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WO1999002512A1 - Dl-2,3-diaryl-2h-1-benzopyrans - Google Patents

Dl-2,3-diaryl-2h-1-benzopyrans Download PDF

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Publication number
WO1999002512A1
WO1999002512A1 PCT/DK1998/000301 DK9800301W WO9902512A1 WO 1999002512 A1 WO1999002512 A1 WO 1999002512A1 DK 9800301 W DK9800301 W DK 9800301W WO 9902512 A1 WO9902512 A1 WO 9902512A1
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Prior art keywords
phenyl
piperidino
ethoxy
benzopyran
carbon atoms
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Ceased
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PCT/DK1998/000301
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French (fr)
Inventor
Kanchan Hajela
Jaya Pandey
Janak Dulari Dhar
Suprabhat Ray
Virender Mohan Labroo
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Novo Nordisk AS
Central Drug Research Institute
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Novo Nordisk AS
Central Drug Research Institute
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Priority to AU81023/98A priority Critical patent/AU8102398A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2

Definitions

  • the present invention relates to optically active d- and /-isomers of ⁇ 7-2, 3-diaryl-2H-1-benzopyran and its derivatives, their preparation by the process of resolution, preparation of pharmaceutical compositions containing such isomers as active ingredients and their use as contraceptives, in the treatment and prophylaxis of breast cancer, osteoporosis, hypercholesteremia, endometriosis, vasoconstriction and endometrial disorders.
  • R 1 and R 2 which may be the same or different are each H, OH, linear or branched chain alkyl or alkoxy of 1 to 17 carbon atoms, linear or branched chain acyloxy of 2 to 18 carbon atoms or a halide group and R 3 is a tertiary amino alkoxy group such as O(CH 2 ) n NR 4 R 5 wherein R 4 and R 5 are same or different, linear or branched chain alkyl substituents of 1-18 carbon atoms or a cyclic ring containing 2 - 10 carbon atoms containing the N atom.
  • R 1 and R 2 are each independently H, OH or C ⁇ -alkoxy.
  • Other preferred embodiments include (i) R 1 being H or (ii) R 1 and R 2 each being an acyl, alkyl, alkoxy or a halide group.
  • R 3 is preferably a 2-piperidinoethoxy group.
  • the present invention therefore provides as new compounds laevo and dextro forms of d/-2,3-diaryl-2H-1-benzopyrans specifically: d-2-(4-(2-(1-Piperidino)ethoxy)phenyl)- 3-phenyl-2H-1-benzopyran, /-2-(4-(2-(1-Piperidino)ethoxy)phenyl) -3-phenyl-2H -1-benzopyran, /-2-(4-(2-(1 -Piperidino)ethoxy)phenyl)-3-(4-hydroxyphenyl)-2H-1 -benzopyran, /-2-(4-(2-(1-Piperidino)ethoxy)phenyl)-3-phenyl-7-methoxy-2H-1-benzopyran, /-2-(4-(2-(1 -Piperidino)ethoxy)phenyl)-3-(4-hydroxyphenyl)-7-hydroxy
  • R , R and R 3 have the meanings as stated above.
  • the invention includes within its scope the optically active /-acid and d-acid salts of the new compounds referred to above. These salts are characterized by the general formula
  • the present invention provides a process for the preparation of optically active / and d isomers of d/-2,3-diaryl-2H-1-benzopyrans and optically active salts thereof which comprises reacting a d/-2,3-diaryl-2H-1 -benzopyran compound of the general formula
  • R 1 and R 2 which may be the same or different are each H, OH, linear or branched chain alkyl or alkoxy of 1 to 17 carbon atoms, linear or branched chain acyloxy of 2 to 18 carbon atoms or a halide group and R 3 is a tertiary amino alkoxy group such as O(CH 2 ) n NR 4 R 5 wherein R 4 and R 5 are same or different, linear or branched chain alkyl substituents of 1-18 carbon atoms or a cyclic ring containing 2 - 10 carbon atoms containing the N atom with an optically active acid in a protic solvent to produce optically active salt of the formula
  • X denotes the optically active acid anion
  • the invention provides a process for the preparation of /-2-4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran of the general formula
  • R 1 , R 2 , R 3 have the meanings stated herein and optically active /-acid salts thereof, which comprises reacting d/-2-(4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H -1 -benzopyran of the general formula
  • R 1 , R 2 , R 3 have the meanings stated above with an optically active /-acid in a protic solvent to produce on fractional crystallization of the reaction mixture /-2-(4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran /-acid salt of the general formula
  • the invention provides a process for the preparation of d-2-(4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H-1-benzopyran of the general formula
  • R ⁇ R 2 and R 3 have the meanings stated as above and optically active d-acid salt thereof which comprises reacting d/-2-(4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran of the general formula
  • R ⁇ R 2 , R 3 have the meanings as stated above with an optically active d-acid in a protic solvent to produce on fractional crystallization of the reaction mixture d-2-(4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H-1-benzopyran d-acid salts of the general formula
  • the preferred optically active /-acid is di-p-toluoyl-/-tartaric acid while the preferred optically active d-acid is di-p-toluoyl-d-tartaric acid monohydrate.
  • the protic solvents which may be employed in the reaction include ethanol or methanol.
  • the invention provides a post-coital antifertility composition
  • a post-coital antifertility composition comprising as active ingredient /-2-(4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran or an optically ac- tive acid derivative thereof in combination with a pharmaceutically acceptable carrier or excipient thereof.
  • the carriers or excipients with which the active ingredient may be combined to provide the above-mentioned composition include starch, dicalcium phosphate and calcium stearate and combinations of any of these.
  • novel /-2-(4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran was found to be two folds more active as an antifertility agent in female albino rats as compared to the corresponding d/-compound in a single day post-coital oral administration schedule.
  • the compounds of the invention are effective over a wide dosage range.
  • dosages from about 0.05 to about 100 mg, preferably from about 0.1 to about 100 mg, per day may be used.
  • a most preferable dosage is about 0.1 mg to about 70 mg per day.
  • the exact dosage will depend upon the mode of administration, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
  • the route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral or par- enteral e.g. rectal, transdermal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
  • oral or par- enteral e.g. rectal, transdermal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
  • compositions include a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other con- tainer.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other con- tainer.
  • the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container.
  • the carrier When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container for example in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • the formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • the pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in poly- hydroxylated castor oil.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • the compounds are dispensed in unit form comprising from about 0.1 to about 100 mg in a pharmaceutically acceptable carrier per unit dosage.
  • a typical tablet appropriate for use in this method, may be prepared by conventional tabletting techniques and contains:
  • the compounds according to this invention may be suitable for administration to an animal.
  • animals include both domestic animals, for example livestock, laboratory animals, and household pets, and non-domestic animals such as wildlife. More preferably, the animal is a vertebrate.
  • a compound according to this invention shall be administered to a mammal. It is especially preferred that the animal is a domestic mammal or a human. The most preferred mammal is a human.
  • a compound of this invention may be administered as a feed additive or in bulk form.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to therapeutically active 2,3-diaryl-2H-1-benzopyrans, a method of preparing the same and to pharmaceutical compositions comprising the compounds. The novel compounds are useful in the prevention or treatment of estrogen related diseases or syndromes.

Description

d/-2,3-Diaryl-2H-1 -benzopy rans
The present invention relates to optically active d- and /-isomers of α7-2, 3-diaryl-2H-1-benzopyran and its derivatives, their preparation by the process of resolution, preparation of pharmaceutical compositions containing such isomers as active ingredients and their use as contraceptives, in the treatment and prophylaxis of breast cancer, osteoporosis, hypercholesteremia, endometriosis, vasoconstriction and endometrial disorders.
2,3-Diaryl-2H-1-benzopyrans have recently emerged as a novel group of non-steroidal compounds which are anti-estrogenic and possess significant activity against egg implantation and breast cancer ( see Kapil et al., U.S. Pat. No. 5,254,568 dt. Oct.19, 1993; Saeed et al., J. Med. Chem., 33, 3210-3216, 1990; Sharma et al., J. Med. Chem., 33, 3216-3222, 3222-3229,1990). They have also been shown to be effective in the treatment of bone loss due to osteoporosis and other conditions, including post- menopausal osteoporosis and glucocorticoid -related osteoporosis, Paget s disease, hyperparathyroidism, hypercalcemia of malignancy and other conditions characterized by excessive rates of bone resorption and/ or decreased rates of bone formation (see Labroo et al., U.S. Pat. No. 5,389,646 dt. Feb.14, 1995 ). Further, they are also useful for lowering serum cholesterol ( see Eli Lilly & Company, Eur. Pat. No. 0,652,006 A1 dt. Nov.2, 1994). Indian Patent Appl. Nos. 173335, 173336, 173337 and 1141/DEL/91 describe the process for the preparation of α7-2,3-diaryl-2H-1-benzopyran and derivatives thereof. The invention provides compounds of the formula
Figure imgf000003_0001
wherein R1 and R2 which may be the same or different are each H, OH, linear or branched chain alkyl or alkoxy of 1 to 17 carbon atoms, linear or branched chain acyloxy of 2 to 18 carbon atoms or a halide group and R3 is a tertiary amino alkoxy group such as O(CH2)nNR4R5 wherein R4 and R5 are same or different, linear or branched chain alkyl substituents of 1-18 carbon atoms or a cyclic ring containing 2 - 10 carbon atoms containing the N atom.
There are several preferred embodiments. In one preferred embodiment R1 and R2 are each independently H, OH or C^-alkoxy. Other preferred embodiments include (i) R1 being H or (ii) R1 and R2 each being an acyl, alkyl, alkoxy or a halide group. R3 is preferably a 2-piperidinoethoxy group.
With the increasing appreciation that the enantiomers of a chiral drug can differ in their biological activity, pharmacokinetically and/or pharmacodynamically, there is considerable interest in the resolution of such molecules into their pure enantiomeric forms. As 2,3-diaryl-2H-1-benzopyran and its derivatives evince potent antiestro- genic, antiimplantation, antibreast cancer, antioesteoporosis and serum cholesterol lowering activities, the applicants have affected additional research by affecting the resolution of racemic compound into its optically active laevo ( / ) and dextro (d) iso- meric forms. The achieved compounds particularly the /-isomer exhibits increased anti-implantation and antiestrogenic activities over the known dl- isomer.
The present invention therefore provides as new compounds laevo and dextro forms of d/-2,3-diaryl-2H-1-benzopyrans specifically: d-2-(4-(2-(1-Piperidino)ethoxy)phenyl)- 3-phenyl-2H-1-benzopyran, /-2-(4-(2-(1-Piperidino)ethoxy)phenyl) -3-phenyl-2H -1-benzopyran, /-2-(4-(2-(1 -Piperidino)ethoxy)phenyl)-3-(4-hydroxyphenyl)-2H-1 -benzopyran, /-2-(4-(2-(1-Piperidino)ethoxy)phenyl)-3-phenyl-7-methoxy-2H-1-benzopyran, /-2-(4-(2-(1 -Piperidino)ethoxy)phenyl)-3-(4-hydroxyphenyl)-7-hydroxy -2H-1 - benzopyran, /-2-(4-(2-(1-Piperidino)ethoxy)phenyl)-3-(4-methoxyphenyl)-2H-1 -benzopyran, d-2-(4-(2-(1 -Piperidino)ethoxy)phenyl)-3-(4-methoxyphenyl)-2H-1 -benzopyran. The new compounds correspond to the general formula
Figure imgf000005_0001
wherein R , R and R3 have the meanings as stated above.
The invention includes within its scope the optically active /-acid and d-acid salts of the new compounds referred to above. These salts are characterized by the general formula
Figure imgf000005_0002
wherein X denotes the optically active anion and R\ R2 and R3 have the meanings as stated above.
According to a preferred feature, the present invention provides a process for the preparation of optically active / and d isomers of d/-2,3-diaryl-2H-1-benzopyrans and optically active salts thereof which comprises reacting a d/-2,3-diaryl-2H-1 -benzopyran compound of the general formula
Figure imgf000006_0001
wherein R1 and R2 which may be the same or different are each H, OH, linear or branched chain alkyl or alkoxy of 1 to 17 carbon atoms, linear or branched chain acyloxy of 2 to 18 carbon atoms or a halide group and R3 is a tertiary amino alkoxy group such as O(CH2)nNR4R5 wherein R4 and R5 are same or different, linear or branched chain alkyl substituents of 1-18 carbon atoms or a cyclic ring containing 2 - 10 carbon atoms containing the N atom with an optically active acid in a protic solvent to produce optically active salt of the formula
Figure imgf000006_0002
wherein X denotes the optically active acid anion, subjecting the reaction mixture to repeated fractional crystallization to obtain the said salt in crystalline form and subjecting the crystalline salt to alkaline hydrolysis to obtain the desired isomer.
According to a further feature, the invention provides a process for the preparation of /-2-4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran of the general formula
Figure imgf000007_0001
wherein R1, R2, R3 have the meanings stated herein and optically active /-acid salts thereof, which comprises reacting d/-2-(4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H -1 -benzopyran of the general formula
Figure imgf000007_0002
wherein R1, R2, R3 have the meanings stated above with an optically active /-acid in a protic solvent to produce on fractional crystallization of the reaction mixture /-2-(4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran /-acid salt of the general formula
Figure imgf000007_0003
wherein X denotes the optically active anion and R1, R2, R3 have the meanings stated above and subjecting the said crystalline salt to alkaline hydrolysis to obtain the desired /-isomer.
According to a still further feature, the invention provides a process for the preparation of d-2-(4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H-1-benzopyran of the general formula
Figure imgf000008_0001
wherein R\ R2 and R3 have the meanings stated as above and optically active d-acid salt thereof which comprises reacting d/-2-(4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran of the general formula
Figure imgf000008_0002
wherein R\ R2, R3 have the meanings as stated above with an optically active d-acid in a protic solvent to produce on fractional crystallization of the reaction mixture d-2-(4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H-1-benzopyran d-acid salts of the general formula
Figure imgf000009_0001
wherein X denotes the optically active anion and R\ R2, R3 have the meanings stated as above and subjecting the said crystalline salt to alkaline hydrolysis to obtain the desired d-isomer.
The preferred optically active /-acid is di-p-toluoyl-/-tartaric acid while the preferred optically active d-acid is di-p-toluoyl-d-tartaric acid monohydrate. Examples of the protic solvents which may be employed in the reaction include ethanol or methanol.
According to yet another embodiment the invention provides a post-coital antifertility composition comprising as active ingredient /-2-(4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran or an optically ac- tive acid derivative thereof in combination with a pharmaceutically acceptable carrier or excipient thereof. Examples of the carriers or excipients with which the active ingredient may be combined to provide the above-mentioned composition include starch, dicalcium phosphate and calcium stearate and combinations of any of these. The novel /-2-(4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran was found to be two folds more active as an antifertility agent in female albino rats as compared to the corresponding d/-compound in a single day post-coital oral administration schedule.
The compounds of the invention are effective over a wide dosage range. For ex- ample, in the treatment of adult humans, dosages from about 0.05 to about 100 mg, preferably from about 0.1 to about 100 mg, per day may be used. A most preferable dosage is about 0.1 mg to about 70 mg per day. In choosing a regimen useful in the prevention or treatment of estrogen related diseases or syndromes it may frequently be necessary to begin with a dosage of from about 20 to about 70 mg per day and when the condition is under control to reduce the dosage as low as from about 0.1 to about 10 mg per day. The exact dosage will depend upon the mode of administration, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
The route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral or par- enteral e.g. rectal, transdermal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
Typical compositions include a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other con- tainer. In making the compositions, conventional techniques for the preparation of pharmaceutical compositions may be used. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container for example in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone. The formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents. The formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in poly- hydroxylated castor oil.
Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
Generally, the compounds are dispensed in unit form comprising from about 0.1 to about 100 mg in a pharmaceutically acceptable carrier per unit dosage.
A typical tablet, appropriate for use in this method, may be prepared by conventional tabletting techniques and contains:
Active compound 5.0 mg
Lactosum 67.8 mg Ph.Eur.
Avicel® 31.4 mg
Amberlite® 1.0 mg Magnesii stearas 0.25 mg Ph. Eur. The compounds according to this invention may be suitable for administration to an animal. Such animals include both domestic animals, for example livestock, laboratory animals, and household pets, and non-domestic animals such as wildlife. More preferably, the animal is a vertebrate. Most preferably, a compound according to this invention shall be administered to a mammal. It is especially preferred that the animal is a domestic mammal or a human. The most preferred mammal is a human. For such purposes, a compound of this invention may be administered as a feed additive or in bulk form.
The preparation of the novel compounds and its derivatives are described in the following non-limitative examples.
Example I
/-2-(4-(2-(1 -Piperidino)ethoxy)pheny l)-3-pheny I-2H-1 -benzopyran di-p-toluolyl -/-tartrate
d/-2-(4-(2-(1-Piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran and di-p-toluoyl-/-tartaric acid in 1 :1 equivalent molar ratio were dissolved by warming in distilled ethanol and the mixture stirred for 3 hrs. Excess of ethanol was removed and the residue allowed to stand overnight to get crystals of /-2-(4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran di-p-toluoyl-/-tartrate, m.p. 126° C, [α] 0 D = -72.2 (c 1 in EtOH).
Example II
/-2-(4-(2-(1 -Piperidino)ethoxy)pheny l)-3-pheny I-2H-1 -benzopyran The /-2-(4-(2-(1 -piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran di-p-toluoyl-/-tartrate salt obtained from the example I was hydrolyzed by dissolving it in ethyl acetate and treating it with aqueous alkali. The organic layer was washed with water to neutral, dried over anhydrous sodium sulphate and concentrated to yield colorless crystalline
/-(2-(4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran, m.p.75° C, [α]20 D = -34.3 (c 1 in EtOH).
Example III
d-2-(4-(2-(1-Piperidino)ethoxy)phenyl)-3-phenyl-2H-1-benzopyran di-p-toluoyl-d-tartrate
d/-2-(4-(2-(1-Piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran and di-p-toluoyl-d-tartaric acid monohydrate in 1 :1 equivalent molar ratio were dissolved in ethanol and the mixture stirred for 3 hrs. Excess of ethanol was removed and the residue allowed to stand overnight to get crystals of pure d-2-(4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H-1-benzopyran di-p-toluoyl-d-tartrate as colorless solid m.p.132° C, [α] 20 D = +72.2 (c 1 in EtOH).
Example IV
d-2-(4-(2-(1 -Piperidino)ethoxy)pheny l)-3-pheny I-2H-1 -benzopyran
The d-2-(4-(2-(1 -piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran di-p-toluoyl-d-tartrate salt obtained from example III was hydrolyzed by dissolving the salt in ethyl acetate and treating it with aqueous alkali. The organic layer was washed with water to neutral, dried over anhydrous sodium sulphate and concentrated to yield colorless, crystalline solid m.p. 69°C, [α]20 D = +34.3 (c 1 in EtOH). Example V
/-2-(4-(2-(1 -Piperidino)ethoxy)pheny l-3-(4-methoxy pheny l)-2H-1 -benzopyran di- p-toloulyl-/-tartrate
d/-2-(4-(2-(1 -Piperidino)ethoxy)phenyl-3-(4-methoxyphenyl)-2H-1 -benzopyran of the general formula I and di-p-toloulyl-/-tartaric acid in 1 :1 equivalent molar ratio were dissolved by warming in distilled ethanol and the mixture stirred for 3 hrs. Excess of ethanol was removed and the residue allowed to stand overnight to get the crystals of /-2-(4-(2-(1 -piperidino)ethoxy)phenyl-3-(4-methoxyphenyl)-2H-1 -benzopyran di-p- toloulyl- artrate, m.p.122°C, [α]20 D= -83.9 (c 1 in EtOH).
Example VI
/-2-(4-(2-(1-Piperidino)ethoxy)phenyl-3-(4-methoxyphenyl)-2H-1 -benzopyran
The /-2-(4-(2-(1-piperidino)ethoxy)phenyl-3-(4-methoxyphenyl)-2H-1 -benzopyran di- p-toloulyl-/-tartrate salt obtained from example V was hydrolysed by dissolving it in ethyl acetate and treating it with aqueous alkali. The organic layer was washed with water to neutral, dried over anhydrous sodium sulphate and concentrated to yield colorless crystalline /-2-(4-(2-(1 -piperidino)ethoxy)phenyl-3-(4-methoxyphenyl)-2H-1 - benzopyran, m.p. 92°C, [α]20 D= -40.3 (c 1 in EtOH).
Example VII
d-2-(4-(2-(1-Piperidino)ethoxy)phenyl-3-(4-methoxyphenyl)-2H-1 -benzopyran di- p-toloulyl-d-tartrate d/-2-(4-(2-(1 -Piperidino)ethoxy)phenyl-3-(4-methoxyphenyl)-2H-1 -benzopyran and di- p-toloulyl-d-tartaric acid monohydrate in 1:1 equivalent molar ratio were dissolved in ethanol and the mixture stirred for 3 hrs. Excess of ethanol was removed and the residue allowed to stand overnight to get crystals of pure d-2-(4-(2-(1- piperidino)ethoxy)phenyl-3-(4-methoxyphenyl)-2H-1-benzopyran di-p-toloulyl-d- tartrate as colorless solid, m.p. 128°C, [α]20 D= +83.9 (c 1 in EtOH).
Example VIM
d-2-(4-(2-(1-Piperidino)ethoxy)phenyl-3-(4-methoxyphenyl)-2H-1-benzopyran
The d-2-(4-(2-(1 -piperidino)ethoxy)phenyl-3-(4-methoxyphenyl)-2H-1 -benzopyran di- p-toloulyl-d-tartrate salt obtained from example VII was hydrolysed by dissolving the salt in ethyl acetate and treating it with aqueous alkali. The organic layer was washed with water to neutral, dried over anhydrous sodium sulphate and concentrated to yield colorless crystals, m.p. 89°C, [α]20 D= +40.3 (c 1 in EtOH).

Claims

Claims
1. An /-isomer of a compound of the formula
Figure imgf000016_0001
wherein R1 and R2 which may be the same or different are each H, OH, linear or branched chain alkyl or alkoxy of 1 to 17 carbon atoms, linear or branched chain acyloxy of 2 to 18 carbon atoms or a halide group and R3 is a tertiary amino alkoxy group such as O(CH2)nNR4R5 wherein R4 and R5 are same or different, linear or branched chain alkyl substituents of 1-18 carbon atoms or a cyclic ring containing 2 - 10 carbon atoms containing the N atom.
2. A d-isomer of a compound of the formula
Figure imgf000016_0002
wherein R\ R2, and R3 have the meanings as stated as above in claim 1.
3. Compounds as claimed in claim 1 and 2 in which R1 and R2 each independently are H, OH, halide, or C^-alkoxy.
4. Compounds as claimed in claim 1 and 2 in which R1 is H.
5. Compounds as claimed in claim 1 and 2 in which R3 is
Figure imgf000017_0001
6. /-2-(4-(2-(1-Piperidino)ethoxy)phenyl)-3-(4-hydroxyphenyl)-2H-1 -benzopyran according to claim!
7. /-2-(4-(2-(1 -Piperidino)ethoxy)phenyl)-3-phenyl-7-methoxy-2H-1 -benzopyran according to claim!
8. /-2-(4-(2-(1-Piperidino)ethoxy)phenyl)-3-(4-hydroxyphenyl)-7-hydroxy-2H-1- benzopyran according to claim 1.
9. /-2-(4-(2-(1-Piperidino)ethoxy)phenyl)-3-(4-methoxyphenyl)-2H-1 -benzopyran according to claim 1.
10. /-2-(4-(2-(1 -Piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran according to claim 1.
11. d-2-(4-(2-(1 -Piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran according to claim 2.
12. d-2-(4-(2-(1-Piperidino)ethoxy)phenyl)-3-(4-methoxyphenyl)-2H-1 -benzopyran according to claim 2.
13. A pharmaceutical composition which comprises an effective dose of a com- pound according to claim 1 and 2 and a pharmaceutically acceptable carrier or diluent.
14. The use of a compound according to claim 1 and 2 for the preparation of a medicament for prevention or treatment of estrogen related diseases or syndromes.
PCT/DK1998/000301 1997-07-09 1998-07-02 Dl-2,3-diaryl-2h-1-benzopyrans Ceased WO1999002512A1 (en)

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001068634A1 (en) * 2000-03-15 2001-09-20 Schering Aktiengesellschaft 4-fluoroalkyl-2h-benzopyrans with anti-estrogenic activity
JP2002522533A (en) * 1998-08-14 2002-07-23 シェーリング コーポレイション Enantioselective synthesis
WO2003044006A1 (en) * 2001-11-19 2003-05-30 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor-beta agonists
US6630508B1 (en) 2002-02-11 2003-10-07 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor β agonists
US6710059B1 (en) * 1999-07-06 2004-03-23 Endorecherche, Inc. Methods of treating and/or suppressing weight gain
EP1790644A1 (en) * 2001-11-19 2007-05-30 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor-beta agonists
US7279499B2 (en) 2003-04-21 2007-10-09 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor-beta agonists
US7442812B2 (en) 2003-04-21 2008-10-28 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor-beta agonists
US8703810B2 (en) 2010-06-10 2014-04-22 Seragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
US8853423B2 (en) 2010-06-17 2014-10-07 Seragon Pharmaceuticals, Inc. Indane estrogen receptor modulators and uses thereof
US9018244B2 (en) 2011-12-16 2015-04-28 Olema Pharmaceuticals, Inc. Benzopyran compounds, compositions and uses thereof
US9187460B2 (en) 2011-12-14 2015-11-17 Seragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
US10865199B2 (en) 2015-10-27 2020-12-15 Sun Pharma Advanced Research Company Limited Heterocyclic antiestrogens
WO2021014386A1 (en) 2019-07-22 2021-01-28 Sun Pharma Advanced Research Company Limited Selective estrogen receptor degrader

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993010741A2 (en) * 1991-12-02 1993-06-10 Endorecherche Inc. Sex steroid activity inhibitors
US5254568A (en) * 1990-08-09 1993-10-19 Council Of Scientific & Industrial Research Benzopyrans as antiestrogenic agents
WO1996026201A1 (en) * 1995-02-21 1996-08-29 Endorecherche, Inc. Benzopyran-containing compounds and method for their use

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5254568A (en) * 1990-08-09 1993-10-19 Council Of Scientific & Industrial Research Benzopyrans as antiestrogenic agents
WO1993010741A2 (en) * 1991-12-02 1993-06-10 Endorecherche Inc. Sex steroid activity inhibitors
WO1996026201A1 (en) * 1995-02-21 1996-08-29 Endorecherche, Inc. Benzopyran-containing compounds and method for their use

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002522533A (en) * 1998-08-14 2002-07-23 シェーリング コーポレイション Enantioselective synthesis
US6710059B1 (en) * 1999-07-06 2004-03-23 Endorecherche, Inc. Methods of treating and/or suppressing weight gain
US8609695B2 (en) 1999-07-06 2013-12-17 Endorecherche, Inc. Methods of treating and/or suppressing insulin resistance
WO2001068634A1 (en) * 2000-03-15 2001-09-20 Schering Aktiengesellschaft 4-fluoroalkyl-2h-benzopyrans with anti-estrogenic activity
US6844336B2 (en) 2000-03-15 2005-01-18 Schering Ag 4-fluoroalkyl-2h-benzopyrans with anti-estogenic activity
WO2003044006A1 (en) * 2001-11-19 2003-05-30 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor-beta agonists
EA007382B1 (en) * 2001-11-19 2006-10-27 Эли Лилли Энд Компани Substituted benzopyrans as selective estrogen receptor-beta agonists
CN1312147C (en) * 2001-11-19 2007-04-25 伊莱利利公司 Substituted benzopyrans as selective estrogen receptor-beta agonists
US7217734B2 (en) 2001-11-19 2007-05-15 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor-beta agonists
EP1790644A1 (en) * 2001-11-19 2007-05-30 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor-beta agonists
US6630508B1 (en) 2002-02-11 2003-10-07 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor β agonists
US7585985B2 (en) 2003-04-21 2009-09-08 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor-beta agonists
US7442812B2 (en) 2003-04-21 2008-10-28 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor-beta agonists
US7842822B2 (en) 2003-04-21 2010-11-30 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor-beta agonists
US7279499B2 (en) 2003-04-21 2007-10-09 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor-beta agonists
US9078871B2 (en) 2010-06-10 2015-07-14 Seragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
US8703810B2 (en) 2010-06-10 2014-04-22 Seragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
US8853423B2 (en) 2010-06-17 2014-10-07 Seragon Pharmaceuticals, Inc. Indane estrogen receptor modulators and uses thereof
US9187460B2 (en) 2011-12-14 2015-11-17 Seragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
US9193714B2 (en) 2011-12-14 2015-11-24 Seragon Pharmaceuticals, Inc. Fluorinated estrogen receptor modulators and uses thereof
US9018244B2 (en) 2011-12-16 2015-04-28 Olema Pharmaceuticals, Inc. Benzopyran compounds, compositions and uses thereof
US10865199B2 (en) 2015-10-27 2020-12-15 Sun Pharma Advanced Research Company Limited Heterocyclic antiestrogens
US11465990B2 (en) 2015-10-27 2022-10-11 Sun Pharma Advanced Research Company Ltd. Heterocyclic antiestrogens
WO2021014386A1 (en) 2019-07-22 2021-01-28 Sun Pharma Advanced Research Company Limited Selective estrogen receptor degrader
US11014915B2 (en) 2019-07-22 2021-05-25 Sun Pharma Advanced Research Company Limited Selective estrogen receptor degrader

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