JP2001500101A - Use of the 1-enantiomer of St. chroman for the manufacture of a pharmaceutical composition for the treatment and prevention of breast cancer - Google Patents

Use of the 1-enantiomer of St. chroman for the manufacture of a pharmaceutical composition for the treatment and prevention of breast cancer

Info

Publication number
JP2001500101A
JP2001500101A JP09524767A JP52476797A JP2001500101A JP 2001500101 A JP2001500101 A JP 2001500101A JP 09524767 A JP09524767 A JP 09524767A JP 52476797 A JP52476797 A JP 52476797A JP 2001500101 A JP2001500101 A JP 2001500101A
Authority
JP
Japan
Prior art keywords
breast cancer
enantiomer
phenyl
treatment
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
JP09524767A
Other languages
Japanese (ja)
Inventor
サルミ，ミハエル
プラカシュ カンボイ，ベデ
プラサド アスタナ，オムカー
レイ，スプラブハット
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novo Nordisk AS
Original Assignee
Novo Nordisk AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novo Nordisk AS filed Critical Novo Nordisk AS
Publication of JP2001500101A publication Critical patent/JP2001500101A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

(57)【要約】 本発明は、乳癌の治療又は予防のための医薬組成物の製造のための、医薬として許容される担体と組み合わせた、セントクロマンのｌ−鏡像異性体又はその医薬として許容される塩の新しい使用を提供する。   (57) [Summary] The present invention relates to a new use of the 1-enantiomer of St. chroman or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, for the manufacture of a pharmaceutical composition for the treatment or prevention of breast cancer. I will provide a.

Description

【発明の詳細な説明】 乳癌の治療及び予防のための医薬組成物の製造のためのセントクロマンのｌ−鏡 像異性体の使用 発明の分野 本発明は、乳癌を患う患者の治療及びその予防のための、セントクロマン（３ ，４−トランス−２，２−ジメチル−３−フェニル−４−〔４−（２−（ピロリ ジン−１−イル）エトキシ）フェニル〕−７−メトキシクロマン）の単離したｌ −鏡像異性体又はその医薬として許容される塩の使用に関する。本発明は、セン トクロマンのｌ−鏡像異性体又はその医薬として許容される塩を含む医薬組成物 、並びに上述の化合物及びそれらの医薬組成物を用いる方法に関する。 発明の背景 乳癌は、女性において最も一般的な悪性腫瘍であり、癌による死の原因となる 。女性においては約20％が癌による死である。しかしながら、何年もの密度の濃 い調査及び新しいタイプの治療にかかわらず、西洋における乳癌からの年齢に沿 った死が、過去30年間にわたって実質的に安定であり続けている。用語“乳癌” は、胸の管構造及び腺構造内に生ずる癌を含む。乳癌は、去勢されている女性に おいてはまれであり；35歳前の卵巣摘出はその危険性を３分の１に削減する。18 歳前に最初の子供を有する女性は、30歳まで最初の子供が遅くなった女性と比べ て、その危険性は３分の１である。乳癌の成長はエストロゲンの存在と関連する 。それゆえ、乳癌の治療の道筋は、卵巣摘出又は子宮摘出によるエストロゲンソ ースの切除で ある。この外科的試みのかわりは、標的部位においてエストロゲン濃度を枯渇さ せるためにエストロゲンアンタゴニストを用いることによる内分泌治療である。 セントクロマンは、抗エストロゲン活性を有することが知られている非ステロ イド化合物である。それは、経口的避妊薬としてインドで用いられている（例え ば、Salmanら.,米国特許明細書第4,447,622号；Singhら.,Acta Endocrinol ．（C openh）126 (1992),444-450；Grubb，Curr ．Opin．Obstet．Gynecol．3(1991)，4 91-495；Sankaranら，Contraception 9(1974)，279-289；インド特許明細書第12 918号を参照のこと）。セントクロマンは、進行した乳癌の治療のための抗癌剤 としても研究されている(Misraら、Int ．J．Cancer 43(1989)，781〜783)。現在 、ラセミ体としてのセントクロマンは、血清濃縮物の大きな減少により示される 潜在的なコレステロール低下医薬として見い出されている(S.D.Bainら、J.Min B on.Res.9 (1994)，394)。しかしながら、セントクロマンの単離されたｌ−エナン チオマーが乳癌の治療に役立つことは開示されていない。 今日、乳癌の治療及び予防において有用で安全である組成物及び方法について 、当該技術における必要性がある。 本発明の１つの目的は、乳癌の治療又は予防に有効に用いることができる化合 物を提供することである。 発明の詳細な記載 本発明は、乳癌の治療及び予防のための医薬組成物の製造のためのセントクロ マン（３，４−トランス−２，２−ジメチル−３−フェニル−４−〔４−（２− （ピロリジン−１−イル）エトキシ）フェニル〕−７−メトキシクロマン）の単 離されたｌ−鏡像異性体又 はその医薬として許容される塩の使用に関する。 ３，４−ジアリールクロマンは、その内容が引用により本明細書に組み込まれ るCarneyらの米国特許明細書第3,340,276号、Bolgerの米国特許明細書第3,822,2 87号、RayらのJ.Med Chem．19．(1976)，276-279に開示されるような周知の方法 によって調製される。有機金属塩基が触媒する再配列によるシス異性体のトラン ス形態への転換は、米国特許明細書第3,822,287号に開示される。光学的に活性 なｄ−及びｌ−鏡像異性体は、光学的に活性な酸塩を形成しそれをアルカリ加水 分解して要求される鏡像異性体を形成することにより、（引用により本明細書に 組み込まれる）米国特許明細書第4,447,622号において、Salmanらにより開示さ れるように調製することができる。 本発明において、セントクロマンのｌ−鏡像異性体は、医薬として許容される 塩、特に、有機酸及び鉱酸の塩を含む酸付加塩の形態で調製することができる。 このような塩の例は、有機酸、例えばギ酸、フマル酸、酢酸、プロピオン酸、グ リコール酸、乳酸、ピルビン酸、シュウ酸、コハク酸、リンゴ酸、酒石酸、クエ ン酸、安息香酸、及びサリチル酸等の塩を含む。 適切な無機酸付加塩は、塩酸、臭化水素酸、硫酸及びリン酸等の塩を含む。酸 付加塩は、化合物合成の直接生成物として得ることができる。かわりに、遊離塩 基は、適切な酸を含む適切な溶媒に溶かし、そしてその塩を、その溶媒をエバポ レートし、又はその塩と溶媒とを分離することによって単離することができる。 セントクロマンのｌ−鏡像異性体及びその塩は、ヒト及び獣医学において、例 えば乳癌を患う患者の治療において役立つ。本発明に用いるために、セントクロ マンのｌ−鏡像異性体又はその医薬として許容される塩は、医薬として許容され る担体と共に製剤化されて 、慣用的な方法に従う非経口、経口、鼻、直腸、皮下、皮内又は経皮投与のため の薬剤を供する。製剤は、更に、１又は複数の希釈剤、充填剤、乳化剤、防腐剤 、緩衝液、賦形剤等を含み得、そして、流体、粉末、エマルション、坐剤、リポ ソーム、経皮パッチ、徐放剤、皮膚インプラント、錠剤等のような形態で供され 得る。当業者は、適切な方法で、Remington's Pharmaceutical Sciences ，Genna ro，ed.，Mack Publishing Co.，Easton，PA，1990に開示されるように、許容さ れる実施形態に従ってセントクロマンのｌ−鏡像異性体又はその医薬として許容 される塩を製剤化することができる。 経口投与が好ましい。これにより、活性なセントクロマンのｌ−鏡像異性体又 はその医薬として許容される塩は、錠剤又はカプセルのような経口投与に適した 形態で調製される。典型物には、セントクロマンのｌ−鏡像異性体の医薬として 許容される塩は、担体と組み合わされ、錠剤内に流し込まれる。この点に関して 適切な担体は、デンプン、糖、リン酸二カルシウム、ステアリン酸カルシウム、 及びステアリル酸マグネシウム等を含む。このような組成物は、１又は複数の補 助物質、例えば湿潤剤、乳化剤、防腐剤、安定剤、着色添加物等を更に含み得る 。 セントクロマンのｌ−鏡像異性体の化合物又はその医薬として許容される塩を 含む医薬組成物は、１日又は週当り１又は複数回、投与される。このような医薬 組成物の有効量は、乳癌に対する臨床的に有意な効果を供する量である。このよ うな量は、一部は、治療される特定の条件、患者の年齢、体重及び全般的な健康 状態、並びに当該技術で明らかな他の因子によるであろう。典型的な１回の投与 量は、本発明の化合物の１日当り患者１kg当り約0.001〜約75mgの非毒性投与範 囲を含むであろう。 セントクロマンのｌ−鏡像異性体又はその医薬として許容される 塩を含む医薬組成物は、１日又は週当り１回又は複数回、単位投与形態で投与す ることができる。かわりに、それらは、皮膚移植に適した制御放出性製剤として 供され得る。数年までであり得る要求される期間にわたっての、活性化合物の放 出を供するようにインブラントは製剤化される。制御放出性製剤は、例えば、引 用により本明細書に組み込まれるSandersら(J.Pharm ．Sci.73(1964)，1294〜129 7)、米国特許明細書第4,489,056号；及び米国特許明細書第4,210,644号により開 示される。 本発明は、以下の実施例により更に詳説される。しかしながらそれは、保護の 範囲を限定するものとして解決されるべきでない。 先の試験及び次の実施例に開示される特徴は、別個に、そしてそれらのいずれ かの組合せにおいて、その別個の形態で本発明を認識するための材料となり得る 。 実施例 テスト 15〜45のヌード（胸腺欠損）マウスをフェノバルビタール麻酔下で卵巣摘出す る。１週間の回復の後、エストロゲンにセンシティブなヒト腫瘍細胞系（MCF7、 乳癌繊維芽細胞７）を、これらの動物の各々に連続的に移植する。次に、マウス を、プランーボ（陰性対照）、17−β−エストラジオール（陽性対照）、又はテ スト化合物のいずれかで処理する。エストロゲンで刺激した腫瘍の成長を、約８ 週間の投与期間、週に２回、腫瘍の大きさを測定することにより評価する。The present invention relates to the use of the 1-enantiomer of St. chroman for the manufacture of a pharmaceutical composition for the treatment and prevention of breast cancer. The invention relates to the treatment and prevention of patients suffering from breast cancer. Of centchroman (3,4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidin-1-yl) ethoxy) phenyl] -7-methoxychroman) To the use of the 1-enantiomer or a pharmaceutically acceptable salt thereof. The present invention relates to pharmaceutical compositions comprising the 1-enantiomer of St. chroman or a pharmaceutically acceptable salt thereof, and to methods of using the compounds described above and their pharmaceutical compositions. Background of the Invention Breast cancer is the most common malignancy in women and causes death from cancer. About 20% of women die from cancer. However, despite years of intense research and new types of treatment, age-related deaths from breast cancer in the West have remained substantially stable over the past 30 years. The term "breast cancer" includes cancers that occur in the ductal and glandular structures of the breast. Breast cancer is rare in women who have been castrated; ovariectomy before age 35 reduces the risk by a factor of three. Women who have their first child before the age of 18 are at one-third risk as women who have their first child delayed until age 30. Breast cancer growth is associated with the presence of estrogen. Therefore, the course of treatment for breast cancer is the removal of the estrogen source by ovariectomy or hysterectomy. An alternative to this surgical approach is endocrine therapy by using estrogen antagonists to deplete estrogen levels at the target site. Saint chroman is a non-steroidal compound known to have anti-estrogenic activity. It has been used in India as an oral contraceptive (eg, Salman et al., US Pat. No. 4,447,622; Singh et al., Acta Endocrinol . (C openh) 126 (1992), 444-450; Grubb, Curr .Opin.Obstet.Gynecol.3 (1991), 4 91-495 ; Sankaran et al., Contraception 9 (1974), 279-289 ; see Indian patent specification No. 12 918). St. chroman has also been studied as an anticancer agent for the treatment of advanced breast cancer (Misra et al., Int. J. Cancer 43 (1989), 781-783). St. chroman as a racemate is now being discovered as a potential cholesterol lowering drug indicated by a large reduction in serum concentrates (SDBain et al., J. Min Bon. Res. 9 (1994), 394). However, it is not disclosed that the isolated 1-enantiomer of St. chroman is useful for treating breast cancer. Today, there is a need in the art for compositions and methods that are useful and safe in the treatment and prevention of breast cancer. One object of the present invention is to provide compounds that can be used effectively for treating or preventing breast cancer. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for preparing a pharmaceutical composition for the treatment and prevention of breast cancer, comprising centchroman (3,4-trans-2,2-dimethyl-3-phenyl-4- [4- (4- ( 2- (pyrrolidin-1-yl) ethoxy) phenyl] -7-methoxychroman) or the pharmaceutically acceptable salt thereof. 3,4-Diarylchromans are disclosed in Carney et al., U.S. Pat.No. 3,340,276, Bolger U.S. Pat.No. 3,822,287, Ray et al., J. Med Chem , the contents of which are incorporated herein by reference. . 19. (1976), 276-279. The conversion of the cis isomer to the trans form by organometallic base catalyzed rearrangement is disclosed in US Pat. No. 3,822,287. Optically active d- and l-enantiomers are formed by forming the optically active acid salt and subjecting it to alkaline hydrolysis to form the required enantiomer (herein incorporated by reference). No. 4,447,622, incorporated by reference), can be prepared as disclosed by Salman et al. In the present invention, the 1-enantiomer of St. chroman can be prepared in the form of pharmaceutically acceptable salts, especially acid addition salts, including salts of organic and mineral acids. Examples of such salts include organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, and the like. Including salts. Suitable inorganic acid addition salts include salts such as hydrochloric, hydrobromic, sulfuric, and phosphoric acids. Acid addition salts can be obtained as direct products of compound synthesis. Alternatively, the free base can be dissolved in a suitable solvent containing the appropriate acid and the salt isolated by evaporating the solvent or separating the salt and solvent. The 1-enantiomer of St. chroman and its salts are useful in human and veterinary medicine, for example in the treatment of patients with breast cancer. For use in the present invention, the 1-enantiomer of St. chroman or a pharmaceutically acceptable salt thereof is formulated with a pharmaceutically acceptable carrier and is administered parenterally, orally, nasally, rectally according to conventional methods. , For subcutaneous, intradermal or transdermal administration. The formulation may further include one or more diluents, fillers, emulsifiers, preservatives, buffers, excipients, and the like, and may include fluids, powders, emulsions, suppositories, liposomes, transdermal patches, sustained release It can be provided in the form of an agent, a skin implant, a tablet and the like. The skilled artisan will appreciate in a suitable manner that the 1-enantiomer of St. chroman according to the accepted embodiments, as disclosed in Remington's Pharmaceutical Sciences , Gennaro, ed., Mack Publishing Co., Easton, PA, 1990. Alternatively, a pharmaceutically acceptable salt thereof can be formulated. Oral administration is preferred. Thus, the active 1-enantiomer of centchroman or a pharmaceutically acceptable salt thereof is prepared in a form suitable for oral administration such as a tablet or capsule. Typically, a pharmaceutically acceptable salt of the 1-enantiomer of St. chroman is combined with a carrier and poured into tablets. Suitable carriers in this regard include starch, sugars, dicalcium phosphate, calcium stearate, magnesium stearylate, and the like. Such compositions may further comprise one or more auxiliary substances such as wetting agents, emulsifiers, preservatives, stabilizers, coloring additives and the like. A pharmaceutical composition comprising a compound of the 1-enantiomer of St. chroman or a pharmaceutically acceptable salt thereof is administered one or more times per day or week. An effective amount of such a pharmaceutical composition is an amount that provides a clinically significant effect on breast cancer. Such amounts will depend, in part, on the particular condition being treated, the age, weight and general health of the patient, and other factors apparent in the art. A typical single dose will contain a non-toxic dosage range of about 0.001 to about 75 mg / kg patient per day of a compound of the present invention. A pharmaceutical composition comprising the 1-enantiomer of St. chroman or a pharmaceutically acceptable salt thereof can be administered in unit dosage form, one or more times per day or week. Alternatively, they can be provided as a controlled release formulation suitable for skin grafting. Implants are formulated to provide for release of the active compound over a required period of time which may be up to several years. Controlled release formulations are described, for example, in Sanders et al. (J. Pharm . Sci. 73 (1964), 129-1297), U.S. Pat. No. 4,489,056; and U.S. Pat. No. 4,210,644. The present invention is further described by the following examples. However, it should not be settled as limiting the scope of protection. The features disclosed in the preceding test and in the following examples, separately and in any combination thereof, may be the material for recognizing the invention in its distinct form. Example Test 15-45 nude (thymic) mice are ovariectomized under phenobarbital anesthesia. After one week of recovery, an estrogen-sensitive human tumor cell line (MCF7, breast cancer fibroblast 7) is serially implanted into each of these animals. The mice are then treated with either plumbo (negative control), 17-β-estradiol (positive control), or test compound. Estrogen-stimulated tumor growth is assessed by measuring tumor size twice weekly for a dosing period of about 8 weeks.

───────────────────────────────────────────────────── フロントページの続き (81)指定国 ＥＰ(ＡＴ，ＢＥ，ＣＨ，ＤＥ， ＤＫ，ＥＳ，ＦＩ，ＦＲ，ＧＢ，ＧＲ，ＩＥ，ＩＴ，Ｌ Ｕ，ＭＣ，ＮＬ，ＰＴ，ＳＥ)，ＯＡ(ＢＦ，ＢＪ，ＣＦ ，ＣＧ，ＣＩ，ＣＭ，ＧＡ，ＧＮ，ＭＬ，ＭＲ，ＮＥ， ＳＮ，ＴＤ，ＴＧ)，ＡＰ(ＫＥ，ＬＳ，ＭＷ，ＳＤ，Ｓ Ｚ，ＵＧ)，ＥＡ(ＡＭ，ＡＺ，ＢＹ，ＫＧ，ＫＺ，ＭＤ ，ＲＵ，ＴＪ，ＴＭ)，ＡＬ，ＡＭ，ＡＴ，ＡＵ，ＡＺ ，ＢＡ，ＢＢ，ＢＧ，ＢＲ，ＢＹ，ＣＡ，ＣＨ，ＣＮ， ＣＵ，ＣＺ，ＤＥ，ＤＫ，ＥＥ，ＥＳ，ＦＩ，ＧＢ，Ｇ Ｅ，ＨＵ，ＩＬ，ＩＳ，ＪＰ，ＫＥ，ＫＧ，ＫＰ，ＫＲ ，ＫＺ，ＬＣ，ＬＫ，ＬＲ，ＬＳ，ＬＴ，ＬＵ，ＬＶ， ＭＤ，ＭＧ，ＭＫ，ＭＮ，ＭＷ，ＭＸ，ＮＯ，ＮＺ，Ｐ Ｌ，ＰＴ，ＲＯ，ＲＵ，ＳＤ，ＳＥ，ＳＧ，ＳＩ，ＳＫ ，ＴＪ，ＴＭ，ＴＲ，ＴＴ，ＵＡ，ＵＧ，ＵＺ，ＶＮ (72)発明者 アスタナ，オムカー プラサド インド国，ラックナウ 226004，チャーバ グ，ロックマン ガンジ 2237 (72)発明者 レイ，スプラブハット インド国，ラックナウ 226001，サロジニ ナイドゥ マーグ，ケーエイチエー 16 ／３，ビハインド マソニック ロッジ────────────────────────────────────────────────── ─── Continuation of front page    (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, L U, MC, NL, PT, SE), OA (BF, BJ, CF) , CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (KE, LS, MW, SD, S Z, UG), EA (AM, AZ, BY, KG, KZ, MD , RU, TJ, TM), AL, AM, AT, AU, AZ , BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, G E, HU, IL, IS, JP, KE, KG, KP, KR , KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, P L, PT, RO, RU, SD, SE, SG, SI, SK , TJ, TM, TR, TT, UA, UG, UZ, VN (72) Inventor Astana, Omkar Prasad             India, Lucknow 226004, Charva             Gu, Rockman Ganj 2237 (72) Inventor Ray, Slab Hat             India, Lucknow 226001, Salodini               Naido Marg, KA 16             / 3, Behind Masonic Lodge

Claims (1)

【特許請求の範囲】 １．乳癌の治療又は予防のための医薬組成物の製造のための、医薬として許容 される担体と組み合わせた、３，４−トランス−２，２−ジメチル−３−フェニ ル−４−〔４−（２−（ピロリジン−１−イル）エトキシ）フェニル〕−７−メ トキシクロマンのｌ−鏡像異性体又はその医薬として許容される塩の使用。 ２．前記組成物が経口投与に適した形態であることを特徴とする請求項１に記 載の使用。 ３．前記化合物が、１日当り患者１kg当り約0.001〜75mgの範囲の投与量とし て投与されることを特徴とする先の請求項のいずれか一に記載の使用。 ４．前記組成物が、１日又は週当り、１又は複数回投与されることを特徴とす る先の請求項のいずれか一に記載の使用。 ５．前記組成物が皮膚のインプラントの形態であることを特徴とする先の請求 項のいずれか一に記載の使用。 ６．乳癌の治療及び予防のための方法であって、乳癌を治療又は防止するのに 十分な量において、先の請求項のいずれか一に記載される３，４−トランス−２ ，２−ジメチル−３−フェニル−４−〔４−（２−（ピロリジン−１−イル）エ トキシ）フェニル〕−７−メトキシクロマンのｌ−鏡像異性体又はその医薬とし て許容される塩の臨床的に有効な量を、患者に投与することを含む方法。 ７．乳癌を治療又は防止する方法であって、臨床的に有効な量の、３，４−ト ランス−２，２−ジメチル−３−フェニル−４−〔４−（２−（ピロリジン−１ −イル）エトキシ）フェニル〕−７−メトキシクロマンのｌ−鏡像異性体の化合 物又はその塩及び該化合物を含む医薬として許容される組成物を、治療の必要な 患者に投与す ることを含む方法。[Claims]   1. Pharmaceutically acceptable for the manufacture of a pharmaceutical composition for the treatment or prevention of breast cancer 3,4-trans-2,2-dimethyl-3-phenyl in combination with a carrier to be Ru-4- [4- (2- (pyrrolidin-1-yl) ethoxy) phenyl] -7-me Use of the 1-enantiomer of toxicloman or a pharmaceutically acceptable salt thereof.   2. The composition of claim 1, wherein the composition is in a form suitable for oral administration. Use.   3. The compound may be administered in a dosage ranging from about 0.001 to 75 mg / kg patient per day. The use according to any one of the preceding claims, characterized in that it is administered in a controlled manner.   4. Wherein the composition is administered one or more times per day or week. Use according to any one of the preceding claims.   5. The preceding claim, wherein the composition is in the form of a skin implant Use according to any one of the preceding clauses.   6. A method for treating and preventing breast cancer, wherein the method is for treating or preventing breast cancer. In a sufficient amount, the 3,4-trans-2 according to any one of the preceding claims is present. , 2-Dimethyl-3-phenyl-4- [4- (2- (pyrrolidin-1-yl) e Toxi) phenyl] -7-methoxychroman 1-enantiomer or a medicament thereof Administering to a patient a clinically effective amount of a tolerable salt.   7. A method for treating or preventing breast cancer, comprising administering a clinically effective amount of 3,4-to- Lance-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidine-1 -Yl) ethoxy) phenyl] -7-methoxychroman l-enantiomer Or a pharmaceutically acceptable composition comprising the compound or a salt thereof, and the compound required for treatment. Administer to patient A method that includes:
JP09524767A 1996-01-11 1997-01-09 Use of the 1-enantiomer of St. chroman for the manufacture of a pharmaceutical composition for the treatment and prevention of breast cancer Pending JP2001500101A (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US1000096P 1996-01-11 1996-01-11
DK60/010,000 1996-07-11
DK0776/96 1996-07-11
DK77696 1996-07-11
PCT/DK1997/000007 WO1997025034A1 (en) 1996-01-11 1997-01-09 Use of the l-enantiomer of centchroman for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of breast cancer

Publications (1)

Publication Number Publication Date
JP2001500101A true JP2001500101A (en) 2001-01-09

Family

ID=26064631

Family Applications (1)

Application Number Title Priority Date Filing Date
JP09524767A Pending JP2001500101A (en) 1996-01-11 1997-01-09 Use of the 1-enantiomer of St. chroman for the manufacture of a pharmaceutical composition for the treatment and prevention of breast cancer

Country Status (12)

Country Link
EP (1) EP0873119A1 (en)
JP (1) JP2001500101A (en)
KR (1) KR19990077157A (en)
AU (1) AU1367197A (en)
BR (1) BR9706966A (en)
CA (1) CA2241462A1 (en)
CZ (1) CZ217198A3 (en)
HU (1) HUP9901633A3 (en)
IL (1) IL124881A0 (en)
NO (1) NO983177L (en)
PL (1) PL328135A1 (en)
WO (1) WO1997025034A1 (en)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1028724A1 (en) * 1997-11-10 2000-08-23 Novo Nordisk A/S Transdermal delivery of 3,4-diarylchromans
US7005428B1 (en) 1998-06-11 2006-02-28 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
US6465445B1 (en) * 1998-06-11 2002-10-15 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
AU2004200099B2 (en) * 1998-06-11 2006-11-02 Endorecherche, Inc. Medical Uses of A Selective Estrogen Receptor Modulator in Combination with Sex Steroid Precursors
AU2011253842B2 (en) * 1998-06-11 2014-08-14 Endorecherche Inc. Medical Uses of a Selective Estrogen Receptor Modulator in Combination with Sex Steroid Precursors
HUE025651T2 (en) 2004-10-20 2016-04-28 Endorecherche Inc Sex steroid precursor in combination with a selective estrogen receptor modulator for the prevention and treatment of vaginal atrophy in postmenopausal women
US8268806B2 (en) 2007-08-10 2012-09-18 Endorecherche, Inc. Pharmaceutical compositions
BRPI0818637A2 (en) 2007-10-16 2015-04-07 Repros Therapeutics Inc Methods of treating symptom of impaired fasting glucose, metabolic syndrome, metabolic syndrome, and impaired fasting glucose in subjects with secondary or idiopathic hypogonadotropic hypogonadism
US20100317635A1 (en) 2009-06-16 2010-12-16 Endorecherche, Inc. Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators
KR101731008B1 (en) 2010-06-16 2017-04-27 앙도르쉐르슈 인코포레이티드 Methods of treating or preventing estrogen-related diseases
JP2015508825A (en) 2012-02-29 2015-03-23 レプロス セラピューティクス インコーポレイティド Combination therapy to treat androgen deficiency
US9744177B2 (en) 2014-03-10 2017-08-29 Endorecherche, Inc. Treatment of male androgen deficiency symptoms or diseases with sex steroid precursor combined with SERM
EP3373967B9 (en) 2015-11-10 2023-10-04 Paracrine Therapeutics AB Treatment of er-negative breast cancer with an pdgf-cc inhibitor and an anti estrogen

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4447622A (en) * 1981-09-22 1984-05-08 Council Of Scientific And Industrial Research Rafi Marg Preparation of l- and d-isomers of dl-3,4-trans-2,2-disubstituted-3,4-diarylchromans and derivatives thereof

Also Published As

Publication number Publication date
HUP9901633A3 (en) 2000-02-28
NO983177L (en) 1998-07-10
IL124881A0 (en) 1999-01-26
AU1367197A (en) 1997-08-01
KR19990077157A (en) 1999-10-25
EP0873119A1 (en) 1998-10-28
CZ217198A3 (en) 1998-11-11
CA2241462A1 (en) 1997-07-17
WO1997025034A1 (en) 1997-07-17
BR9706966A (en) 1999-05-04
PL328135A1 (en) 1999-01-18
HUP9901633A2 (en) 1999-10-28

Similar Documents

Publication Publication Date Title
AU2009200258B2 (en) Methods of treating and/or suppressing weight gain
CA2522761C (en) Folic acid-containing pharmaceutical compositions, and related methods and delivery systems
JP2000506508A (en) Use of 3,4-diphenylchroman for the manufacture of a pharmaceutical composition for the treatment or prevention of benign prostatic hyperplasia
US20060106004A1 (en) Unique methods and formulations of bio-identical sex steroids for the treatment of pathophysiologic aberrations of menopause
JP2001500101A (en) Use of the 1-enantiomer of St. chroman for the manufacture of a pharmaceutical composition for the treatment and prevention of breast cancer
JP2000506506A (en) Use of 3,4-diphenylchroman for the manufacture of a pharmaceutical composition for the treatment or prevention of skin and / or mucosal atrophy
JPH10511962A (en) Use of 3,4-diphenylchroman for the manufacture of a pharmaceutical composition for treating or preventing gynecological diseases
EP0873122B1 (en) Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of prostatic carcinoma
KR19990077156A (en) Use of 3,4-diphenylchrome for the preparation of pharmaceutical compositions for the treatment or prevention of menopausal symptoms
JP2002505280A (en) Fluoxetine hydrochloride to reduce transient hot sensations
US5756539A (en) 3, 4-diphenyl chromans for inhibiting one or more psychiatric disorders
JPH10511961A (en) 3,4-diphenyl for the treatment or prevention of hyperlipoproteinemia, hypertriglyceridemia, hyperlipidemia or hypercholesterolemia, or for the manufacture of a pharmaceutical composition for anticoagulation treatment Use of chroman
JPH08507774A (en) Use of granisetron for the treatment of postoperative nausea and vomiting
US6008242A (en) Use of 1-centchroman for the manufacture of a pharmaceutical composition for the treatment of obesity
JP2000514441A (en) Use of 3,4-diphenylchroman for the manufacture of a pharmaceutical composition for inhibiting one or more symptoms of premenstrual syndrome
US5780502A (en) Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for inhibiting one or more symptoms of premenstrual syndrome
JPH10513154A (en) Use of 3,4-diphenylchroman in the manufacture of a pharmaceutical composition for the treatment or prevention of vasodilation
JPH10511960A (en) Use of 3,4-diphenyl chroman for the manufacture of a pharmaceutical preparation for the treatment or prevention of idiopathic or physiological gynecomastia
JP2999539B2 (en) Prevention and treatment of leukopenia
CN1207037A (en) Use of the L-enantiomer of centchroman for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of breast cancer
CN1207038A (en) Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of menopausal symptoms
WO1999048497A1 (en) USE OF 3,4-DIPHENYLCHROMANS FOR THE MANUFACTURE OF A PHARMACEUTICAL COMPOSITION FOR LOWERING PLASMA LEVELS OF Lp(a) IN A HUMAN OR SUB-HUMAN PRIMATE