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Compounds with hydroxycarbonyl-halogenoalkyl side chains

a technology of hydroxycarbonyl halogenoalkyl and side chains, which is applied in the direction of antineoplastic agents, steroids, organic chemistry, etc., can solve the problems of reducing the therapeutic effect of oral administration, unable to inhibit the effect induced through the estrogen receptor, and unable to achieve the effect of blocking estrogen production, so as to improve the stability of oral activity, improve the effect of absorption from the intestinal tract and increase oral activity

Inactive Publication Date: 2005-09-01
CHUGAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009] The object of the present invention is to provide hydroxycarbonyl-halogenoalkyl derivatives designed to significantly increase oral activity of compounds having low activity following oral administration, compounds having anti-tumor activity, compounds having estrogenic activity or compounds having anti-estrogenic activity by enhancing their absorption from the intestinal tract and / or improving their stability against metabolism.
[0010] Our research efforts were directed to achieving the above object, and we have found that a side chain of general formula (1) allowed estrogenic compounds to show a significantly increased activity by oral route when attached to the parent scaffolds of the compounds. The present invention has been accomplished on the basis of this finding.
[0046] The present invention provides compounds wherein a moiety is chemically bonded to a group, wherein said moiety containing a compound having low activity following oral administration, a compound having anti-tumor activity, a compound having estrogenic activity or a compound having anti-estrogenic activity or the parent scaffolds of these compounds and said group having the general formula (1). As used herein, the term “chemically bonded” means that the group is bonded through a covalent bond and the like, including a C—C bond, a C—O bond, a C—N bond, etc. The moiety containing the above-mentioned compounds or their parent scaffolds may take any structure as long as these bonds are possible. A C—C bond is preferably used to improve stability against metabolism and hence activity by oral route.

Problems solved by technology

However, such conventional technique for blocking estrogen production could not sufficiently inhibit the effect induced through the estrogen receptor.
However, this agent has a disadvantage that it exhibits estrogenic activity in some organs (see, M. Harper and A. Walpole, J. Reprod. Fertile., 1967, 13, 101).
Although the existing anti-estrogenic compounds having no agonistic effect show a substantial therapeutic effect when administered via intravenous or subcutaneous injection, they show a highly reduced therapeutic effect when administered orally, due to their low bioavailability by oral route.

Method used

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  • Compounds with hydroxycarbonyl-halogenoalkyl side chains
  • Compounds with hydroxycarbonyl-halogenoalkyl side chains
  • Compounds with hydroxycarbonyl-halogenoalkyl side chains

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of 6-methoxy-2-(4-methoxyphenyl)-1-(2-propenyl)-naphthalene

[0200]

[0201] 6-Methoxy-2-naphthol (22.1 g, 127.0 mmol) was dissolved in acetone (200 ml). Potassium carbonate (70.2 g, 508.0 mmol) and allyl bromide (16.5 ml, 191.0 mmol) were added to the resulting solution followed by stirring for 2 days at room temperature. After the reaction mixture was filtered, the organic solvent was distilled off under reduced pressure. Water was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The organic solvent was distilled off again to give 6-methoxy-2-(2-propenyloxy)naphthalene (24.9 g, Yield 91%) as a crude product.

[0202]1H-NMR(270 MHz, CDCl3): δ 7.66-7.60 (m, 2H, Ar—H), 7.18-7.10 (m, 4H, Ar—H), 6.20-6.05 (m, 1H, CH2═CHCH2—), 5.45 (dd, J=18.8, 1.3 Hz, 1H, CH2═CHCH2—), 5.31 (dd, J=10.5, 1.3 Hz, 1H, CH2═CHCH2—), 4.62 (d, J=5.3 Hz, 2H, CH2═CHCH2—), 3.90 (s, 3H...

example 2

Synthesis of diethyl 2-(5-hexenyl)-2-(4,4,5,5,5-pentafluoropentyl)malonate

[0209]

[0210] A solution of diethyl 2-(4,4,5,5,5-pentafluoropentyl)malonate (4.0 g, 12.5 mmol) in dimethyl sulfoxide (30 ml) was cooled to 10° C. To this solution, 60% sodium hydride (600 mg, 15 mmol) was added, and the resulting mixture was stirred for 1 hour at room temperature. 6-Bromo-1-hexene (2.5 ml, 18.75 mmol) was slowly added dropwise to the reaction mixture, followed by stirring for 3 hours at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane=1 / 9) to give diethyl 2-(5-hexenyl)-2-(4,4,5,5,5-pentafluoropentyl)malonate (3.86 g, Yield 77%).

[0211]1H-NMR(270 MHz, CDCl3): δ 5.82-5.72 (m, 1H, —CH═CH2), 5.02-4...

example 3

Synthesis of 9-[6-hydroxy-2-(4-hydroxyphenyl)naphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)nonanoic acid

[0212]

[0213] The diethyl 2-(5-hexenyl)-2-(4,4,5,5,5-pentafluoropentyl)-malonate prepared in Example 2 (1.83 g, 4.55 mmol) and benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (94 mg, 0.11 mmol) were added to a solution of 6-methoxy-2-(4-methoxyphenyl)-1-(2-propenyl)naphthalene (692 mg, 2.28 mmol) in dichloromethane (10 ml), followed by heating under reflux for 20 hours under argon atmosphere. After distilling off the solvent, the residue was purified by silica gel flash column chromatography (eluent: hexane / ethyl acetate=10 / 1) to give the desired olefin (1.8 g) as a mixture of cis- and trans-forms and side chain dimer. This mixture was dissolved in ethyl acetate (20 ml), and 10% palladium carbon (236 mg) was added to the resulting solution followed by stirring for 2 hours at room temperature under hydrogen atmosphere. The catalyst was removed by filtration and the solvent w...

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Abstract

The present invention provides a compound consisting of a moiety and a group chemically bonded to said moiety, wherein said moiety contains a compound having low activity following oral administration or its parent scaffold and said group has the following general formula (1): in which R1 represents a hydrogen atom, etc., R2 represents a C1-C7 halogenoalkyl group, etc., m represents an integer of 2 to 14, and n represents an integer of 2 to 7, or enantiomers of the compound, or hydrates or pharmaceutically acceptable salts of the compound or enantiomers thereof. The above compound is advantageous in pharmaceutical use because the group of general formula (1) allows compounds such as anti-estrogenic ones to show a significantly increased activity following oral administration when attached to the parent scaffolds of the compounds.

Description

CROSS-REFERENCE OF RELATED APPLICATIONS [0001] The present application is a division of co-pending parent application Ser. Nos. 10 / 281,993 and 10 / 149,752, filed on Oct. 29, 2002 and Jun. 13, 2002, the entire contents of which are hereby incorporated by reference.TECHNICAL FIELD [0002] The present invention relates to hydroxycarbonyl-halogenoalkyl derivatives designed to significantly increase oral activity of compounds having low activity following oral administration, compounds having anti-tumor activity, compounds having estrogenic activity or compounds having anti-estrogenic activity. BACKGROUND ART [0003] In treating diseases caused by abnormal tissue growth that is dependent upon a certain sexual steroidal hormone such as estrogen, it is highly important to significantly inhibit, more preferably completely eliminate, the effect induced by the hormone. For this purpose, it is desirable to reduce the level of hormone capable of acting on the steroidal hormone receptor site. For i...

Claims

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Application Information

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IPC IPC(8): A61P5/24C07C51/38C07C59/54C07C59/56C07C59/64
CPCC07C51/38C07C59/54C07C59/56C07C59/64A61P35/00A61P5/24A61P5/32
Inventor JO, JAECHONKWON, HEEANLIM, HYUNSUKCHOI, JAEYOUNGMORIKAWA, KAZUMIKANBE, YOSHITAKENISHIMOTO, MASAHIROKIM, MYUNGHWANISHIMURA, YOSHIKAZU
Owner CHUGAI PHARMA CO LTD
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