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Date: 2013-03-08 00:00:00Written By

2013年2月FDA批准新药奥培米芬OSPEMIFENE

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2013年2月26日美国食品药品监督管理局(FDA)批准Osphena(ospemifene)治疗 妇女经受中度至严重性交痛[dyspareunia],一种由于绝经外阴和阴道萎缩的症状。

性交痛是一种绝经期间雌激素的激素水平下降伴随情况。雌激素较低可能使阴道组织变薄,变干和更加脆弱,导致性交时疼痛。

Osphena,一种每天1次与食物口服的药物,其作用如同雌激素作用于阴道组织使它们变厚,和不那么脆弱,导致妇女经受性交疼痛量减低。

FDA药物评价和研究中心的药物评价III副室主任Victoria Kusiak,M.D.说:“性交痛是绝经后妇女最频发报道的问题,”“Osphena对寻求缓解的妇女提供另一种治疗选择。”

在1,889例有外阴和阴道萎缩症状的绝经后妇女的三项临床研究确定Osphena的安全性和有效性。妇女 被随机地赋予接受Osphena或一种安慰剂。在12周治疗后,来自前两项试验的结果显示Osphena-治疗妇女与接受安慰剂妇女比较性交疼痛 统计显著改善。来自第三项研究结果支持在性交痛治疗的长期安全性。

正在被批准Osphena有一个黑框警告提醒妇女和卫生保健专业人员该药其作用像雌激素对阴道组织,曾被显示可刺激子宫衬里(子宫内膜)和致之变厚。在有生育力妇女中,在绝经前,每月发生子宫内膜的这种变厚。绝经后妇女永远不再有月经,而被刺激的子宫内膜不是正常的。妇女如经常经历不寻常出血应找她们的卫生保健专业人员因为可能是子宫内膜癌征象或一种情况导致子宫内膜癌。Osphena处方应符合个别妇女最短的时间与治疗目标和风险。

黑框警告还陈述血栓性和出血性卒中的发生率(分别为每一千妇女0.72和1.45)和深静脉血栓形成发生率(每一千妇女1.45)。这些发生率代表低风险相反单独雌激素治疗见到卒中和深静脉血栓形成风险增加。

在临床试验期间最常报道的副作用包括潮热,阴道排泄物,肌肉痉挛,生殖器排泄物和出汗过多。
.
Osphena由总部在新泽西的盐野义制药公司Shionogi Inc上市。

http://www.shionogi.com/pdf/PI/Osphena-PI.pdf

处方资料重点
这些重点不包括安全和有效使用OSPHENA所需所有资料。请参阅下文为OSPHENA的完整处方资料
OSPHENATM(ospemifene)片,为口服使用
美国初次批准 :2013


适应证和用途
OSPHENA是一种雌激素激动剂/拮抗剂适用于中度至严重性交痛[dyspareunia],一种由于绝经外阴和阴道萎缩症状的治疗。(1)

剂量和给药方法
每天1次与食物口服1片。(2.1)

剂型和规格
片:60 mg (3)

禁忌证
(1) 未确诊的生殖器异常出血 (4)
(2) 已知或怀疑雌激素-依赖性肿瘤 (4,5.2)
(3) 活动性DVT,肺栓塞(PE),或这些情况史 (4,5.1)
(4) 活动性动脉血栓栓塞病(例如,卒中和心肌梗死[MI]),或这些情况史 (4,5.1)
(5) 已知或怀疑妊娠(4,8.1)

警告和注意事项
(1)静脉血栓栓塞病:DVT和肺栓塞的风险(5.1)
(2)已知,怀疑,或乳癌史(5.2)
(3)严重肝受损 (5.3,8.7,12.3)

不良反应
不良反应(≥1 %)包括:潮热,阴道排泄物,肌肉痉挛,生殖器排泄物,多汗症. (6.1)
报告怀疑不良反应,联系盐野义制药公司Shionogi Inc. 电话1-855-OSPHENA (1-855-677-4362)或FDA电话1-800-FDA-1088或www.fda.gov/medwatch.

药物相互作用
(1) 不要使用雌激素 or雌激素激动剂/拮抗剂与OSPHENA同时 (7.1,12.3)
(2) 不要与OSPHENA同时使用氟康唑[fluconazole]。氟康唑增加OSPHENA的血清浓度 (7.2,12.3)
(3)不要与OSPHENA同时使用利福平[rifampin]。利福平减低OSPHENA的血清浓度 (7.2,12.3)

特殊人群中使用
哺乳母亲:不知道OSPHENA是否排泄在人乳汁中。(8.3)

一般描述
OSPHENA是一种雌激素激动剂/拮抗剂。化学结构如下:

化学名称是Z-2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethanol,和经验式C24H23ClO2,分子量378.9。

作用机制
OSPHENA是一种有组织选择性作用的雌激素激动剂/拮抗剂。其生物学作用是通过与雌激素受体结合介导。这个结合导致在某些组织中雌激素通路的激活(激动作用)和阻断其他雌激素通路(拮抗作用)。

临床研究
在3项安慰剂-对照临床试验(两项12-周疗效试验和一项52-周长期安全性试验)检查OSPHENA对中度至严重外阴和阴道萎缩的症状在绝经后妇女的有效性和安全性。在3项安慰剂-对照试验,总共787例妇女接受安慰剂和1102例妇女接受60 mg OSPHENA。
第一项临床试验是12-周,随机化,双盲,安慰剂-对照,平行组研究纳入826例一般健康绝经后妇女41至81岁间(均数59岁)在基线时一个阴道涂片有表层细胞≤5 %,阴道 pH >5.0,和妇女鉴定至少1种中度至严重阴道症状被认为她是最麻烦的(阴道干燥,性交痛,或阴道刺激/瘙痒)。治疗组包括30 mg OSPHENA(n=282),60 mg OSPHENA(n=276),和安慰剂(n=268)。所有妇女被评估for improvement in the均数变化从基线至12周共-主要疗效变量:最麻烦的症状(MBS)外阴和阴道萎缩(被定义为个体中度至严重症状在基线被妇女鉴定为最麻烦),在阴道涂片上阴道表层和阴道副基底层细胞[parabasal cells]的百分率,和阴道pH。完成12-周后,有完整子宫妇女被允许纳入40-周双盲延伸研究,而无完整子宫妇女被允许纳入52-周开放延伸研究。
第二项临床试验是一项12-周,随机化,双盲,安慰剂-对照,平行组研究纳入919例一般上健康41至79间岁(均数59岁)绝经后妇女她在基线时在阴道涂片有≤5 %表层细胞,阴道pH >5.0,和被鉴定为或中度至严重阴道干燥(干燥队列)或中度至严重性交痛(性交痛队列)为对她在基线时最麻烦。治疗组包括60 mg OSPHENA (n=463)和安慰剂(n=456)。主要终点和研究进行与试验1相似。
第三临床试验是一项52-周,随机化,双盲,安慰剂-对照,长期安全性研究,纳入426例一般上健康绝经后妇女年龄49至79岁间(均数62岁)有完整子宫。治疗组包括60 mg OSPHENA(n=363)和安慰剂(n=63)。
对性交痛影响
在第一和第二临床试验中,修饰的意向治疗妇女人群用OSPHENA治疗当与安慰剂比较时,显示统计显著改善(从基线至第12周最小平方均数变化)在中度至严重最麻烦的症状(MBS)性交痛(第一试验p=0.0012,第二试验p<0.0001)。见表2。还显示阴道涂片表层细胞比例统计显著增加和相应的副底层细胞比例统计显著减低(两者p<0.0001)。基线和第12周间阴道pH均数也统计显著减低(p<0.0001)。

产品信息和合成路线如下:

 

Name Ospemifene;FC-1271a
Chemical Name 2-[4-[4-Chloro-1,2-diphenyl-1(Z)-butenyl]phenoxy]ethanol
CAS 128607-22-7
Related CAS  
Formula C24H23ClO2
Structure
Formula Weight 378.90271
Stage II/III 期临床
Company Orion Corp. (Originator), Hormos (Codevelopment)
Activity/Mechanism Bone Diseases, Treatment of, ENDOCRINE DRUGS, Gynecological Disorders, Treatment of , Hormone Replacement Therapy, METABOLIC DRUGS, Treatment of Osteoporosis, Treatment of Postmenopausal Syndrome , Selective Estrogen Receptor Modulators (SERM)
Syn. Route 3
Route 1
  the condensation of desoxybenzoin (i) with tetrahydropyranyl ether (ii) in aq. 48% naoh containing tebac gives 1,2-diphenyl-4-(tetrahydropyranyloxy)-1-butanone (iii), which by a grignard condensation with 4-methoxyphenylmagnesium bromide (iv) in thf yields the monoprotected triphenylbutanediol (v). the deprotection of (v) with h2so4 in ethanol/water at room temperature affords the triphenylbutane-1,4-diol (vi), which is cyclized with h2so4 in hot ethanol/water to provide 2-(4-methoxyphenyl)-2,3-diphenyltetrahydrofuran (vii). the reaction of (vii) with 48% hbr in refluxing acetic acid gives a mixture of (e)- and (z)-4-(4-hydroxyphenyl)-3,4-diphenyl-1-butanol that is separated by chemical working up to obtain the desired (z)-isomer (viii). the condensation of the phenolic oh of (viii) with benzyl protected 2-bromoethanol (ix) by means of naoh and tetrabutylammonium bromide in refluxing toluene/water gives the benzyloxyethyl ether (x). the reaction of the aliphatic oh group of (x) with pph3 and ccl4 in acetonitrile yields the corresponding chloro derivative (xi), which is finally debenzylated by hydrogenation with h2 over pd/c in ethyl acetate/ethanol.
 
 
List of intermediates No.
2-[(3s)-3-amino-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2h)-yl]acetic acid (ii)
1-benzyl-3-(bromomethyl)-2(1h)-quinoxalinone (ix)
benzyl (3r,4r)-4-fluoro-3-(6-fluoro-2-phenyl-1h-indol-3-yl)-1-piperidinecarboxylate (iv)
(2s)-3-hydroxy-2-{[(2s)-2-({[(2s,4r)-4-hydroxypyrrolidinyl]carbonyl}amino)propanoyl]amino}propanoic acid (i)
tert-butyl 3-[[1-(4-fluorobenzyl)-1h-benzimidazol-2-yl](methyl)amino]propyl(methyl)carbamate (iii)
n-[1-(4-fluorobenzyl)-1h-benzimidazol-2-yl]-n-methyl-n-[3-(methylamino)propyl]amine (v)
phenyl 3,5-bis(trifluoromethyl)benzylcarbamate (vi)
[(2s)-1-[(2,4-dichloro-3-[[(2,4-dimethyl-8-quinolinyl)oxy]methyl]phenyl)sulfonyl]pyrrolidinyl](1-piperazinyl)methanone (vii)
(e)-3-(dimethylamino)-1-(4-methylphenyl)-2-propen-1-one (viii)
5-(4-methylphenyl)isoxazole (x)
5-[4-(bromomethyl)phenyl]isoxazole (xi)
Reference 1:
toivola, r.j.; karjalainen, a.j.; kurkela, k.o.a.; soderwall, m.-l.; kangas, l.v.m.; blanco, g.l.; sundquist, h.k. (orion corporation); tri-phenyl alkene derivs. and their oestrogenic, anti-oestrogenic and progestanic uses. us 4996225; us 5491173 .
Reference 2:
h?rk?nen, p.; miettinen, t.; m?ntyl?, e.; kangas, l.; degregorio, m. (orion corporation); serum cholesterol lowering agent. wo 9732574 .
Reference 3:
laine, a.; degregorio, m.; harkonen, p.; wiebe, v.; vaananen, k.; kangas, l.v.m. (orion corporation); triphenylethylenes for the prevention and treatment of osteoporosis. wo 9607402 .

Route 2
  the condensation of desoxybenzoin (i) with 2-(benzyloxy)ethyl bromide (ii) by means of aqueous 48% naoh containing triethylbenzylammonium chloride (tebac) gives 4-(benzyloxy)-1,2-diphenyl-1-butanone (iii), which by reaction with the grignard reagent (iv) - prepared from 4-(tetrahydropyranyloxy)phenyl bromide (v) and mg in thf - yields the triphenylbutanol derivative (vi). elimination of the thp-protecting group of compound (vi) by means of h2so4 in ethanol/water at room temperature affords the triphenylbutanol derivative (vii), which is debenzylated by hydrogenation with h2 over pd/c in ethanol to provide the butane-1,4-diol derivative (viii). cyclization of the butane-1,4-diol (viii) by means of h2so4 in hot ethanol/water gives 2-(4-hydroxyphenyl)-2,3-diphenyltetrahydrofuran (ix), which is treated with 48% hbr in refluxing acoh to yield a mixture of (e)- and (z)-4-(4-hydroxyphenyl)-3,4-diphenyl-3-buten-1-ol (x), which is separated by chemical work up. the phenolic oh group of the desired (z)-isomer (x) is condensed with 2-(benzyloxy)ethyl bromide (ii) by means of naoh and tetrabutylammonium bromide in refluxing toluene/ water to afford the benzyloxyethyl ether (xii). reaction of the aliphatic oh group of ether (xii) with pph3 and ccl4 in acetonitrile provides the corresponding chloro derivative (xiii), which is finally debenzylated with h2 over pd/c in ethyl acetate/ethanol.
 
 
List of intermediates No.
(1s,2s,3r,6s,7r)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol (iv)
1-benzyl-3-(bromomethyl)-2(1h)-quinoxalinone (ii)
(2s)-3-hydroxy-2-{[(2s)-2-({[(2s,4r)-4-hydroxypyrrolidinyl]carbonyl}amino)propanoyl]amino}propanoic acid (i)
(e)-3-(dimethylamino)-1-(4-methylphenyl)-2-propen-1-one (x)
5-(4-methylphenyl)isoxazole (xii)
5-[4-(bromomethyl)phenyl]isoxazole (xiii)
Reference 1:
sorbera, l.a.; castaner, j.; bayes, m.; ospemifene. drugs fut 2004, 29, 1, 38.
Reference 2:
toivola, r.j.; karjalainen, a.j.; kurkela, k.o.a.; soderwall, m.-l.; kangas, l.v.m.; blanco, g.l.; sundquist, h.k. (orion corporation); tri-phenyl alkene derivs. and their oestrogenic, anti-oestrogenic and progestanic uses. us 4996225; us 5491173 .
Reference 3:
laine, a.; degregorio, m.; harkonen, p.; wiebe, v.; vaananen, k.; kangas, l.v.m. (orion corporation); triphenylethylenes for the prevention and treatment of osteoporosis. wo 9607402 .

Route 3
  condensation of desoxybenzoin (i) with 2-(tetra-hydropyranyloxy)ethyl bromide (xiv) by means of aqueous naoh and tebac as before gives 1,2-diphenyl-4-(tetrahydropyranyloxy)-1-butanone (xv), which by a grignard condensation with 4-methoxyphenylmagnesium bromide (xvi) -prepared from 4-bromoanisole (xvii) and mg in thf- provides the triphenylbutanol derivative (xviii). cleavage of the thp-protecting group of compound (xviii) with h2so4 in ethanol/water at room temperature affords the butane-1,4-diol derivative (xix), which is cyclized by means of h2so4 in hot ethanol/ water to yield 2-(4-methoxyphenyl)-2,3-diphenyltetrahydrofuran (xx). finally, this compound is treated with 48% hbr in refluxing acoh to give 4-(4-hydroxyphenyl)-3,4-diphenyl-3-buten-1-ol (x) as a (z):(e)-isomeric mixture, from which the desired (z)-isomer is separated by chemical work up.
 
 
List of intermediates No.
2-chloro-1-[4-(2,3,4-trimethoxybenzyl)-1-piperazinyl]-1-ethanone (xxiii)
2-[(3s)-3-amino-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2h)-yl]acetic acid (xiv)
tert-butyl (1s)-2-[[(1s)-2-hydroxy-1-isobutylhexyl]amino]-1-(1h-imidazol-5-ylmethyl)-2-oxoethylcarbamate (xxi)
benzyl (3r,4r)-4-fluoro-3-(6-fluoro-2-phenyl-1h-indol-3-yl)-1-piperidinecarboxylate (xvi)
(2s)-3-hydroxy-2-{[(2s)-2-({[(2s,4r)-4-hydroxypyrrolidinyl]carbonyl}amino)propanoyl]amino}propanoic acid (i)
tert-butyl 3-[[1-(4-fluorobenzyl)-1h-benzimidazol-2-yl](methyl)amino]propyl(methyl)carbamate (xv)
n-[1-(4-fluorobenzyl)-1h-benzimidazol-2-yl]-n-methyl-n-[3-(methylamino)propyl]amine (xviii)
phenyl 3,5-bis(trifluoromethyl)benzylcarbamate (xix)
[(2s)-1-[(2,4-dichloro-3-[[(2,4-dimethyl-8-quinolinyl)oxy]methyl]phenyl)sulfonyl]pyrrolidinyl](1-piperazinyl)methanone (xx)
(e)-3-(dimethylamino)-1-(4-methylphenyl)-2-propen-1-one (x)
Reference 1:
sorbera, l.a.; castaner, j.; bayes, m.; ospemifene. drugs fut 2004, 29, 1, 38.
Reference 2:
toivola, r.j.; karjalainen, a.j.; kurkela, k.o.a.; soderwall, m.-l.; kangas, l.v.m.; blanco, g.l.; sundquist, h.k. (orion corporation); tri-phenyl alkene derivs. and their oestrogenic, anti-oestrogenic and progestanic uses. us 4996225; us 5491173 .
 2013年2月FDA批准癌症新药泊利度胺Pomalidomide <-- 上一篇

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