 2H), 3.36 (m, 2H), 3.60 (s, 6H), 3.88 (s, 3H), 5.25 (s, 2H), 6.53 (s, 2H), 7.04 (m, 2H), 7.25-7.32 (m, 3H). MS (TOF, ES+) m/z 499 (M + Na)
Compound No. 3
3-Benzyl-8-chloro-4-oxo-2-(3,4,5-trimethoxyphenyl)-3,4,5,6-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine-7-carbaldehyde
Figure imgf000050_0002
POCI3 (3.5 ml) was added slowly to a cold, dry DMF (2.3 ml). 3-Benzyl-2-(3,4,5- trimethoxyphenyl)-6J-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione (compound No. 2) (0.5 g, 1.1 mmol) in 1 ,2-dichloroethane was added slowly to the Vilsmeier reagent and stirred at room temperature for three hours after which the reaction mixture was refluxed for 15 minutes. After stirring overnight at room temperature the reaction mixture was diluted with dichloromethane and neutralized with NaOAc-solution (12 g/10O ml). The product was extracted with dichloromethane (3 x 30 ml). Organic phase was washed with water and dried. The crude product was purified by flash chromatography. The yield was 0.45 g (82%).
NMR: 2.85 (dd, 2H), 3.36 (dd, 2H), 3.60 (s, 6H), 3.86 (s, 3H), 5.25 (s, 2H), 6.52 (s, 2H), 7.28 (m, 5H), 10.24 (s, 1H).
MS (TOF, ES+) m/z 523/525 (M+)
Compound No. 4
3-Benzyl-4-oxo-8-phenoxy-2-(3,4,5-trimethoxyphenyl)-3,4,5,6-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine-7-carbaldehyde
Figure imgf000051_0001
3-Benzyl-8-chloro-4-oxo-2-(3,4,5-trimethoxyphenyl)-3,4,5,6-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine-7-carbaldehyde (Compound No. 3) (50 mg, 96 μmol), phenol (13.5 mg, 143.4 μmol), KOH powder (8.0 mg, 143.4 μmol) and TBAB (1.0 mg) were heated at 85 °C for five hours and at 60 °C for 4,5 hours. The reaction mixture was filtered through cotton wool and evaporated. The crude product was purified by flash-chromatography. The compound No. 5 was isolated as a by-product.
NMR (CDCI3): 2.88 (dd, 2H), 3.60 (s, 6H), 3.86 (s, 3H), 4.31 (dd, 2H), 5.23 (s, 2H), 6.46 (s, 2H), 7.04-7.34 (m, 10H), 10.14 (s, 1 H). MS (TOF, ES+) m/z 581 (M + 1).
Compound No. 5
3-Benzyl-4-oxo-8-phenoxy-2-(3,4,5-trimethoxyphenyl)-3,4-dihydro-benzo[4,5]thieno[2,3- d]pyrimidine-7-carbaldehyde
Figure imgf000051_0002
NMR (CDCI3): 3.59 (s, 6H), 3.87 (s, 3H), 5.56 (s, 2H), 6.53 (s, 2H) , 6.98-7.34 (m, 10H), 8.62 (d, 1H), 8.66 (1 H), 10.44 (s, 1H). MS (TOF, ES+) m/z 579 (M + 1).
Compound No. 6
3-Benzyl-8-ethylsulfanyl-4-oxo-2-(3,4,5-trimethoxyphenyl)-3,4,5,6-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidine-7-carbaldehyde
Figure imgf000052_0001
According to the method described for the compound No. 4 using ethanethiol instead of phenol.
NMR: 1.30 (t, 3H), 2.76-2.99 (m, 4H), 3.31 (m, 2H), 3.60 (s, 6H), 3.86 (s, 3H), 5.23 (s, 2H), 6.51 (s, 2H), 7.02-7.34 (m, 5H), 10.52 (s, 1H). MS (TOF, ES+) m/z 549 (M + 1).
Compound No. 7
3-Benzyl-8-ethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-3,4,5,6-tetrahycIro-benzo[4,5]thieno[2,3- d]pyrimidine-7-carbaldehyde
Figure imgf000052_0002
According to the method described for the compound 4 using ethanol instead of phenol.
NMR: 1.57 (t, 3H), 2.76 (m, 2H), 3.29 (m, 2H), 3.60 (s, 6H), 3.86 (s, 3H), 5.25 (s, 2H), 6.51 (s, 2H), 7.02-7.55 (m, 5H), 10.19 (s, 1H). MS (TOF, ES+) m/z 533 (M + 1).
Compound No. 8
3-Benzyl-4-oxo-8-phenylsulfanyl-2-(3,4,5-trimethoxyphenyl)-3,4,5,6-tetrahydro- benzo[4,5]thieno[2,3-d]pyrimidine-7-carbaldehyde
Figure imgf000053_0001
According to the method described for the compound No. 4 using benzenethiol instead of phenol. The compound No. 9 was isolated as a by-product.
NMR (CDCI3): 2.90 (m, 2H), 3.32 (m, 2H), 3.56 (s, 6H), 4.30 (s, 3H), 5.21 (s, 2H), 6.46 (s, 2H), 7.04-7.26 (m, 10H), 10.54 (s, 1H). MS (TOF, ES+) m/z 597 (M + 1).
Compound No. 9 3-Benzyl-4-oxo-8-phenylsulfanyl-2-(3,4,5-trimethoxyphenyl)-3,4-dihydro-benzo[4,5]thieno[2,3- d]pyrimidine-7-carbaldehyde
Figure imgf000053_0002
NMR (CDCI3): 3.60 (s, 6H), 3.86 (s, 3H), 5.36 (s, 2H), 6.53 (s, 2H), 7.04-7.52 (m, 10H), 8.20 ( d, 1H), 8.84 (d, 1 H), 10.81 (s, 1H). MS (TOF, ES+) m/z 595 (M + 1).
Compound No. 10
3-Phenyl-2-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4- one
Figure imgf000053_0003
According to the method described for the compound No. 1 using Λ/-phenyl-3,4,5- trimethoxylbenzamide as an amide. NMR: 1.88 (m, 4H), 2.83 (m, 2H), 3.03 (m, 2H), 3.66 (s, 6H), 3.77 (s, 3H), 6.54 (s, 2H), 7.15- 7.40 (m, 5H). MS (TOF ES+) m/z 449 (M +1).
Compound No. 11 3-Phenyl-2-(3,4,5-trimethoxyphenyl)-6J-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8- dione
Figure imgf000054_0001
According to the method described for the compound No. 2 using the compound No.10 as a starting material.
NMR: 2.28 (m, 2H), 2.72 (m, 2H), 3.36 (m, 2H), 3.60 (s, 6H), 3.88 (s, 3H), 6.53 (s, 2H), 7.04 (m,
2H), 7.25-7.32 (m, 3H).
MS (TOF, ES+) m/z 463 (M + 1)
Compound No. 12
3-Benzyl-2-(p-methoxyphenyl)-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000054_0002
According to the method described for the compound No. 1 using Λ/-benzyl-p- methoxybenzamide as an amide.
NMR: 1.88 (m, 4H), 2.80 (m, 2H), 3.06 (m, 2H), 3.83 (s, 3H), 5.27 (s, 2H), 6.84-6.99 (m, 4H), 7.17-7.30 (m, 5H). MS (TOF ES+) m/z 403 (M + 1).
Compound No. 13 3-Benzyl-2-(p-methoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thienoi;2,3-d]pyrimidine-4,8-dione
Figure imgf000054_0003
According to the method described for the compound No. 2 using the compound No. 12 as a starting material.
NMR: 2.25 (m, 2H), 2.69 (m, 2H), 3.33 (m, 2H), 3.85 (s, 3H), 5.30 (s, 2H), 6.89-7.00 (m, 4H), 7.25-7.36 (m, 5H). MS (TOF, ES+) m/z 417 (M + 1)
Compound No. 14
8-Chloro-2-(p-methoxyphenyl)-4-oxo-3-phenyl-3,4,5,6-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine-7-carbaldehyde
Figure imgf000055_0001
According to the method described for the compound No. 3 using the compound No. 13 as a starting material. The compound No. 15 was isolated as a by-product.
NMR (CDCI3): 2.82 (m, 2H), 3.33 (m, 2H), 3.85 (s, 3H), 5.30 (s, 2H), 6.90-7.01 (m, 4H), 7.19-
7.36 (m, 5H) 10.22 (s, 1H).
MS (TOF, ES+) m/z 463/465 (M+)
Compound No. 15
3-Benzyl-2-(p-methoxyphenyl)-4-oxo-3,4,5,6-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine-7- carboxylic acid ethyl ester
Figure imgf000055_0002
NMR (CDCI3): 1.41 (t, 3H), 2.88 (m, 2H), 3.34 (m, 2H), 3.84 (s, 3H), 4.15 (q, 2H), 5.30 (s, 2H), 6.89-6.98 (m, 5H), 7.04-7.55 (m, 5H). MS (TOF, ES+) m/z 473 (M+1)
Compound No. 16 3-Benzyl-8-ethylsulfanyl-2-(p-methoxyphenyl)-4-oxo-3,4,5,6-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine-7-carbaldehyde
Figure imgf000056_0001
According to the method described for the compound No. 4 using the compound No. 14 as a starting material and ethanethiol instead of phenol. The compounds No. 17 and 18 were isolated as a by-product.
NMR (CDCI3): 129 (t, 3H), 2.75-2.98 (m, 4H), 3.28 (m, 2H), 3.85 (s, 3H), 5.30 (s, 2H), 6.89-7.02 (m, 4H), 7.24-7.35 (m, 5H), 10.51 (s, 1H). MS (TOF, ES+) m/z 489 (M + 1).
Compound No. 17
3-Benzyl-2-(p-methoxyphenyl)-4-oxo-3,4-dihydro-benzo[4,5]thieno[2,3-d]pyrimidine-7- carbaldehyde
Figure imgf000056_0002
NMR (CDCI3): 3.87 (s, 3H), 5.43 (s, 2H), 6.92-7.06 (m, 4H), 7.26-7.41 ( , 5H), 8.03 (d, 1 H), 8.39 (s, 1H), 8.83 (d, 1H), 10.13 (s, 1H). MS (TOF, ES+) m/z 426 (M + 1).
Compound No. 18 3-Benzyl-8-ethylsulfanyl-2-(p-methoxyphenyl)-4-oxo-3,4-dihydro-ben2:o[4,5]thieno[2,3- d]pyrimidine-7-carbaldehyde
Figure imgf000056_0003
NMR (CDCI3): 1.25 (t, 3H), 3.00 (q, 2H), 3.87 (s, 3H), 5.42 (s, 2H), β.92-7.05 (m, 5H), 7.25- 7.43 (m, 4H), 8.11 (d, 1H), 8.74 (d, 1 H), 10.86 (s, 1H). MS (TOF, ES+) m/z 487 (M + 1). Compound No. 19 3-Benzyl-8-ethylsulfanyl-7-hydroxymethyl-2-(p-methoxyphenyl)-3,4-dihydro-3H- benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000057_0001
NaBH (26.2 mg, 0.05 μmol) was dissolved in ethyl acetate (2 ml). The compound No. 16 was dissolved in ethyl acetate (3 ml) and added to the reaction mixture. The reaction was completed in 2.5 hours and 20 ml of EtOAc was added. The reaction mixture was poured into water (10 ml) and saturated NH CI-solution (10 ml) was added. The phases were separated and the water phase was extracted with EtOAc (3 x 10 ml). Organic phase was washed with brine and evapo- rated.
NMR (CDCI3): 1.23 (t, 3H), 2.00 (br s, 1H), 2.64-2.79 (m, 4H), 3.25 (rn, 2H), 3.83 (s, 3H), 4.60 (s, 2H), 5.28 (s, 2H), 6.86-7.01 (m, 4H), 7.15-7.35 (m, 5H). MS (TOF, ES+) m/z 491 (M + 1).
Compound No. 20
3-Benzyl-7-hydroxymethyl-2-(p-methoxyphenyl)-8-phenoxy-3H-benzo[4-,5]thieno[2,3- d]pyrimidin-4-one
Figure imgf000057_0002
The compound No. 14 (49.9 mg, 108 μmol), phenol (21.1 mg, 216 μmol), KOH powder (13.0 mg, 216 μmol) and TBAB (2.3 mg) in THF (2 ml) were refluxed for 2.5 hours. The solvent was evaporated and the precipitate was dissolved in dichloromethane. The reaction mixture was filtered through cotton wool and evaporated. The crude product was purified by flash- chromatography. The compound No. 21 was isolated as a by-product.
NMR (CDCI3): 3.84-3.89 (m, 4H), 4.80 (d, 2H), 5.41 (s, 2H), 6.88-7.42 (14 H), 7.69 (d, 1 H), 8.56 (d, 1 H).
MS (TOF, ES+) m/z 521 (M+1)
Compound No. 21
3-Benzyl-7-methyl-2-(p-methoxyphenyl)-8-phenoxy-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000058_0001
NMR (CDCI3): 2.56 (s, 3H), 3.86 (s, 3H), 5.41 (s, 2H), 6.85-7.40 (m, 15H), 8.5 (d, 1H). MS (TOF, ES+) m/z 505 (M+1)
Compound No. 22
3-Phenyl-2-(p-methoxyphenyl)-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000058_0002
According to the method described for the compound No. 1 using Λ/-phenyl-p- methoxybenzamide as an amide.
NMR: 1.88 (m, 4H), 2.81 (m, 2H), 3.05 (m, 2H), 3.74 (s, 3H), 6.69 (m, 2H), 7.12-7.40 (m, 7H). MS (TOF ES+) m/z 389 (M + 1).
Compound No. 23
3-Phenyl-2-(p-methoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidin-4,8-dione
Figure imgf000058_0003
According to the method described for the compound 2 using the compound No. 22 as a starting material.
NMR: 2.25 (m, 2H), 2.70 (m, 2H), 3.30 (m, 2H), 3.76 (s, 3H), 6.71 (d, 2H), 7.14-7.36 (m, 7H). MS (TOF, ES+) m/z 403 (M + 1 )
Compound No. 24
2-Methyi-3-phenyl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin- -one
Figure imgf000059_0001
According to the method described for the compound No. 1 using Λ/-phenyl-acetamide as an amide.
NMR: 1.84 (m, 4H), 2.20 (s, 3H), 2.76 (m, 2H), 2.97 (m, 2H), 7.20-7.26 (m, 2H), 7.45-7.6 (m, 3H). MS (TOF ES+) m/z 297 (M + 1).
Compound No. 25 2-Methyl-3-phenyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
Figure imgf000059_0002
According to the method described for the compound No. 2 using the compound No.24 as a starting material.
NMR: 2.19 (m, 2H), 2.27 (s, 3H), 2.68 (m, 2H), 3.24 (m, 2H), 7.22-7.27 (rn, 2H), 7.53-7.56 (m, 3H). MS (TOF ES+) m/z 311 (M + 1).
Compound No. 26 -(acetic acid methyl ester)-3-benzyl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4- one
Figure imgf000059_0003
According to the method described for the compound No. 1 using Λ/-benzyl-malonamic acid methyl ester as an amide.
NMR: 1.87 (m, 4H), 2.79 (m, 2H), 3.05 (m, 2H), 3.68 (s, 3H), 3.80 (s, 2H), 5.36 (s, 2H), 7.13- 7.32 (m, 5H). MS (TOF ES+) m/z 369 (M + 1)
Compound No. 27
3-Benzyl-2-methoxymethyl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000060_0001
According to the method described for the compound No. 1 using Λ/-benzyl-2-methoxy- acetamide as an amide.
NMR (CDCIs): 1.86 (m, 4H), 2.79 (m, 2H), 3.05 (m, 2H), 3.41 (s, 3H), 4.39 (s, 2H), 5.51 (s, 2H), 7.15-7.36 (m, 5H). MS (TOF ES+) m/z 341 (M + 1).
Compound No. 28
3-Benzyl-2-hydroxymethyl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000060_0002
The compound No. 27 (1.0 g, 2.94 mmol) was dissolved in dichloromethane (30 ml), cooled with ice-bath and BBr3 (2.9 ml, 2.94 mmol) was added. Stirring was continued at room temperature for five hours. Water (1 ml) was added and the solvent was evaporated. 10% NaOH-solution (10 ml) was added and stirred well for 10 min. The solution was acidified by HCI-addition. The product was extracted with EtOAc and organic phase was washed with brine. The crude prod- uct was recrystallized from ethanol.
NMR (CDCI3): 1.25 (s, 1H), 1.88 (m, 4H), 2.80 (m, 2H), 3.05 (m, 2H), 4.55 (s, 2H), 5.21 (s, 2H), 7.15-7.40 (m, 5H). MS (TOF ES+) m/z 327 (M + 1). Compound No. 29
Acetic acid 3-benzyl-4-oxo-3,4,5,6,7,8-hexahydro-benzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethyl ester
Figure imgf000061_0001
The compound No. 28 (200 mg, 0.61 mmol) was dissolved in a solution of acetic acid anhydride (2 ml) and pyridine (1 ml) and stirred for an hour at room temperature. Water (5 ml) was added and the solid precipitate was isolated. The yield of the acetylated product was 213 mg (95%).
NMR (CDCI3): 1.88 (m, 4H), 1.99 (s, 3H), 2.80 (m, 2H), 3.07 (m, 2H), 5.04 (s, 2H), 5.36 (s, 2H), 7.12-7.36 (m, 5H).
MS (TOF ES+) m/z 391 (M + Na).
Compound No. 30
Acetic acid 3-benzyl-4,8-dioxo-3,4,5,6,7,8-hexahydro-benzo[4,5]thieno[2,3-d]pyrimidin-2- ylmethyl ester
Figure imgf000061_0002
According to the method described for the compound No.2 using the compound No. 29 as a starting material.
NMR (CDCI3): 2.07 (s, 3H), 2.26 (m, 2H), 2.70 (m, 4H), 5.08 (s, 2H), 5.37 (s, 2H), 7.15-7.37 (m, 5H). MS (TOF ES+) m/z 383 (M + 1).
Compound No. 31 3-Benzyl-2-methoxymethyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidϊne-4,8-dione
Figure imgf000062_0001
According to the method described for the compound No. 2 using the compound No. 27 as a starting material. The compound No. 32 was isolated as a by-product in the oxidation.
NMR: 2.25 (m, 2H), 2.69 (m, 2H), 3.33 (m, 2H), 3.45 (s, 3H), 4.44 (s, 2H), 5.52 (s, 2H), 7.17- 7.54 (m, 5H). MS (TOF ES+) m/z 355 (M + 1)
Compound No. 32 3-Benzyl-4,8-dioxo-3,4,5,6,7,8-hexahydro-benzo[4,5]thieno[2,3-d]pyrimidine-2-carboxyIic acid methyl ester
Figure imgf000062_0002
NMR (CDCI3): 2.27 (m, 2H), 2.70 (m, 2H), 3.33 (m, 2H), 3.35 (s, 3H), 5.51 (s, 2H), 7.18-7.33 (m, 5H).
MS (TOF ES+) m/z 368 (M + Na)
Compound No. 33
3-Benzyl-4,9,9-trioxo-4,5,6,7,8,9-hexahydro-3H-9lambda*6*-benzo[4,5]thieno[2,3-d]pyrimidine- 2-carbaldehyde
Figure imgf000062_0003
Se02 in a dioxane-water solution was heated in 50-55 °C until all the solid material was dissolved. The compound No. 27 was added and the reaction mixture was heated in a microwave reactor for 15 minutes at 160 °C. The reaction mixture was filtered and the filterate was evaporated. The crude product was purified by chromatography.
NMR (CDCI3): 1.89 (m, 4H), 2.8 (m, 2H), 3.09 (m, 2H), 5.84 (s, 2H), 7.26 (m, 5H), 9.60 (s, 1 H). MS (TOF ES+) m/z 357 (M + 1 )
Compound No. 34 3-Benzyl-8-chloro-2-methoxymethyl-4-oxo-3,4,5,6-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine- 7-carbaldehyde
Figure imgf000063_0001
According to the method described for the compound No.- 3 using the compound No. 31 as a starting material.
NMR (CDCI3): 2.82 (m, 2H), 3.32 (m, 2H), 3.50 (s, 3H), 4.43 (s, 2H), 5.52 (s, 2H), 7.17-7.78 (m, 5H), 10.23 (s, 1H).
MS (TOF ES+) m/z 401 (M + 1)
Compound No. 36
2-Methoxymethyl-3-phenyl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000063_0002
According to the method described for the compound No. 1 using Λ/-phenyl-2-methoxy- acetamide as an amide.
NMR: 1.87 (m, 4H), 2.79 (m, 2H), 2.99 (m, 2H), 3.28 (s, 3H), 4.09 (s, 2H), 7.24-7.32 (m, 2H), 7.46-7.60 (m, 3H). MS (TOF ES+) m/z 327 (M + 1)
Compound No. 37
2-Methoxymethyl-3-phenyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidin-4,8-dione
Figure imgf000064_0001
According to the method described for the compound No. 2 using the compound No. 36 as a starting material.
NMR (CDCI3): 2.33 (m, 2H), 2.69 (m, 2H), 3.26 (m, 2H), 3.32 (s, 3H), 4.12 (s, 2H), 7.19-7.29 (m, 2H), 7.52-7.56 (m, 3H). MS (TOF ES+) m/z 341 (M + 1)
Compound No. 38 2-Hydroxymethyl-3-phenyl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000064_0002
According to the method described for the compound No. 28 using the compound No. 36 as a starting material.
NMR (CDCI3): 1.85 (m, 4H), 2.81 (m, 2H), 2.98 (m, 2H), 3.82 (br s, 1H), 4.13 (s, 2H), 7.20-7.57 (m, 5H). MS (TOF ES+) m/z 313 (M + 1)
Compound No. 39 Acetic acid 4-oxo-3-phenyl-3,4,5,6,7,8-hexahydro-benzo[4,5]thieno[2,3-d]pyrimidin-2-ylmet yl ester
Figure imgf000064_0003
According to the method described for the compound No. 29 using the compound No. 38 as a starting material.
NMR (CDCI3): 1.80-1.90 (m, 4H), 2.06 (s, 3H), 2.80 (m, 2H), 2.97 (m, 2H), 4.72 (s, 2H), 7.1 5-
7.60 (m, 5H).
MS (TOF ES+) m/z 377 (M + Na) Compound No. 40
4-Oxo-3-phenyI-3,4,5,6,7,8-hexahydro-benzo[4,5]thieno[2,3-d]pyrimidine-2-carboxylic acid ethyl ester
Figure imgf000065_0001
According to the method described for the compound No. 1 using ethyl oxanilate as an amide.
NMR: 1.00 (t, 3H), 1.87 (m, 4H), 2.83 (m, 2H), 3.01 (m, 2H), 4.06 (q, 2H), 7.26-7.51 (m, 5H). MS (TOF ES+) m/z 355 (M + 1)
Compound No. 41
3-Benzyl-2-(3,4,5-trihydroxyphenyl)-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4- one
Figure imgf000065_0002
The compound No. 1 (100 mg, 0.22 mmol) was dissolved in dichloromethane. BBr3 (1M - solution, 220 μl, 0.22 mmol) was added. The reaction mixture was stirred at room temperature and boron tribromide was added several times (portion-wise 100 μl) until the reaction was completed. The reaction mixture was washed with water. Water phase was extracted with ethyl acetate and organic phase was washed with brine. The crude product was purified by crystallization from CH2CI2.
NMR (DMSO-d6): 1.79 (m, 4H), 2.76 (m, 2H), 2.87 (m, 2H) 5.22 (s, 2H), 6.37 (s, 2H), 6.93-6.97
(m, 2H), 7.13-7.31 (m, 3H).
MS (TOF, ES+) m/z 421 (M + 1).
Compound No. 42
3-Phenyl-2-(3,5-dihydroxy-4-methoxyphenyl)-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
Figure imgf000066_0001
ccording to the method described for the compound No. 41 using ice-bath during the reagent addition. The compound No. 43 was isolated as a by-product.
NMR (CDCl3): 1.85-1.88 (m, 4H), 2.78-2.81 (m, 2H), 3.03 (m, 2H), 3.62 (s, 3H), 5.61 (br s, 2H), 6.33 (d, 1 H), 6.63 (d, 1 H), 7.12-7.35 (m, 5H). MS (TOF, ES+) m/z 421 (M + 1).
Compound No. 43 3-Phenyl-2-(3,4,5-trihydroxyphenyl)-5,6J,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4- one
Figure imgf000066_0002
NMR (DMSO-d6): 1.78 (m, 4H), 2.77-2.85 (m, 4H), 3.39 (br m, 3H), 6.25 (s, 2H), 7.19-7.34 (m, 5H).
MS (TOF, ES+) m/z 407 (M + 1).
Compound No. 44
7-Bromo-2-methyl-3-phenyl-6J-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
Figure imgf000066_0003
The compound No. 25 (250 mg, 0.81 mmol) was dissolved in dichloromethane (10 ml) and benzoyl peroxide (1-2 mg) was added. The reaction mixture was refluxed and bromine (85 μl, 1.61 mmol, 200 mol-%) was added. Refluxing was continued until the reaction was compleated. The reaction mixture was washed with water (10 ml). The organic phase was evaporated and the precipitate was purified by flash chromatography. The compound No. 45 was isolated as a by-product. NMR (CDCI3): 2.28 (s, 3H), 2.57-2.78 (m, 2H), 3.08-3.17 (m, 2H), 4.70 (m, 1H), 7.20-7.30 (5H). MS (TOF, ES+) m/z 411/413 (M + Na).
Compound No.45 7,7-Dibromo-2-methyl-3-phenyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-' ,8-dione
Figure imgf000067_0001
NMR (CDCI3): 2.28 (s, 3H), 2.50-2.70 (m, 1H), 3.12-3.36 (m, 3H), 7.21-7.27 (m, 5H). MS (TOF, ES+) m/z 487/489/591 (M + Na).
Compound No.46
3-benzyl-7-bromo-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
Figure imgf000067_0002
The compound No. 2 (2.0 g, 4. mmol, 100 mol-%) and benzoylperoxide (99 mg, 0.4 mmol, 10 mmol%) were dissolved in dichloromethane (40 ml). While the reaction mixture was refluxing bromine (440 μl, 8.4 mmol, 200 mol-%) in dichloromethane (16 ml) was added. Trie reaction was completed in 3.5 hours. The cooled reaction mixture was washed with water (40 ml). The organic phase was evaporated. The crude product was purified by chromatography using dichloromethane-EtOAc as an eluent. The compounds No. 47, 48 and 49 were isolated as byproducts.
NMR (CDCI3): 2.62-2.66 (m, 2H), 3.23-3.69 (m, 8H), 3.96 (s, 3H), 4.74 (m,1H), 5.26 (s, 2H), 6.53 (s, 2H), 7.03-7.35 (m, 5H). MS (TOF, ES+) m/z 555/557 (M+).
Compound No. 47
3-benzyl-7-bromo-2-(2-bromo-3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]t ieno[2,3- d]pyrimidine-4,8-dione
Figure imgf000068_0001
NMR (CDCI3): 2.59-2.67 (m, 2H), 3.29-3.46 (m, 4H), 3.56-3.73 (m, 1H), 3.92 (s, 3H), 3.96 (s, 3H), 4.46 (dd,1 H), 4.75 (m, 1H), 5.91 (dd, 1 H), 6.14 (d, 1H), 6.89 (m, 2H), 7.21-7.27 (m, 3H). MS (TOF, ES+) m/z 633/635/637 (M+).
Compound No. 48
3-benzyl-7,7-dibromo-2-(2-bromo-3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
Figure imgf000068_0002
NMR (CDCI3): 3.21 (m, 2H), 3.46-3.54 (m, 5H), 3.92 (s, 3H), 3.96 (s, 3H), 4.46 (d,1 H), 5.90 (d, 1H), 6.14 (s, 1H), 6.87 (m, 2H), 7.17-7.20 (m, 3H). MS (TOF, ES+) m/z 711/713/715/717 (M+).
Compound No. 49
3-Benzyl-2-(2-bromo-3,4,5-trimethoxyphenyl)-8-hydroxy-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4- one
Figure imgf000068_0003
The compound No. 47 (0.6 g, 1.0 mmol), NaOAc (1.66 g, 20.2 mmol) was dissolved in acetic acid (4 ml) in a microwave vial. The reaction mixture was heated with microwaves at 180 °C for an hour. Water (20 ml) was added to the reaction mixture and the product was extracted with EtOAc (5 x 30 ml). The crude product was purified by flash chromatography. The compounds No. 50, 51 and 52 were isolated as by-products. NMR (CDCI3): 3.44 (s, 3H), 3.92 (s, 3H), 3.95 (s, 3H), 4.53 (d, 1H), 6.06 (d, 1 H), 6.17 (s, 1 H), 6.31 (br s, 1H), 6.88-6.92 (m, 3H), 7.18-7.24 (m, 3H), 7.41 (dd, 1H), 8.34 (d, 1H). MS (TOF, ES+) m/z 553/555 (M+).
Compound No. 50
Acetic acid 3-benzyl-2-(2-bromo-3,4,5-trimethoxyphenyl)-4-oxo-3,4-dihydro- benzo[4,5]thieno[2,3-d]pyrimidin-8-yl ester
Figure imgf000069_0001
NMR (CDCI3): 2.44 (s, 3H), 3.45 (s, 3H), 3.90 (s, 3H), 3.97 (s, 3H), 4.84 (d,1H), 6.06 (d, 1 H), 6.17 (s, 1H), 6.87-6.93 (m, 2H), 7.18-7.32 (m, 3H), 7.36 (d, 1H), 7.60 (d, 1 H), 8.61 (d, 1H). MS (TOF, ES+) m/z 595/597 (M+).
Compound No. 51 3-benzyl-2-(2-bromo-3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one '■
Figure imgf000069_0002
NMR (CDCI3): 3.45 (s, 3H), 3.90 (s, 3H), 3.96 (s, 3H), 4.52 (d, 1H), 6.04 (d, 1H), 6.12 (s, 1 H), 6.87-6.92 (m, 2H), 7.20-7.60 (m, 5H), 7.79 (d, 1H), 8.50 (d, 1H). MS (TOF, ES+) m/z 537/539 (M+).
Compound No. 52
3-benzyl-7-bromo-2-(2-bromo-3,4,5-trimethoxyphenyl)-8-hydroxy-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
Figure imgf000069_0003
NMR (CDCI3): 3.46 (s, 3H), 3.89 (s, 3H), 3.93 (s, 3H), 4.55 (d, 1H), 6.05 (m, 2H), 6.19 (s, 1H), 6.92 (m, 2H), 7.21-7.29 (m, 3H), 7.65 (d, 1H), 8.23 (d, 1H). MS (TOF, ES+) m/z 631/633/635 (M + 1).
Compound No. 53
3-Benzyl-8-hydroxy-2-(3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000070_0001
According to the method described for the compound No. 49 using the compound No. 46 as a starting material. The compound No. 54 was isolated as a by-product.
NMR (CDCI3): 3.60 (s, 6H), 3.93 (s, 3H), 5.53 (d, 2H), 6.58 (d, 2H), 6.93 (d, 1H), 7.08 (m, 2H), 7.22-7.43 (m, 4H), 8.19 (d, 1H). MS (TOF, ES+) m/z 475 (M + 1).
Compound No. 54
Acetic acid 3-benzyl-2-(3,4,5-trimethoxyphenyl)-4-oxo-3,4-dihydro-benzo[4,5]thieno[2,3- d]pyrimidin-8-yl ester
Figure imgf000070_0002
NMR (CDCI3): 2.44 (s, 3H), 3.61 (s, 6H), 3.93 (s, 3H), 5.53 (d, 2H), 6.55 (d, 2H), 7.05 (rn, 2H), 7.24-7.32 (m, 4H), 7.57 (m, 1H), 8.58 (d, 1 H). MS (TOF, ES+) m/z 517 (M + 1).
Compound No. 55 3-benzyl-7-bromo-9-oxo-2-(3,4,5-trimethoxyphenyl)-5,6,7,9-tetrahydro-3H-9lambda*4* benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
Figure imgf000071_0001
The compound No. 46 (157 mg, 0.28 mmol) was dissolved in pyridine (4 ml). Powdered NaOH (23 mg, 0.56 mmol) dissolved in water (1 ml) was added to the reaction mixture. Stirring was continued at room temperature for 1.5 hours and the reaction mixture was poured into 1% HCI (10 ml) and the product was extracted with EtOAc (3 x 10 ml). The organic phase was washed with 5% NaHC03-solution (3 x 10 ml), water (3 x 10 ml) and brine (3 x 10 ml). The crude product was purified by flash chromatography.
NMR (CDCI3): 2.18-2.28 (m, 2H), 2.58 (m, 2H), 2.95 (m, 2H), 3.89 (s, 3H), 3.92 (s, 3H), 3.94 (s, 3H), 4.64 (d, 2H), 6.20 (m, 1H), 7.05-7.36 (m, 7H). MS (TOF, ES+) m/z 595/597 (M + 1).
Compound No. 56
3-Benzyl-2-phenyl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000071_0002
According to the method described for the compound No. 1 using Λ/-benzylbenzamide as a starting material.
NMR (CDCI3): 1.87 (m, 4H), 2.80 (m, 2H), 3.09 (m, 2H), 5.23 (s, 2H), 6.89-6.96 (m, 2H), 7.14- 7.30 (8H).
MS (TOF, ES+) m/z 373 (M + 1)
Compound No. 57
3-Benzyl-2-phenyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
Figure imgf000072_0001
According to the method described for the compound No. 2 using the compound No. 56 as a starting material.
NMR (CDCl3): 2.23 (m, 2H), 2.70 (m, 2H), 3.34 (m, 2H), 5.27 (s, 2H), 6.93 (m, 2H), 7.21-7.38 (m, 8H). MS (TOF, ES+) m/z 439 (M + Na)
Compound No. 58 3-Benzyl-7-bromo-2-phenyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
Figure imgf000072_0002
According to the method described for the compound No. 46 using the compound No. 57 as a starting material. The compound No.59 was isolated as a by-product.
NMR (CDCI3): 2.60 (m, 2H), 3.15-3.74 (m, 2H), 4.73 (t, 1H), 5.28 (s, 2H), 6.94 (m, 2H), 7.12- 7.60 (m, 8H). MS (TOF, ES+) m/z 487/489 (M + Na).
Compound No. 59 3-Benzyl-7,7-dibromo-2-phenyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
Figure imgf000072_0003
NMR (CDCI3): 3.16 (dd, 2H), 3.47 (dd, 2H), 5.30 (s, 2H), 6.95 (m, 2H), 7.12-7.60 (m, 8H). MS (TOF, ES+) m/z 565/567/569 (M + Na). Compound No. 60 3-Benzyl-8-hydroxy-2-phenyl-3H-benzo[4,5]thieno[2,3-d]pyrimidine-4-one
Figure imgf000073_0001
According to the method described for the compound No. 49 using the compound No. 58 as a starting material.
NMR (CDCI3): 5.38 (s, 2H), 6.95 (m, 3H), 7.24 (m, 3H), 7.33-7.58 (m, 6H), 8.18 (dd, 1 H). MS (TOF, ES+) m/z 407 (M +.1).
Compound No. 61 3-Benzyl-2-thiophen-2-yl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000073_0002
According to the method described for the compound No. 1 using thiophene-2-carboxylic acid benzylamide as a starting material.
NMR (CDCI3): 1.86-1.91 (m, 4H), 2.80 (m, 2H), 3.04 (m, 2H), 5.47 (s, 2H), 6.96 (dd, 1 H), 7.08 (m, 2H), 7.20-7.35 (m, 4H), 7.45 (d, 1 H). MS (TOF, ES+) m/z 379.
Compound No. 62 3-Benzyl-2-thiophen-2-yl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
Figure imgf000073_0003
According to the method described for the compound No. 2 using the compound No. 61 as a starting material. NMR (CDC ): 2.24 (m, 2H), 2.68 (m, 2H), 3.30 (m, 2H), 5.52 (s, 2H), 7.00 (dd, 1 H), 7.10 (m, 2H), 7.25-7.40 (m, 4H), 7.54 (d, 1H). MS (TOF, ES+) m/z 415 (M + Na).
Compound No. 63 3-Benzyl-2-thiophen-2-yl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
Figure imgf000074_0001
According to the method described for the compound No. 46 using the compound No. 62 as a starting material. The compounds No.64, No. 65 and No. 66 were isolated as by-products.
NMR (CDCI3): 2.57-2.63 (m, 2H), 3.22-3.61 (m, 2H), 4.72 (t, 1H), 5.54 (s, 2H), 6.95-7.17 (s, 1H), 7.22 (m, 2H), 7.30 (m, 4H), 7.60 (d, 1H). MS (TOF, ES+) m/z 493/495 (M + Na).
Compound No. 64
3-Benzyl-2-(5-bromothiophen-2-yl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8- dione
Figure imgf000074_0002
NMR (CDCI3): 2.23 (m, 2H), 2.68 (m, 2H), 3.29 (m, 2H), 5.52 (s, 2H), 6.94-7.01 (m, 2H), 7.10- 7.17 (m, 2H), 7.30-7.44 (m, 3H). MS (TOF, ES+) m/z 472 (M + 1).
Compound No. 65
3-Benzyl-7-bromo-2-(5-bromothiophen-2-yl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
Figure imgf000075_0001
NMR (CDCI3): 2.56 (m, 2H), 3.30-3.52 (m, 2H), 4.71 (t, 1 H), 5.53 (s, 2H), 6.95-7.03 (m, 2H), 7.13-7.17 (m, 2H), 7.32-7.36 (m, 3H). MS (TOF, ES+) m/z 571/573/575 (M+ Na).
Compound No. 66
3-Benzyl-7,7-dibromo-2-(5-bromothiophen-2-yl)-6J-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
Figure imgf000075_0002
NMR (CDCI3): 3.16 (m, 2H), 3.41 (m, 2H), 5.53 (s, 2H), 6.96-7.05 (m, 2H), 7.13-7.17 (m, 2H),
7.28-7.45 (m, 3H).
MS (TOF, ES+) m/z 623/625/627/629
Compound No. 67
3-Benzyl-8-hydroxy-2-thiophen-2-yl-3H-benzo[4,5]thieno[2,3-d]pyrimidine-4-one
Figure imgf000075_0003
According to the method described for the compound No. 49 using the compound No. 63 as a starting material.
NMR (CDCI3): 5.62 (s, 2H), 6.90 (dd, 1H), 7.01 (dd, 1H), 7.15 (m, 2H), 7.24-7.42 (m, 6H), 7.55
(dd, 1 H), 8.18 (dd, 1 H).
MS (TOF, ES+) m/z 391 (M + 1)
Compound No. 68 3-Benzyl-2-(5-bromothiophen-2-yl)-8-hydroxy-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000076_0001
According to the method described for the compound No. 49 using the compound No. S5 as a starting material.
NMR (CDCI3 + MeOH-d4): 5.62 (s, 2H), 6.90-7.01 (m, 3H), 7.15-7.42 (m, 6H), 8.13 (dd, 1H). MS (TOF, ES-) m/z 467/469
Compound No. 69 Thiophene-2-carboxylic acid 2-(4-oxo-2-thiohen-2-yl-5,6,7,8-tetrahydro-4H- benzo[4,5]thieno[2,3-d]pyrimidin-3-yl)-ethyl ester
Figure imgf000076_0002
According to the method described for the compound No. 1 using amide thiophene-2-carboxylic acid 2-[(thiophene-2-carbonyl)-amino]-ethyl ester as one starting material. The amide thio- phene-2-carboxylic acid 2-[(thiophene-2-carbonyl)-amino]-ethyl ester was prepared as usually using thiophene carbonyl chloride and ethanolamine as starting materials.
NMR (CDCI3): 1.85-1.96 (m, 4H), 2.76-2.80 (m, 2H), 3.01-3.06 (m, 2H), 4.50-4.71 (m, 4H), 7.01 (m, 2H), 7.40-7.55 (m, 3H), 7.65 (d, 1H). MS (TOF, ES+) m/z 465 (M + Na)
Compound No. 70
Thiophene-2-carboxylic acid 2-(4,8-dioxo-2-thiohen-2-yl-5,6,7,8-tetrahydro-4H- benzo[4,5]thieno[2,3-d]pyrimidin-3-yl)-ethyl ester
Figure imgf000077_0001
According to the method described for the compound No. 2 using the compound No. 69 as a starting material.
NMR (CDCI3): 2.20-2.32 (m, 2H), 2.69 (dd, 2H), 3.27 (dd, 2H), 4.63-4.80 (m, 4H), 7.05-7.16 (m, 2H), 7.54-7.58 (m, 2H), 7.64-7.71 (m, 2H). MS (TOF, ES+) m/z 457 (M + 1)
Compound No. 71 Thiophene-2-carboxylic acid 2-(7-bromo-4,8-dioxo-2-thiohen-2-yl-5,6,7,8-tetrahydro-4H- benzo[4,5]thieno[2,3-d]pyrimidin-3-yl)-ethyl ester
Figure imgf000077_0002
According to the method described for the compound No. 46 using the compound No. 70 as a starting material. The compound No. 72 was isolated as a by-product.
NMR (CDCIs): 3.17 (dd, 2H), 3.39-3.44 (m, 2H), 4.63-4.86 (m, 5H), 7.04-7.15 (m, 2H), 7.54-7.62 (m, 2H), 7.67-7.72 (m, 2H).
Compound No. 72 Thiophene-2-carboxylic acid 2-(7,7-dibromo-4,8-dioxo-2-thiohen-2-yl)-5,6,7,8-tetrahydro-4H- benzo[4,5]thieno[2,3-d]pyrimidin-3-yl)-ethyl ester
Figure imgf000077_0003
NMR (CDCI3): 2.55-2.64 (m, 2H), 3.22-3.50 (m, 2H), 4.62-4.85 (m, 4H), 7.04-7.19 (m, 2H), 7.54- 7.59 (m, 2H), 7.66-7.70 (m, 2H).
Compound No. 73 Thiophene-2-carboxylic acid 2-(8-hydroxy-4-oxo-2-thiohen-2-yl)-4H-benzo[4,5]thieno[2,3- d]pyrimidin-3-yl)-ethyl ester
Figure imgf000078_0001
According to the method described for the compound No. 49 using the compound No. 71 as a starting material.
NMR (CDCI3 + MeOH-d4): 4.56-4.88 (m, 4H), 6.91 (dd, 1H), 7.10 (2 x dd, 2H), 7.37 (dd, 1 H), 7.54-7.80 (m, 4H), 8.15 (dd, 1 H). MS (TOF, ES-) m/z 477 (M + Na).
Compound No. 74
3-(2-Methoxyethyl)-2-thiophen-2-yl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4- one
Figure imgf000078_0002
According to the method described for the compound No. 1 using amide thiophene-2-carboxylic acid 2-(2-methoxy-ethyl)-amide as one starting material. The amide thiophene-2-carboxylic acid 2-(2-methoxy-ethyl)-amide was prepared as usually using thiophene carbonyl chloride and 2- methoxyethylamine as starting materials.
NMR (CDCI3): 1.87 (m, 4H), 2.79 (m, 2H), 3.04 (m, 2H), 3.30 (s, 3H), 3.77 (dd, 2H), 4.44 (dd, 2H), 7.12 (m, 1H), 7.52 (dd, 1 H), 7.66 (dd, 1H). MS (TOF, ES+) m/z 369 (M + Na)
Compound No. 75 3-(2-Methoxyethyl)-2-thiophen-2-yl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8- dione
Figure imgf000079_0001
According to the method described for the compound No. 2 using the compound No. 74 as a starting material. The product was used directly to bromination.
Compound No. 76 7-Bromo-3-(2-methoxyethyl)-2-thiophen-2-yl-6J-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
Figure imgf000079_0002
According to the method described for the compound No. 46 using the compound No. 75 as a starting material.
NMR (CDCI3): 2.57-2.59 (m, 2H), 3.26-3.61 (m, 5H), 3.81 (dd, 2H), 2.52 (dd, 2H), 4.72 (t, 1 H), 7.11-7.30 (m, 2H), 7.71 (d, 1H). MS (TOF, ES+) m/z 439/441
Compound No. 77 3-Benzyl-2-thiophen-2-yl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000079_0003
According to the method described for the compound No. 1 using the amide thiophene-2- carboxylic acid butylamide as a starting material. NMR (CDCI3): 0.90 (t, 3H), 1.20-1.54 (m, 2H), 1.71-1.89 (m, 6H), 2.78 (m, 2H), 3.05 (m, 2H), 4.16 (m, 2H), 7.12 (dd, 1H), 7.41 (dd, 1H), 7.55 (dd, 1H). MS (TOF, ES+) m/z 345 (M + 1)
Compound No. 78 3-Benzyl-2-( r7-methoxyphenyl)-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
c
Figure imgf000080_0001
According to the method described for the compound No. 1 using Λ/-benzyl-3- methoxybenzamide as a starting material.
NMR (CDCl3): 1.89 (m, 4H), 2.81 (m, 2H), 3.08 (m, 2H), 3.59 (s, 3H), 5.23 (s, 2H), 6.73 (m, 1H), 10 6.90-6.99 (m, 3H), 7.19-7.34 (m, 5H) MS (TOF, ES+) m/z 403 (M + 1)
Compound No. 79 3-Benzyl-2-(m-methoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
-jc
Figure imgf000080_0002
According to the method described for the compound No. 2 using the compound No 78 as a starting material.
NMR (CDCI3): 2.23 (m, 2H), 2.69 (dd, 2H), 3.34 (dd, 2H), 3.61 (s, 3H), 5.26 (s, 2H), 6.78 (s, 1H), 0 6.94-6.98 (m, 3H), 7.03-7.36 (m, 5H). MS (TOF, ES+) m/z 439 (M + Na)
Compound No. 80 3-Benzyl-7-bromo-2-(A77-methoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine- 5 4,8-dione
Figure imgf000081_0001
According to the method described for the compound No. 46 using the compound No. 79 as a starting material. The bromides No. 81 and 82 were isolated as by-products.
MS (TOF, ES+) m/z 495/497
Rf (toluene-ethyl acetate, 9:1) = 0.38
Compound No. 81
3-Benzyl-7,7-dibromo-2-(/7?-methoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
Figure imgf000081_0002
MS (TOF, ES+) m/z 573/575/577 Rf (toluene-ethyl acetate, 9:1) = 0.52
Compound No. 82
3-Benzyl-7,7-dibromo-2-(5-bromo-3-methoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
Figure imgf000081_0003
MS (TOF, ES+) m/z 651/653/655/657 Rf (toluene-ethyl acetate, 9:1) = 0.62 Compound No. 83
3-Benzyl-8-hydroxy-2-(/77-methoxyphenyl)- 3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000082_0001
According to the method described for the compound No. 49 using the compound No. 80 as a starting material. The compound No. 84 was isolated as a by-product.
NMR (CDCI3): 3.61 (s, 3H), 5.36 (s, 2H), 6.79 (m, 1H), 6.80-7.05 (m, 4H), 7.24-7.40 (m, 6H), 8.10 (d, 1H).
Rf (toluene-methanol, 9.5:0.5) = 0.32 MS (TOF, ES+) m/z 415 (M + 1)
Compound No. 84
Acetic acid 3-benzyl-4-oxo-2-(m-methoxyphenyl)-3,4-dihydro-benzo[4,5]thieno[2,3-d]pyrimidin- 8-yl ester
Figure imgf000082_0002
Rf (toluene-methanol, 9.5:0.5) = 0.61 MS (TOF, ES+) m/z 457 (M + 1)
Compound No. 85
3-Butyl-2-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000082_0003
According to the method described for the compound No. 1 using Λ/-butyl-3,4,5- trimethoxybenzamide as a starting material.
NMR (CDCI3): 0.82 (t, 3H), 1.18-1.39 (m, 2H), 1.43-1.89 (m, 2H), 1.88 (m, 4H), 2.79 (m, 2H), 3.07 (m, 2H),3.89 (s, 9H), 3.90-3.99 (m, 2H), 6.69 (s, 2H). Rf (toluene-MeOH, 9.5:0.5) = 0.57 MS (TOF, ES+) m/z 429 (M + 1)
Compound No. 86 3-Butyl-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8- dione
Figure imgf000083_0001
According to the method described for the compound No. 2 using the compound No. 85 as a starting material.
Rf (toluene-MeOH, 9.5:0.5) = 0.46 MS (TOF, ES+) m/z 443 (M + 1)
Compound No. 87 7-Bromo-3-butyI-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
Figure imgf000083_0002
According to the method described for the compound No. 46 using the compound No. 86 as a starting material. The bromide No. 88 was isolated as a by-product.
MS (TOF, ES+) m/z 521/523.
Rf (toluene-ethyl acetate, 9:1) = 0.29
Compound No. 88 3-Butyl-7,7-dibromo-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4, 8-dione
Figure imgf000084_0001
MS (TOF, ES+) m/z 597/599/601. Rf (toluene-ethyl acetate, 9:1) = 0.67
Compound No. 89
3-Butyl-8-hydroxy-2-(3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000084_0002
According to the method described for the compound No. 49 using the compound No 87 as a starting material.
NMR (CDCIs): 0.84 (t, 3H), 1.30 (m, 2H), 1.78 (m, 2H), 3.91 (s, 9H), 4.10 (m, 2H), 6.77 (s, 2H), 6.90 (d, 1H), 7.43 (dd, 1H), 8.28 (d, 1H). Rf (toluene-methanol, 9.5:0.5) = 0.26 MS (TOF, ES+) m/z 441 (M + 1)
Compound No. 90 7-Bromo-3-butyl-8-hydroxy-2-(3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4- one
Figure imgf000084_0003
According to the method described for the compound No. 49 using the compound No 88 as a starting material. NMR (CDC ): 0.81 (t, 3H), 1.28 (m, 2H), 1.74 (m, 2H), 3.91 (s, 9H), 4.10 (m, 2H), 6.12 (s, 2H), 7.62 (d, 1H), 8.15 (d, 1H). Rf (toluene-methanol, 9.5:0.5) = 0.44 MS (TOF, ES-) m/z 517/519
Compound No. 91 3-Benzyl-8-methoxy-2-(2-bromo-3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4- one
Figure imgf000085_0001
The compound No. 49 (50 mg, 0.09 mmol), dimethylsulphate (11 mg, 0.09 mmol) and anhydrous K2C03 (25 mg, 018 mmol) were dissolved in acetone (1.5 ml) and refluxed for two hours. The solid material was filtered and washed with cold acetone. The crude product was purified by chromatography using toluene-EtOAc (99:1) as an eluent.
NMR (CDCI3): 3.45 (s, 3H), 3.92 (s, 3H), 3.96 (s, 3H), 4.04 (s, 3H), 4.51 (d, 1H), 6.07 (d, ,1H), 6.18 (s, 1H), 6.89-7.00 (m, 3H), 7.20 (m, 3H), 7.54 (t, 1H), 8.35 (d, 1H). Rf (toluene-EtOAc, 9: 1 ) = 0.50 MS (TOF, ES+) m/z 567/569
Compound No. 92
3-Benzyl-7-bromo-8-hydroxy-2-phenyl-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000085_0002
The compound No. 59 (100 mg, 0.18 mmol) and Li2C03 (10 mg, 0.14 mmol) were dissolved in DMF (2.5ml) and warmed at 100 °C for three hours. After stirring overnight at room temperature water (0.3 ml) and acetic acid (0.4 ml) were added. The product precipitated and it was washed with water-ethanol (v/v1:1). NMR (DMSO-d6): 5.26 (s, 2H), 6.97 (m, 2H), 7.23 (m, 3H), 7.50 (m, 5H), 7.72 (m, 1 H), 7.96 (d, 1H).
Rf (toluene-EtOAc, 9:1) = 0.50 MS (TOF, ES+) m/z 485/487 (M + Na)
Compound No. 93
Acetic acid 3-benzyl-7-bromo-4-oxo-2-phenyl-3,4-dihydro-benzo[4,5]thieno[2,3-d]pyrimidin-8-yl ester
Figure imgf000086_0001
According to the method described for the compound No. 49 using the compound No. 59 as a starting material.
NMR (CDCI3): 2.48 (s, 3H), 5.37 (s, 2H), 6.96 (m, 2H), 7.34 (m, 3H), 7.35-7.60 (m, 5H), 7.74 (d, 1H), 8.50 (d, 1 H). Rf (toluene-methanol, 9.5:0.5) = 0.74 MS (TOF, ES+) m/z 527/529 (M + Na)
Compound No. 94
3-(2-Methoxybenzyl)-2-propyl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000086_0002
According to the method described for the compound No. 1 using 2-methoxy-Λ/- benzylbutyramide as a starting material.
NMR (CDCI3): 0.95 (t, 3H), 1.68-1.89 (m, 6H), 2.62 (dd, 2H), 2.77 (m, 2H), 3.02 (m, 2H), 3.90 (s, 3H), 5.34 (s, 2H), 6.73-6.87 (m, 3H), 7.22 (m, 1H). Rf (toluene-methanol, 9.5:0.5) = 0.74 MS (TOF, ES+) m/z 391 (M + Na)
Compound No. 95 3-(2-Methoxybenzyl)-2-propyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
Figure imgf000087_0001
According to the method described for the compound No. 2 using the compound No. 94 as a starting material.
NMR (CDCI3): 0.96 (t, 3H), 1.68-1.87 (m, 2H), 2.17-2.29 (m, 2H), 2.67 (m, 4H), 3.29 (m, 2H), 3.91 (s, 3H), 5.36 (s, 2H), 6.75-6.94 (m, 3H), 7.27 (m, 1H). Rf (toluene-methanol, 9.5:0.5) = 0.57 MS (TOF, ES+) m/z 383 (M + 1)
Compound No. 96
7-Bromo-3-(2-methoxybenzyl)-2-propyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine- 4,8-dione
Figure imgf000087_0002
According to the method described for the compound No. 46 using the compound No. 95 as a starting material. The bromide No.97 was isolated as a by-product.
NMR (CDCI3): 0.97 (t, 3H), 1.70-1.85 (m, 2H), 2.54-2.72 (m, 4H), 3.23-3.49 (m, 1H), 3.51-3.90 (m, 1H), 3.90 (s, 3H), 4.72 (t, 1H), 5.30 (s, 2H), 6.83 (dd, 2H), 7.39 (dd, 1H). Rf (toluene-EtOAc, 9: 1 ) = 0.41
MS (TOF, ES+) m/z 561/563/565 (M + Na)
Compound No. 97
7,7-Dibromo-3-(5-bromo-2-methoxybenzyl)-2-propyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
Figure imgf000088_0001
NMR (CDCI3): 0.96 (t, 3H), 1.70-1.85 (m, 2H), 2.68 (m, 2H), 3.17 (dd, 2H), 3.43 (dd, 2H), 3.90 (s, 3H), 5.30 (s, 2H), 6.83 (dd, 2H), 7.39 (dd, 1 H). Rf (toluene-EtOAc, 9:1) = 0.59 MS (TOF, ES+) m/z 639/641/643/645 (M + Na)
Compound No. 98
3-Benzyl-3-(5-bromo-2-methoxybenzyl)-8-hydroxy-2-propyl-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
Figure imgf000088_0002
According to the method described for the compound No. 49 using the compound No. 96 as a starting material. The compound No. 99 was isolated as a by-product.
NMR (CDCI3): 1.00 (t, 3H), 1.77-1.93 (dd, 2H), 2.68-2.76 (dd, 2H), 3.90 (s, 3H), 5.42 (s, 2H), 6.78-6.90 (m, 3H), 7.33-7.40 (m, 3H), 8.14 (d, 1H). Rf (toluene-methanol, 9.5:0.5) = 0.24 MS (TOF, ES+) m/z 459/461
Compound No. 99 Acetic acid 3-benzyl-3-(5-bromo-2-methoxybenzyl)-4-oxo-2-propyl-3,4-dihydro- benzo[4, 5]th ieno[2 , 3-d]pyrimid in-8-yl ester
Figure imgf000088_0003
Rf (toluene-methanol, 9.5:0.5) = 0.59 MS (TOF, ES+) m/z 523/525 Compound No. 100
3-(5-Bromo-2-hydroxybenzyl)-8-hydroxy-2-propyl-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000089_0001
The compound No. 98 (50 mg, 0.11 mmol) was dissolved in dry dichloromethane (2 ml). Boron tribromide (100 μl, 1M in CH2CI2) was added to cooled solution. After 30 minutes stirring was continued at room temperature for four hours. NaOH-solution (5ml, 10%-solution) was added and stirred well for 10 minutes. The solution was acidified with dilute HCI-solution. The product was extracted into EtOAc and washed with brine. The crude product was purified by chromatography using toluene: EtOAc 4:1 as an eluent.
NMR (CDCI3 + MeOH-d4): 1.03 (t, 3H), 1.81 (m, 2H), 2.84 (dd, 2H), 5.41 (s, 2H), 6.75 (d, 1 H), 6.95 (m, 1H), 7.22 (m, 2H), 7.38 (m, 1H), 8.12 (d, 1H). Rf (toluene-methanol, 9:1) = 0.31 MS (TOF, ES+) m/z 467/469 (M + Na)
Compound No. 101
3-(Furan-2-ylmethyl)-2-propyl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000089_0002
According to the method described for the compound No. 1 using Λ/-furan-2-ylmethyl- butyramide as a starting material.
NMR (CDCI3): 1.06 (t, 3H), 1.78-1.92 (m, 6H), 2.75 (m, 2H), 2.90-3.03 (m, 4H), 5.29 (s, 2H), 6.31-6.37 (m, 2H), 7.34 (d, 1H). Rf (toluene-methanol, 9.5:0.5) = 0.71 MS (TOF, ES+) m/z 351 (M + Na)
Compound No. 102
3-(Furan-2-ylmethyl)-2-propyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
Figure imgf000090_0001
According to the method described for the compound No. 2 using the compound No. 101 as a starting material.
NMR (CDCIa): 1 -08 (t, 3H), 1.85 (m, 2H), 2.22 (m, 2H), 2.66 (m, 2H), 3.00 (m, 2H), 3.28 (m, 2H), 5.29 (s, 2H), 6.33-6.42 (m, 2H), 7.36 (d, 1H). Rf (toluene-methanol, 9.5:0.5) = 0.53 MS (TOF, ES+) m/z 365 (M + Na)
Compound No. 103
7-Bromo-3-(5-bromofuran-2-ylmethyl)-2-propyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
Figure imgf000090_0002
According to the method described for the compound No. 46 using the compound No. 102 as a starting material. The bromide No. 104 was isolated as a by-product.
NMR (CDCI3): 1.08 (t, 3H), 1.90 (m, 2H), 2.55 (m, 2H), 3.00 (m, 2H), 3.19-3.51 (m, 1H), 3.54- 3.58 (m, 1H), 4.69 (t, 1H), 5.25 (s, 2H), 6.27 (d, 1H), 7.41 (d, 1 H). Rf (toluene-EtOAc, 9:1) = 0.44 MS (TOF, ES+) m/z 521/523/525 (M + Na)
Compound No. 104
7J-Dibromo-3-(5-bromofuran-2-ylmethyl)-2-propyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
Figure imgf000090_0003
Rf (toluene-EtOAc, 9:1) = 0.59 MS (TOF, ES+) m/z 601/603/605/607 (M + Na)
Compound No. 105 3-(5-Bromofuran-2-ylmethyl)-8-hydroxy-2-propyl-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000091_0001
According to the method described for the compound No. 49 using the compound No. 103 as a starting material. The compound No. 106 was isolated as a by-product. NMR (CDCI3 + MeOH-d4): 1.08 (t, 3H), 1.92 (m, 2H), 3.04 (m, 2H), 5.36 (s, 2H), 6.27 (d, 1H), 6.35 (d, 1H), 6.87 (d, 1H), 7.31-7.44 (m, 1 H), 8.10 (d, 1H). Rf (toluene-methanol, 9.5:0.5) = 0.24 MS (TOF, ES+) m/z 441/443 (M+ Na)
Compound No. 106
Acetic acid 3-(5-bromofuran-2-ylmethyl)-4-oxo-2-propyl-3,4-dihydro-benzo[4,5]thieno[2,3- d]pyrimidin-8-yl ester
Figure imgf000091_0002
NMR (CDCI3): 1.11 (t, 3H), 1.91 (m, 2H), 2.42 (s, 3H), 3.03 (m, 2H), 5.35 (s, 2H), 6.24 (d, 1 H), 6.43 (d, 1 H), 7.22 (d, 1H), 7.55 (dd, 1H), 8.45 (d, 1H). Rf (toluene-methanol, 9.5:0.5) = 0.44 MS (TOF, ES+) m/z 483/485 (M + Na)
Compound No. 107
7-Bromo-3-(5-bromofuran-2-ylmethyl)-8-hydroxy-2-propyl-3H-benzo[4,5]thieno[2,3-d]pyrimidin- 4-one
Figure imgf000092_0001
According to the method described for the compound No. 92 using the compound No. 104 as a starting. NMR (CDCI3 + MeOH-d4): 1.10 (t, 3H), 1.91 (m, 2H), 3.04 (m, 2H), 5.32 (s, 2H), 6.28 (d, 1 H), 6.45 (d, 1H), 7.57 (d, 1H), 7.98 (dd, 1H). Rf (toluene-EtOAc, 9:1) = 0.53 MS (TOF, ES-) m/z 497/499 Compound No. 108 3-(2-Methoxyethyl)-2-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
Figure imgf000092_0002
According to the method described for the compound No. 1 using Λ-(2-methoxyethyi)-3,4,5- trimethoxybenzamide as a starting material.
NMR (CDCI3): 1.88 (m, 4H), 2.88 (m, 2H), 3.06 (m, 2H), 3.24 (s, 3H), 3.52-3.75 (m, 2H), 3.89 (s, 9H), 4.23 (m, 2H), 6.83 (s, 2H). Rf (toluene-methanol, 9.5:0.5) = 0.53 MS (TOF, ES+) m/z 431 (M + 1)
Compound No. 109 3-(2-Methoxyethyl)-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
Figure imgf000092_0003
According to the method described for the compound No. 2 using the compound No. 108 as a starting material.
NMR (CDCI3): 2.27 (m, 2H), 2.70 (m, 2H), 3.26 (s, 3H), 3.34 (m, 2H), 3.72 (m, 2H), 3.90 (s, 9H), 4.28 (m, 2H), 6.87 (s, 2H). Rf (toluene-methanol, 9.5:0.5) = 0.47 MS (TOF, ES+) m/z 467 (M + Na)
Compound No. 110 7,7-Dibromo-2-(2-bromo-3,4,5-trimethoxyphenyl)-3-(2-methoxy-ethyl)-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
Figure imgf000093_0001
According to the method described for the compound No. 46 using the compound No. 109 as a starting material. The bromide No.111 was isolated as a by-product.
Rf (toluene-methanol, 9.5:0.5) = 0.41 MS (TOF, ES+) m/z 523/525
Compound No. 111 7-Bromo-2-(2-bromo-3,4,5-trimethoxyphenyl)-3-(2-methoxyethyl)-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
Figure imgf000093_0002
NMR (CDCI3): 2.61 (m, 2H), 3.19 (s, 3H), 3.38-3.76 (m, 5H), 3.89 (s, 3H), 3.94 (s, 6H), 4.42- 4.51 (m, 1H), 4.73 (t, 1H), 6.88 (s, 1H). Rf (toluene-methanol, 9.5:0.5) = 0.56 MS (TOF, ES+) m/z 623/625/627 (M + Na)
Compound No. 112 2-(2-Bromo-3,4,5-trimethoxyphenyl)-8-hydroxy-3-(2-methoxyethyl)-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
Figure imgf000094_0001
According to the method described for the compound No. 49 using the compound No. 111 as a 5 starting material.
NMR (CDCI3): 3.21 (s, 3H), 3.50-3.77 (m, 1H), 3.81-3.94 (m, 11H), 4.52-4.63 (m, 1H), 6.87 (d, 1H), 6.98 (s, 1 H), 7.36 (dd, 1 H), 8.18 (d, 1H). Rf (toluene-methanol, 9.5:0.5) = 0.29 10 MS (TOF, ES+) m/z 543/545 (M + Na)
Compound No. 113 3-lsobutyl-2-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4- one
-|g
Figure imgf000094_0002
According to the method described for the compound No. 1 using Λ/-isobutyl-3,4,5-trimethoxy- benzamide as a starting material.
NMR (CDCI3): 0.74 (s, 3H), 0.77 (s, 3H), 1.88 (m, 4H), 2.03 (m, 1H), 2.79 (m, 2H), 3.06 (m, 2H), 20 3.86-3.98 (m, 11 H), 6.67 (s, 2H). Rf (toluene-methanol, 9.5:0.5) =0.44 MS (TOF, ES+) m/z 429 (M + 1)
Compound No. 114
25 3-lsobutyl-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8- dione
Figure imgf000095_0001
According to the method described for the compound No. 2 using the compound No. 113 as a starting material.
NMR (CDCI3): 0.76 (s, 3H), 0.79 (s, 3H), 2.03 (m, 1 H), 2.28 (m, 2H), 2.70 (m, 2H), 3.34 (m, 2H), 3.91 (s, 9H), 4.00 (m, 2H), 6.71 (s, 2H). Rf (toluene-methanol, 9.5:0.5) =0.38 MS (TOF, ES+) m/z 443 (M + 1)
Compound No. 115
7-Bromo-3-isobutyl-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
Figure imgf000095_0002
According to the method described for the compound No. 46 using the compound No. 114 as a starting material. The compound No.116 was isolated as a by-product.
NMR (CDCI3): 0.77 (s, 3H), 0.80 (s, 3H), 2.03 (m, 1H), 2.60 (m, 2H), 3.29-3.63 (m, 2H), 3.91 (s, 9H), 4.03 (m, 2H), 4.73 (t, 1H), 6.70 (s, 2H). Rf (toluene-EtOAc, 9:1) = 0.12 MS (TOF, ES+) m/z 543/545 (M + Na)
Compound No. 116
7-Bromo-2-(2-bromo-3,4,5-trimethoxyphenyl)-3-isobutyl-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
Figure imgf000095_0003
Rf (toluene-EtOAc, 9:1) = 0.23 MS (TOF, ES+) m/z 599/601/603
Compound No. 117
8-Hydroxy-3-isobutyl-2-(2-bromo-3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidin- 4-one
Figure imgf000096_0001
According to the method described for the compound No. 49 using the compound No. 116 as a starting material. The compound No. 118 was isolated as a by-product.
NMR (CDCIs): 0.73 (d, 3H), 0.90 (d, 3H), 2.15 (m, 1 H), 3.42 (m, 1H), 3.89 (s, 3H), 3.96 (s, 6H), 4.38 (m, 1 H), 6.88 (m, 2H), 7.45 (dd, 1H), 8.35 (d, 1 H). Rf (toluene-methanol, 9.5:0.5) = 0.23 MS (TOF, ES+) m/z 519/521
Compound No. 118
Acetic acid 2-(2-bromo-3,4,5-trimethoxyphenyl)-3-isobutyl-4-oxo-3,4-dihydro-benzo[4,5]- thieno[2,3-d]pyrimidin-8-yl ester
Figure imgf000096_0002
NMR (CDCI3): 0.75 (d, 3H), 0.90 (d, 3H), 2.18 (m, 1 H), 2.47 (s, 3H), 3.42 (m, 1 H), 3.90 (s, 3H), 3.97 (s, 6H), 4.34 (m, 1 H), 6.86 (m, 1H), 7.19 (m, 1H), 7.65 (dd, 1H), 8.40 (d, 1 H). Rf (toluene-methanol, 9.5:0.5) =0.43 MS (TOF, ES+) m/z 561/563 (M+ Na)
Compound No. 119
3-(Furan-2-ylmethyl)-2-(3,4,5-trimethoxylphenyl)-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
Figure imgf000097_0001
According to the method described for the compound No. 1 using Λ/-furan-2-ylmethyl-3,4,5- trimethoxy-benzamide as a starting material.
NMR (CDCI3): 1.87 (m, 4H), 2.80 (m, 2H), 3.06 (m, 2H), 3.81 (s, 6H), 3.88 (s, 3H), 5.16 (s, 2H), 6.20 (dd, 1H), 6.32 (dd, 1 H), 6.73 (s, 2H), 7.30 (m, 1H). Rf (toluene-methanol, 9.5:0.5) = 0.56 MS (TOF, ES+) m/z 475 (M + Na)
Compound No. 120
3-(Furan-2-yImethyl)-2-(3,4,5-trimethoxylphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4, 8-dione
Figure imgf000097_0002
According to the method described for the compound No. 2 using the compound No. 119 as a starting material.
NMR (CDCI3): 2.25 (m, 2H), 2.66 (m, 2H), 3.34 (m, 2H), 3.83 (s, 6H), 3.88 (s, 3H), 5.20 (s, 2H), 6.24 (dd, 1 H), 6.35 (dd, 1H), 6.77 (s, 2H), 7.33 (m, 1H). Rf (toluene-methanol, 9.5:0.5) = 0.38 MS (TOF, ES+) m/z 467 (M + 1)
Compound No. 121
7-Bromo-3-(5-bromofuran-2-ylmethyl)-2-(2-bromo-3,4,5-trimethoxylphenyl)-6,7-dihydro-3H,5H- benzo[4, 5]thieno[2, 3-d]py rimidine-4, 8-dione
Figure imgf000098_0001
According to the method described for the compound No. 46 using the compound No. 120 as a starting material.
Rf (toluene-methanol, 9.5:0.5) =0.59 MS (TOF, ES+) m/z 623/625/627
Compound No. 122
3-(5-Bromofuran-2-ylmethyi)-8-hydroxy-2-(3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
Figure imgf000098_0002
According to the method described for the compound No. 49 using the compound No. 121 as a starting material.
NMR (CDCI3): 3.91 (s, 6H), 3.92 (s, 3H), 5.25 (s, 2H), 6.26 (d, 1H), 6.42 (d, 1 H), 6.81-6.93 (m, 3H), 7.40 (dd, 1 H), 8.24 (d, 1 H). Rf (toluene-methanol, 9.5:0.5) =0.17 MS (TOF, ES-) m/z 541/543
Compound No. 123
3-Benzyl-7-chloro-2-(2-chloro-3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
Figure imgf000098_0003
The compound No. 2 (500 mg, 1.05 mmol) was dissolved in CCI4 (5 ml). Freshly distilled sulfuryl chloride (94 μl, 116 mmol) was added under nitrogen. The reaction mixture was warmed 45-55 °C. Additional portion of sulfuryl chloride (94 μl) was added after two hours. The crude product was purified by chromatography using toluene-EtOAc (9.8:0.2) as an eluent.
NMR (CDCI3): 2.65 (m, 2H), 3.48 (s, 3H), 3.56 (m, 2H), 3.93 (s, 3H), 3.96 (s, 3H), 4.49 (dd, 1 H), 4.66 (t, 1 H), 5.89 (dd, 1 H), 6.15 (d, 1 H), 7.22 (m, 5H). Rf (toluene-methanol, 9.5:0.5) =0.65 MS (TOF, ES+) m/z 545/547/549
Compound, o. 124
3-Benzyl-2-(2-chloro-3,4,5-trimethoxyphenyl)-8-hydroxy-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4- one
Figure imgf000099_0001
According to the method described for the compound No. 92 using the compound No. 123 as a starting material.
NMR (CDCI3): 3.47 (s, 3H), 3.92 (s, 3H), 4.01 (s, 3H), 4.56 (d, 1H), 6.05 (d, 1H), 6.20 (s, 1H), 6.92 (m, 3H), 7.20 (m, 3H), 7.40 (dd, 1H), 8.32 (d, 1H). Rf (toluene-methanol, 9.5:0.5) =0.16 MS (TOF, ES+) m/z 509/5 1
Compound No. 125
3-(2-Methylbutyl)-2-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
Figure imgf000099_0002
According to the method described for the compound No. 1 using 3,4,5-trimethoxy-Λ/-(2- methylbutyl)-benzamide as a starting material. NMR (CDCI3): 0.70 (d, 3H), 0.74 (t, 3H), 1.22 (m, 2H), 1.85 (m, 5H), 2.79 (m, 2H), 3.07 (m, 2H), 3.86 (s, 9H), 3.98 (m, 2H), 6.67 (s, 2H). Rf (toluene-EtOAc, 9:1) =0.25 MS (TOF, ES+) m/z 443 (M + 1)
Compound No. 126
3-(2-Methylbutyl)-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4, 8-dione
Figure imgf000100_0001
According to the method described for the compound No. 2 using the compound No. 125 as a starting material.
NMR (CDCI3): 0.74 (m, 6H), 1.12 (m, 2H), 1.80 (m, 1H), 2.30 (m, 2H), 2.70 (m, 2H), 3.34 (m, 2H), 3.90 (s, 9H), 4.01 (m, 2H), 6.70 (s, 2H). Rf (toluene-methanol, 9.5:0.5) =0.51 MS (TOF, ES+) m/z 457 (M + 1)
Compound No. 127
7-Bromo-3-(2-methylbutyl)-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
Figure imgf000100_0002
According to the method described for the compound No. 46 using the compound No. 126 as a starting material. The compound No.128 was isolated as a by-product.
NMR (CDCI3): 0.72 (m, 6H), 0.88-1.31 (m, 2H), 1.79 (m, 1H), 2.60 (m, 2H), 3.34-3.63 (m, 2H), 3.91 (s, 9H), 4.06 (m, 2H), 4.73 (t, 1H), 6.71 (s, 2H). Rf (toluene-EtOAc, 9:1) =0.15 MS (TOF, ES+) m/z 535/537 Compound No. 128
7,7-Dibromo-2-(2-bromo-3,4,5-trimethoxyphenyl)-3-(2-methy!butyl)-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
Figure imgf000101_0001
Rf (toluene-EtOAc, 9:1) =0.56 MS (TOF, ES+) m/z 691/693/695
Compound No. 129
8-Hydroxy-3-(2-methylbutyl)-2-(3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4- one
Figure imgf000101_0002
According to the method described for the compound No. 92 using the compound No. 127 as a starting material.
NMR (CDCI3): 0.76 (m, 6H), 1.08 (m, 2H), 1.88 (m, 1H), 3.92 (s, 9H), 4.14 (m, 2H), 6.76 (s, 2H), 6.91 (dd, 1H), 7.41 (dd, 1 H), 8.22 (dd, 1H). Rf (toluene-methanol, 9.5:0.5) =0.13 MS (TOF, ES+) m/z 455 (M + 1)
Compound No. 130
3-(Tetrahydrofuran-2-ylmethyl)-2-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydro-3H- benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000101_0003
According to the method described for the compound No. 1 using 3,4,5-trimethoxy-/V- (tetrahydrofuran-2-ylmethyl)-benzamide as a starting material.
Rf (toluene-MeOH, 9:1) =0.40 MS (TOF, ES+) m/z 457 (M + 1)
Compound No. 131 3-(Tetrahydrofuran-2-ylmethyl)-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
Figure imgf000102_0001
According to the method described for the compound No. 2 using the compound No. 130 as a starting material.
NMR (CDCI3): 1.44 (m, 1H), 1.74 (m, 2H), 2.02 (m, 1H), 2.28 (m, 2H), 2.70 (m, 2H), 3.33 (m, 2H), 3.57 (m, 2H), 3.89 (s, 9H), 3.99 (m, 1H), 4.22 (m, 2H), 6.81 (s, 2H). Rf (toluene-methanol, 9:1) =0.44 MS (TOF, ES+) m/z 471 (M + 1)
Compound No. 132 7-Bromo-2-(2-bromo-3,4,5-trimethoxyphenyl)-3-(tetrahydrofuran-2-ylmethyl)-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
Figure imgf000102_0002
According to the method described for the compound No. 46 using the compound No. 131 as a starting material.
NMR (CDCI3): 1.58 (m, 3H), 2.07 (m, 1H), 2.58 (m, 2H), 3.26-3.67 (m, 5H), 3.94 (s, 3H), 3.95 (s, 3H), 3.96 (s, 3H), 4.44 (m, 2H), 4.73 (t, 1 H), 7.00 (s, 1H). Rf (toluene-MeOH, 9,5:0,5) =0.59 MS (TOF, ES+) m/z 649/651/653 (M + Na) Compound No. 133 2-(2-Bromo-3,4,5-trimethoxyphenyl)-8-hydroxy-3-(tetrahydrofuran-2-ylmethyl)-3H- benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000103_0001
The compound No.132 (50 mg, 0.08 mmol) was dissolved in methanol (1.5 ml). NaOH (13 mg, 0.32 mmol) was added. The reaction mixture was heated using microwaves (120 °C, 2 min.). The solvent was evaporated and the precipitate was dissolved into ethylacetate, washed with 1N HCI and water. Purified by using chromatography (eluent: CH2CI2-diethyl ether 9:1).
NMR (CDCI3): 1.45-1.93 (m, 4H), 2.15 (m, 1H), 3.34-3.79 (m, 2H), 3.94 (s, 3H), 3.95 (s, 3H), 3.96 (s, 3H), 4.60 (m, 2H), 6.77 (d, 1H), 7.13 (s, 1H), 7.31 (dd, 1 H), 8.03 (d, 1H). Rf (toluene-methanol, 9.5:0.5) =0.32 MS (TOF, ES+) m/z 547/549
Compound No. 134
3-Butyl-2-thiophen-2-yl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
Figure imgf000103_0002
According to the method described for the compound No. 2 using the compound No. 77 as a starting material.
NMR (CDCI3): 0.95 (t, 3H), 1.36 (m, 2H), 1.81 (m, 2H), 2.26 (m, 2H), 2.69 (m, 2H), 3.32 (m, 2H), 4.24 (m, 2H), 7.18 (dd, 1 H), 7.58 (dd, 2H). Rf (toluene-methanol, 9:1) =0.49 MS (TOF, ES+) m/z 359 (M + 1)
Compound No. 135
5-Bromo-3-isobutyl-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]py rimidine-4, 8-dione
Figure imgf000104_0001
The compound No. 114 (200 mg, 0.45 mmol), NBS (40 mg, 0.23 mmol) and benzoylperoxide (27 mg, 0.11 mmol) were dissolved in carbon tetrachloride (4 ml) and refluxed for1.5 hours. After 30 minutes a new portion of NBS (40 mg) was added. The reaction mixture was filtered and the solid was washed carefully with dichloromethane. The filterate was washed with water and evaporated. The crude product was purified by chromatography using toluene-EtOAc (4:1) as an eluent.
NMR (CDCI3): 0.79 (dd, 6H), 2.04 (m, 1H), 2.74 (m, 3H), 3.15 (m, 1H), 3.90 (s, 6H), 3.91 (s, 3H), 3.95 (1H), 4.17 (m, 1 H), 6.20 (t, 1 H), 6.71 (s, 2H). Rf (toluene-methanol, 9.5:0.5) =0.53 MS (TOF, ES+) m/z 521/523
Compound No. 136 3-lsobutyl-8-methoxy-2-(3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000104_0002
The compound No.135 (50 mg) was dissolved in a mixture of dichloromethane and methanol (v/v 1:1 , 2ml) and warmed at 40 °C for two days. The solvent was evaporated. The crude product was purified by chromatography using toluene-EtOAc (9:1) as an eluent.
NMR (CDCI3): 0.78 (s, 3H), 0.81 (s, 3H), 2.13 (m, 1 H), 3.92 (s, 9H), 4.03 (s, 3H), 4.10 (m, 2H), 6.75 (s, 2H), 6.95 (d, 1 H), 7.51 (dd, 1H), 8.29 (d, 1 H). Rf (toluene-methanol, 9.5:0.5) =0.35 MS (TOF, ES+) m/z 455 (M + 1)
Compound No. 137
3-Benzyl-5-bromo-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione
Figure imgf000105_0001
According to the method described for the compound No. 135 using the compound No. 2 as a starting material.
NMR (CDCI3): 2.74 (m, 3H), 3.21 (m, 1H), 3.61 (s, 6H), 3.86 (s, 3H), 5.29 (dd, 2H), 6.20 (t, 1 H), 6.53 (s, 2H), 7.06 (m, 2H), 7.30 (m, 3H). Rf (toluene-methanol, 9.5:0.5) =0.59 MS (TOF, ES+) m/z 555/557 Compound No. 138
3-Benzyl-8-methoxy-2-(3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000105_0002
According to the method described for the compound No. 136 using the compound No. 137 as a starting material.
NMR (CDCI3): 3.61 (s, 6H), 3.86 (s, 3H), 4.04 (s, 3H), 5.34 (s, 2H), 6.56 (s, 2H), 6.96 (d, 1H), 7.08 (m, 2H), 7.30 (m, 3H), 7.51 (dd, 1H), 8.33 (d, 1H). Rf (toluene-methanol, 9.5:0.5) =0.56 MS (TOF, ES+) m/z 489 (M + 1)
Compound No. 139
7-Chloro-2-(2-chloro-3,4,5-trimethoxyphenyl)-3-(tetrahydrofuran-2-ylmethyl)-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
Figure imgf000105_0003
According to the method described for the compound No. 123 using the compound No. 131 as a starting material.
Rf (toluene-methanol, 9.5:0.5) =0.53
Compound No. 140
2-(2-Chloro-3,4,5-trimethoxyphenyl)-8-hydroxy-3-(tetrahydrofuran-2-ylmethyl)-3H- benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000106_0001
According to the method described for the compound No. 92 using the compound No. 139 as a starting material.
NMR (CDCI3): 1.46-1.94 (m, 3H), 2.16 (m, 1H), 3.33-3.81 (m, 2H), 3.95 (m, 1 H), 3.96 (s, 9H), 4.64 (m, 2H), 6.73 (d, 1H), 7.12 (s, 1H), 7.54 (m, 1H), 7.86 (d, 1H). Rf (toluene-methanol, 9:1) =0.29 MS (TOF, ES+) m/z 503/505
Compound No. 141
7-Chloro-2-(2-chloro-3,4,5-trimethoxyphenyl)-3-(2-methylbutyl)-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
Figure imgf000106_0002
According to the method described for the compound No. 123 using the compound No. 126 as a starting material. The compound No.142 was isolated as a by-product.
NMR (CDCI3): 0.65 (m, 3H), 0.75 (m, 4H), 0.82-1.30 (m, 2H), 2.62 (m, 2H), 3.41-3.55 (m, 3H), 3.90 (s, 3H), 3.95 (s, 6H), 4.27 (m, 1H), 4.65 (m, 1H), 6.79 (s, 1H). Rf (toluene-methanol, 9.5:0.5) =0.37 MS (TOF, ES+) m/z 525/527 Compound No. 142
7,7-Dichloro-2-(2-chloro-3,4,5-trimethoxyphenyl)-3-(2-methylbutyl)-6,7-dihydro-3H,5H- benzo[4,5]thieno[2,3-d]pyrimidine-4,8-dione
Figure imgf000107_0001
NMR (CDCI3): 0.68 (t, 3H), 0.86 (m, 4H), 1.00-1.30 (m, 2H), 2.62 (dd, 2H), 3.34-3.61 (m, 3H), 3.89 (s, 3H), 3.90 (s, 6H), 4.26 (m, 1H), 6.78 (s, 1H). Rf (toluene-methanol, 9.5:0.5) =0.53 MS (TOF, ES+) m/z 559/561/563
Compound No. 143
2-(2-Chloro-3,4,5-trimethoxyphenyl)-8-hydroxy-3-(2-methylbutyl)-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
Figure imgf000107_0002
According to the method described for the compound No. 133 using the compound No. 141 as a starting material.
NMR (CDCI3): 0.61-0.88 (m, 6H), 1.20 (m, 3H), 3.54 (m, 1H), 3.88 (s, 3H), 3.95 (s, 6H), 4.41 (m, 1H), 6.87 (d, 1H), 6.92 (dd, 1 H), 7.40 (dd, 1H), 8.28 (d, 1H). Rf (toluene-methanol, 9.5:0.5) =0.12 MS (TOF, ES+) m/z 489/491
Compound No. 144
3-Pyridin-3-ylmethyl-2-(3,4,5-trimethyl-phenyl)-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
Figure imgf000108_0001
According to the method described for the compound No. 1 using 3,4,5-trimethoxy-Λ/-pyridin-3- ylmethyl-benzamide as a starting material.
NMR (CDCI3): 1.90 (m, 4H), 2.82 (m, 2H), 3.07 (m, 2H), 3.81 (s, 3H), 3.86 (s, 3H), 3.91 (s, 3H), 5.26 (s, 2H), 6.49 (s, 2H), 7.44 (dd, 1H), 7.68 (dd, 1H), 8.55 (m, 2H). MS (TOF, ES+) m/z 464 (M + 1)
Compound No. 145 3-Benzyl-8-hydroxy-2-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one
Figure imgf000108_0002
The compound No. 2 (200 mg, 0.42 mmol) was dissolved in EtOAc (10 ml) and added to mixture of NaBH4 (32 mg, 0.84 mmol) in EtOAc (5 ml) and stirred overnight at room temperature. The reaction mixture was diluted with EtOAc, washed with saturated ammonium chloride and brine. After evaporation of solvent, the crude product was purified by chromatography.
NMR (CDCI3): 1.91 (m, 1H), 1.97-2.23 (m, 4H), 3.09 (m, 2H), 3.58 (s, 6H), 3.84 (s, 3H), 4.89 (br s, 1 H), 5.22 (d, 2H), 6.51 (s, 2H), 7.01 (m, 2H), 7.20 (m, 3H). Rf (toluene-methanol, 9:1) =0.38 MS (TOF, ES+) m/z 501 (M + Na)
Compound No. 146
3-Benzyl-7-bromo-2-p-methoxyphenyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine-4,8- dione
Figure imgf000109_0001
According to the method described for the compound No. 46 using the compound No. 13 as a starting material. The compound No.147 was isolated as a by-product. NMR (CDCI3): 2.58 (m, 2H), 3.25-3.64 (m, 2H), 3.85 (s, 3H), 4.72 (t, 1H), 5.32 (s, 2H), 7.0 (m, 4H), 7.30 (m, 5H). MS (TOF, ES+) m/z 495/497
Compound No. 147 3-Benzyl-7,7-dibromo-2-p-methoxyphenyl-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3-d]pyrimidine- 4,8-dione
Figure imgf000109_0002
NMR (CDCI3): 3.17 (dd, 2H), 3.45 (dd, 2H), 3.85 (s, 3H), 5.29 (s, 2H), 6.98 (m, 4H), 7.30 (m, 5H).
MS (TOF, ES+) m/z 595/597/599 (M + Na)
Compound No. 148
7-Bromo-8-hydroxy-3-(2-methoxyethyl)-2-thiophen-2-yl-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4- one
Figure imgf000109_0003
According to the method described for the compound No. 133 using the compound No. 76 as a starting material. NMR (CDCI3 + MeOH-d4): 3.56 (s, 3H), 3.85 (m, 2H), 4.58 (m, 2H), 6.91 (d, 1H), 7.13 (d, 1H), 7.39 (m, 1H), 7.64 (m, 1 H), 8.12 (d, 1H). Rf (toluene-methanol, 9:1) =0.47 MS (TOF, ES-) m/z 435/437
Compound No. 149
7-B romo-8-hydroxy-3-(2-hydroxyethy l)-2-th iophen-2-y l-3H-benzo[4 , 5]th ieno[2 , 3-d]py rim idin-4- one
Figure imgf000110_0001
According to the method described for the compound No. 100 using the compound No. 76 as a starting material.
NMR (DMSO-d6): 3.80 (m, 2H), 4.39 (m, 2H), 5.16 (dd, 1H), 6.95 (d, 1H), 7.40 (m, 2H), 7.90 (m, 2H), 10.69 (s, 1H). Rf (toluene-methanol, 9:1) =0.31 MS (TOF, ES-) m/z 421/423
Compound No. 150
3-Benzyl-8-chloro-2-(2-chloro-3,4,5-trimethoxyphenyl)-4-oxo-3,4-dihydro-benzo[4,5]thieno[2,3- d]pyrimidine-7-carbaldehyde
Figure imgf000110_0002
The compound No.3 (200 mg, 0.38 mmol), sulfurylchloride (46 μl, 0.57 mmol) in chloroform (s 2 ml) were refluxed under nitrogen atmosphere for 45 minutes. The reaction mixture was diluted with dichloromethane and washed with water. After evaporation the crude product was purified with chromatography using toluene-EtOAc (9.9:0.1) as an eluent.
NMR (CDCI3): 3.50 (s, 3H), 3.95 (s, 3H), 3.98 (s, 3H), 4.58 (d, 1H), 6.03 (d, 1H), 6.20 (s, 1 H), 6.93 (m, 2H), 7.20 (m, 3H), 8.13 (d, 1H), 8.74 (d, 1H), 10.61 (s, 1 H). Rf (toluene-EtOAc, 9:1) =0.44 MS (TOF, ES+) m/z 555/557/559 Compound No. 151 8-Hydroxy-3-isobutyl-2-(3,4,5-trimethoxypheny!)-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one
Figure imgf000111_0001
The compound No. 135 (50 mg, 0.1 mmol) and K2C03 (25 mg) were stirred in ethanol for two hours. The solvent was evaporated. The precipitate was dissolved in dichloromethane and washed with water.
NMR (CDCI3): 0.77 (s, 3H), 0.81 (s, 3H), 2.13 (m, 1H), 3.91 (s, 9H), 4.11 (d, 2H), 6.75 (s, 2H), 6.90 (d, 1H), 7.42 (d, 1 H), 8.28 (d, 1H). Rf (toluene-methanol, 9:1) =0.31 MS (TOF, ES+) m/z 441 (M + 1)
Further compounds of general formula q falling under the scope of general formula I can prepared by parallel chemistry using a reaction as shown in the following scheme 5 (according to the general flow scheme 1):
Scheme 5: General route to Benzothienopyrimidinones.
Figure imgf000111_0002
Figure imgf000111_0003
In a reaction vessel at room temperature are put together sequentially 0.25 M primary amine
R1-NH2, M diisopropylethylamine and 0.25 M acid chloride R2 -CO-CI. To this mixture is added 0.25 M 2-amino-benzo[b]thiophene-3-carboxylic acid ethyl ester followed by 0.25 M POCI3. Of all reactants one equivalent is used as solution or suspension in chlorobenzene. After shaking for 80 hours at 100°C, the mixtures are cooled to room temperature, washed with 5% NaOAc and extracted with EtOAc. The organic layers are collected and concentrated to yield the desired compound. The obtained material of the formula q was thereafter analyzed by LC- MS.
The LC-MS system consists of 2 Perkin Elmer series 200 micro-pumps. The pumps are connected to each other by a 50 μ tee mixer. The mixer is connected to the Gilson 215 autosampler. The LC methode consists of the following steps:
Step total time flow (ul/min) A(%) B(%)
0 0 2300 95 5
1 1.8 2300 0 100
2 2.5 2300 0 100
3 2.7 2300 95 5
4 3.0 2300 95 5
Solution A= 100% Water with 0.025% HCOOH and 10mmol NH4HCOO pH= +/- 3
Solution B= 100% MeOH with 0.025% HCOOH
The auto sampler has a 2 μl injection loop. The auto sampler is connected to a Varian Polaris C18 A 30*4.6 mm column with 3 μm particles. The column is thermo stated in a Perkin Elmer series 200 column oven at 40°C. The column is connected to an Applied Biosystems ABI 785 UV meter with a 2.7 μl flowcel. The wavelength is set to 254 nm. The UVmeter is connected to a Sciex API 150EX mass spectrometer having the following parameters (Scanrange: 150-900 Amu, Polarity: positive, Scan mode: profile, Resolution Q1: UNIT, Step size: 0.10 amu, Time per scan: 0.500 sec, NEB: 10, CUR: 10, IS: 5200, TEM: 325, DF: 30, FP: 225, EP: 10). The light scattering detector is connected to the Sciex API 150. The light scattering detector is a Sedere Sedex 55 operating at 50°C and 3 bar N2 pressure. The complete systems is controlled by a Dell optiplex GX400 computer operating under Windows NT.
The following table 1 lists compounds No. 152 to 616 of the general formula q, which were prepared according to Scheme 5 starting with the primary amines R1-NH2 and the acide chlorides R2-CO-CI. In addition, the Molecular Weight and the Retention Time of the synthesized compounds determined by the LC-MS analysis are shown. Table 1: Compounds No. 152 to 616 of the general formula q:
Figure imgf000113_0001
Figure imgf000113_0002
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Further compounds of general formula r falling under the scope of general formula I can prepared by parallel chemistry using a reaction as shown in the following scheme 6 (according to the general flow scheme 1): Scheme 6: General route to 8-Hydroxy-benzothienopyrimidinones.
Figure imgf000125_0001
Figure imgf000125_0002
In a reaction vessel at room temperature are put together sequentially 0.25 M primary amine R1-NH2, 1 M diisopropylethylamme and 0.25 M acid chloride R2 -CO-CI. To this mixture is added 0.25 M 2-amino-7-hydroxy-benzo[b]thiophene-3-carboxylic acid ethyl ester a" followed by 0.25 M POCI3. Of all reactants one equivalent is used as solution or suspension in chlorobenzene. After shaking for 80 hours at 100°C, the mixtures are cooled to room temperature, washed with 5% NaOAc and extracted with EtOAc. The organic layers are collected and concentrated to yield the desired compound. The obtained material of the formula r was thereafter analyzed by LC-MS according to the procedure described in scheme 5.
Preparation of 2-amino-7-hydroxy-benzo[b]thiophene-3-carboxylic acid ethyl ester
Scheme 7; Synthesis route to 2-amino-7-hydroxy-benzo[b]thiophene-3-carboxylic acid ethyl esfer (compound of formula a")
Figure imgf000125_0003
The thiophene t was prepared from 1-N-morpholino-cyclohexene s and equimolar amounts of cyanoethyl acetate and S8 in ethanol. After acylation compound u was obtained [Perrissin M et al. (1980) Eur. J. Med. Chem. Chi . Ther. 15:413-418]. Oxidation of u with K2Cr207 gave ketone v in a moderate yield, but starting material could also be recovered [Kharizomenova A et al. (1984) Chem. Heterocycl. Compd. (Engl. Transl.) 20:1339-1342] 1984, 20, 1339-1342]. α- Bromination of ketone v with Br2 in CHCI3 gave a mixture of starting material, monobrominated product w and dibrominated product [Kharizomenova A et al. (1984) Chem. Heterocycl. Compd. (Engl. Transl.) 20:1339-1342] 1984, 20, 1339-1342 and Kapustina MV et al. (1990) Chem. Heterocycl. Compd. (Engl. Transl.) 24:1269-271]. After column chromatography w was obtained in 11% yield. Elimination was achieved with LiBr/Li2C03 and gave x in 74% yield [Samanta et al. (1997) J. Chem. Soc; Perkin Trans. I, 3673-3677]. Compound a" was prepared in 78% yield from xwith H2S04 in MeOH.
Detailed Experimental Protocol:
2-Amino-4,5, 6, 7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester t A solution of 4-cyclohex-1-enyl-morpholine (s) (1003 g, 6.0 mol) in abs. EtOH (1.51 L) was added dropwise to a mixture of sulfur (192.4 g, 6.0 mol) and ethylcyanoacetate (678.7 g, 6.0 mmol) in abs. EtOH (1.5 L) at 95°C at such a rate that reflux was maintained. After complete addition the mixture was stirred for 2 h and then, without cooling, poured into a mixture of ice and H20 (~10 L). The resulting precipitate was filtered off and washed with H20 (2 L) and EtOH (3 L). The compound was dried in air to give 2 (1201 g, 5.33 mol, 89%) as a slight yellow solid.
2-Acetylamino-4, 5, 6, 7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester u Ac20 (450 mL) was added dropwise to a solution of compound t (600 g, 2.66 mol) in acetic acid (3 L). The reaction was slightly exothermic. After complete addition the mixture was heated to 85°C for 3 h. The hot mixture was poured on ice (10 L). The resulting precipitate was filtered, washed with H20 (2 L) and dried in air to give u (672 g, 2.51 mol, 94%) as a brown solid.
2-Acetylamino- 7-oxo-4, 5, 6, 7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester v
A solution of compound u (660 g, 2.47 mol) in AcOH (3.5 L) was heated to 60°C with mechical stirring. Then a solution of K2Cr207 (1000 g, 5.15 mol) in H20 (1 L) was added dropwise keeping the internal temperature below 80°C. After complete addition the mixture was cooled to RT within 3 h. The mixture was poured into H20 (10 L) and left standing for crystallization during 2 h. The resulting precipitate was filtered off and washed with H20 (2 x 2 L). The solid was dissolved in CH2CI2 (3 L) and some water was separated. The solution was concentrated in vacuo to a volume of 1 L and heptane was added (3 L). A part of CH2CI2 (400 L) was removed to induce precipitation. The resulting solid (350 g) was filtered giving a 5:1 -mixture of product and starting material. The solid was recrystallized from a 1:1-mixture of CHCI3 and heptane (700 ml) to give compound v (230 g, 0.82 mol, 33%) as a brown solid.
2-Acetylamino-6-bromo-7-oxo-4,5,6, 7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester w
A solution of compound v (230 g, 0.82 mol) in CHCI3 (2 L) was heated to reflux and a solution of Br2 (138 g, 0.86 mol) in CHCI3 (2 L) was added dropwise. After complete addition the mixture was stirred for 2 h and then it was cooled to RT. The reaction mixture was washed acid free with H20 (5 x 250 mL). The solvent was removed in vacuo and the residue was stirred with EtOH (1 L). The resulting precipitate was filtered off and dried in air. The solid consisted of starting material, product and dibrominated ketone and was subjected to column chromatography on Si02 using CH2CI2 as eluent to give compound w (34 g, 94 mmol, 11%). The dibrominated compound (80.1 g, 182 mmol, 22%) was isolated as well as was the starting compound v (29 g, 103 mmol, 12%).
2-Acetylamino-7-hydroxy-benzo[b]thiophene-3-carboxylic acid ethyl ester x. A flame dried three-necked flask was purged with N2 and charged with bromo ketone w (32.0 g, 91.4 mmol), LiBr (15.9 g, 183 mmol, 2.0 equiv.), Li2C03 (13.7 g, 183 mmol, 2.0 equiv.) and DMF (1 L). The resulting suspension was refluxed overnight under N2. The reaction mixture was concentrated to ~100 mL and neutralized by the addition of 1 N HCI until no gas evolved and H20 was added (300 mL). The crude product was isolated by extraction with EtOAc (3 x 400 mL). The combined organic layers were washed with H20 (400 mL), brine (400 mL) and dried over Na2S04. Evaporation of the solvents gave the crude product which was purified by column chromatography (CH2CI2/EtOAc = 3/2) and crystallization from MeOH/H20 to give x as a pink solid (19.0g, 68.0 mmol, 74%).
2-Amino-7-hydroxy-benzo[b]thiophene-3-carboxylic acid ethyl ester a" Compound x (27.8 g, 100 mmol) was dissolved in MeOH, H2S04 was added and the mixture was stirred for 7 days. The mixture was concentrated to half of the original volume. Water was added and the pH was cautiously adjusted to 6 with cone. NH3. The resulting precipitate was filtered off, washed with MeOH/H20 and dried to give a" (18.4 g, 78 mmol, 78 %) as a grey solid.
The following table 2 lists compounds No. 617 to 682 of the general formula r, which were prepared according to Scheme 6 starting with the primary amines R1-NH2 and the acide chlorides R2-CO-CI. In addition, the determined Molecular Weight and the Retention Time from the LC-MS analysis of the synthesized compounds are shown. Table 2: Compounds No. 617 to 682 of the general formula r:
Figure imgf000128_0001
Figure imgf000128_0002
Figure imgf000129_0001
BIOLOGICAL TESTING MATERIALS AND METHODS 1. Inhibition of the 176-hvdroxysteroid dehydrogenase type 1. type 2 and type 3 enzyme
The compounds were screened in respect of 17β-HSD enzyme activity in vitro on established MCF-7 cell lines, each stably expressing one of the respective 17β-HSD isoenzymes. The interconversion of substrate by each isoenzyme and the 17β-HSD inhibiting activity of chemical compounds in these cell lines were detected by HPLC system.
Varying amounts of the test compounds were incubated in the growth medium of the 17β- HSD expressing cells together tritium labeled substrate (2nM estrone for 17β-HSD type 1; 2 nM estradiol for 17β-HSD type 2; and 2 nM androstenedione for 17β-HSD type 3). The medium samples were removed after exact incubation time and the reaction is stopped by trichloroacetic acid (TCA). The samples were analyzed by HPLC-coupled flow scintillation analysis.
For each enzyme type, the HSD-inhibiting activity of an individual test compound was calculated by comparing the conversion of a control sample without any test compound (re- ferred to as "Negative Control") to the (reduced) conversion of the test sample containing the particular compound to be tested (referred to as "Test Sample").
Conversion in Negative Control - Conversion in Test Sample % inhibition = 100 * Conversion Negative Control
The obtained results are shown in Table 3 below. Two concentrations of each compound were used. The number of the compound refers to the numbers indicated in the Experimental Section.
Table 3: % Inhibition of the 17β-HSD enzymes type 1 , type 2 and type 3 by the compounds of the invention
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
2. Estrogen Receptor Binding Assay
The binding affinity of the compounds of the invention to the estrogen receptor α and to the estrogen receptor β may be determined according to the in vitro ER binding assays described by Koffmann et al. [Koffmann B et al. (1991) J. Steroid. Biochem . Mol . Biol . 38:135]. Alternatively, an estrogen receptor binding assay may be performed according to international patent application PCT/US/17799 (published as WO 00/07996).
3. Estrogen Receptor Transactivation Assays
Compounds of the invention showing binding affinity towards the estrogen receptor may be further tested with regard to their individual estrogenic or anti-estrogenic potential (agonistic binding or antagonistic binding to the ERα or ERβ). The determination of the estrogen receptor agonist activity may be performed according to an in vitro assay system using the MMTV-ERE- LUC reporter system which is for example described within US patent application No. 10/289079 (published as US 2003/0170292):
To assay estrogen receptor agonist activity, Hela cells are grown in 24-well microtiter plates and then transiently co-transfected with two plasmids using lipofectamine. The first plasmid comprises DNA encoding human estrogen receptor (either ER-alpha or ER-beta), and the second plasmid comprises an estrogen-driven reporter system comprising: a luciferase reporter gene (LUC) whose transcription is under the control of upstream regulatory elements comprising 4 copies of the vitellogenin estrogen response element (ERE) cloned into the mouse mammary tumor virus (MMTV) promoter (the full name for the reporter system being "MMTV- ERE-LUC"). Cells are exposed to the compounds of the invention in RPMI 1640 medium, supplemented with 10% charcoal-treated fetal calf serum, 2 mM L-glutamine, 0.1 mM non-essential amino acids and 1 mM sodium pyruvate for 42-48 hours at 37°C in a 5% carbon dioxide incuba- tor. Concurrently, cells exposed to estradiol (1 nM) serve as positive controls. Replicate wells exposed to the solvent in which the compounds of the invention are dissolved (i.e. ethanol or methanol) are used as negative controls. After the 42-48 hr incubation period, cells are rinsed with phosphate buffered saline (PBS), lysis buffer (Promega Corp) is added, and cell lysates are collected for measurement of luciferase activity with a luminometer. Estrogenic activity of the compounds of the invention is expressed as fold-increase in luciferase activity as compared to that observed in negative control cells.
Alternatively, the determination of the estrogen receptor transactivation activity (estrogenicity assay or agonist assay) and of the inhibitory potency of transactivation activity (anti- estrogenicity assay or antagonist assay) may be performed according to international patent application PCT/US/17799 (published as WO 00/07996).
CITED LITERATURE
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• Labrie F et al. (1997) "The key role of 17 beta-hydroxysteroid dehydrogenases in sex steroid biology." Steroids, 62:148-58 • Tamaya et al. (1985) "Comparison of cellular levels of steroid receptors in uterine leio- myoma and myometrium." Acta Obstet Gynecol Scand., 64:307-9
• Poirier D. (2003) "Inhibitors of 17 beta-hydroxysteroid dehydrogenases" Curr Med Chem. 10:453-77
• Geissler WM et al. (1994) "Male pseudohermaphroditism caused by mutations of testicular 17beta-hydroxysteroid dehydrogenase 3." Nat Genet., 7:34-9.
• Oefelein MG & Cornum R (2000) "Failure to achieve castrate levels of testosterone during luteinizing hormone releasing hormone agonist therapy: the case for monitoring serum testosterone and a treatment decision algorithm." J Urol.; 164:726-9.
• WO 01/42181 • WO 98/32724
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• WO 99/12540 • Andersson S. (1995) ..Molecular genetics of androgenic 17β-Hydroxysteroid Dehydrogenases. J. Steroid Biochem. Molec. Biol., 55:533-534].
• Dong Y et al. (1998) "17β-hydroxysteroid dehydrogenases in human bone cells" J. Bone Min. Res., 13:1539-1546 • WO 02/26706 . JP48042271B
• US 5,597,823
• JP62132884
• Manhas MS, Sharma SD, Amin SG. (1972) "Heterocyclic compounds. 4. Synthesis and antiinflammatory activity of some substituted thienopyrimidinones." J Med Chem. 15(1): 106-7.
• Gadad AK, Kapsi SG, Anegundi Rl, Pattan SR, Mahajanshetti CS, Shishoo CJ. (1996) "Synthesis and antihyperlipaemic activity of some 2-aminomethyl-3-aryl-5,6,7,8- tetrahydrobenzo(b) / 5,6-dimethylthieno (2,3-d)-pyrimidin-4-ones." Arzneimittelforschung. 46(10):981-5.
• Manjunath KS, Mohan S, Naragund LV, Shishoo CJ. (1997) "Synthesis and evaluation of 2-chloromethyl-3-N-substituted arylthieno(2,3-d)pyrimidin-4-ones and derivatives for central nervous system depressant activity." Arzneimittelforschung. 47(9):1005-8.
• Kapustina, M.V., Kharizomenova, I A, Shvedov, V.I., (1991) Chem. Heterocycl. Compd. (Engl. Trans.) 425.
• Koeller S & Lellouche JP (1999) "Preparation of Formate Esters from O-TBDMS/O-TES Protected Alcohols. A One-Step Conversion Using the Vilsmeier-Haack Complex POCI3/DMF" Tetrahedron Letters 40(38):7043-7046.
• Kapustina, M.V, Nikolaeva, I.S., Kharizomenova, I A, Shvedov, V.I., Pushkina, T.V., Fomina, A. N. (1992) Pharm. Chem. J. 789.
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• Perrissin M, Due CL, Narcisse G, Bakri-Logeais F, Huguet F (1980) "Tetrahydro-4,5,6,7 benzo-[b] et tetrahydro-5,6,7,8 (4H)-cyclohepta[b]thiophene; Eur. J. Med. Chem. Chim. Ther. 15:413-418.
• Kharizomenova A, Kapustina MV, Grinev AN, Sheinker YN, Alekseeva LM, Kuleshova EF (1984) "Synthesis and structure of derivatives of 7-oxo-4,5,6,7-tetrahydrobenzo [b]- thiophene and 7-hydroxy [bjthiophene" Chem. Heterocycl. Compd. (Engl. Transl.) 20:1339- 1342. • Kapustina MV, Kharizomenova A, Shvedov VI, Fomina AN, Nikolaeva IS, Golovanova EM, Bogdanova GA , Alekseeva LM (1990) "Synthesis and antiviral activity of 7-oxo- and 7- hydroxy-4,5,6,7-tetrahydrobenzo[b]-thiophene derivatives" Chem. Heterocycl. Compd. (Engl. Transl.) 24:1269-271. Samanta SS, Ghosh SC, De A (1997) "Studies in sulfur heterocycles. Part 12.1 Use of 5,6- dihydrobenzo[b]thiophen-7(4H)-one in the synthesis of condensed sulfur heterocycles" J. Chem. Soc; Perkin Trans. I, 3673-3677.
Koffman B, Modarress KJ, Beckerman T, Bashirelahi N. (1991) "Evidence for involvement of tyrosine in estradiol binding by rat uterus estrogen receptor." J Steroid Biochem Mol Biol. 38(2): 135-9. WO 00/07996 US 2003/0170292

Claims

1. Use of a compound of formula (I)
Figure imgf000137_0001
wherein
X is S, SO or S02
R1 and R2 are individually selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloheteroalkyl, substituted cycloheteroalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloheteroalkyl-alkyl, substituted cycloheteroalkyl-alkyl, or R2 itself may be independently selected from acyl, carboxyl, or amido, whereby R1 and R2 cannot be simultaneously unsubstituted alkyl,
the hydrocarbon chain -C(R3)-C(R4)-C(R5)-C(R6)- of the six-membered ring is saturated or contains one or two double bonds between the carbon atoms;
R3 and R4 are individually selected from the group consisting of hydrogen, oxo, halogen or dihalogen, acyl, alkyl, substituted alkyl, hydroxyl, carboxyl, amido, amino, nitrile, thio, alkoxy, acyloxy, aryloxy, alkylthio and arylthio;
R5 represents hydrogen, and
R6 is hydrogen or halogen,
for the manufacture of a medicament for the treatment and/or prevention of a steroid hormone dependent disease or disorder, preferably for a steroid hormone dependent disease or disorder requiring the inhibition of a 17β-hydroxysteroid dehydrogenase (17β-HSD) enzyme, most pref- erably requiring the inhibition of the 17β-HSD type 1, 17β-HSD type 2 or 17β-HSD type 3 enzyme.
2. Use of a compound of formula (I) according to claim 1 , wherein
R1 and R2 are individually selected from the group consisting of -Cι-C12-alkyl, which alkyl can be linear, cyclic, branched or partially unsaturated, and which can be optionally substituted with up to three substituents individually selected from the group consisting of hydroxyl, CrCι2-alkoxy, thiol, Cι-C12-alkylthio, aryloxy, aryla- cyl, -CO-OR, -O-CO-R, heteroaryl-acyloxy, and -N(R)2; whereby said aryl group is phenyl or naphthyl, and can be optionally substituted with up to three halogen; whereby said heteroaryl group is thienyl, furyl or pyridinyl aryl and
Figure imgf000138_0001
which aryl is selected from the group consisting of phenyl, biphenyl, naphthyl, indanyl, indenyl and fluorenyl, whereby the alkyl moiety can be optionally substituted with one or two hydroxyl groups, and whereby the aryl moiety can be optionally substituted with up to five substituents individually selected from the group consisting of halogen, hydroxyl, Cι-C|2- alkoxy, nitro, nitrile, Cι-C12-alkyl, halogenated Cι-Cι2-alkyl, -S02-N(R)2, and d-C^-alkylsulphonyl; or which aryl may be optionally substituted by two groups which are attached to ad- jacent carbon atoms and are combined into a saturated cyclic 5, 6 or 7 membered ring system, optionally containing up to three heteroatoms, such as N or O, the number of N atoms being 0-3 and the number of O atoms each being 0-2, whereby the cyclic ring system may optionally be further substituted by an oxo group; heteroaryl and heteroaryl-CrC^-alkyl, which heteroaryl is selected from the group consisting of pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, benzoimidazolyl, 1,3- dihydro-benzoimidazolyl, benzofuran, and benzo[b]thiophene, whereby the heteroaryl group can be optionally substituted with up to three substituents individually selected from the group consisting of halogen, C C12- alkyl, halogenated d-Ca-alkyl, -CO-OR, aryl or aryloxy, whereby the aryl group is selected from phenyl or naphthyl and can be optionally substituted with up to three halogen atoms; cycloheteroalkyl and cycloheteroalkyl-CrCa-alkyl, which cycloheteroalkyl moiety is selected from the group consisting of piperidinyl, pyrrolidinyl, tetrahydrofuryl, dioxolyl, morpholinyl, tetrahydrothiophenyl, tetrahydropyridinyl, azetidinyl, thiazolidinyl, oxazolidinyl, thiomor- pholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, thiazepanyl, dihydro-1H-pyrrolyl, and 1,3-dihydro-benzoimidazolyl, whereby the cycloheteroalkyl moiety can be optionally substituted with up to two substituents individually selected from the group consisting of oxo, C C12-alkyl, hydroxyl, Cι-C12-aIkoxy and aryl-Cι-Cι2-alkyl;
or R2 itself may be independently selected from -CO-R, -CO-O-R, or -CO-N(R)2;
R3 and R4 are individually selected from the group consisting of hydrogen, oxo, thio, halogen or dihalogen, -CO-R, preferably CHO, -CO-O-R, nitrile, -CO-N(R)2, -O-CO-R, -O-R, -S-R, -N(R)2, -Ci-Gu-alkyl, which alkyl can be linear, cyclic, branched or partially unsaturated, and which alkyl can be optionally substituted with up to three substituents individually selected from the group consisting of hydroxyl, C Cι2-alkoxy, thiol, and -N(R)2;
wherein R represents hydrogen, C C12-alkyl, phenyl-C-i-C4-alkyl or phenyl, optionally substituted in the phenyl moiety with up to three substituents selected from the group consisting of halogen, hydroxyl, and C|-C4-alkoxy, preferably methoxy.
3. A compound of formula (I)
Figure imgf000139_0001
wherein
X is S, SO or S02
R1 and R2 are individually selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloheteroalkyl, substituted cyclohet- eroalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloheteroalkyl-alkyl, substituted cycloheteroalkyl-alkyl, or R2 itself may be independently selected from acyl, carboxyl, or amido, whereby R1 and R2 cannot be simultaneously unsubstituted alkyl, and whereby R2 has to be different from methyl if all substituents R3, R5 and R6 simultaneously represent hydrogen and R4 represents hydrogen or methyl; R3 and R4 are individually selected from the group consisting of hydrogen, oxo, halogen or dihalogen, acyl, alkyl, substituted alkyl, hydroxyl, carboxyl, amido, amino, nitrile, thio, alkoxy, acyloxy, aryloxy, alkylthio and arylthio;
R5 represents hydrogen,
R6 is hydrogen or halogen, and
the hydrocarbon chain -C(R3)-C(R4)-C(R5)-C(R6)- of the six-membered ring is saturated or contains one or two double bonds between the carbon atoms; whereby the six-membered ring comprising the hydrocarbon chain -C(R3)-C(R4)-C(R5)-C(R6)- has to be an aromatic ring if all the substituents R3, R4, R5 and R6 are simultaneously hydrogen;
for use in therapy.
4. A compound of formula (I) for use in therapy according to claim 3, wherein
R1 and R2 are individually selected from the group consisting of -Cι-Ci2-alkyl, which alkyl can be linear, cyclic, branched or partially unsaturated, and which can be optionally substituted with up to three substituents individually selected from the group consisting of hydroxyl, CrCι2-alkoxy, thiol, C^C^-alkylthio, aryloxy, aryla- cyl, -CO-OR, -O-CO-R, heteroaryl-acyloxy, and -N(R)2; whereby said aryl group is phenyl or naphthyl, and can be optionally substituted with up to three halogen; whereby said heteroaryl group is thienyl, furyl or pyridinyl aryl and
Figure imgf000140_0001
which aryl is selected from the group consisting of phenyl, biphenyl, naphthyl, indanyl, indenyl and fluorenyl, whereby the alkyl moiety can be optionally substituted with one or two hydroxyl groups, and whereby the aryl moiety can be optionally substituted with up to five substituents individually selected from the group consisting of halogen, hydroxyl, C C12- alkoxy, nitro, nitrile, Cι-C1 -alkyl, halogenated C1-C12-alkyl, -Sθ2-N(R)2, C Ci2-alkylsulphonyl; or which aryl may be optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated cyclic 5, 6 or 7 membered ring system, optionally containing up to three heteroatoms, such as N or O, the number of N atoms being 0-3 and the number of O atoms each being 0-2, 140
whereby the cyclic ring system may optionally be further substituted by an oxo group; heteroaryl and heteroaryl-Cι-C12-alkyl, which heteroaryl is selected frqm the group consisting of pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolyl, oxazυ»,yl, isoxazolyl, pyrazolyl, 5 pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl^ benzoimidazolyl, 1 ,3- dihydro-benzoimidazolyl, benzofuran, and benzo[b]thiophene, whereby the heteroaryl group can be optionally substituteα w;ιth up to three sub- stituents individually selected from the group consisting of halogen, Cι-C12- alkyl, halogenated CrCβ-alkyl, -CO-OR, aryl or aryloxy, 10 whereby the aryl group is selected from phenyl or naphthyl and can be optionally substituted with up to three halogen atoms; cycloheteroalkyl and cycloheteroalkyl-CrC8-alkyl, which cycloheteroalkyl moiety is selected^ from the group consisting of piperidinyl, pyrrolidinyl, tetrahydrofuryl, dioxolyl, morpholinyl, tetrahydrothiophenyl, tetrahydropyridinyl, azetidinyl, thiazolidinyl, oxazolidinyl, thiomor- 15 pholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, thiazepanyl, dihydro-1 H-pyrrolyl, and 1,3-dihydro-benzoimidazolyl, whereby the cycloheteroalkyl moiety can be optionally substituted with up to two substituents individually selected from the group consisting of oxo, CrC12-alkyl, hydroxyl, CrC12-alkoxy and aryl-CrC^-alkyl; 20 or R2 itself may be independently selected from -CO-R, -CO-O-R, or -CO-N(R)2;
R3 and R4 are individually selected from the group consisting of hydrogen, oxo, thio, halogen or dihalogen, -CO-R, preferably CHO, -CO-O-R, nitrile, -CO-N(R)2, -O-CO-R, -O-R, -S-R, -N(R)2, -Cι-Cι2-alkyl, which alkyl can be linear, cyclic, branched or partially unsaturated, 25 and which alkyl can be optionally substituted with up to three substituents individually selected from the group consisting of hydroxyl, C C12-alkoxy, thiol, and -N(R)2; wherein R represents hydrogen, C C12-alkyl, phenyl-C-ι-C -alkyl or phenyl, optionally substituted in the phenyl moiety with up to three substituents selected from the group consisting 30 of halogen, hydroxyl, and Cι-C4-alkoxy, preferably methoxy.
5. A novel compound of formula (I)
Figure imgf000141_0001
wherein
X is S, SO or S02
R1 and R2 are individually selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloheteroalkyl, substituted cycloheteroalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloheteroalkyl-alkyl, substituted cycloheteroalkyl-alkyl, or R2 itself may be independently selected from acyl, carboxyl, or amido, whereby R1 and R2 cannot be simultaneously unsubstituted alkyl, and whereby R2 has to be different from methyl if all substituents R3, R5 and R6 simultaneously represent hydrogen and R4 represents hydrogen or methyl;
R3 and R4 are individually selected from the group consisting of hydrogen, oxo, halogen or dihalogen, acyl, alkyl, substituted alkyl, hydroxyl, carboxyl, amido, amino, nitrile, thio, alkoxy, acyloxy, aryloxy, alkylthio and arylthio;
R5 represents hydrogen,
R6 is hydrogen or halogen, and
the hydrocarbon chain -C(R3)-C(R4)-C(R5)-C(R6)- of the six-membered ring is saturated or contains one or two double bonds between the carbon atoms; whereby the six membered ring comprising the hydrocarbon chain -C(R3)-C(R4)-C(R5)-C(R6)- has to be an aromatic ring if all the substituents R3, R4, R5 and R6 are simultaneously hydrogen;
under the proviso that said compound is not (3-Benzyl-7-tert-butyl-4-oxo-3,4,5,6,7,8-hexahydro- benzo[4,5]thieno[2,3-d]pyrimidin-2-yl)-acetic acid methyl ester or 2,3-Dibenzyl-7-tert- butyl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one.
6. A compound of formula (I) for use in therapy according to claim 3, wherein
R1 and R2 are individually selected from the group consisting of -C Ci2-alkyl, which alkyl can be linear, cyclic, branched or partially unsaturated, and which can be optionally substituted with up to three substituents individually selected from the group consisting of hydroxyl, C,-Cι2-alkoxy, thiol,
Figure imgf000142_0001
aryloxy, aryla- cyl, -CO-OR, -O-CO-R, heteroaryl-acyloxy, and -N(R)2; whereby said aryl group is phenyl or naphthyl, and can be optionally substituted with up to three halogen; whereby said heteroaryl group is thienyl, furyl or pyridinyl aryl and aryl-CrCι2-alkyl, which aryl is selected from the group consisting of phenyl, biphenyl, naphthyl, indanyl, indenyl and fluorenyl, whereby the alkyl moiety can be optionally substituted with one or two hydroxyl groups, and whereby the aryl moiety can be optionally substituted with up to five substituents individually selected from the group consisting of halogen, hydroxyl, C C12- alkoxy, nitro, nitrile, Cι-C12-alkyl, halogenated d-C^-alkyl, -S02-N(R)2, C C12-alkylsulphonyl; or which aryl may be optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated cyclic 5, 6 or 7 membered ring system, optionally containing up to three heteroatoms, such as N or 0, the number of N atoms being 0-3 and the number of O atoms each being 0-2,/ whereby the cyclic ring system may optionally be further substituted by an oxo group; heteroaryl and heteroaryl-CrC12-alkyl, which heteroaryl is selected from the group consisting of pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, benzoimidazolyl, 1 ,3- dihydro-benzoimidazolyl, benzofuran, and benzo[b]thiophene, whereby the heteroaryl group can be optionally substituted with up to three substituents individually selected from the group consisting of halogen, C Cι2- alkyl, halogenated Cι-C8-alkyl, -CO-OR, aryl or aryloxy, whereby the aryl group is selected from phenyl or naphthyl and can be optionally substituted with up to three halogen atoms; cycloheteroalkyl and cycloheteroalkyl-C C8-alkyl, which cycloheteroalkyl moiety is selected from the group consisting of piperidinyl, pyrrolidinyl, tetrahydrofuryl, dioxolyl, morpholinyl, tetrahydrothiophenyl, tetrahydropyridinyl, azetidinyl, thiazolidinyl, oxazolidinyl, thiomor- pholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, thiazepanyl, dihydro-1 H-pyrrolyl, and 1,3-dihydro-benzoimidazolyl, whereby the cycloheteroalkyl moiety can be optionally substituted with up to two substituents individually selected from the group consisting of oxo, C C12-alkyl, hydroxyl, CτC12-alkoxy and aryl-CrCι2-alkyl;
or R2 itself may be independently selected from -CO-R, -CO-O-R, or -CO-N(R)2; R3 and R4 are individually selected from the group consisting of hydrogen, oxo, thio, halogen or dihalogen, -CO-R, preferably CHO, -CO-O-R, nitrile, -CO-N(R)2, -O-CO-R, -O-R, -S-R, -N(R)2, -Cι-Ci2-alkyl, which alkyl can be linear, cyclic, branched or partially unsaturated, and which alkyl can be optionally substituted with up to three substituents individually se- lected from the group consisting of hydroxyl, C C12-alkoxy, thiol, and -N(R)2;
wherein R represents hydrogen, CτC12-alkyl, phenyl-Cι-C4-alkyl or phenyl, optionally substituted in the phenyl moiety with up to three substituents selected from the group consisting of halogen, hydroxyl, and C C4-alkoxy, preferably methoxy.
7. A compound of formula (I) according to claim 5 or 6, wherein the six-membered ring comprising the hydrocarbon chain -C(R3)-C(R4)-C(R5)-C(R6)- is an aromatic ring.
8. A compound of formula (I) according to claim 5 or 6, wherein the six-membered ring comprising the hydrocarbon chain -C(R3)-C(R4)-C(R5)-C(R6)- is other than an aromatic ring and wherein at least one of the substituents R3 to R6 is different from hydrogen.
9. A compound of formula (I) according to any of the preceding claims 5 to 8, wherein R2 is selected from the group consisting of -Cι-C8-alkyl, which alkyl can be linear, cyclic, branched or partially unsaturated, and which can be optionally substituted with up to three substituents individually selected from the group consisting of hydroxyl, d-Qj-alkoxy, thiol, C C8-alkylthio, aryloxy, -CO-O- C C8-alkyl, and -O-CO-R'; whereby said aryl group is phenyl or naphthyl, and can be optionally substituted with up to three halogen; aryl and aryl-Cι-C8-alkyl, which aryl is selected from the group consisting of phenyl, biphenyl, naphthyl, indanyl, indenyl and fluorenyl, whereby the aryl moiety can be optionally substituted with up to five substituents individually selected from the group consisting of halogen, hydroxyl, Cι-C8-alkoxy, nitro, nitrile, halogenated C C8-alkyl, -S02-N(R')2, heteroaryl and heteroaryl-C C8-alkyl, which is selected from the group consisting of pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, benzoimidazolyl, 1,3-dihydro- benzoimidazolyl, benzofuran, and benzo[b]thiophene, whereby the heteroaryl group can be optionally substituted with up to three substituents individually selected from the group consisting of halogen, CrCβ-alkyl, halogenated CrCs-alkyl, aryl or aryloxy, whereby the aryl group is selected from phenyl or naphthyl and can be optionally substituted with up to three halogen atoms; -CO-R',
-CO-N(R')2, and -CO-O-R';
wherein R' represents hydrogen or Cι-C8-alkyl.
10. A compound of formula (I) according to claim 8, wherein R2 is i) a residue of formula (II)
Figure imgf000145_0001
wherein
R7 is hydrogen, halogen, hydroxyl or d-d-alkoxy, preferably methoxy,
R8 is hydrogen, d-d-alkoxy, preferably methoxy, hydroxyl, nitrile, halogen, or halogenated d- C4-alkyl, preferably trifluormethyl, R9 is hydrogen, d-C4-alkoxy, preferably methoxy, hydroxyl, nitrile, halogen, or N,N-di-C C4- alkyl-sulphonamide
R10 is hydrogen, d-C4-alkoxy, preferably methoxy, hydroxyl, nitrile, halogen, or halogenated d-C4-alkyl, preferably trifluormethyl R11 is hydrogen, halogen, hydroxyl or d-d-alkoxy, preferably methoxy
or ii)
-d-C8-alkyl, which alkyl can be linear, cyclic, branched or partially unsaturated; -d-C4-alkyl, substituted with one or two substituents selected from the group consisting of -CO-O-R"; -O-R"; -O-Ar, whereby Ar is phenyl optionally substituted with halogen; -O-CO-R", phenyl or biphenyl, optionally substituted in the phenyl moiety with up to three C C4- alkoxy, preferably methoxy, groups; -CO-O-R", -CO-R", preferably -CHO -naphthyl,
-heteroaryl which can be selected from the group consisting of thienyl, furyl, pyridinyl, ben- zothienyl, and pyrazoloyl, whereby the heteroaryl group can be optionally substituted by one or two substituents individually selected from the group consisting of halogen, d-d-alkyl, halogenated Cι-C -alkyl, preferably trifluormethyl, phenyl and phenoxy, whereby the phenyl group can be optionally substituted with up to three halogen;
wherein R" represents hydrogen or C C4-alkyl, preferably methyl or ethyl.
11. A compound of formula (I) according to claim 10, wherein R2 is selected from the group consisting of phenyl, methoxyphenyl, trimethoxyphenyl, trihydroxyphenyl, 3,5-dihydroxy-4- methoxyphenyl, 2-bromo-3,4,5-trimethoxyphenyl, 2-bromo-5-methoxyphenyl, 2-chloro-3,4,5- trimethoxyphenyl, cyanophenyl, fluorophenyl, di-trifluoromethylphenyl, difluorophenyl, dichloro- phenyl, 4-N,N-dipropylsulphonamide, methyl, cyclopropyl, cyclopentylethyl, 1-ethylpentyl, 2 - methylprop-1-enyl, propyl, benzyl, phenethyl, biphenylmethyl, dimethoxybenzyl, naphthyl, thienyl, furyl, pyridinyl, benzothienyl, bromothienyl, 1-phenyl-5-trifluoromethyl-4H-pyrazol-4-yl, 2- (4-Chloro-phenoxy)-pyridin-3-yl, hydroxymethyl, acetyl-oxymethyl, methoxymethyl, methoxy- acyl-methyl, ethoxy-acyl-methyl, ethoxy-acyl-ethyl, 1-(3-Chloro-phenoxy)-1 -methyl-ethyl, carbonyl, and methoxyacyl.
12. A compound of formula (I) according to claim 11, wherein R2 is methoxyphenyl, trimethoxyphenyl, 2-bromo-3,4,5-trimethoxyphenyl, 2-chloro-3,4,5-trimethoxyphenyl, thienyl, or propyl.
13. A compound of formula (I) according to any of the preceding claims 5 to 12, wherein R1 is selected from the group consisting of -Cι-C8-alkyl, which alkyl can be linear, cyclic, branched or partially unsaturated, and which can be optionally substituted with up to three substituents individually selected from the group consisting of hydroxyl, d-C8-alkoxy, thiol, -NH2, d-C8-alkylthio, aryloxy, arylacyl, -CO-0-d-C8-alkyl, Cι-C8-alkylacyloxy, heteroaryl-acyloxy, and d-d- alkylamino; whereby said aryl group is phenyl or naphthyl, and can be optionally substituted with up to three halogen; whereby said heteroaryl group is thienyl, furyl or pyridinyl, aryl and aryl-C C8-alkyl, which aryl moiety is selected from the group consisting of phenyl, biphenyl, naphthyl, indanyl, indenyl, and fluorenyl, wherein the alkyl moiety can be optionally substituted with one or two hydroxyl groups, and wherein the aryl moiety can be optionally substituted with up to five substituents individually selected from the group consisting of halogen, hydroxyl, Cι-C8-alkoxy, d-Cs-alkylsulphonyl, -Sθ2-N(C C8-alkyl)2, C C8-alkyl, halogenated C C8-alkyl; or which aryl may be optionally substituted by two groups which are attached to adjacent carbon atoms and are combined into a saturated cyclic 5 or 6 membered ring system, optionally containing up to three heteroatoms, such as N or O, the number of N atoms being 0-3 and the number of O atoms each being 0-2, whereby the cyclic ring system may optionally be further substituted by an oxo group; heteroaryl and heteroaryl-d-Ca-alkyl, which heteroaryl moiety is selected from the group consisting of quinolinyl, thiazolyl, pyrimidinyl, furyl, pyridinyl, thienyl, pyrrolyl, imidazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyrazinyl, indolyl, isoquinolinyl, benzoimida- zolyl, 1 ,3-dihydro-benzoimidazolyl, benzofuran, and benzo[b]thiophene, whereby the heteroaryl group can be optionally substituted with up to three substituents individually selected from the group consisting of halogen, Cι-C8-alkyl, and -CO-O- d-Ca-alkyl; cycloheteroalkyl and cycloheteroalkyl-d-C8-alkyl, which cycloheteroalkyl moiety is selected from the group consisting of piperidinyl, pyrrolidinyl, tetrahydrofuryl, dioxolyl, morpholinyl, tetrahydrothiophenyl, tetrahydropyridinyl, azetidinyl, thiazolidinyl, oxazolidinyl, thiomor- pholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, thiazepanyl, dihydro-1H-pyrrolyl, and 1,3-dihydro-benzoimidazolyl, whereby the cycloheteroalkyl moiety can be optionally substituted with up to two substituents individually selected from the group consisting of oxo, d-C8-alkyl, hydroxyl, d-d-alkoxy and aryl-Cι-C8-alkyl.
14. A compound of formula (I) according to claim 13, wherein R1 is selected from the group consisting of -Ci-Cs-alkyl, which alkyl can be linear, cyclic or branched,
-Cι-C -alkyl, substituted with one or two substituents independently selected from the group consisting of -O-R"; -O-Ar, -O-CO-HetAr, -CO-Ar, -CO-O-R", and -N(R")2, aryl and aryl-Cι-C4-alkyl, which aryl moiety is selected from the group consisting of phenyl, in- danyl, and fluorenyl, wherein the alkyl moiety can be optionally substituted with a hydroxyl group; and wherein the aryl moiety can be optionally substituted with up to three substituents individually selected from the group consisting of halogen, -O-R"; -S02-R", -S02- N(R")2, or which aryl may be optionally substituted by two groups which are attached to ad- jacent carbon atoms and are combined into a saturated cyclic 5 or 6 membered ring system, optionally containing up to two O atoms, whereby the cyclic ring system may optionally be further substituted by an oxo group; heteroaryl and heteroaryl-d-d-alkyl, which heteroaryl moiety is selected from the group consisting of quinolinyl, thiazolyl, pyrimidinyl, furyl, pyridinyl, pyrazinyl, and thienyl, whereby the heteroaryl group can be optionally substituted with one or two su b- stituents individually selected from the group consisting of halogen, -C C4-alkyl, and -CO-O-R"; cycloheteroalkyl and cycloheteroalkyl-C C4-alkyl, which cycloheteroalkyl moiety is selected from the group consisting of piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuryl, and dioxolyl, whereby the cycloheteroalkyl moiety can be optionally substituted with up to two substituents individually selected from the group consisting of oxo, Cι-C -alkyl, preferably methyl, and -Cι-C4-alkyl-Ar, preferably benzyl or phenethyl. wherein Ar represent phenyl, optionally substituted with halogen or methoxy, HetAr represents thienyl, furyl, pyridinyl, and R" represents hydrogen or Cι-d-alkyl, preferably methyl or ethyl.
15. A compound of formula (I) according to claim 14, wherein R1 is selected from the group consisting of cycloprop yl, butyl, isobutyl, 3-methylbutyl, cyclohexyl, benzyl, phenethyl, 2- hydroxy-2-phenyl-ethyl, methoxybenzyl, 5-bromo-2-methoxybenzyl, 5-bromo-2-hydroxybenzyl, 3,4-dichlorobenzyl, 3,4-dihydroxybenzyl, 4-methylsulfonylbenzyl, 4-aminosulfonylphenethyl, 2,3- dihydrobenzofuranyl, Benzo[1,3]dioxolyl, phenyl, fluorenyl, indanyl, 3-oxo-2,3-dihydro- benzofuranyl, quinolinyl, methyl-thiazolyl, 2-methoxyacyl-pyrazinyl, furylmethyl, pyridinylmethyl, thienylethyl, thienylmethyl, pyridinylethyl, bromo-furylmethyl, benzylpiperidinyl, morpholinylethyl, 2-oxo-pyrrolidinylpropyl, tetrahydrofurylmethyl, 2,2-dimethyl-[1,3]dioxolan-4-ylmethyl, hy- droxyethyl, methoxyethyl, 2-oxo-2-phenyl-ethyl, methoxy-acyl-propyl, phenoxyethyl, thiophene- 2-carboxylic acid ethyl ester, and dimethylaminoethyl.
16. A compound of formula (I) according to claim 15, wherein R1 is selected from the group consisting of isobutyl, 3-methylbutyl, benzyl, tetrahydrofurylmethyl, furylmethyl, 5-bromo-furan- 2-ylmethyl, 5-bromo-2-methoxybenzyl, thiophene-2-carboxylic acid ethyl ester, and methoxyethyl.
17. A compound of formula (I) according to any of the preceding claims 5 to 16, wherein R3 is selected from the group consisting of hydrogen, oxo, -O-R', -O-Ar, -O-CO-R', halogen, thio, -S-R', and -S-Ar, wherein R' represents hydrogen or d-d-alkyl, Ar represents phenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy or methoxy.
18. A compound of formula (I) according to claim 17, wherein R3 is selected from the group consisting of hydrogen, hydroxyl, oxo, chloro, bromo, phenoxy, phenylthio, d-C -alkoxy, d-d- alkylthio, and -0-CO-C C4-alkyl.
19. A compound of formula (I) according to claim 18, wherein R3 is selected from the group consisting of hydroxyl, oxo, -0-CO-CH3, and -S-ethyl.
20. A compound of formula (I) according to any of the preceding claims 5 to 19, wherein R4 is selected from the group consisting of hydrogen, d-C8-alkyl, optionally substituted with hydroxyl; -CO-R', -CO-O-R', halogen and dihalogen, wherein R' represents hydrogen or d-C8-alkyl.
21. A compound of formula (I) according to claim 20, wherein R4 is selected from the group consisting of hydrogen, carbonyl, ethoxyacyl, bromo, dibromo, chloro, dichloro, hydroxymethyl, and methyl.
22. A compound of formula (I) according to claim 21 , wherein R4 is selected from the group consisting of hydrogen, bromo and carbonyl.
23. A compound of formula (I) according to any of the preceding claims 5 to 22, wherein R6 is hydrogen.
24. A novel compound of formula (I) according to claim 6,
Figure imgf000149_0001
wherein
X is S, SO or S02
R1 is selected from the group consisting of: -Cι-C8-alkyl, which alkyl can be linear, cyclic or branched, -d-d-alkyl, substituted with one or two substituents independently selected from the group consisting of -O-R"; -O-Ar, -O-CO-HetAr, -CO-Ar, -CO-O-R", and -N(R")2l aryl and aryl-d-C -alkyl, which aryl moiety is selected from the group consisting of phenyl, in- danyl, and fluorenyl, wherein the alkyl moiety can be optionally substituted with one hydroxyl group; and wherein the aryl moiety can be optionally substituted with up to three substituents individually selected from the group consisting of halogen, -O-R"; -S02-R", - S02-N(R")2, or which aryl may be optionally substituted by two groups which are attached to ad- jacent carbon atoms and are combined into a saturated cyclic 5 or 6 membered ring system, optionally containing up to two O atoms, whereby the cyclic ring system may optionally be further substituted by an oxo group; heteroaryl and heteroaryl-d-C4-alkyl, which heteroaryl moiety is selected from the group con- sisting of quinolinyl, thiazolyl, pyrimidinyl, furyl, pyridinyl, pyrazinyl, and thienyl, whereby the heteroaryl group can be optionally substituted with one or two su b- stituents individually selected from the group consisting of halogen, -d-d- alkyl, and -CO-O-R"; cycloheteroalkyl and cycloheteroalkyl-Cι-C4-alkyl, which cycloheteroalkyl moiety is selected from the group consisting of piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuryl, and dioxolyl, whereby the cycloheteroalkyl moiety can be optionally substituted with up to two substituents individually selected from the group consisting of oxo, d-d-alkyl, preferably methyl, and -Cι-C4-alkyl-Ar, preferably benzyl or phenethyl;
R2 is selected from the group consisting of i) a residue of formula (II)
Figure imgf000150_0001
wherein
R7 is hydrogen, halogen, hydroxyl or C C4-alkoxy, preferably methoxy, R8 is hydrogen, d-d-alkoxy, preferably methoxy, hydroxyl, nitrile, halogen, or halogenated C C4-alkyl, preferably trifluormethyl, R9 is hydrogen, C C4-alkoxy, preferably methoxy, hydroxyl, nitrile, halogen, or N,N-di-C C4- alkyl-sulphonamide R10 is hydrogen, d-C4-alkoxy, preferably methoxy, hydroxyl, nitrile, halogen, or halogenated d-d-alkyl, preferably trifluormethyl R11 is hydrogen, halogen, hydroxyl or C C4-alkoxy, preferably methoxy
and ii)
-d-d-alkyl, which alkyl can be linear, cyclic, branched or partially unsaturated; -d-d-alkyl, substituted with one or two substituents selected from the group consisting of -CO-O-R"; -O-R"; -O-Ar, whereby Ar is phenyl optionally substituted with halogen; -O-CO-R", and -phenyl or biphenyl, optionally substituted in the phenyl moiety with up to three d-C4-alkoxy, preferably methoxy, groups; -CO-O-R",
-CO-R", preferably -CHO -naphthyl, and
-heteroaryl which can be selected from the group consisting of thienyl, furyl, pyridinyl, benzothienyl, and pyrazoloyl, whereby the heteroaryl group can be optionally substituted by one or two substituents individually selected from the group consisting of halogen, d-d-alkyl, na'o- genated Cι-C -alkyl, preferably trifluormethyl, phenyl and phenoxy, whereby the phenyl group can be optionally substituted with up to three halogen;
R3 is selected from the group consisting of hydrogen, oxo, -O-R", -O-Ar, -O-CO-R", halogen, thio, -S-R", and -S-Ar;
R4 is selected from the group consisting of hydrogen, d-C4-alkyl, optionally substituted with hydroxyl; -CO-R", -CO-O-R", halogen and dihalogen,
wherein Ar represent phenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy or methoxy, HetAr represents thienyl, furyl, pyridinyl, and R" represents hydrogen or d-C4-alkyl, preferably methyl or ethyl.
25. A novel compound of formula (I) according to claim 24, wherein
R1 is selected from the group consisting of: -C3-C8-alkyl, which alkyl can be linear, cyclic or branched, -d-d-alkyl, substituted with one or two substituents independently selected from the group consisting of d-C -alkoxy, hydroxyl, and -O-CO-HetAr, phenyl-d-d-alkyl, wherein the aryl moiety can be optionally substituted with up to three substituents individually selected from the group consisting of halogen, d-C4-alkoxy, and hydroxyl, heteroaryl-d-d-alkyl, which heteroaryl moiety is selected from the group consisting of pyrimid- inyl, furyl, pyridinyl, and thienyl, whereby the heteroaryl group can be optionally substituted with one or two su b- stituents individually selected from the group consisting of halogen, d-d-alkoxy, and hydroxyl, and cycloheteroalkyl-Ci-d-alkyl, which cycloheteroalkyl moiety is selected from the group consisting of tetrahydrofuryl, piperidinyl, morpholinyl, and pyrrolidinyl,
R2 is selected from the group consisting of i) a residue of formula (II)
Figure imgf000152_0001
wherein
R7 is hydrogen, bromo, chloro, orfluoro,
R8 is hydrogen, C1-C4-alkoxy, preferably methoxy, or hydroxyl,
R9 is hydrogen, d-C4-aIkoxy, preferably methoxy, or hydroxyl, R10 is hydrogen, Crd-alkoxy, preferably methoxy, or hydroxyl,
R11 is hydrogen,
and ii)
-d-d-alkyl, which alkyl can be linear, cyclic, or branched; optionally substituted with an -O- CO-(C C4)-alkyl or -CO-0-(d-C4)-alkyl group ;
-heteroaryl which can be selected from the group consisting of thienyl, furyl, pyridinyl, benzothienyl, and pyrazoloyl; R3 is selected from the group consisting of hydrogen, oxo, hydroxyl, C C4-alkoxy, -O-CO-d- d-alkyl, and d-d-alkylthio;
R4 is selected from the group consisting of hydrogen, halogen, carbonyl, -CO-C C4-alkyl, and
R6 is hydrogen or bromo.
26. A novel compound of formula (I) according to claim 25, wherein
R1 is selected from the group consisting of isobutyl, 3-methylbutyl, benzyl, tetrahydrofuryl- methyl, furylmethyl, 5-bromo-furan-2-ylmethyl, 5-bromo-2-methoxybenzyl, thiophene-2- carboxylic acid ethyl ester, and methoxyethyl; R2 is selected from the group consisting of methoxyphenyl, trimethoxyphenyl, 2-bromo-3,4,5- trimethoxyphenyl, 2-chloro-3,4,5-trimethoxyphenyl, thienyl, and propyl; R3 is selected from the group consisting of hydroxyl, oxo, -0-CO-CH3, and -S-ethyl; R4 is selected from the group consisting of hydrogen, bromo and carbonyl; and R6 is hydrogen or bromo.
27. A novel compound of formula (I) according to claim 25, wherein R1 is linear, cyclic or branched -C3-C8-alkyl, R2 is trimethoxyphenyl, 2-bromo-3,4,5-trimethoxyphenyl, or 2-chloro-3,4,5-trimethoxyphenyl,
R3 is hydrogen or hydroxyl,
R4 is hydrogen,
R6 is hydrogen or bromo, and wherein the six-membered ring comprising the hydrocarbon chain -C(R3)-C(R4)-C(R5)-C(R6)- is an aromatic ring.
28. A compound of formula (I) according to any of the preceeding claims 5 to 27, wherein X represents S.
29. A novel compound of formula (I) according to claim 6 selected from the group consisting of: 3-Benzyl-8-ethylsulfanyl-2-(p-methoxyphenyl)-4-oxo-3,4,5,6-tetrahydro-benzo[4,5]thieno[2,3- d]pyrimidine-7-carbaldehyde, 3-Benzyl-2-(p-methoxyphenyl)-4-oxo-3,4-dihydro-benzo[4,5]thieno[2,3-d]pyrimidine-7- carbaldehyde,
3-Benzyl-8-ethylsulfanyl-2-(p-methoxyphenyl)-4-oxo-3,4-dihydro-benzo[4,5]thieno[2,3- d]pyrimidine-7-carbaldehyde, 3-Benzyl-8-hydroxy-2-thiophen-2-yl-3H-benzo[4,5]thieno[2,3-d]pyrimidine-4-one, Thiophene-2-carboxylic acid -(8-hydroxy-4-oxo-2-thiohen-2-yl-4H-benzo[4,5]thieno[2,3- d]pyrimidin-3-yl)-ethyl ester, 3-Butyl-8-hydroxy-2-(3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one, 3-Benzyl-3-(5-bromo-2-methoxybenzyl)-8-hydroxy-2-propyl-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one, Acetic acid 3-benzyl-3-(5-bromo-2-methoxybenzyl)-4-oxo-2-propyl-3,4-dihydro- benzo[4,5]thieno[2,3-d]pyrimidin-8-yl ester, 3-(5-Bromofuran-2-ylmethyl)-8-hydroxy-2-propyl-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one, Acetic acid 3-(5-bromofuran-2-ylmethyl)-4-oxo-2-propyl-3,4-dihydro-benzo[4,5]thieno[2,3- d]pyrimidin-8-yl ester, 8-Hydroxy-3-isobutyl-2-(2-bromo-3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidin- 4-one, 3-BenzyI-2-(2-chloro-3,4,5-trimethoxyphenyl)-8-hydroxy-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4- one, 7-Bromo-3-(2-methylbutyl)-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione, 8-Hydroxy-3-(2-methylbutyl)-2-(3,4,5-trimethoxyphenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4- one, 5-Bromo-3-isobutyl-2-(3,4,5-trimethoxyphenyl)-6,7-dihydro-3H,5H-benzo[4,5]thieno[2,3- d]pyrimidine-4,8-dione,
2-(2-Chloro-3,4,5-trimethoxypheny))-8-hydroxy-3-(tetrahydrofuran-2-ylmethyl)-3H- benzo[4,5]thieno[2,3-d]pyrimidin-4-one, 2-(2-Chloro-3,4,5-trimethoxyphenyl)-8-hydroxy-3-(2-methylbutyl)-3H-benzo[4,5]thieno[2,3- d]pyrimidin-4-one, 7-Bromo-8-hydroxy-3-(2-methoxyethyl)-2-thiophen-2-yI-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4- one, 3-Butyl-8-hydroxy-2-(2-methoxy-phenyl)-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one, and 3-Butyl-2-(2,4-difluoro-phenyl)-8-hydroxy-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one, or a physiologically acceptable salt thereof.
30. A compound of formula (I) according to any of the preceding claims 5 to 29 for use in therapy.
31. Use of a compound of formula (I) as defined in any of the preceding claims 5 to 29 for the treatment or prevention of a steroid hormone dependent disease or disorder.
32. Use according to claim 31 , wherein the steroid hormone dependent disease or disorder is a disease or disorder requiring the inhibition of a 17β-hydroxysteroid dehydrogenase enzyme, preferably of the 17β-HSD type 1, 17β-HSD type 2 or 17β-HSD type 3.
33. Use of a compound of formula (I) as defined in any of the preceding claims 5 to 29 for th e manufacture of a medicament for the treatment and/or prevention of a steroid hormone dependent disease or disorder, preferably for a steroid hormone dependent disease or disorder requiring the inhibition of a 17β-hydroxysteroid dehydrogenase enzyme, most preferably of the 17β-HSD type 1 , 17β-HSD type 2 or 17β-HSD type 3 enzyme.
34. Use according to claim 32 or 33, wherein the steroid hormone dependent disease or disorder is selected from the group consisting of breast cancer, prostate carcinoma, ovarian caro- cer, uterine cancer, endometrial cancer and endometrial hyperplasia, endometriosis, uterine fibroids, uterine leiomyoma, adenomyosis, dysmenorrhea, menorrhagia, metrorrhagia, pros- tadynia, benign prostatic hyperplasia, prostatitis, acne, seborrhea, hirsutism, androgenic alopecia, precocious puberty, adrenal hyperplasia, polycystic ovarian syndrome, urinary dysfunction , osteoporosis, multiple sclerosis, rheumatoid arthritis, Alzheimer's disease, colon cancer, tissue wounds, skin wrinkles and cataracts.
35. A pharmaceutical composition comprising as active agent at least one of the compounds of formula (I) as defined in any of the preceding claims 5 to 29, and at least a pharmaceutically acceptable carrier.
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IL172316A0 (en) 2011-08-01
EP1635839A2 (en) 2006-03-22
RU2006100033A (en) 2007-07-20
RU2412190C2 (en) 2011-02-20
BRPI0411295A (en) 2006-08-01
AU2004277311B2 (en) 2010-04-29
AR044650A1 (en) 2005-09-21
EP1635839B1 (en) 2010-09-01
JP2006527226A (en) 2006-11-30
AU2004277311B8 (en) 2010-05-27
WO2005032527A3 (en) 2005-08-04
ES2352552T3 (en) 2011-02-21
AU2004277311A1 (en) 2005-04-14
SA04250159B1 (en) 2008-06-21
ATE479437T1 (en) 2010-09-15
MXPA05012745A (en) 2006-05-17
WO2005032527B1 (en) 2005-09-22
CN1791412A (en) 2006-06-21
DK1635839T3 (en) 2011-01-03
KR20060054189A (en) 2006-05-22
US20050038053A1 (en) 2005-02-17

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