RESUMO
Nomegestrol acetate (NOMAc) is a synthetic progesterone analog and classified as a fourth-generation progestin. It has been approved in many countries for oral contraception, hormonal replacement therapy (HRT), and treatment of various gynecological disorders. There are several synthetic routes reported for the synthesis of NOMAc and they all share the very similar last three to five steps toward the conversion of 6-methylene to 6-methyl-6,7-unsaturated structure. Therefore the final product from different processing routes may have similar impurity profiles. In the analysis of NOMAc, we identified two impurities, impurity A (listed in EP 8.0) and impurity B (not specified in EP 8.0). Both impurities were further confirmed by synthesis. In addition, both impurities and NOMAc were evaluated for their in vitro cytotoxicities against L02 liver cells, mesenchymal stem cells, MCF-7 breast cancer cells, and C33A cervical cancer cells. These three analogs are not cytotoxic to the four cell lines at low concentrations (<20 µM). NOMAc and impurity A showed cytotoxicity to L02, MCF-7, and C33A cells at high concentrations, while impurity B did not show significant cytotoxicity to any of the cell lines tested.
Assuntos
Antineoplásicos Hormonais/síntese química , Descoberta de Drogas/métodos , Megestrol/síntese química , Norpregnadienos/síntese química , Congêneres da Progesterona/síntese química , Antineoplásicos Hormonais/química , Antineoplásicos Hormonais/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Contaminação de Medicamentos , Humanos , Megestrol/química , Megestrol/farmacologia , Estrutura Molecular , Norpregnadienos/química , Norpregnadienos/farmacologia , Congêneres da Progesterona/química , Congêneres da Progesterona/farmacologiaRESUMO
A variety of novel 11beta-aryl-17,17-spiro[(4'H,5'-methylene)oxazol]-substituted steroids have been synthesized in moderate to good yields via copper-catalyzed cyclization of acylaminoacetylenes. The best result was obtained with a catalytic amount of CuI in 1:1 benzene-Et3N at 90 degrees C for 30 min (Ar = 3,4-difluorophenyl; R = ethyl; 97% yield).
Assuntos
Acetileno/química , Cobre/química , Oxazóis/química , Compostos de Espiro/síntese química , Esteroides/química , Acilação , Aminação , Catálise , Ciclização , Espectroscopia de Ressonância Magnética , Metilação , Estrutura Molecular , Congêneres da Progesterona/síntese química , Congêneres da Progesterona/química , Compostos de Espiro/química , Esteroides/síntese químicaRESUMO
Selective progesterone receptor modulators (SPRMs) represent a new class of progesterone receptor ligands that exert clinically relevant tissue-selective progesterone agonist, antagonist, partial, or mixed agonist/antagonist effects on various progesterone target tissues in an in vivo situation depending on the biological action studied. The SPRM asoprisnil is being studied in women with symptomatic uterine leiomyomata and endometriosis. Asoprisnil shows a high degree of uterine selectivity as compared to effects on ovulation or ovarian hormone secretion in humans. It induces amenorrhea and decreases leiomyoma volume in a dose-dependent manner in the presence of follicular phase estrogen concentrations. It also has endometrial antiproliferative effects. In pregnant animals, the myometrial, i.e. labor-inducing, effects of asoprisnil are blunted or absent. Studies in non-human primates played a key role during the preclinical development of selective progesterone receptor modulators. These studies provided the first evidence of uterus-selective effects of asoprisnil and structurally related compounds, and the rationale for clinical development of asoprisnil.
Assuntos
Avaliação Pré-Clínica de Medicamentos , Modelos Animais , Primatas/fisiologia , Congêneres da Progesterona/síntese química , Congêneres da Progesterona/uso terapêutico , Receptores de Progesterona/agonistas , Receptores de Progesterona/antagonistas & inibidores , Animais , Endométrio/efeitos dos fármacos , Estrenos/química , Estrenos/farmacologia , Feminino , Humanos , Leiomioma/tratamento farmacológico , Glândulas Mamárias Animais/efeitos dos fármacos , Modelos Biológicos , Modelos Moleculares , Especificidade de Órgãos , Oximas/química , Oximas/farmacologia , Congêneres da Progesterona/farmacologia , Receptores de Progesterona/metabolismo , Hemorragia Uterina/tratamento farmacológico , Neoplasias Uterinas/tratamento farmacológico , Útero/efeitos dos fármacosRESUMO
Gestodene acidic treatment afforded a single rearrangement product, namely 13-beta-ethyl-18,19-dinorpregna-4,14,16-trien-3,20-dione 3, which was originated through HCl-catalyzed Rupe rearrangement. Drospirenone acidic treatment yielded two epimeric lactones by addition of HCl to the 6beta,7beta-cyclopropane ring, namely 7beta-(chloromethyl)-15beta,16beta-methylene-3-oxo-17beta-pregn-4-ene-21,17-carbolactone 4 and 7beta-(chloromethyl)-15beta,16beta-methylene-3-oxo-17alpha-pregn-4-ene-21,17-carbolactone 5. The structure of the compounds was assessed by spectroscopic and crystallographic methods.
Assuntos
Androstenos/química , Norpregnenos/química , Congêneres da Progesterona/síntese química , Cristalografia por Raios X , Modelos Biológicos , Modelos Moleculares , Estrutura MolecularRESUMO
A series of 7(8 leads to 11 alpha)abeo steroids was synthesized by a modification of the previously described total synthesis of this class of compounds and evaluated for biological activity. In general, there was a marked reduction in the relative binding affinities of these compounds for the rabbit uterus estrogen and progestin receptor proteins. None of the compounds which were subjected to uterotropic, antiuterotropic, postcoital, progestational, antiprogestational, or antiandrogenic assays showed any significant activity.
PIP: Synthesis, antifertility activity, and protein binding afinity of 7(8 to 11alph) abeo-estranes and -pregnanes are described. There was a marked reduction in the relative binding affinities of these compounds for the rabbit uterus estrogen and progestin receptor proteins. None of the compounds subjected to uterotropic, antiuterotropic, postcoital, progestational, antiprogestational, or antiandrogenic assays revealed any marked activity.
Assuntos
Fertilidade/efeitos dos fármacos , Esteroides/síntese química , Animais , Ligação Competitiva , Congêneres do Estradiol/síntese química , Estranos/síntese química , Estranos/metabolismo , Estranos/farmacologia , Feminino , Técnicas In Vitro , Masculino , Pregnanos/síntese química , Pregnanos/metabolismo , Pregnanos/farmacologia , Congêneres da Progesterona/síntese química , Ligação Proteica , Coelhos , Ratos , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Relação Estrutura-Atividade , Congêneres da Testosterona/síntese química , Útero/efeitos dos fármacos , Útero/metabolismoRESUMO
Five putative iodinated progesterone receptor (PR) binding ligands were synthesized and evaluated as potential imaging agents for PR-positive human breast tumours. Two compounds (E- and Z-17-hydroxy-21-iodo-19-nor-17alpha-pregna-4,20-dien-3-one; E- and Z-IPG1) were previously described, but are re-evaluated. The other three were novel compounds: two nortestosterone analogues derived from ORG 3236 (E- and Z-13-ethyl-17-hydroxy-21-iodo-11-methylene-18,19-dinor-17alpha-pre gna-4,20-diene-3-one; E- and Z-IPG2) and one norprogesterone analogue derived from ORG 2058 (21-[4-iodophenoxy]-16alpha-ethyl-19-norpregn-4-ene-3, 20-dione; IPG3). The E-iodovinyl nortestosterone compounds were obtained by a new route of synthesis. Competitive binding studies were performed to determine their binding affinities for the PR in three types of tissue (human MCF-7 breast tumour cells and rat uterine and mammary tumour tissue) and for the androgen receptor (AR) in human MCF-7 breast tumour cells, as well as for the sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG) in human plasma. All four 17alpha-iodovinyl nortestosterone derivatives displayed high binding affinity for the human PR, that of Z-IPG1 and E- and Z-IPG2 being even higher than that of ORG2058. Their affinities for the rat PR were somewhat lower, especially those of both E-isomers. The affinity of IPG3 was lower for both the human and rat PR. The nortestosterone derivatives also showed AR binding, the relative binding affinities ranging from 4.3 to 17.0% as compared with 5alphaDHT. Additionally, neither of these steroids displayed any significant binding to either SHBG or CBG in human plasma. We conclude that the in vitro binding properties of all four 17alpha-iodovinyl nortestosterone derivatives warrant evaluation of the distribution characteristics of their 123I-labelled analogues to determine their usefulness as PR imaging agents.
Assuntos
Neoplasias da Mama/diagnóstico por imagem , Congêneres da Progesterona/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Receptores de Progesterona/metabolismo , Animais , Neoplasias da Mama/metabolismo , Cromatografia em Gel , Feminino , Humanos , Radioisótopos do Iodo , Ligantes , Espectroscopia de Ressonância Magnética , Nandrolona/análogos & derivados , Nandrolona/química , Nandrolona/metabolismo , Congêneres da Progesterona/síntese química , Compostos Radiofarmacêuticos/síntese química , Ratos , Tomografia Computadorizada de Emissão de Fóton Único , Células Tumorais CultivadasRESUMO
Newer, nonsteroidal, orally active, tissue-selective progestins are being developed through a molecular approach to compound selection with human progesterone receptor (hPR) serving as the molecular target. The co-transfection and binding assays are used to test receptor selectivity and cross reactivity with a panel of receptors. Transcriptional products are used to further profile new progestin compounds. Desirable new progestins will suppress estrogen-induced endometrial stimulation, show no or minimal proliferative activity, maintain pregnancy, inhibit ovulation, contain no androgenic, mineralocorticoid or glucocorticoid activity, and possess minimal adverse physiologic effects. Newer progestins that possess many of these desirable properties are in development.
Assuntos
Desenho de Fármacos , Congêneres da Progesterona/síntese química , Congêneres da Progesterona/uso terapêutico , Feminino , Humanos , Gravidez , Congêneres da Progesterona/efeitos adversos , Receptores de Progesterona/efeitos dos fármacos , Receptores de Progesterona/fisiologiaRESUMO
The synthesis of 17-ethynyl-11-oxatestosterone, both from 11-oxa-5 alpha-pregnane-3,20-dione and, via a 3,17-dioxygenated 9-oxo 9,12-seco 11-nor 5 alpha-androstane-12-oic ester, from 3 beta-acetoxy-17-hydroxy-5 alpha-pregnan-12-one--two products available from hecogenin--is reported. The new hormone analogue shows significant progestational activity in the Clauberg test and relatively weak activity in a post-coital antifertility assay.
Assuntos
Congêneres da Progesterona/síntese química , Esteroides Heterocíclicos/síntese química , Testosterona/análogos & derivados , Testosterona/síntese químicaRESUMO
16-Methylene-17 alpha-hydroxy-19-norpregn-4-ene-3,20-dione 1 and its 17 alpha-acylated derivatives were synthesized. The length of the 17 alpha-side-chain ranges from C2-C6. As anticipated, compound 1 did not show any progestational activity or receptor binding activity; whereas, the acylated compounds, especially the butyrate, showed remarkable ability to bind to progesterone receptors. These compounds also showed progestational activity in an in vitro T47D cell culture assay in which progestins increase alkaline phosphatase activity and in an in vivo ovulation inhibition assay. All of the compounds synthesized were without estrogenic activities. The results showed that acylation of 16-methylene-17 alpha-hydroxy-19-norprogesterone can increase progestational activity. The progestational activities of these compounds varied with the 17 alpha-side chain.
Assuntos
Anticoncepcionais Femininos/síntese química , Norprogesteronas/síntese química , Congêneres da Progesterona/síntese química , Animais , Feminino , Humanos , Norprogesteronas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Progesterona/metabolismoRESUMO
16 alpha-Ethyl-21-hydroxy-19-norpregn-4-ene-3,20-dione (ORG 2058) is a ligand widely used in progesterone receptor assays. An improved synthesis of the compound is reported, starting from norethisterone acetate. The preparation of the tritiated radioligand [3H]ORG 2058 is also described.
Assuntos
Marcação por Isótopo , Pregnenodionas/síntese química , Congêneres da Progesterona/síntese química , Trítio , Estrutura Molecular , Noretindrona/análogos & derivados , Noretindrona/química , Acetato de NoretindronaRESUMO
Using the strategy based on the Hansch method which analyses effects of substituents on biological activity in terms of their hydrophobic, electronic and steric effects we selectively synthesised a series of 11beta-substituted-17alpha-ethynyl-4-estren-17beta-ols that combine ease of synthesis with good discrimination between these factors aiming at finding the compounds with optimum biological activity in that series. The compounds were tested quantitatively in the Clauberg test (rabbit) and the ovulation inhibition test (rat). The differences in biological activity could reasonably be correlated with two steric effects introduced by the 11beta-substituent. These were a change in the overall shape of the 11beta-substituent and the angular methyl group, and direct steric hindrance of the steroid-receptor protein binding. Some exceptions were found possibly due to metabolic conversion of these compounds to the corresponding 11beta-substituted-17alpha-ethynyl-1,3,5(10)-estra-triene-3,17beta-diols.
Assuntos
Linestrenol/análogos & derivados , Ovulação/efeitos dos fármacos , Congêneres da Progesterona/síntese química , Animais , Feminino , Linestrenol/síntese química , Linestrenol/farmacologia , Espectroscopia de Ressonância Magnética , Conformação Molecular , Rotação Ocular , Coelhos , Ratos , Análise de Regressão , Relação Estrutura-AtividadeRESUMO
The progestational activity of second- and third-generation progestins in oral contraceptives were markedly increased by addition of an 18-methyl group. A new progestin, the 18-methyl analog of Nestorone, 16-methylene-17alpha-hydroxy-18-methyl-19-norpregn-4-ene-3,2 0-dione acetate (10), was synthesized. The relative binding affinity and biologic activity of 10 was compared with Nestorone, levonorgestrel, and progesterone using a binding assay for rat progesterone receptors, the Clauberg assay in the rabbit, and by assessing pregnancy maintenance in the rat. These studies, as summarized in Table 4, show that 10 is three to ten times more potent than Nestorone. The addition of the 18-methyl group to Nestorone markedly increased its potency as noted above, but is unlikely to change its rate of delivery from sustained release systems. 10 should be ideally suited for administration by implants or small skin patches.
Assuntos
Norprogesteronas/síntese química , Norprogesteronas/farmacologia , Animais , Bioensaio , Anticoncepcionais Femininos/farmacologia , Relação Dose-Resposta a Droga , Endométrio/efeitos dos fármacos , Feminino , Levanogestrel/farmacologia , Masculino , Gravidez , Manutenção da Gravidez/efeitos dos fármacos , Progesterona/análogos & derivados , Progesterona/farmacologia , Congêneres da Progesterona/síntese química , Congêneres da Progesterona/farmacologia , Coelhos , Ratos , Ratos Sprague-DawleyRESUMO
A new apolar impurity (3,17 alpha-diethinyl-13-ethyl-3,5-gonadiene-17-ol, IIb) was detected and identified in norgestrel with the aid of thin-layer and high-performance chromatography and spectroscopic techniques. IIb is the product of the acid-catalysed dehydration of an overethinylated side product (Ib) of the ethinylation step in the synthesis of norgestrel. IIb can be determined by thin-layer densitometry and high-performance liquid chromatography. Another impurity (17 alpha-ethinyl-13-ethyl-4-gonene-17-ol, IV), originating from a side product of the Birch reduction step in the synthesis of norgestrel was also detected and identified. The spot of IV overlaps with that of IIb in the TLC system of USP XXIII but can be separated and quantification by more selective TLC systems and by gas chromatography.
Assuntos
Anticoncepcionais Orais Sintéticos/isolamento & purificação , Norgestrel/isolamento & purificação , Congêneres da Progesterona/isolamento & purificação , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Fina , Anticoncepcionais Orais Sintéticos/síntese química , Norgestrel/análogos & derivados , Norgestrel/síntese química , Congêneres da Progesterona/síntese química , Análise EspectralRESUMO
PIP: The more than 145 pharmacologically different oral contraceptive (OC) products available throughout the world are based on a wide range of synthetic estrogens and progestogens. The active substance of all the estrogens is ethinyl estradiol, to which the other compounds are metabolized. Attempts to use natural estrogens have been unsuccessful. The more numerous synthetic progestogens are of 3 main types: pregnanes, used in OCs only in Eastern Europe and the People's Republic of China, and gonanes and estranes which are used worldwide. In the US only 2 estrogens are available, ethinyl estradiol (EE) and mestranol, which rapidly metabolizes to EE. The pharamacologic literature on the 2 is confusing, but the compound of 1st choice on theoretical grounds is EE, which is used by all the manufacturers of low-dose OCs. The choice of progestogens is between several estranes and 1 gonane, norgestrel, a totally synthetic steroid, unlike the estranes, which are commonly manufactured by chemical alteration of the plant steroid diosgenin. The original synthesis of norgestrel produces a racemate: an equal mixture of 2 enantiomers (2 molecules with identical composition but mirror images of each other). The naming of the enantiomers has caused much confusion. All the hormonal activity of norgestrel resides in the enantiomer named levonorgestrel by the World Health Organization but also correctly called d-norgestrel or d(-)-norgestrel by chemists. Although levonorgestrel replaced racemic norgestrel in OCs worldwide at least 5 years ago, it is only now being introduced in the US. OCs should be chosen according to the essential pharmacologic princple of exposing a person to the lowest effective dose of the drug. 3 obvious criteria for selecting among OCs are contraceptive efficacy, cycle control, and systemic risk effects and safety. A low dose OC should be chosen for general use whenever possible. The contraceptive efficacy of low-dose levongestrel/ethinyl estradiol is very high, cycle control is good and improves after the initial cycles, and laboratory tests have disclosed minimal systemic effects.^ieng
Assuntos
Anticoncepcionais Orais Sintéticos/administração & dosagem , Anticoncepcionais Orais/administração & dosagem , Congêneres do Estradiol/administração & dosagem , Congêneres da Progesterona/administração & dosagem , Anticoncepcionais Orais Sintéticos/efeitos adversos , Anticoncepcionais Orais Sintéticos/síntese química , Congêneres do Estradiol/efeitos adversos , Congêneres do Estradiol/síntese química , Feminino , Humanos , Congêneres da Progesterona/efeitos adversos , Congêneres da Progesterona/síntese química , EstereoisomerismoRESUMO
Highly enantioselective and very short syntheses of the bioactive forms of estrone (3) and desogestrel (4) are described using a chiral oxazaborolidinium catalyst (2) in the key initial step. Enantiomerically pure estrone was synthesized in eight steps from the readily available starting materials diene 5 and alpha,beta-enal 6 via intermediates 8 and 9. Desogestrel was synthesized using a similar strategy from diene 5 and alpha,beta-enal 11 via intermediates 12-17. The efficient syntheses of the chiral catalyst 2 and its enantiomer are also presented.
Assuntos
Desogestrel/síntese química , Estrona/síntese química , Congêneres da Progesterona/síntese química , Amino Álcoois/química , Catálise , Indicadores e Reagentes , EstereoisomerismoRESUMO
The synthesis of 17 alpha-CH2X-substituted 19-nortestosterone derivatives (X = halogen, CN, N3, OH, NH2 etc.) is described. Starting with 1,4-dihydroestradiol 3-methyl ether the 17 alpha-CH2X-17 beta-hydroxy-moiety was introduced via a 17 beta-spiroepoxide which could be cleaved with various nucleophilic agents giving the desired derivatives. In the McPhail assay with immature rabbits some of these substances showed good progestagenic activity on oral administration. The influence of structural modifications on the activity is discussed. The best effect is observed if an additional double bond is introduced in position 9(10). While the 19-nortestosterone derivative with X = CN has only an activity of about 20% of that of norethisterone acetate, the introduction of a second double bond leads to a compound (STS 557) which has an oral potency more than ten times as high as levonorgestrel.
Assuntos
Nandrolona/análogos & derivados , Congêneres da Progesterona/síntese química , Animais , Feminino , Nandrolona/síntese química , Nandrolona/farmacologia , Coelhos , Relação Estrutura-AtividadeRESUMO
For purification of the human uterine progesterone receptor, an affinity adsorbent was synthesized in which the specific ligand (16 alpha-ethyl-3-oxo-19nor-androst-4-ene 17 beta-carboxylic acid) was bound to derivatized celulose using a disulfide-group-containing spacer. The purified receptor protein, isolated by reductive cleavage of the disulfide bond, bound the synthetic gestagen R5020 with high affinity (Kd 12.2 nmol/l). The affinity gel was highly efficient. A 24000-fold purification of progesterone receptor with a recovery of 40% could be achieved in a single step within 6 h. By means of dodecyl sulphate/polyacrylamide gel electrophoresis two main polypeptides with molecular weights of about 43000 and 108000 could be demonstrated.
Assuntos
Pregnenodionas/síntese química , Congêneres da Progesterona/síntese química , Receptores de Progesterona/isolamento & purificação , Resinas Sintéticas/síntese química , Útero/metabolismo , Adsorção , Ligação Competitiva , Centrifugação com Gradiente de Concentração , Cromatografia de Afinidade/métodos , Citosol/metabolismo , Eletroforese em Gel de Poliacrilamida , Feminino , HumanosRESUMO
We have prepared and evaluated three metal conjugates of a progestin-monoamine-monoamide (MAMA') bisthiol chelate system. These conjugates of rhenium and technetium-99 and -99m, are structural analogs of the bisamino-bisthiol (BAT) conjugates we have described recently, but the MAMA' chelate, being more polar than the BAT system, gives a conjugate that is much less lipophilic, having an octanol-water partition coefficient that is nearly 80-fold lower. In competitive binding assays, the Re- and 99Tc-MAMA'-progestin conjugates bind to the progesterone receptor with affinities greater than that of progesterone itself, and in a direct binding assay, the equilibrium dissociation constant (Kd) of the 99mTc-MAMA' conjugate was 0.97 nM. As is typical for 11 beta-substituted progestins, these conjugates also have substantial binding affinity for glucocorticoid receptors. In tissue distribution studies in immature female rats, the progestin-99mTc-MAMA' conjugates show selective uptake for principal target tissue (such as uterus) over that of blood and nontarget tissue (such as muscle); these uptake ratios reach maximum levels of 5 and 4, respectively. Uptake by fat, liver, and kidney is quite high; however, only the uptake in uterus is displaceable upon coinjection of the selective progestin ORG2058. Metabolism studies show that the radioactivity in the uterus is essentially unmetabolized out to 4 h, while liver activity is completely due to metabolites. Other tissues show an intermediate fraction of unmetabolized conjugates that decreases with time. The in vivo behavior of the progestin-99mTc-MAMA' conjugate is similar to that of the labeled BAT conjugate: its uptake selectivity is somewhat greater than that of the BAT conjugate, but its target tissue uptake is lower. Factors that may be responsible for limiting the target tissue uptake properties of these conjugates are their moderate affinity for progesterone receptor, their substantial binding to glucorticoid receptors, and their large overall molecular size.