- A method of preparation he male amine
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The invention belongs to the field of pharmaceutical chemistry, and relates to a high-yield method for preparing dutasteride, which comprises the following steps: (1) under the action of a catalyst, reacting aza-5-androst-1-alkenyl-3-keto-17beta-carboxylic acid (I) with alcohol to generate 4-aza-5-androst-1-alkenyl-3-keto-17beta-carboxylate (II); and (2) in the presence of a catalyst, reacting the 4-aza-5-androst-1-alkenyl-3-keto-17beta-carboxylate (II) with 2,5-ditrifluoromethylaniline in an organic solvent at certain reaction temperature to obtain the dutasteride (III) at high yield. The method has the characteristics of accessible raw material, mild reaction conditions and high product yield, and is easy to control.
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Paragraph 0010-0011
(2018/09/26)
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- Method for forming double bonds between 1-position and 2-position during synthesis of finasteride and dutasteride
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The invention provides a method for forming double bonds between the 1-position and the 2-position during synthesis of finasteride and dutasteride. According to the process, a dihydrogen finasteride iodide and a dihydrogen dutasteride iodide are oxidized by oxone for systhesis of finasteride and dutasteride, and the method has the characteristics that reaction operation is simple and convenient, raw materials are low in price and easy to obtain, and the yield and the purity are high. In particular, oxone is non-toxic, stable, easy to operate and more suitable for large-scale industrial production, and reagents which are harmful to the environment and high in price are avoided. The method can be further applied to forming of double bonds between the 1-position and the 2-position of an intermediate in other finasteride and dutasteride processes. The invention further provides a synthesis method of dihydrogen dutasteride; according to the method, a corresponding ester raw material has a one-pot reaction with 2,5-bis(trifluoromethyl)aniline under the activation of boron tribromide, and dihydrogen dutasteride with the yield of 93% is obtained.
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Paragraph 0064; 0065; 0066
(2016/12/01)
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- PROCESS FOR PREPARING ANDROSTENONE DERIVATIVES
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Provided is a process for preparing androstenone derivatives, specifically 3-oxo-4-aza-5α-androstene-17β-carboxylic acid of Formula I, a key intermediate for dutasteride.
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Page/Page column 16
(2012/04/04)
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- METHOD OF PRODUCING 17BETA-(SUBSTITUTED)-3-OXO-DELTA 1,2-4-AZASTEROIDS AND INTERMEDIATES
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The 17β-(substituted)-3-oxo-Δ1,2-azasteroids (I), wherein R1 is C1-C4 alkyl, OR2, wherein R2 is a C1-C4 alkyl radical, or NR3R4 , wherein R3 and R4, equal or different, represent hydrogen or a C1-C4 alkyl radical, can be obtained by means of a process comprising cleaving the oxazolidinedione ring present in a 2-(substituted)-3-hydroxyoxazolidinedione of formula (IV), wherein R5 is Br or trichloromethylsulfonyl, and removing the substituent at position 2, to form a double bond at position 1,2. Some compounds (I) are testosterone-5α-reductase inhibitors and can be used in the treatment of hyperandrogenic disorders.
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- Method of prevention of prostatic carcinoma with 17β-N-monosubstituted-carbamoyl-4-aza-5α-androst-1-en-3-ones
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17β-N-monosubstituted-carbamoyl-4-aza-5α-androst-1-en-3-ones of the formula wherein R1is selected from hydrogen, methyl and ethyl and R2is a straight or branched chain alkyl, cycloalkyl, aralkyl of from 1-12 carbons, or monocyclic aryl optionally containing 1 or more lower alkyl substituents of 1-2 carbon atoms and/or 1 or more halogens, and R′, R″, R″′ are hydrogen or methyl are useful for the prevention of prostatic carcinoma.
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- Method of treatment for prostatic cancer
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Disclosed is a new treatment for men with prostatic cancer involving combination therapy of a 5α-reductase inhibitor, i.e., a 17β-substituted 4-azasteroid, a 17β-substituted non-azasteroid, 17β-acyl-3-carboxyandrost-3,5-diene, benzoylaminophenoxybutanoic acid derivative, fused benz(thio)amide or cinnamoylamide derivative, aromatic 1,2-diethers or thioethers, aromatic ortho acylaminophenoxy alkanoic acids, ortho thioalkylacylamino-phenoxy alkanoic acids, pharmaceutically acceptable salts and esters thereof, and particularly finasteride, in combination with an antiandrogen, i.e. flutamide. Pharmaceutical compositions useful for treatment are also disclosed.
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- Method of treatment for benign prostatic hyperplasia
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Disclosed is an improved treatment for men with benign prostatic hyperplasia (BPH), involving combination therapy of a 5α-reductase inhibitor, e.g. a 17β-substituted 4-azasteroid, a 17β-substituted non-azasteroid, 17β-acyl-3-carboxy-androst-3,5-diene, benzoylaminophenoxybutanoic acid derivative, fused benz(thio)amide or cinnamoylamide derivative, aromatic 1,2-diethers or thioethers, aromatic ortho acylaminophenoxy alkanoic acids, ortho thioalkylacylaminophenoxy alkanoic acids, pharmaceutically acceptable salts and esters thereof, and particularly finasteride, in combination with an α1 -adrenergic receptor blocker, i.e., terazosin. The combination provides therapy at the molecular level for the underlying cause of the disease as well as providing symptomatic relief. Pharmaceutical compositions useful for treatment are also disclosed.
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- Method of treatment of chronic prostatitis with 17β-N-monosubstituted-carbamoyl-4-aza-5α-androst-1-en-3-ones
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The present invention is concerned with the use of 17β-N-monosubstituted-carbamaoyl-4-aza-5α-androst-1-en-3-one compounds as testosterone-5α-reductase inhibitors for the treatment of chronic prostatitis.
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- Substituted 4-aza-5α-androstan-ones as 5α-reductase inhibitors
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Described are new 16-substituted and 7,16-disubstituted 4-aza-5α-androstan-3-ones and related compounds as 5α-reductase inhibitors.
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- 17B-N-Substituted adamantyl/norbonanyl carbamoyl-4-aza-5a-and-rost-1-en-3-ones and androstan-3 ones
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17 beta-N-substituted adamantyl/norbornanyl carbamoyl-4-aza-5alpha-androst-1-en-3-ones and androstan-3-ones as 5alpha-reductase inhibitors of the formula I
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- TRIALKYLSILYL TRIFLUOROMETHANESULFONATE MEDIATED ALPHA-METHYLENIC CARBON FUNCTIONALIZATION OF 4-AZA-5ALPHA-ANDROSTAN-3-ONE STEROIDS
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A novel single-pot trialkylsilyl trifluoromethanesulfonate (R3Si?OTf) mediated process produces derivatives of 4-aza 3-keto steroids at the alpha-methylenic carbon through electrophilic substitution. These derivatives are useful in the preparation, through elimination of the substituent on the alpha-methylene carbon, of delta-1 olefin 4-aza 3-keto steroids which are potent inhibitors of 5-alpha reductase.
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- SELECTED 17 BETA-POLYAROYL-4-AZA-5 ALPHA-ANDROST-1-EN-3-ONES AS STEROIDAL REDUCTASE INHIBITORS
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Selected 17?-Polyaroyl-4-aza-5a-androst-1-en-3-ones as steroidal reductase inhibitors of the formula: wherein R is selected from hydrogen, methyl and ethyl R 2 is polycyclic aromatic radical which can be substituted with one or more of: --OH, protected --
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- Specific 17β-thiobenzoyl-4-aza-5α-androst-1-en-3-ones as antiandrogen agents
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Specific 17β-thiobenzoyl-4-aza-5α-androst-1-en-3-ones as antiandrogenic agents of the formula: STR1 wherein R is selected from hydrogen, methyl and ethyl andR 2 is phenyl substituted with one or more of: --SH, --SC 1 --C 4 alkyl, --SO--C 1 --C 4 alkyl, --SO 2 --C 1 --C 4 alkyl, --SO 2 N--(C 1 -C 4 alkyl) 2, C 1 -C 4 alkyl, --(CH 2) m SH, --S(CH 2) n OCOCH 3, where m is 1-4, n is 1-3, and providing C 1 -C 4 alkyl is only present when one of the above sulfur-containing radicals is present, wherein the dotted line can represent a double bond, and pharmaceutically acceptable esters and salts thereof. Also included is a pharmaceutical formulation thereof. The above compounds are active as antiandrogenic agents and thus are useful topically for treatment of acne, seborrhea, female hirsutism, and systemically in treatment of benign prostatic hypertrophy.
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- 17beta hydroxybenzoyl-4-aza-5alpha-androst-1-en-3-ones as testosterone reductase inhibitors
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Novel 17beta-hydroxybenzoyl-4-aza-5alpha-androst-1-en-3-ones as tetosterone reductase inhibitors of the formula. wherein R is selected from hydrogen, methyl and ethy and R 2 is phenyl substituted with one or more of: --OH, --OFC 1 -C 4 alkyl, C 1 -C 4 alk
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- 17beta-N-monosubstituted adamantyl/norbornanyl carbamoyl-4-aza-5alpha-androst-1-en-3-ones and androstan-3-ones
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17β-N-Monosubstituted adamantyl/norbornanyl carbamoyl-4-aza-5α-androst-1-en-3-ones and androstan-3-ones of the formula: wherein R is selected from hydrogen, methyl and ethyl and R2 is a hydrocarbon radical selected from substituted or unsubstituted 1- or 2-adamantyl or 1- or 2-norbornanyl and wherein the dotted line represents a double bond which can be present; are 5α-reductase inhibitors.
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- 17β-aminobenzoyl-4-aza-5α-androst-1-en-3-ones as benign prostatic hypertrophy agents
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New 17β-aminobenzoyl-4-aza-5α-androst-1-en-3-ones as benign prostatic hypertrophy agents of the formula: STR1 wherein R is selected from hydrogen, methyl and ethyl and R2 is phenyl substituted with --N(R3)2, which can be p
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- Azasteroids: Structure-activity relationships for inhibition of 5α-reductase and of androgen receptor binding
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A series of steroids, primarily 4-azasteroids, were prepared and tested in vitro as inhibitors of human and rat prostatic 5α-reductase and of binding of dihydrotestosterone to the rat androgen receptor. The primary structural modifications were changes of the A ring and of moieties attached at the C-17 position of the steroid nucleus. New A-ring modifications included 4-cyano-3-oxoΔ4 system in the carbocyclic series and 1α-CN, 1α-CH3, 1α,2α-CH2, 2β-F, 2-aza, 2-oxa, and A-homo changes in the 3-oxo-4-aza series. In addition, 4-azasteroids with a D-homo ring or methyl substitution at C-7 (α and β) or C-16 (α and β) were prepared. The majority of the C-17 substituents were prepared from reactive intermediates derived from the 17β-COOH. Enhanced 5α-reductase inhibition in both the human and rat enzyme assays is seen with 4-CN substitution on 3-oxo-Δ4 steroids and with a C-17 side chain incorporating a lipophilically substituted semipolar group on the 4-aza-3-oxo-5α-androstane nucleus. Fewer highly active compounds were found in the human enzyme assay than in the rat assay. Structural requirements for inhibition of the rat androgen receptor are much different from those for inhibition of the enzyme. The 17β-OH moiety enhances potency more than any other feature while introduction of double bonds at C-1 or C-5 in the azasteroid gives a small improvement. Azasteroids unsubstituted at the 4-position show greatly diminished receptor activity.
- Rasmusson,Reynolds,Steinberg,Walton,Patel,Liang,Cascieri,Cheung,Brooks,Berman
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p. 2298 - 2315
(2007/10/02)
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