JPS6149294B2 - - Google Patents
Info
- Publication number
- JPS6149294B2 JPS6149294B2 JP52010847A JP1084777A JPS6149294B2 JP S6149294 B2 JPS6149294 B2 JP S6149294B2 JP 52010847 A JP52010847 A JP 52010847A JP 1084777 A JP1084777 A JP 1084777A JP S6149294 B2 JPS6149294 B2 JP S6149294B2
- Authority
- JP
- Japan
- Prior art keywords
- solution
- diphenyl
- mol
- isomer
- ethanol
- 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.)
- Expired
Links
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 230000008018 melting Effects 0.000 description 11
- 238000002844 melting Methods 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 6
- -1 ethanol -(p-bromophenyl)-1-butanol Chemical compound 0.000 description 5
- 239000002904 solvent Substances 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 229960001603 tamoxifen Drugs 0.000 description 3
- UHKJKVIZTFFFSB-UHFFFAOYSA-N 1,2-diphenylbutan-1-one Chemical compound C=1C=CC=CC=1C(CC)C(=O)C1=CC=CC=C1 UHKJKVIZTFFFSB-UHFFFAOYSA-N 0.000 description 2
- KDKKRJMQCQNZDY-UHFFFAOYSA-N 1-(1,2-diphenylbut-1-enyl)-4-fluorobenzene Chemical class C=1C=CC=CC=1C(CC)=C(C=1C=CC(F)=CC=1)C1=CC=CC=C1 KDKKRJMQCQNZDY-UHFFFAOYSA-N 0.000 description 2
- LSZQQLHQPDOPJW-UHFFFAOYSA-N 1-(4-chlorophenyl)-1,2-diphenylbutan-1-ol Chemical compound C1(=CC=CC=C1)C(C(CC)C1=CC=CC=C1)(O)C1=CC=C(C=C1)Cl LSZQQLHQPDOPJW-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- XWIKPNQTSLCDMC-UHFFFAOYSA-N 1-(4-bromophenyl)-1,2-diphenylbutan-1-ol Chemical compound C1(=CC=CC=C1)C(C(CC)C1=CC=CC=C1)(O)C1=CC=C(C=C1)Br XWIKPNQTSLCDMC-UHFFFAOYSA-N 0.000 description 1
- MOSIKPSTRPODHQ-UHFFFAOYSA-N 1-(4-bromophenyl)-2-phenylethan-1-one Chemical compound C1=CC(Br)=CC=C1C(=O)CC1=CC=CC=C1 MOSIKPSTRPODHQ-UHFFFAOYSA-N 0.000 description 1
- PKWCGWGPYGPHOQ-UHFFFAOYSA-N 1-(4-fluorophenyl)-1,2-diphenylbutan-1-ol Chemical compound C1(=CC=CC=C1)C(C(CC)C1=CC=CC=C1)(O)C1=CC=C(C=C1)F PKWCGWGPYGPHOQ-UHFFFAOYSA-N 0.000 description 1
- NUNRCACEJFCJLA-UHFFFAOYSA-N 1-bromo-4-(1,2-diphenylbut-1-enyl)benzene Chemical compound C=1C=CC=CC=1C(CC)=C(C=1C=CC(Br)=CC=1)C1=CC=CC=C1 NUNRCACEJFCJLA-UHFFFAOYSA-N 0.000 description 1
- NHDODQWIKUYWMW-UHFFFAOYSA-N 1-bromo-4-chlorobenzene Chemical compound ClC1=CC=C(Br)C=C1 NHDODQWIKUYWMW-UHFFFAOYSA-N 0.000 description 1
- AITNMTXHTIIIBB-UHFFFAOYSA-N 1-bromo-4-fluorobenzene Chemical compound FC1=CC=C(Br)C=C1 AITNMTXHTIIIBB-UHFFFAOYSA-N 0.000 description 1
- VUXXHBSIYVYJDA-UHFFFAOYSA-N 1-chloro-4-(1,2-diphenylbut-1-enyl)benzene Chemical class C=1C=CC=CC=1C(CC)=C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 VUXXHBSIYVYJDA-UHFFFAOYSA-N 0.000 description 1
- KVNQDINBFMRKLP-UHFFFAOYSA-N 1-chloro-4-(1,2-diphenylprop-1-enyl)benzene Chemical compound C1(=CC=CC=C1)C(=C(C)C1=CC=CC=C1)C1=CC=C(C=C1)Cl KVNQDINBFMRKLP-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- ARSRBNBHOADGJU-UHFFFAOYSA-N 7,12-dimethyltetraphene Chemical compound C1=CC2=CC=CC=C2C2=C1C(C)=C(C=CC=C1)C1=C2C ARSRBNBHOADGJU-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- VFZRZRDOXPRTSC-UHFFFAOYSA-N DMBA Natural products COC1=CC(OC)=CC(C=O)=C1 VFZRZRDOXPRTSC-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical class C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 150000001344 alkene derivatives Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 201000010198 papillary carcinoma Diseases 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000383 tetramethylene group Chemical class [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
- C07C49/813—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen polycyclic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/35—Preparation of halogenated hydrocarbons by reactions not affecting the number of carbon or of halogen atoms in the reaction
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
- C07C25/24—Halogenated aromatic hydrocarbons with unsaturated side chains
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
【発明の詳細な説明】
本発明は一般式()
（式中、Ｒはエチル基を示し、そしてＸはハロ
ゲン原子を示す）のトリフエニルアルケン誘導体
およびそれらの幾何異性体に関する。[Detailed Description of the Invention] The present invention relates to the general formula () (wherein R represents an ethyl group and X represents a halogen atom) and their geometric isomers.
本発明による化合物は有益な生物学的活性を有
する。更にこれらはタモキシフエン
（Tamoxifen）〔（Ｚ）―１，２―ジフエニル―１
―｛ｐ―〔２―（ジメチルアミノ）―エトキシ〕
―フエニル｝―１―ブテン〕、即ち乳頭癌に対す
る公知薬剤および関連化合物（英国特許明細書第
1013907号および同第1064629号参照）の製造にも
使用できる。 The compounds according to the invention have beneficial biological activities. Furthermore, these are tamoxifen (Tamoxifen) [(Z)-1,2-diphenyl-1
-{p-[2-(dimethylamino)-ethoxy]
-Phenyl}-1-butene], known drugs and related compounds for papillary carcinoma (UK Patent Specification No.
1013907 and 1064629).
１，２―ジフエニル―１―（ｐ―クロロフエニ
ル）―１―プロペンはG.E.Nousa外（「J.Appl.
Chem」（1970年）256頁）が述べているが、その
生物学的活性は調査されていなかつた。その上、
一般止()の化合物の構造に関連した構造を有す
るエチレン誘導体はすでに述べられている。
（Ng.Ph.Buu―Hoi，「J.Chem.Soc.」（1948年）
1080頁；W.Tadros，「J.Chem.Soc.」（1949年），
439頁；Ng.Ph.Buu―Hoi，「J.Org.Chem.」第22
巻1057頁（1957年）；A.Boris外、「Arch.int.
Phamacodyn.」第151巻、475頁（1964年）；H.
N.Fox外，「J.Med.Chem.」第８巻250頁（1965
年））、前記のこれらの公知化合物はアルケン誘導
体の合成に一般的に用いられる方法、即ち対応す
る第三級アルカノール誘導体から水を除去するこ
とによつて調製されてきた。 1,2-diphenyl-1-(p-chlorophenyl)-1-propene is available from GENousa (“J.Appl.
Chem (1970) p. 256), but its biological activity had not been investigated. On top of that,
Ethylene derivatives having a structure related to that of the general compound () have already been described.
(Ng.Ph.Buu-Hoi, “J.Chem.Soc.” (1948)
1080 pages; W. Tadros, “J.Chem.Soc.” (1949),
439 pages; Ng.Ph.Buu-Hoi, “J.Org.Chem.” No. 22
Volume 1057 (1957); A. Boris et al., “Arch.int.
151, p. 475 (1964); H.
N.Fox et al., “J.Med.Chem.” Vol. 8, p. 250 (1965)
), these known compounds mentioned above have been prepared by methods commonly used for the synthesis of alkene derivatives, namely by removing water from the corresponding tertiary alkanol derivatives.
一般式()の新規なトリフエニルアルケン誘導
体およびそれらの幾何異性体は一般式()
（式中、ＲおよびＸは上記と同一の意味をも
ち、そしてR1およびR2はそれぞれ相異なつて、
水素原子もしくはヒドロキシル基を示す）の新規
なトリフエニルアルカノール誘導体を脱水するこ
とによつて製造できる。上記式()中のR1及びR2
の定義は、R1が水素のときはR2がヒドロキシル
基であり、R1がヒドロキシル基のときはR2が水
素であることを意味する。 Novel triphenylalkene derivatives of the general formula () and their geometric isomers are expressed by the general formula () (wherein R and X have the same meanings as above, and R 1 and R 2 are different,
It can be produced by dehydrating a novel triphenylalkanol derivative (representing a hydrogen atom or a hydroxyl group). R 1 and R 2 in the above formula ()
The definition means that when R 1 is hydrogen, R 2 is a hydroxyl group, and when R 1 is a hydroxyl group, R 2 is hydrogen.
脱水、即ち、水の除去は無機酸、たとえば塩
酸、臭化水素酸、リン酸又は有機酸、たとえばト
リフルオロ酢酸もしくは蟻酸の存在下、希釈剤中
もしくは溶媒中たとえば水性エタノール中におい
て実施する。 Dehydration, ie, removal of water, is carried out in the presence of an inorganic acid, such as hydrochloric acid, hydrobromic acid, phosphoric acid, or an organic acid, such as trifluoroacetic acid or formic acid, in a diluent or in a solvent, such as aqueous ethanol.
幾何異性体は分別結晶もしくはクロマトグラフ
イーによつて分離することができる。 Geometric isomers can be separated by fractional crystallization or chromatography.
本発明によるトリフエニルアルケン誘導体は動
物内でDMBAによつて誘発されたホルモンによ
る実験的腫瘍の増殖を有意な程度抑制する。 The triphenylalkene derivatives according to the invention suppress to a significant extent the hormone-induced experimental tumor growth induced by DMBA in animals.
本発明による化合物は一般式()の化合物の少
なくとも一種を無毒性で、治療に適した希釈剤お
よび／又は担体と共に医薬製剤に変換することに
よつて医薬製剤を製造するのに用いることができ
る。本製剤は経口もしくは非経口的に投与でき
る。 The compounds according to the invention can be used to prepare pharmaceutical formulations by converting at least one compound of general formula () into a pharmaceutical formulation together with non-toxic and therapeutically suitable diluents and/or carriers. . The formulation can be administered orally or parenterally.
本発明による化合物および方法は以下の製造例
を以つてより詳しく説明されるが、これらは本発
明の範囲を限定するものではない。 The compounds and methods according to the invention are explained in more detail with the following Preparation Examples, which are not intended to limit the scope of the invention.
製造例 １
エタノール1400ml中の１，２―ジフエニル―１
―（ｐ―ブロモフエニル）―１―ブタノール
135.0g（0.355モル）溶液を36％塩酸300mlと一緒
に５時間沸騰した。エタノールを真空中で留去
し、そして水性残留物を全量1500mlの二酸化メチ
レンで数回に分け抽出した。有機相を中性になる
まで水で洗浄し、次いで乾燥した。溶媒を蒸発し
たところ、粗製の結晶性生成物がエタノールから
再結晶し、120.0g（93％）の１，２―ジフエニル
―１―（ｐ―ブロモフエニル）―１―ブテン（融
点＝64―82℃）を生成した。（Ｚ）異性体と
（Ｅ）異性体の割合は１：１であつた。Production example 1 1,2-diphenyl-1 in 1400ml of ethanol
-(p-bromophenyl)-1-butanol
A 135.0 g (0.355 mol) solution was boiled with 300 ml of 36% hydrochloric acid for 5 hours. The ethanol was distilled off in vacuo and the aqueous residue was extracted in portions with a total volume of 1500 ml of methylene dioxide. The organic phase was washed with water until neutral and then dried. Upon evaporation of the solvent, the crude crystalline product recrystallized from ethanol and yielded 120.0 g (93%) of 1,2-diphenyl-1-(p-bromophenyl)-1-butene (mp = 64-82°C). ) was generated. The ratio of (Z) isomer to (E) isomer was 1:1.
この生成物をイソプロパノールから三回再結晶
したところ、融点が112―115℃の（Ｚ）異性体が
得られた。母液を蒸発乾固し、そして残留物をメ
タノールから２回再結晶したところ、融点89―92
℃の（Ｅ）異性体を生成した。 The product was recrystallized three times from isopropanol to give the (Z) isomer with a melting point of 112-115°C. The mother liquor was evaporated to dryness and the residue was recrystallized twice from methanol, mp 89-92.
The (E) isomer was produced.
出発物質の１，２―ジフエニル―１―（ｐ―ブ
ロモフエニル）―１―ブタノールを以下のように
して得た。 The starting material, 1,2-diphenyl-1-(p-bromophenyl)-1-butanol, was obtained as follows.
無水エタノール600ml中のナトリウム20.6g
（0.90モル）溶液を165.0g（0.60モル）の４―ブ
ロモデオキシベンゾイン（I.L.Kotly―arevskjiお
よびN.I.Popova，「Izv.Akad.Nauk.SSSR.Ser.
Khim」（1967年）208頁）と合併した。この冷却
した溶液をヨウ化エチル140.0g（0.90モル）と合
併し、そして５時間沸騰した。反応混液を氷水に
注いだとき、油状の生成物が得られ、２〜３時間
以内に固化し、過および乾燥した。得られた４
―ブロモ―α―エチル―デオキシベンゾインを蒸
留精製した。収量：155.5g（85.5％）；融点＝50
―53℃；沸点＝173―180℃（0.7トル）
無水エーテル600ml中のマグネシウム14.6g
（0.60モル）を撹拌下で無水エーテル100ml中のブ
ロモベンゼン94.2g（0.60モル）の溶液と反応さ
せた。生成したグリニヤール試薬の冷却溶液に、
無水エーテル300ml中の４―ブロモ―α―エチル
―デオキシベンゾイン151.5g（0.50モル）の溶液
を添加し、そして混合物を１時間沸騰した。次い
で、1.0N塩酸600mlを冷却した反応混液に添加
し、そして有機相を分離した。この水性層をエー
テルで数回抽出し、次いで合併したエーテル相を
10％塩化アンモニウム溶液および水で振盪した。
乾燥後、溶媒を蒸留除去し、そして粗製の結晶性
生成物を90％エタノールから再結晶し、１，２―
ジフエニル―１―（ｐ―ブロモフエニル）―１―
ブタノール152.0g（79.6％）を生成した。融点＝
138―140℃
製造例 ２
エタノール3800ml中の１，２―ジフエニル―１
―（ｐ―フルオロフエニル）―１―ブタノール
320.0g（1.0モル）の溶液に36％塩酸850mlを添加
し、そして混合物を１時間沸騰した。冷却した溶
液から沈殿した結晶を過し、そして中性になる
まで水で数回洗浄した。母液を当初の半量に蒸発
したところ、別の量の生成物が得られた。90％エ
タノールから粗製の生成物（290g）を再結晶し
たところ、１，２―ジフエニル―１―（ｐ―フル
オロフエニル）―１―ブテンの異性体混合物を
257.0g（84.9％）の収量で得た。融点＝65―70
℃；(Z)異性体と(E)異性体の割合は１：１であつ
た。この異性体の混合物は硝酸銀で含浸した、
0.063―0.20mmの粒子サイズを有するシリカゲル
のカラム上で、（石油エーテルもしくはシクロヘ
キサンのような）非極性溶媒で溶出することによ
つて分離した。この混合物5gから77―80℃の融
点を有する(Z)―異性体2.46g（49.3％）および78
―82℃の融点を有する(E)―異性体1.21g（24.2
％）が得られた。 20.6g sodium in 600ml absolute ethanol
(0.90 mol) solution of 165.0 g (0.60 mol) of 4-bromodeoxybenzoin (ILKotly-arevskji and NIPopova, "Izv.Akad.Nauk.SSSR.Ser.
Khim (1967, p. 208). This cooled solution was combined with 140.0 g (0.90 moles) of ethyl iodide and boiled for 5 hours. When the reaction mixture was poured into ice water, an oily product was obtained which solidified within 2-3 hours, filtered and dried. obtained 4
-Bromo-α-ethyl-deoxybenzoin was purified by distillation. Yield: 155.5g (85.5%); Melting point = 50
-53°C; boiling point = 173-180°C (0.7 torr) 14.6 g of magnesium in 600 ml of anhydrous ether
(0.60 mol) was reacted with a solution of 94.2 g (0.60 mol) of bromobenzene in 100 ml of anhydrous ether under stirring. To the cooled solution of Grignard reagent produced,
A solution of 151.5 g (0.50 mol) of 4-bromo-α-ethyl-deoxybenzoin in 300 ml of absolute ether was added and the mixture was boiled for 1 hour. Then 600 ml of 1.0N hydrochloric acid were added to the cooled reaction mixture and the organic phase was separated. This aqueous layer was extracted several times with ether, then the combined ether phase was
Shake with 10% ammonium chloride solution and water.
After drying, the solvent was distilled off and the crude crystalline product was recrystallized from 90% ethanol to give 1,2-
Diphenyl-1-(p-bromophenyl)-1-
152.0g (79.6%) of butanol was produced. Melting point =
138-140℃ Production example 2 1,2-diphenyl-1 in 3800ml of ethanol
-(p-fluorophenyl)-1-butanol
To the 320.0 g (1.0 mole) solution was added 850 ml of 36% hydrochloric acid and the mixture was boiled for 1 hour. The crystals precipitated from the cooled solution were filtered and washed several times with water until neutral. Evaporation of the mother liquor to half the original volume gave another amount of product. Recrystallization of the crude product (290 g) from 90% ethanol yielded a mixture of isomers of 1,2-diphenyl-1-(p-fluorophenyl)-1-butene.
Obtained with a yield of 257.0g (84.9%). Melting point = 65-70
°C; The ratio of (Z) isomer to (E) isomer was 1:1. This mixture of isomers was impregnated with silver nitrate,
Separation was performed on a column of silica gel with a particle size of 0.063-0.20 mm by elution with a non-polar solvent (such as petroleum ether or cyclohexane). From 5 g of this mixture, 2.46 g (49.3%) of the (Z)-isomer with a melting point of 77-80°C and 78
1.21 g (24.2
%)was gotten.
出発物質として用いた１，２―ジフエニル―１
―（ｐ―フルオロフエニル）―１―ブタノールは
以下のように調製した。 1,2-diphenyl-1 used as starting material
-(p-fluorophenyl)-1-butanol was prepared as follows.
無水エーテル150ml中のマグネシウム29.2g
（120モル）を撹拌しながら無水エーテル420ml中
の１―ブロモ―４―フルオロベンゼン210.0g
（1.20モル）溶液と反応させ、次いでこの溶液を
冷却し、そしてエーテル1000ml中のα―エチル―
デオキシベンゾイン（T.E.ZalleskayaおよびO.
A.Netsetskaya，「Zh.Org.Khim.」第５巻1076頁
（1969年））224.3g（1.0モル）の溶液で処理し
た。この反応混液を４時間沸騰し、次いで冷却
し、10％塩化アンモニウム溶液1000mlで分解し、
このエーテル部を分取し、次にこの水相を別のエ
ーテルで抽出し、そして合併したエーテル溶液を
蒸発乾固した。 Magnesium 29.2g in 150ml anhydrous ether
(120 mol) in 420 ml of anhydrous ether with stirring 210.0 g of 1-bromo-4-fluorobenzene
(1.20 mol) solution, the solution is then cooled and α-ethyl-
Deoxybenzoin (TEZalleskaya and O.
A. Netsetskaya, "Zh.Org.Khim." Vol. 5, p. 1076 (1969)) 224.3 g (1.0 mol) of the solution. The reaction mixture was boiled for 4 hours, then cooled and decomposed with 1000 ml of 10% ammonium chloride solution.
The ether portion was separated, the aqueous phase was then extracted with further ether, and the combined ether solutions were evaporated to dryness.
こうして得られた、結晶形態をした１，２―ジ
フエニル―１―（ｐ―フルオロフエニル）―１―
ブタノール（314.0g（98％）；融点＝80―88℃）
はそれ以上の精製をせずに適当なブテン誘導体に
変換できた。90％エタノールからの再結晶の後、
生成物の融点は94―96℃であつた。 The thus obtained crystalline 1,2-diphenyl-1-(p-fluorophenyl)-1-
Butanol (314.0g (98%); melting point = 80-88℃)
could be converted to the appropriate butene derivative without further purification. After recrystallization from 90% ethanol,
The melting point of the product was 94-96°C.
製造例 ３
エタノール400ml中の１，２―ジフエニル―１
―（ｐ―クロロフエニル）―１―ブタノール
33.7g（0.10モル）の溶液に36％塩酸85mlと２時
間沸騰した。この溶液を冷却し、そして沈殿した
結晶を過し、そして水で洗浄し、次に90％エタ
ノールから再結晶したところ、１，２―ジフエニ
ル―１―（ｐ―クロロフエニル）―１―ブテン異
性体の混合物（融点＝67―80℃）28.3g（88.8
％）を生成した。(Z)異性体と(E)異性体の割合は
１：１であつた。Production example 3 1,2-diphenyl-1 in 400ml of ethanol
-(p-chlorophenyl)-1-butanol
A solution of 33.7 g (0.10 mol) was boiled with 85 ml of 36% hydrochloric acid for 2 hours. The solution was cooled and the precipitated crystals were filtered and washed with water and then recrystallized from 90% ethanol, yielding the 1,2-diphenyl-1-(p-chlorophenyl)-1-butene isomer. (melting point = 67-80℃) 28.3g (88.8
%). The ratio of (Z) isomer to (E) isomer was 1:1.
出発物質の１，２―ジフエニル―１―（ｐ―ク
ロロフエニル）―１―ブタノールは以下のように
製造できた。 The starting material, 1,2-diphenyl-1-(p-chlorophenyl)-1-butanol, could be produced as follows.
無水エーテル2.5ml中のマグネシウム4.38g
（0.18モル）をかきまぜながら、無水エーテル70
ml中の１―ブロモ―４―クロロベンゼン34.4g
（0.18モル）溶液と反応させ、次いでこの冷却溶
液に無水エーテル140ml中のα―エチル―デオキ
シベンゾイン33.6g（0.15モル）の溶液を添加
し、そしてこの混液を４時間沸騰した。冷却した
混合物を塩化アンモニウム溶液で分解し、水相を
別のエーテルと共に振盪した。溶媒の蒸留除去後
に得られた粗製の結晶性生成物はエタノールから
再結晶により、１，２―ジフエニル―１―（ｐ―
クロロフエニル）―１―ブタノール（融点＝109
―111℃）44.0g（87.1％）を生成した。 Magnesium 4.38g in 2.5ml anhydrous ether
(0.18 mol) with stirring, anhydrous ether 70
1-bromo-4-chlorobenzene 34.4g in ml
(0.18 mol) solution, then to this cooled solution was added a solution of 33.6 g (0.15 mol) α-ethyl-deoxybenzoin in 140 ml of anhydrous ether, and the mixture was boiled for 4 hours. The cooled mixture was decomposed with ammonium chloride solution and the aqueous phase was shaken with more ether. The crude crystalline product obtained after distillative removal of the solvent was recrystallized from ethanol to 1,2-diphenyl-1-(p-
Chlorophenyl)-1-butanol (melting point = 109
-111℃) produced 44.0g (87.1%).
使用例 １
製造例２で得た１，２―ジフエニル―１―（ｐ
―フルオロフエニル）―１―ブテンを用いて前記
したタモキシフエンを以下のようにして製造し
た。Usage example 1 1,2-diphenyl-1-(p
The above-mentioned tamoxifen was produced using -fluorophenyl)-1-butene as follows.
ナトリウム6.90g（0.3モル）を無水２―（ジメ
チルアミノ）―エタノール53.40g（0.6モル）に
溶かした。得られた溶液を冷却し、１，２―ジフ
エニル―１―（ｐ―フルオロフエニル）―１―ブ
テン45.40g（0.15モル）を合併および170℃で２
〜2.5時間撹拌した。冷却した溶液を水500mlで希
釈しそして少し宛添加した四塩化炭素1500mlで抽
出した。合併した有機相を中性になるまで水で洗
浄し、次いで乾燥した。濾過した四塩化炭素溶液
をガス状塩酸で処理した。１，２―ジフエニル―
１―｛ｐ―〔２―ジメチルアミノ）―エトキシ〕
―フエニル｝―１―ブテン塩酸塩の沈澱異性体混
合物を吸引濾過し、そして五酸化リン上で真空乾
燥した。収量：51.0g（82.5％）；融点＝164ない
し167℃
塩酸塩の異性体混合物を0.06％塩酸からくりか
えし再結晶し、次いで(Z)異性体の塩を単離し
た。収量：26.5g（42.7％）；融点＝190―192℃
この塩酸塩を少量のメタノールに溶かし直ちに
1.0N塩酸と混合した。沈澱した(Z)―１，２―フ
エニル―１―｛ｐ―〔２―（ジメチルアミノ）―
エトキシ〕―フエニル｝―１―ブテンを濾過し、
水で洗浄および塩化カルシウム上で乾燥した。収
量：23.0g（41.4％）；融点＝96〜98.5℃ 6.90 g (0.3 mol) of sodium was dissolved in 53.40 g (0.6 mol) of anhydrous 2-(dimethylamino)-ethanol. The resulting solution was cooled, 45.40 g (0.15 mol) of 1,2-diphenyl-1-(p-fluorophenyl)-1-butene was added, and 2
Stirred for ~2.5 hours. The cooled solution was diluted with 500 ml of water and extracted with 1500 ml of carbon tetrachloride added in portions. The combined organic phases were washed with water until neutral and then dried. The filtered carbon tetrachloride solution was treated with gaseous hydrochloric acid. 1,2-diphenyl-
1-{p-[2-dimethylamino)-ethoxy]
The precipitated isomer mixture of -phenyl}-1-butene hydrochloride was filtered with suction and dried in vacuo over phosphorus pentoxide. Yield: 51.0 g (82.5%); mp = 164-167°C. The isomer mixture of the hydrochloride salt was repeatedly recrystallized from 0.06% hydrochloric acid, and then the salt of the (Z) isomer was isolated. Yield: 26.5g (42.7%); Melting point = 190-192℃ Dissolve this hydrochloride in a small amount of methanol and immediately
Mixed with 1.0N hydrochloric acid. Precipitated (Z)-1,2-phenyl-1-{p-[2-(dimethylamino)-
Filter the ethoxy]-phenyl}-1-butene,
Washed with water and dried over calcium chloride. Yield: 23.0g (41.4%); Melting point = 96-98.5℃
Claims (1)
ゲン原子を示す）のトリフエニルアルケン誘導体
およびそれらの幾何異性体。[Claims] 1. General formula (wherein R represents an ethyl group and X represents a halogen atom) and geometric isomers thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU76GO00001328A HU171269B (en) | 1976-02-05 | 1976-02-05 | Process for preparing new triphenyl-alkene derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS52122352A JPS52122352A (en) | 1977-10-14 |
| JPS6149294B2 true JPS6149294B2 (en) | 1986-10-29 |
Family
ID=10996802
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1084777A Granted JPS52122352A (en) | 1976-02-05 | 1977-02-04 | Triphenyl alkene derivatives and process for preparing same |
Country Status (11)
| Country | Link |
|---|---|
| JP (1) | JPS52122352A (en) |
| AT (1) | AT345804B (en) |
| CA (1) | CA1087212A (en) |
| CH (1) | CH624655A5 (en) |
| DE (1) | DE2704690A1 (en) |
| HU (1) | HU171269B (en) |
| NL (1) | NL7701025A (en) |
| PL (1) | PL105534B1 (en) |
| SE (1) | SE431324B (en) |
| SU (1) | SU856376A3 (en) |
| YU (1) | YU39669B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE2423T1 (en) * | 1978-11-07 | 1983-03-15 | Imperial Chemical Industries Plc | 1-ACYLOXYPHENYL-1,2-DIPHENYLALKEN DERIVATIVES, PROCESS FOR THEIR PREPARATION AND A PHARMACEUTICAL COMPOSITION CONTAINING THESE DERIVATIVES. |
| US5030764A (en) * | 1986-05-23 | 1991-07-09 | Hoffmann-La Roche Inc. | Novel tetrahydronaphthalene and indane derivatives |
| US5030765A (en) * | 1986-05-23 | 1991-07-09 | Hoffmann-La Roche Inc. | Novel tetrahydronaphthalene and indane derivatives |
| ZW7487A1 (en) * | 1986-05-23 | 1987-12-16 | Hoffmann La Roche | Tetrahydronaphthaline and indane derivatives |
| AT388728B (en) * | 1987-03-17 | 1989-08-25 | Hoffmann La Roche | NEW TETRAHYDRONAPHTHALINE AND INDANDERIVATIVES |
| GB9714310D0 (en) * | 1997-07-07 | 1997-09-10 | Smithkline Beecham Plc | Process |
-
1976
- 1976-02-05 HU HU76GO00001328A patent/HU171269B/en unknown
-
1977
- 1977-01-28 SU SU772446005A patent/SU856376A3/en active
- 1977-02-01 AT AT59577A patent/AT345804B/en not_active IP Right Cessation
- 1977-02-01 NL NL7701025A patent/NL7701025A/en not_active Application Discontinuation
- 1977-02-03 SE SE7701213A patent/SE431324B/en not_active IP Right Cessation
- 1977-02-04 YU YU309/77A patent/YU39669B/en unknown
- 1977-02-04 PL PL1977195823A patent/PL105534B1/en unknown
- 1977-02-04 CH CH136077A patent/CH624655A5/en not_active IP Right Cessation
- 1977-02-04 CA CA271,086A patent/CA1087212A/en not_active Expired
- 1977-02-04 DE DE19772704690 patent/DE2704690A1/en active Granted
- 1977-02-04 JP JP1084777A patent/JPS52122352A/en active Granted
Non-Patent Citations (1)
| Title |
|---|
| JOURNAL OF APPLIED CHEMISTRY=1970 * |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS52122352A (en) | 1977-10-14 |
| SE7701213L (en) | 1977-08-06 |
| SE431324B (en) | 1984-01-30 |
| CA1087212A (en) | 1980-10-07 |
| PL105534B1 (en) | 1979-10-31 |
| SU856376A3 (en) | 1981-08-15 |
| HU171269B (en) | 1977-12-28 |
| ATA59577A (en) | 1978-02-15 |
| DE2704690A1 (en) | 1977-08-11 |
| YU30977A (en) | 1982-06-30 |
| CH624655A5 (en) | 1981-08-14 |
| YU39669B (en) | 1985-03-20 |
| DE2704690C2 (en) | 1987-01-29 |
| AT345804B (en) | 1978-10-10 |
| NL7701025A (en) | 1977-08-09 |
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