WO2012036529A2 - (s)-n,n-dimethyl-3-(naphthalen-1-yloxy)-1-phenylpropan-1-amine derivatives, pharmaceutical compositions containing the derivatives and manufacturing methods thereof - Google Patents

(s)-n,n-dimethyl-3-(naphthalen-1-yloxy)-1-phenylpropan-1-amine derivatives, pharmaceutical compositions containing the derivatives and manufacturing methods thereof Download PDF

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WO2012036529A2
WO2012036529A2 PCT/KR2011/006892 KR2011006892W WO2012036529A2 WO 2012036529 A2 WO2012036529 A2 WO 2012036529A2 KR 2011006892 W KR2011006892 W KR 2011006892W WO 2012036529 A2 WO2012036529 A2 WO 2012036529A2
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substituted
group
unsubstituted
dapoxetine
yloxy
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PCT/KR2011/006892
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French (fr)
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WO2012036529A3 (en
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Jung-Hoon Oh
Keun-Ho Ryu
Jae-Sun Kim
Tae Kon Kim
Soo-Min Lee
Bong-Yong Lee
Minseok Park
Seok Hyun Hong
Jung A Lee
Hyuk Min Kim
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Sk Chemicals Co., Ltd.
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Priority claimed from KR1020110082839A external-priority patent/KR20120068678A/en
Application filed by Sk Chemicals Co., Ltd. filed Critical Sk Chemicals Co., Ltd.
Publication of WO2012036529A2 publication Critical patent/WO2012036529A2/en
Publication of WO2012036529A3 publication Critical patent/WO2012036529A3/en

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    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl

Definitions

  • the present invention relates to dapoxetine derivatives in the form of prodrugs, pharmaceutical compositions for premature ejaculation therapy including the dapoxetine derivatives, and methods for the preparation of the dapoxetine derivatives.
  • Premature ejaculation one of the most common sexual complaints, is estimated to affect 30 to 40% of American men. Premature ejaculation means persistent or recurrent ejaculation with minimal sexual stimulation before, upon or shortly after penetration, and before the person wishes it. Such ejaculation that occurs sooner than desired is often disappointing and can lead to other sexual dysfunctions including erectile difficulties, female inorgasmia, low sexual desire, and sexual aversion.
  • dapoxetine (S)-N,N-dimethyl-3-(naphthalen-1-yloxy)-1-phenylpropan-1-amine (dapoxetine), a shortacting selective serotonin reuptake inhibitor (SSRI), is currently used for the treatment of premature ejaculation.
  • SSRI selective serotonin reuptake inhibitor
  • dapoxetine free base has the problem of relatively poor water solubility, making it difficult to process into various formulations.
  • Another problem of dapoxetine free base is poor in vivo solubility, ultimately leading to low in vivo absorption.
  • dapoxetine have been developed in the form of a hydrochloride salt. Since dapoxetine hydrochloride is bitter in taste, prescriptions recommend that formulations of dapoxetine hydrochloride should be swallowed whole along with a full glass of water in order to avoid the bitter taste. Nausea, vomiting and retching are most frequently reported as side effects when taking bitter dapoxetine hydrochloride.
  • the present invention is designed to solve the problems of the prior art, and therefore it is an object of the present invention to provide novel dapoxetine derivatives in the form of prodrugs that have excellent physicochemical properties, can be rapidly and readily absorbed in vivo to exhibit pharmacological effects of dapoxetine, are not bitter in taste, and can be processed into various formulations. It is another object of the present invention to provide pharmaceutical compositions including the dapoxetine derivatives. It is still another object of the present invention to provide efficient methods for preparing the dapoxetine derivatives.
  • the present invention provides compounds having a prodrug structure of dapoxetine in which a pro-group R p is bonded to the tertiary amine group of dapoxetine, represented by Formula 1:
  • pro-group R p is a group having a phosphate bond
  • the present invention provides compounds in which the pro-group R p has a zwitterionic structure of -(CR a R b ) y -O-P(O)(OR c )(O - ), represented by Formula 2:
  • y is an integer from 1 to 4.
  • R a and R b are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a C 1 -C 4 alkoxy group, a substituted or unsubstituted C 1 -C 4 alkyl group, a substituted or unsubstituted C 6 -C 14 aryl group or a substituted or unsubstituted C 7 -C 20 arylalkyl group, or R a and R b are attached together to form a C 3 -C 8 substituted or unsubstituted cycloalkyl group;
  • R c is a hydrogen atom, a substituted or unsubstituted C 1 -C 4 alkyl group, a substituted or unsubstituted C 6 -C 14 aryl group, a substituted or unsubstituted C 7 -C 20 arylalkyl group, a substituted or unsubstituted five to fourteen-membered ring group, a heterocyclic group containing at least one heteroatom selected from N, O and S, or a pharmaceutically acceptable salt-forming cation;
  • R a , R b or R c when R a , R b or R c is substituted with at least one substituent, the substituent is selected from halogen atoms and hydroxyl, C 1 -C 4 alkoxy, amino and C 1 -C 4 alkylamino groups, and
  • the present invention provides compounds in which the pro-group R p is -(CR a R b ) y -O-P(O)(OR c )(OR d )X - , represented by Formula 3:
  • y is an integer from 1 to 4.
  • R a and R b are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a C 1 -C 4 alkoxy group, a substituted or unsubstituted C 1 -C 4 alkyl group, a substituted or unsubstituted C 6 -C 14 aryl group or a substituted or unsubstituted C 7 -C 20 arylalkyl group, or R a and R b are attached together to form a C 3 -C 8 substituted or unsubstituted cycloalkyl group;
  • R c and R d are each independently a hydrogen atom, a substituted or unsubstituted C 1 -C 4 alkyl group, a substituted or unsubstituted C 6 -C 14 aryl group, a substituted or unsubstituted C 7 -C 20 arylalkyl group, a substituted or unsubstituted five to fourteen-membered ring group, a heterocyclic group containing at least one heteroatom selected from N, O and S, or a pharmaceutically acceptable salt-forming cation;
  • R a , R b , R c or R d is substituted with at least one substituent, the substituent is selected from halogen atoms and hydroxyl, C 1 -C 4 alkoxy, amino and C 1 -C 4 alkylamino groups; and
  • X - is a pharmaceutically acceptable anion (salt)
  • dapoxetine prodrugs include, but are not limited to,
  • dapoxetine derivatives of the present invention in which the pro-group R p is introduced into the tertiary amine group of dapoxetine.
  • the dapoxetine derivatives of the present invention are easy to process into preparations and exhibit improved characteristics in terms of dissolution rate, dissolution variation, bioavailability, etc.
  • the dapoxetine derivatives with improved solubility according to the present invention may be degraded to dapoxetine by in vivo enzymatic reactions.
  • Each of the pharmaceutically acceptable salt-forming anions of the dapoxetine derivatives according to the present invention may be derived from an organic or inorganic acid.
  • organic acids suitable for use in the derivatives of the present invention include, but are not limited to, maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, benzenesulfonic, toluenesulfonic, acetic, oxalic, gentisic, trifluoroacetic, trifluoromethanesulfonic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, formic, glycolic and glutamic acids.
  • Suitable inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydrofluoric, hydroiodic, sulfuric, phosphoric and nitric acids.
  • Each of the pharmaceutically acceptable salt-forming cations of the dapoxetine derivatives according to the present invention may be selected from the group consisting of, but not limited to: ammonium; pharmaceutically acceptable metal cations, including but not limited to, cations of alkali metals (for example, Na, K and Li), alkaline earth metals (for example, Ca and Mg), zinc and iron; suitable organic bases, for example, C 1 -C 8 lower alkylamines, such as methylamine, ethylamine and cyclohexylamine, and substituted C 1 -C 8 lower alkylamines, for example, diethanolamine, triethanolamine and hydroxylated alkylamines ( e.g ., tris(hydroxymethyl)aminomethane); bases, such as meglumine (N-methyl-D-glucamine), piperidine and morphiline; and basic amino acids, such as arginine, lysine and glycine.
  • pharmaceutically acceptable metal cations
  • the present invention is also intended to encompass solvates, particularly hydrates, of the dapoxetine derivatives. That is, the dapoxetine derivatives of the present invention may exist in unsolvated as well as solvated forms (for example, hydrated forms).
  • the compounds of the present invention may exist in crystalline or amorphous forms. All such physical forms are within the scope of the present invention.
  • the present invention also provides a pharmaceutical composition including at least one of the dapoxetine derivatives and pharmaceutically acceptable salts thereof as an active ingredient and optionally a pharmaceutically acceptable excipient or additive.
  • the pharmaceutical composition of the present invention is preferably used for the treatment, management or prevention of premature ejaculation.
  • the compound or pharmaceutically acceptable salt thereof may be administered alone or in combination with any convenient carrier, excipient, etc. and is may be provided in a single dosage form or in multiple dosage forms.
  • the pharmaceutical composition of the present invention may be a solid or liquid preparation.
  • solid preparations include powders, granules, tablets, capsules and suppositories. These solid preparations may include suitable excipients, flavors, binders, preservatives, disintegrants, lubricants, fillers, etc.
  • suitable liquid preparations include solutions, such as aqueous solutions and propylene glycol solutions, suspensions, and emulsions. These liquid preparations may include suitable colorants, flavors, stabilizers and thickeners.
  • a powder may be prepared by simply mixing the dapoxetine derivative or salt thereof with a suitable pharmaceutically acceptable excipient, such as lactose, starch or microcrystalline cellulose.
  • a granule may be prepared by mixing the dapoxetine derivative or pharmaceutically acceptable salt, a suitable pharmaceutically acceptable excipient and a suitable pharmaceutically acceptable binder, such as polyvinyl pyrrolidone or hydroxypropyl cellulose, and granulating the mixture using a suitable solvent such as water, ethanol or isopropanol (wet granulation) or by the application of a compressive force (dry granulation).
  • a tablet may be prepared by mixing the granule with a suitable pharmaceutically acceptable lubricant, such as magnesium stearate, and compacting the mixture using a suitable tableting machine.
  • the pharmaceutical composition of the present invention may be administered orally, by injection (for example, intramuscular injection, intraperitoneal injection, intravenous injection, infusion, subcutaneous injection or implantation), by inhalation, nasally, intravaginally, rectally, sublingually, transdermally, topically, etc. depending on the severity of disease and the condition of subjects to be treated.
  • the pharmaceutical composition of the present invention may be prepared into an appropriate unit dosage form including at least one known non-toxic, pharmaceutically acceptable carrier, adjuvant or vehicle, depending on the desired route of administration.
  • the pharmaceutical composition of the present invention may also be prepared into a depot formulation from which the active ingredient can be continuously released for a certain period of time, which is also encompassed within the scope of the present invention.
  • the present invention also provides a method for the management, treatment or prevention of premature ejaculation, the method including administering a therapeutically effective amount of at least one of the dapoxetine derivatives and pharmaceutically acceptable salts thereof to a subject in need of such management, treatment or prevention.
  • the compound or pharmaceutically acceptable salt thereof may be administered in an amount ranging from about 0.001 mg to about 350 mg, preferably from about 0.01 mg to about 200 mg, more preferably from about 0.1 mg to about 120 mg, most preferably from about 1 mg to about 80 mg, in a single dose or in divided doses, if needed, before an activity involving sexual arousal wherein the patient desires to avoid sexual dysfunction, such as premature ejaculation. Examples of such sexual activities are sexual intercourse and masturbation.
  • the dose of the compound or pharmaceutically acceptable salt thereof may be varied depending on the conditions of the patient ( e.g ., age, sex and body weight) and the severity of the particular condition to be treated. For convenience of administration, if needed, the daily dose of the compound or pharmaceutically acceptable salt thereof may be administered in divided doses.
  • the present invention also provides a method for preparing the dapoxetine prodrugs represented by Formula 2, the method including reacting dapoxetine with (R c O) 2 P(O)O(CR a R b ) y -halide (S1a), and a method for preparing the dapoxetine prodrugs represented by Formula 3, the method including reacting dapoxetine with (R c O)(R d O)P(O)O(CR a R b ) y -halide or (R c O) 2 P(O)O(CR a R b ) y -halide (S1b).
  • the reactions are carried out in acetone, ethyl acetate, 1,4-dioxane, acetonitrile or a mixture thereof at 20 to 100 °C.
  • the products can be purified by recrystallization.
  • Each of the halides is preferably a chloride.
  • each of the methods of the present invention may further include substituting R c of the reaction product of dapoxetine and the (R c O)(R d O)P(O)O(CR a R b ) y -halide or (R c O) 2 P(O)O(CR a R b ) y -halide with hydrogen (S2).
  • this substitution reaction is carried out by reacting the reaction product of dapoxetine and the (R c O)(R d O)P(O)O(CR a R b ) y -halide or (R c O) 2 P(O)O(CR a R b ) y -halide with trifluoroacetic acid, acetic acid, hydrochloric acid or a mixture thereof in dichloromethane, tetrahydrofuran, methanol, ethanol, isopropanol, 1,4-dioxane or a mixture thereof (S2a), or by hydrogenating the reaction product of dapoxetine and the (R c O)(R d O)P(O)O(CR a R b ) y -halide or (R c O) 2 P(O)O(CR a R b ) y -halide in the presence of a metal catalyst (S2b).
  • S2b metal catalyst
  • the metal catalyst is a platinum- or palladium-containing compound and is used in an amount of 0.1 to 100 mol%, based on the moles of the reaction product. It is more preferred to carry out the hydrogenation reaction at a hydrogen pressure of 1 to 10 atm.
  • each of the methods of the present invention may further include dispersing the reaction product in which R c is substituted with hydrogen in acetone, diethyl ether, methyl t-butyl ether, ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile, ethanol, isopropyl alcohol or a mixture thereof, stirring the dispersion at 25 to 100 °C, followed by recrystallization at 0 to 25 °C (S3).
  • the dapoxetine prodrugs of the present invention can be obtained from dapoxetine as a starting material through a one-step reaction including step 1 or a two-step reaction including steps 1 and 2, followed by recrystallization, as depicted in Reaction Scheme 1:
  • R c may act as a protecting group, without being bound by this theory.
  • Some of the specific compounds of Formula 3 according to the present invention may be obtained using the (R c O)(R d O)P(O)O(CR a R b ) y -halide in a similar manner as in step 1 or by reacting the compounds of Formula 2 with a base in accordance with a salt formation method known in the art, but the present invention is not limited to such specific preparation methods.
  • novel dapoxetine prodrugs and pharmaceutically acceptable salts thereof according to the present invention are soluble in water, stable, and easy to process into preparations.
  • the compounds of the present invention exhibit improved dissolution rate and taste.
  • the pharmaceutical compositions of the present invention are useful for the treatment, management or prevention of premature ejaculation.
  • the methods of the present invention are suitable for the preparation of the dapoxetine prodrugs.
  • dapoxetine prodrugs represented by Formula 2 according to the present invention can be prepared through two steps, as depicted in Reaction Scheme 1:
  • R a , R b , R c and y are as defined in Formula 2.
  • step 1 of Reaction Scheme 1 dapoxetine represented by Formula (4) is reacted with the compound represented by Formula (5) in an organic solvent at 20 to 100 °C to give the compound represented by Formula (6).
  • the organic solvent is selected from acetone, ethyl acetate, 1,4-dioxane, acetonitrile and mixtures thereof. Acetonitrile is preferred.
  • the compound represented by Formula (6) is purified by recrystallization.
  • step 2 of Reaction Scheme 1 the compound represented by Formula (6) is reacted with an acid to give the compound represented by Formula (2).
  • the acid is selected from trifluoroacetic acid, acetic acid and hydrochloric acid.
  • the acid is used at a concentration of 0.1 to 6 N in an organic solvent.
  • the reaction is carried out at 0 to 50 °C.
  • the organic solvent is selected from dichloromethane, tetrahydrofuran, methanol, ethanol, isopropyl alcohol, 1,4-dioxane and mixtures thereof.
  • a solution of hydrochloric acid in 1,4-dioxane is used.
  • the compound represented by Formula (2) may be prepared by hydrogenation of the compound represented by Formula (6) in the presence of a metal catalyst in step 2 of Reaction Scheme 1.
  • the metal catalyst is a platinum- or palladium-containing compound and is used in an amount of 0.1 to 100 mol%, based on the moles of the reactant.
  • the hydrogenation reaction is carried out at a hydrogen pressure of 1 to 10 atm. It is preferred to use 0.05 to 5 mol% of a compound containing palladium/carbon as the metal catalyst, based on the moles of the reactant, at a hydrogen pressure of 1 atm.
  • the compound represented by Formula (2) in Reaction Scheme 1 is prepared by reacting the compound represented by Formula (6) with the acid or hydrogenating the compound represented by Formula (6) in the presence of the metal catalyst in accordance with. Thereafter, the reaction product is dispersed in an organic solvent, stirred at 25 to 100 °C, and purified by recrystallization at 0 to 25 °C.
  • the organic solvent is selected from acetone, diethyl ether, methyl t-butyl ether, ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile, ethanol, isopropyl alcohol and mixtures thereof.
  • Preferred is acetonitrile or a mixture of acetonitrile and ethanol.
  • the dapoxetine prodrugs represented by Formula 3 according to the present invention can also be prepared in a manner similar to the method for preparing the compounds of Formula 2.
  • Physiological saline was injected subcutaneously in the same amount as the amount of the blood drawn in order to prevent hypovolemic shock in the rats. Immediately after blood drawing, the blood samples were centrifuged at 12,000 rpm for 5 min to separate plasma. The plasma samples were stored at -20 °C before analysis. The AUC last and C max values of the test and control groups were obtained by analysis of the plasma concentrations of dapoxetine using LC/MS/MS under the following conditions:
  • the blood samples were centrifuged at 12,000 rpm for 5 min to separate plasma.
  • the plasma samples were stored at -20 °C before analysis.
  • the AUC last and C max values of the test and control groups were obtained by analysis of the plasma concentrations of dapoxetine under the same conditions as in Experimental Example 1.
  • the prodrug (dapoxetine derivative, Compound C ) prepared in Example 3 and dapoxetine hydrochloride were allowed to stand at 25 °C and 60% RH for 1 week.
  • Each of the test substances was prepared to have a concentration of 0.1 mg/mL.
  • the long-term photostability of the samples was analyzed by HPLC. The test results are shown in Table 3.
  • the prodrug (dapoxetine, Compound C ) had higher solubilities at all pH values 1.2, 4.0, 6.0 and 7.2 than dapoxetine hydrochloride. From these results, it can be predicted that the prodrug will show a smaller difference in in vivo absorption rate than dapoxetine hydrochloride.
  • the tastes of the prodrug (dapoxetine derivative, Compound C ) prepared in Example 3 and dapoxetine hydrochloride were compared and evaluated by sensory tests.
  • An aqueous solution of each of the test substances was prepared to have a concentration of 0.01 M. 0.5 mL portions of the aqueous solution were filled in brown vials. Thereafter, 10 male adults as subjects were allowed to taste the solutions at a 30-minute interval and to respond to questionnaires about taste. The subjects participating in the sensory tests were precluded from knowing what they tasted at first and later. After tasting the first substance, each subject was allowed to drink a glass of water. 30 minutes after drinking, the subject was allowed to taste the second substance. The results are shown in Table 6.

Abstract

Disclosed are novel dapoxetine derivatives and pharmaceutically acceptable salts thereof. The compounds are soluble in water, stable, and easy to process into preparations. In addition, the compounds exhibit improved dissolution rate and taste. Furthermore, the compounds exhibit a small difference in dissolution rate depending on pH. Further disclosed are pharmaceutical compositions including the compounds. The pharmaceutical compositions are useful for the treatment, management or prevention of premature ejaculation. Methods for preparing the dapoxetine derivatives are also disclosed.

Description

(S)-N,N-DIMETHYL-3-(NAPHTHALEN-1-YLOXY)-1-PHENYLPROPAN-1-AMINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THE DERIVATIVES AND MANUFACTURING METHODS THEREOF
The present invention relates to dapoxetine derivatives in the form of prodrugs, pharmaceutical compositions for premature ejaculation therapy including the dapoxetine derivatives, and methods for the preparation of the dapoxetine derivatives.
CrossReference to Related Application
This application claims priority to Korean Patent Application No. 1020100091416 filed in the Republic of Korea on September 17, 2010 and Korean Patent Application No. 1020110082839 filed in the Republic of Korea on August 19, 2011, the entire contents of which are incorporated herein by reference.
Premature ejaculation, one of the most common sexual complaints, is estimated to affect 30 to 40% of American men. Premature ejaculation means persistent or recurrent ejaculation with minimal sexual stimulation before, upon or shortly after penetration, and before the person wishes it. Such ejaculation that occurs sooner than desired is often disappointing and can lead to other sexual dysfunctions including erectile difficulties, female inorgasmia, low sexual desire, and sexual aversion.
(S)-N,N-dimethyl-3-(naphthalen-1-yloxy)-1-phenylpropan-1-amine (dapoxetine), a shortacting selective serotonin reuptake inhibitor (SSRI), is currently used for the treatment of premature ejaculation. However, dapoxetine free base has the problem of relatively poor water solubility, making it difficult to process into various formulations. Another problem of dapoxetine free base is poor in vivo solubility, ultimately leading to low in vivo absorption.
For these reasons, dapoxetine have been developed in the form of a hydrochloride salt. Since dapoxetine hydrochloride is bitter in taste, prescriptions recommend that formulations of dapoxetine hydrochloride should be swallowed whole along with a full glass of water in order to avoid the bitter taste. Nausea, vomiting and retching are most frequently reported as side effects when taking bitter dapoxetine hydrochloride.
The present invention is designed to solve the problems of the prior art, and therefore it is an object of the present invention to provide novel dapoxetine derivatives in the form of prodrugs that have excellent physicochemical properties, can be rapidly and readily absorbed in vivo to exhibit pharmacological effects of dapoxetine, are not bitter in taste, and can be processed into various formulations. It is another object of the present invention to provide pharmaceutical compositions including the dapoxetine derivatives. It is still another object of the present invention to provide efficient methods for preparing the dapoxetine derivatives.
In order to achieve the above objects, the present invention provides compounds having a prodrug structure of dapoxetine in which a pro-group Rp is bonded to the tertiary amine group of dapoxetine, represented by Formula 1:
Figure PCTKR2011006892-appb-I000001
(1)
wherein the pro-group Rp is a group having a phosphate bond, and
pharmaceutically acceptable salts thereof.
Preferably, the present invention provides compounds in which the pro-group Rp has a zwitterionic structure of -(CRaRb)y-O-P(O)(ORc)(O-), represented by Formula 2:
Figure PCTKR2011006892-appb-I000002
(2)
wherein y is an integer from 1 to 4;
Ra and Rb are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C4 alkoxy group, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C14 aryl group or a substituted or unsubstituted C7-C20 arylalkyl group, or Ra and Rb are attached together to form a C3-C8 substituted or unsubstituted cycloalkyl group;
Rc is a hydrogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted C7-C20 arylalkyl group, a substituted or unsubstituted five to fourteen-membered ring group, a heterocyclic group containing at least one heteroatom selected from N, O and S, or a pharmaceutically acceptable salt-forming cation;
provided that when Ra, Rb or Rc is substituted with at least one substituent, the substituent is selected from halogen atoms and hydroxyl, C1-C4 alkoxy, amino and C1-C4 alkylamino groups, and
pharmaceutically acceptable salts thereof.
Preferably, the present invention provides compounds in which the pro-group Rp is -(CRaRb)y-O-P(O)(ORc)(ORd)X-, represented by Formula 3:
Figure PCTKR2011006892-appb-I000003
(3)
wherein y is an integer from 1 to 4;
Ra and Rb are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C4 alkoxy group, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C14 aryl group or a substituted or unsubstituted C7-C20 arylalkyl group, or Ra and Rb are attached together to form a C3-C8 substituted or unsubstituted cycloalkyl group;
Rc and Rd are each independently a hydrogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted C7-C20 arylalkyl group, a substituted or unsubstituted five to fourteen-membered ring group, a heterocyclic group containing at least one heteroatom selected from N, O and S, or a pharmaceutically acceptable salt-forming cation;
provided that when Ra, Rb, Rc or Rd is substituted with at least one substituent, the substituent is selected from halogen atoms and hydroxyl, C1-C4 alkoxy, amino and C1-C4 alkylamino groups; and
X- is a pharmaceutically acceptable anion (salt), and
pharmaceutically acceptable salts thereof.
Preferably, specific examples of the dapoxetine prodrugs according to the present invention include, but are not limited to,
(S)-tert-butyl((dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl) phosphate,
(S)-benzyl((dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl) phosphate,
(S)-(dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl hydrogen phosphate,
(S)-2-(dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)ethyl 2-hydroxyethyl phosphate,
(S)-3-(dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)propyl 2-hydroxyethyl phosphate,
sodium salt of (S)-(dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl phosphate,
calcium salt of (S)-(dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl phosphate chloride,
(S)-5-amino-5-carboxypentane-1-aminium salt of (S)-(dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl phosphate, and
(S)-1-(4-amino-4-carboxybutyl)guanidinium salt of (S)-(dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl phosphate.
The problems of dapoxetine, such as substantial water insolubility and bitterness, are solved by the dapoxetine derivatives of the present invention in which the pro-group Rp is introduced into the tertiary amine group of dapoxetine. In addition, the dapoxetine derivatives of the present invention are easy to process into preparations and exhibit improved characteristics in terms of dissolution rate, dissolution variation, bioavailability, etc. Without wishing to be bound by theory, it is believed that the dapoxetine derivatives with improved solubility according to the present invention may be degraded to dapoxetine by in vivo enzymatic reactions.
Each of the pharmaceutically acceptable salt-forming anions of the dapoxetine derivatives according to the present invention may be derived from an organic or inorganic acid. Examples of organic acids suitable for use in the derivatives of the present invention include, but are not limited to, maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, benzenesulfonic, toluenesulfonic, acetic, oxalic, gentisic, trifluoroacetic, trifluoromethanesulfonic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, formic, glycolic and glutamic acids. Suitable inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydrofluoric, hydroiodic, sulfuric, phosphoric and nitric acids.
Each of the pharmaceutically acceptable salt-forming cations of the dapoxetine derivatives according to the present invention may be selected from the group consisting of, but not limited to: ammonium; pharmaceutically acceptable metal cations, including but not limited to, cations of alkali metals (for example, Na, K and Li), alkaline earth metals (for example, Ca and Mg), zinc and iron; suitable organic bases, for example, C1-C8 lower alkylamines, such as methylamine, ethylamine and cyclohexylamine, and substituted C1-C8 lower alkylamines, for example, diethanolamine, triethanolamine and hydroxylated alkylamines (e.g., tris(hydroxymethyl)aminomethane); bases, such as meglumine (N-methyl-D-glucamine), piperidine and morphiline; and basic amino acids, such as arginine, lysine and glycine.
The present invention is also intended to encompass solvates, particularly hydrates, of the dapoxetine derivatives. That is, the dapoxetine derivatives of the present invention may exist in unsolvated as well as solvated forms (for example, hydrated forms). The compounds of the present invention may exist in crystalline or amorphous forms. All such physical forms are within the scope of the present invention.
The present invention also provides a pharmaceutical composition including at least one of the dapoxetine derivatives and pharmaceutically acceptable salts thereof as an active ingredient and optionally a pharmaceutically acceptable excipient or additive.
The pharmaceutical composition of the present invention is preferably used for the treatment, management or prevention of premature ejaculation. The compound or pharmaceutically acceptable salt thereof may be administered alone or in combination with any convenient carrier, excipient, etc. and is may be provided in a single dosage form or in multiple dosage forms.
The pharmaceutical composition of the present invention may be a solid or liquid preparation. Non-limiting examples of such solid preparations include powders, granules, tablets, capsules and suppositories. These solid preparations may include suitable excipients, flavors, binders, preservatives, disintegrants, lubricants, fillers, etc. Non-limiting examples of such liquid preparations include solutions, such as aqueous solutions and propylene glycol solutions, suspensions, and emulsions. These liquid preparations may include suitable colorants, flavors, stabilizers and thickeners.
For example, a powder may be prepared by simply mixing the dapoxetine derivative or salt thereof with a suitable pharmaceutically acceptable excipient, such as lactose, starch or microcrystalline cellulose. A granule may be prepared by mixing the dapoxetine derivative or pharmaceutically acceptable salt, a suitable pharmaceutically acceptable excipient and a suitable pharmaceutically acceptable binder, such as polyvinyl pyrrolidone or hydroxypropyl cellulose, and granulating the mixture using a suitable solvent such as water, ethanol or isopropanol (wet granulation) or by the application of a compressive force (dry granulation). A tablet may be prepared by mixing the granule with a suitable pharmaceutically acceptable lubricant, such as magnesium stearate, and compacting the mixture using a suitable tableting machine.
There is no restriction on the route of administration of the pharmaceutical composition according to the present invention. For example, the pharmaceutical composition of the present invention may be administered orally, by injection (for example, intramuscular injection, intraperitoneal injection, intravenous injection, infusion, subcutaneous injection or implantation), by inhalation, nasally, intravaginally, rectally, sublingually, transdermally, topically, etc. depending on the severity of disease and the condition of subjects to be treated. The pharmaceutical composition of the present invention may be prepared into an appropriate unit dosage form including at least one known non-toxic, pharmaceutically acceptable carrier, adjuvant or vehicle, depending on the desired route of administration. The pharmaceutical composition of the present invention may also be prepared into a depot formulation from which the active ingredient can be continuously released for a certain period of time, which is also encompassed within the scope of the present invention.
The present invention also provides a method for the management, treatment or prevention of premature ejaculation, the method including administering a therapeutically effective amount of at least one of the dapoxetine derivatives and pharmaceutically acceptable salts thereof to a subject in need of such management, treatment or prevention.
For the treatment of premature ejaculation, the compound or pharmaceutically acceptable salt thereof may be administered in an amount ranging from about 0.001 mg to about 350 mg, preferably from about 0.01 mg to about 200 mg, more preferably from about 0.1 mg to about 120 mg, most preferably from about 1 mg to about 80 mg, in a single dose or in divided doses, if needed, before an activity involving sexual arousal wherein the patient desires to avoid sexual dysfunction, such as premature ejaculation. Examples of such sexual activities are sexual intercourse and masturbation. The dose of the compound or pharmaceutically acceptable salt thereof may be varied depending on the conditions of the patient (e.g., age, sex and body weight) and the severity of the particular condition to be treated. For convenience of administration, if needed, the daily dose of the compound or pharmaceutically acceptable salt thereof may be administered in divided doses.
The present invention also provides a method for preparing the dapoxetine prodrugs represented by Formula 2, the method including reacting dapoxetine with (RcO)2P(O)O(CRaRb)y-halide (S1a), and a method for preparing the dapoxetine prodrugs represented by Formula 3, the method including reacting dapoxetine with (RcO)(RdO)P(O)O(CRaRb)y-halide or (RcO)2P(O)O(CRaRb)y-halide (S1b). More preferably, the reactions are carried out in acetone, ethyl acetate, 1,4-dioxane, acetonitrile or a mixture thereof at 20 to 100 ℃. The products can be purified by recrystallization. Each of the halides is preferably a chloride.
Depending on the specific chemical structures of the dapoxetine prodrugs, each of the methods of the present invention may further include substituting Rc of the reaction product of dapoxetine and the (RcO)(RdO)P(O)O(CRaRb)y-halide or (RcO)2P(O)O(CRaRb)y-halide with hydrogen (S2). Preferably, this substitution reaction is carried out by reacting the reaction product of dapoxetine and the (RcO)(RdO)P(O)O(CRaRb)y-halide or (RcO)2P(O)O(CRaRb)y-halide with trifluoroacetic acid, acetic acid, hydrochloric acid or a mixture thereof in dichloromethane, tetrahydrofuran, methanol, ethanol, isopropanol, 1,4-dioxane or a mixture thereof (S2a), or by hydrogenating the reaction product of dapoxetine and the (RcO)(RdO)P(O)O(CRaRb)y-halide or (RcO)2P(O)O(CRaRb)y-halide in the presence of a metal catalyst (S2b). The metal catalyst is a platinum- or palladium-containing compound and is used in an amount of 0.1 to 100 mol%, based on the moles of the reaction product. It is more preferred to carry out the hydrogenation reaction at a hydrogen pressure of 1 to 10 atm.
More preferably, each of the methods of the present invention may further include dispersing the reaction product in which Rc is substituted with hydrogen in acetone, diethyl ether, methyl t-butyl ether, ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile, ethanol, isopropyl alcohol or a mixture thereof, stirring the dispersion at 25 to 100 ℃, followed by recrystallization at 0 to 25 ℃ (S3).
Specifically, the dapoxetine prodrugs of the present invention can be obtained from dapoxetine as a starting material through a one-step reaction including step 1 or a two-step reaction including steps 1 and 2, followed by recrystallization, as depicted in Reaction Scheme 1:
Figure PCTKR2011006892-appb-I000004
(1)
Some of the specific compounds of Formula 2 according to the present invention are prepared after step 1 and some thereof are prepared after both steps 1 and 2. When the compounds of Formula 2 are prepared after steps 1 and 2, Rc may act as a protecting group, without being bound by this theory.
Some of the specific compounds of Formula 3 according to the present invention may be obtained using the (RcO)(RdO)P(O)O(CRaRb)y-halide in a similar manner as in step 1 or by reacting the compounds of Formula 2 with a base in accordance with a salt formation method known in the art, but the present invention is not limited to such specific preparation methods.
The novel dapoxetine prodrugs and pharmaceutically acceptable salts thereof according to the present invention are soluble in water, stable, and easy to process into preparations. In addition, the compounds of the present invention exhibit improved dissolution rate and taste. The pharmaceutical compositions of the present invention are useful for the treatment, management or prevention of premature ejaculation. The methods of the present invention are suitable for the preparation of the dapoxetine prodrugs.
Hereinafter, the present invention will be described in detail with reference to embodiments. The embodiments are provided to assist in a further understanding of the present invention. The embodiments of the present invention, however, may take several other forms, and the scope of the invention should not be construed as being limited to the following examples. The embodiments of the present invention are provided to more fully explain the present invention to those having ordinary knowledge in the art to which the present invention belongs.
<Synthesis of Dapoxetine Prodrugs>
The dapoxetine prodrugs represented by Formula 2 according to the present invention can be prepared through two steps, as depicted in Reaction Scheme 1:
Figure PCTKR2011006892-appb-I000005
(1)
wherein Ra, Rb, Rc and y are as defined in Formula 2.
In step 1 of Reaction Scheme 1, dapoxetine represented by Formula (4) is reacted with the compound represented by Formula (5) in an organic solvent at 20 to 100 ℃ to give the compound represented by Formula (6). The organic solvent is selected from acetone, ethyl acetate, 1,4-dioxane, acetonitrile and mixtures thereof. Acetonitrile is preferred. After the reaction, the compound represented by Formula (6) is purified by recrystallization.
In step 2 of Reaction Scheme 1, the compound represented by Formula (6) is reacted with an acid to give the compound represented by Formula (2). The acid is selected from trifluoroacetic acid, acetic acid and hydrochloric acid. The acid is used at a concentration of 0.1 to 6 N in an organic solvent. The reaction is carried out at 0 to 50 ℃. The organic solvent is selected from dichloromethane, tetrahydrofuran, methanol, ethanol, isopropyl alcohol, 1,4-dioxane and mixtures thereof. Preferably, a solution of hydrochloric acid in 1,4-dioxane is used.
Alternatively, the compound represented by Formula (2) may be prepared by hydrogenation of the compound represented by Formula (6) in the presence of a metal catalyst in step 2 of Reaction Scheme 1. The metal catalyst is a platinum- or palladium-containing compound and is used in an amount of 0.1 to 100 mol%, based on the moles of the reactant. The hydrogenation reaction is carried out at a hydrogen pressure of 1 to 10 atm. It is preferred to use 0.05 to 5 mol% of a compound containing palladium/carbon as the metal catalyst, based on the moles of the reactant, at a hydrogen pressure of 1 atm.
As described above, the compound represented by Formula (2) in Reaction Scheme 1 is prepared by reacting the compound represented by Formula (6) with the acid or hydrogenating the compound represented by Formula (6) in the presence of the metal catalyst in accordance with. Thereafter, the reaction product is dispersed in an organic solvent, stirred at 25 to 100 ℃, and purified by recrystallization at 0 to 25 ℃. The organic solvent is selected from acetone, diethyl ether, methyl t-butyl ether, ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile, ethanol, isopropyl alcohol and mixtures thereof. Preferred is acetonitrile or a mixture of acetonitrile and ethanol.
The dapoxetine prodrugs represented by Formula 3 according to the present invention can also be prepared in a manner similar to the method for preparing the compounds of Formula 2.
Example 1
(S)-tert-butyl((dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl) phosphate (Compound A)
(S)-N,N-dimethyl-3-(naphthalen-1-yloxy)-1-phenylpropan-1-amine (5 g, 16.4 mmol) was dissolved in acetonitrile (25 mL), and NaHCO3 (1.38 g, 1.31 mmol) and di-tert-butyl chloromethyl phosphate (8.47 g, 32.7 mmol) were added thereto. The mixture was stirred at 50 ℃ for 70 hr. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by preparative HPLC (C18 column, Water/ACN). The obtained fraction was freeze-dried to yield 650 mg (8%) of Compound A as a white solid.
MS (ESI): 472 [MH+]
1H NMR (300 MHz, CDCl3) δ 7.97 (m, 1H), 7.75 (m, 1H), 7.54-7.22 (m, 9H), 6.55 (d, 1H), 5.26 (t, 1H), 5.17 (t, 1H), 5.07 (dd, 1H), 4.06 (m, 1H), 3.87 (m, 1H), 3.25 (s, 3H), 3.08 (s, 3H), 3.05-2.70 (m, 2H), 1.46 (s, 9H)
Example 2
(S)-benzyl((dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl)phosphate (Compound B)
(S)-N,N-dimethyl-3-(naphthalen-1-yloxy)-1-phenylpropan-1-amine (43.8 g, 114 mmol) was added to acetonitrile (287 mL), and dibenzyl chloromethyl phosphate (56.3 g, 172 mmol) was added thereto at room temperature. The mixture was stirred for at least 16 hr and filtrated to obtain a solid. The solid was dried at 30 ℃ for 6 hr to yield 54.6 g (75%) of Compound B as a white solid.
MS (ESI): 506 [MH+]
1H NMR (300 MHz, DMSO-d6) δ 8.00 (m, 1H), 7.79-7.16 (m, 15H), 6.61 (d, 1H), 5.02 (dd, 1H), 4.93 (t, 1H), 4.89 (d, 2H), 4.81 (t, 1H), 4.03 (m, 1H), 3.71 (m, 1H), 3.08 (s, 3H), 2.89 (s, 3H), 2.97-2.73 (m, 2H)
Example 3
(S)-(dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl hydrogen phosphate (Compound C)
Method 1: Trifluoroacetic acid (0.25 mL, 3.3 mmol) was added to a solution of (S)-tert-butyl((dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl) phosphate (Compound A, 73 mg, 0.16 mmol) in dichloromethane (15 mL). The mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (C18 column, 0.1% TFA-water/ACN) to yield 62 mg (96%) of Compound C as a white solid.
Method 2: (S)-benzyl((dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl) phosphate (Compound B, 6.7 g, 13.3 mmol) was added to a 4 N HCl-dioxane solution (20.1 mL). The mixture was stirred at room temperature for 12 hr. After the reaction mixture was concentrated under reduced pressure, the aqueous layer was washed twice with water (20.1 mL) and ethyl acetate (6.7 mL). The washed aqueous layer was loaded onto a column packed with a Dianion HP20 resin (Mitsubishi) and was continuously washed with water to remove the excess HCl and the filtered salt. Subsequently, MeOH washing gave a fraction. The methanol fraction was concentrated under reduced pressure. 20 mL of acetonitrile was added to the concentrate. The resulting mixture was stirred at 50 ℃ for 3 hr and filtered to obtain a solid. The above procedure was repeated twice. The solids were collected and dried under reduced pressure at 30 ℃ for 6 hr to yield 3.3 g (60%) of Compound C as a white solid.
Method 3: (S)-Benzyl((dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl) phosphate (Compound B, 30 g, 59.3 mmol) was added to a 4 N HCl-dioxane solution (90 mL). The mixture was stirred at room temperature for 12 hr. After the reaction mixture was concentrated under reduced pressure, the aqueous layer was washed twice with water (90 mL) and ethyl acetate (30 mL). Propylene oxide (60 mL) was added to the aqueous layer with stirring to adjust the pH to about 3.3-3.5. After washing once with ethyl acetate (30 mL), the aqueous layer was concentrated under reduced pressure. 90 mL of acetonitrile was added to the concentrate. The resulting mixture was stirred at 50 ℃ for 3 hr and filtered to obtain a solid. The above procedure was repeated twice. The solids were collected and dried under reduced pressure at 30 ℃ for 6 hr to yield 16.4 g (66%) of Compound C as a white solid.
MS (EIS): 415[M+]
Method 4: (S)-Benzyl((dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl) phosphate (Compound B, 300 g, 593 mmol) was dissolved in methanol (2000 mL) in a reactor. After Pd/C (45 g) was added to the solution, the reactor walls were washed with methanol (100 mL). The mixture was stirred for about 4 hr under a hydrogen atmosphere at a pressure of 1 atm. The reaction mixture was filtered through Celite under reduced pressure and washed with methanol. 2,000 mL of hexane was added to the methanol solution. After sufficient stirring, the methanol layer was separated and concentrated under reduced pressure. The concentrate was recrystallized from a mixture of acetonitrile and ethanol to yield 153 g (62%) of Compound C as a white solid.
MS (EIS): 415 [M+]
1H NMR (300 MHz, DMSO-d6) δ 7.99 (m, 1H), 7.79-7.19 (m, 10H), 6.63 (d, 1H), 5.06 (dd, 1H), 4.99 (t, 1H), 4.90 (t, 2H), 4.03 (m, 1H), 3.75 (m, 1H), 3.10 (s, 3H), 2.92 (s, 3H), 3.02-2.77 (m, 2H)
Example 4
(S)-2-(dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)ethyl (2-hydroxyethyl) phosphate (Compound D)
Sodium iodide (2.9 g, 19.6 mmol), sodium carbonate (260 mg, 2.5 mmol) and 2-chloroethanol (1.3 mL, 19.6 mmol) were added to a solution of (S)-N,N-dimethyl-3-(naphthalene-1-yloxy)-1-phenylpropan-1-amine (3.0 g, 9.8 mmol) in acetonitrile (32.7 mL). The mixture was stirred at 90 ℃ for 16 hr. After cooling to room temperature, the precipitate was filtered off. The filtrate was concentrated under reduced pressure and purified by column chromatography (MPLC, 0-10% MeOH/MC) to obtain 3.6 g of a white solid. The solid (223 mg, 0.64 mmol) was dissolved in dichloromethane (4.4 mL), and triethylamine (0.27 mL, 1.91 mmol) was added thereto. The mixture was stirred. 2-Chloro-1,3,2-dioxaphospholane-2-oxide (0.066 mL, 0.70 mmol) was slowly added dropwise to the mixture at 0 ℃, followed by stirring for 24 hr. Water (0.44 mL) was added to the reaction mixture. The mixture was concentrated under reduced pressure and purified by column chromatography (MPLC, 15% MeOH/MC) to yield 136 mg (45%) of Compound C as a white solid.
MS (ESI): 473 [MH+]
1H NMR (300 MHz, CDCl3) δ 8.06 (m, 1H), 7.67 (m, 1H), 7.36 (d, 2H), 7.28-7.18 (m, 6H), 7.16 (m, 2H), 6.64 (m, 1H), 4.76 (m, 1H), 4.44 (m, 2H), 4.16 (m, 2H), 4.02 (m, 2H), 3.87 (m, 2H), 3.82 (m, 2H), 3.27 (s, 3H), 3.10 (s, 3H), 2.52 (m, 1H)
Example 5
(S)-3-(dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)propyl (2-hydroxyethyl) phosphate (Compound E)
Acetonitrile (2.0 mL) was put into (S)-N,N-dimethyl-3-(naphthalen-1-yloxy)-1-phenylpropan-1-amine (200 mg, 0.66 mmol) in a seal tube. To the mixture were added 3-chloropropan-1-ol (0.11 mL, 1.31 mmol), sodium iodide (196 mg, 1.31 mmol) and sodium carbonate (17 mg, 0.16 mmol) with stirring. The resulting mixture was stirred at 70 ℃ for 16 hr. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (MPLC, 0-10% MeOH/MC) to obtain 290 mg of a yellow solid. The solid (253 mg, 0.70 mmol) was dissolved in dichloromethane (4.4 mL), and triethylamine (0.29 mL, 2.10 mmol) was added thereto. The mixture was stirred. To the mixture was slowly added dropwise 2-chloro-1,3,2-dioxaphospholane 2-oxide (0.072 mL, 0.77 mmol) at 0 ℃, followed by stirring at room temperature for 24 hr. Water (0.44 mL) was added to the reaction mixture. The resulting mixture was concentrated under reduced pressure and purified by column chromatography (MPLC, 15% MeOH/MC) to yield to 110 mg (32%) of Compound E as a white solid.
MS (ESI): 487 [MH+]
1H NMR (300 MHz, CDCl3) δ 8.05 (m, 1H), 7.70 (m, 1H), 7.43 (m, 4H), 7.297.10 (m, 6H), 6.85 (d, 1H), 4.76 (s, 1H), 3.96 (m, 4H), 3.91 (m, 2H), 3.43 (m, 2H), 3.38 (s, 3H), 3.24 (s, 3H), 2.58 (m, 3H), 2.14 (m, 2H).
Example 6
Sodium salt of (S)-(dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl phosphate (Compound F)
(S)-(dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl hydrogen phosphate (Compound C, 300.2 mg, 0.72 mmol) was added to a solution of sodium hydroxide (31.5 mg, 0.79 mmol) in water (4.8 mL). The mixture was stirred at 65 ℃ for 5 hr. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, recrystallized from water/isopropyl alcohol, and filtered to obtain a solid. The solid was washed with isopropyl alcohol and dried under reduced pressure to yield to 297 mg (94%) of Compound F as a white solid.
MS (EIS): 438 [M+Na]+
1H NMR (300 MHz, MeOD) δ 8.00 (d, 1H) 7.76-7.35 (m, 9H), 7.25 (t, 1H), 6.64 (d, 1H), 5.07 (dd, 1H), 4.96-4.83 (m, 2H), 4.14-4.07 (m, 1H), 3.97-3.87 (m, 1H), 3.14 (s, 3H), 3.09-2.88 (m, 2H), 2.99 (s, 3H)
Example 7
Calcium salt of (S)-(dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl phosphate chloride (Compound G)
A solution of sodium bicarbonate (22.2 mg, 0.27 mmol) in water (3 mL) was slowly added dropwise to a solution of (S)-(dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl hydrogen phosphate (Compound C, 100 mg, 0.24 mmol) in water (1.5 mL). The mixture was stirred at room temperature for 2 hr. To the mixture was added a solution of calcium chloride (15 mg, 0.13 mmol) in water (3.0 mL), followed by additional stirring at room temperature for 2 hr. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, recrystallized from water/ethanol, and filtered to obtain a solid. The solid was washed with ethanol and dried under reduced pressure to yield 40 mg (34%) of Compound G as a white solid.
MS (EIS): 415 [M+]
1H NMR (300 MHz, MeOD) δ 8.00-7.96 (m, 1H), 7.75-7.19 (m, 10H), 6.60-6.56 (m, 1H), 5.08-5.02 (m, 2H), 4.95-4.81 (m, 1H), 4.05-4.01 (m, 1H), 3.79-3.76 (m, 1H), 3.20 (s, 3H), 3.08-2.84 (m, 2H), 3.01 (s, 3H)
Example 8
(S)-5-amino-5-carboxypentan-1-aminium salt of (S)-(dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl phosphate (Compound H)
L-lysine (35.2 mg, 0.241 mmol) was added to a solution of (S)-(dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl hydrogen phosphate (Compound C, 100 mg, 0.24 mmol) in ethanol (8.0 mL). The mixture was stirred at 65 ℃ for 2 hr. Water (2.0 mL) was slowly added until the resulting mixture became transparent, followed by additional stirring at 65 ℃ for 1 hr. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, recrystallized from ethanol/t-BuOMe, and filtered to obtain a solid. The solid was washed with t-BuOMe and dried under reduced pressure to yield 52 mg (38.5%) of Compound H as a white solid.
MS (EIS): 415 [MH+]
1H NMR (MeOD, 300MHz) δ 8.02-8.00 (m, 1H), 7.76-7.35 (m, 9H), 7.28-7.22 (m, 1H), 6.64 (d, 1H), 5.09-5.05 (m, 1H), 4.96-4.82 (m, 2H), 4.13-4.09 (m, 1H), 3.90-3.87 (m, 1H), 3.55-3.53 (m, 1H), 3.16 (s, 3H), 3.00 (s, 3H), 2.95-2.90 (m, 4H), 1.94-1.82 (m, 2H), 1.72-1.64 (m, 2H), 1.56-1.49 (m, 2H)
Example 9
(S)-1-(4-amino-4-carboxybutyl)guanidinium salt of (S)-(dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl phosphate (Compound I)
L-arginine (41.9 mg, 0.24 mmol) was added to a solution of (S)-(dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl hydrogen phosphate (Compound C, 100 mg, 0.24 mmol) in ethanol (8.0 mL). The mixture was stirred at 65 ℃ for 2 hr. Water (2.0 mL) was slowly added until the resulting mixture became transparent, followed by additional stirring at 65 ℃ for 1 hr. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, recrystallized from water/ethanol, and filtered to obtain a solid. The solid was washed with ethanol and dried under reduced pressure to yield 86 mg (60%) of Compound I as a white solid.
MS (EIS): 589 [M1+M2]+
1H NMR (300 MHz, D2O) δ 7.83 (d, 2H), 7.59-7.22 (m, 9H), 6.58 (d, 1H), 4.94-4.66 (m, 3H), 4.09-4.05 (m, 1H), 3.79-3.70 (m, 2H), 3.17 (t, 2H), 3.07 (s, 3H), 2.92 (s, 3H), 2.86-2.69 (m, 2H), 1.93-1.81 (m, 2H), 1.75-1.57 (m, 2H)
<Experimental Example 1> Pharmacokinetic Evaluation of the Dapoxetine Prodrug in Rats
Single-dose pharmacokinetic (PK) tests were conducted on the prodrug (dapoxetine derivative, Compound C) prepared in Example 3 and dapoxetine hydrochloride in male Sprague-Dawley (SD) rats. Each of the test substances was given to the rats (n = 6) until the dapoxetine concentrations reached 10 mg/kg. Upon administration, a 50% aqueous solution of PEG 400 was used as a vehicle. Blood was drawn from the retro-orbital plexus of the rats using capillary tubes at 15 min, 30 min, 1 hr, 2 hr, 4 hr, 6 hr, 10 hr and 24 hr after administration. The blood samples were collected in K2-EDTA tubes. Physiological saline was injected subcutaneously in the same amount as the amount of the blood drawn in order to prevent hypovolemic shock in the rats. Immediately after blood drawing, the blood samples were centrifuged at 12,000 rpm for 5 min to separate plasma. The plasma samples were stored at -20 ℃ before analysis. The AUClast and Cmax values of the test and control groups were obtained by analysis of the plasma concentrations of dapoxetine using LC/MS/MS under the following conditions:
- Acetonitrile: 10 mM ammonium acetate = 60: 40
- Flow rate: 0.3 mL/min
- Column: Shiseido Capcell Pak C18 MG3 (5 μm, 2.0 × 50 mm)
- MS conditions: Dapoxetine ([M+H]+ Q1: 306.17/Q3: 261.1)
Internal standard SK3304 ([M+H]+ Q1: 520.066 / Q3: 376.7)
The test results are shown in Table 1.
Table 1
Figure PCTKR2011006892-appb-T000001
As can be seen from the results in Table 1, the AUClast and Cmax values of the test group were very similar to those of the control group. From these results, it could be concluded that the prodrug (dapoxetine derivative, Compound C) was degraded in vivo to dapoxetine.
<Experimental Example 2> Pharmacokinetic Evaluation of the Dapoxetine Prodrug in Beagles
Single-dose crossover PK tests were conducted on the prodrug (dapoxetine derivative, Compound C) prepared in Example 3 and dapoxetine hydrochloride in beagles. Each of the test substances was given to the beagles (n = 3) until the dapoxetine concentrations reached 30 mg/kg. For administration, the drugs were filled in capsules. Blood was drawn from the cephalic vein of the beagles using syringes prior to administration and at 10 min, 30 min, 45 min, 1 hr, 1.25 hr, 1.5 hr, 2 hr, 4 hr, 7 hr, 10 hr and 24 hr after administration. The blood samples were collected in K2-EDTA tubes. Immediately after blood drawing, the blood samples were centrifuged at 12,000 rpm for 5 min to separate plasma. The plasma samples were stored at -20 ℃ before analysis. The AUClast and Cmax values of the test and control groups were obtained by analysis of the plasma concentrations of dapoxetine under the same conditions as in Experimental Example 1.
Table 2
Figure PCTKR2011006892-appb-T000002
As can be seen from the results in Table 2, the AUClast and Cmax values of the test group were very similar to those of the control group. From these results, it could be concluded that the prodrug (dapoxetine derivative, Compound C) was degraded in vivo to dapoxetine.
<Experimental Example 3> Evaluation of Photostability of the Dapoxetine Prodrug
The prodrug (dapoxetine derivative, Compound C) prepared in Example 3 and dapoxetine hydrochloride were allowed to stand at 25 ℃ and 60% RH for 1 week. Each of the test substances was prepared to have a concentration of 0.1 mg/mL. The long-term photostability of the samples was analyzed by HPLC. The test results are shown in Table 3.
Table 3
Figure PCTKR2011006892-appb-T000003
As can be seen from the results in Table 3, the prodrug (dapoxetine derivative, Compound C) was more stable under extreme UV and visible conditions for 1 week than dapoxetine hydrochloride. These results indicate improved photostability of the prodrug (dapoxetine derivative, Compound C).
<Experimental Example 4> Evaluation of Solubility of the Dapoxetine Prodrug in Water
Solubility tests were conducted on the prodrug (dapoxetine derivative, Compound C) prepared in Example 3 and dapoxetine hydrochloride. After an excess of each of the compounds was dissolved in purified water, the solution was shaken for 24 hr. A calibration curve of the concentration of the compound was constructed by UPLC to quantitatively determine the solubility of the compound. The results are shown in Table 4.
Table 4
Figure PCTKR2011006892-appb-T000004
The results in Table 4 show that the solubility of the prodrug (dapoxetine derivative, Compound C) was higher than that of dapoxetine hydrochloride.
<Experimental Example 5> Evaluation of pH-Dependent Solubility of the Dapoxetine Prodrugs
Solubility tests were conducted on the prodrug (dapoxetine derivative, Compound C) prepared in Example 3 and dapoxetine hydrochloride at different pH values. Each of the test substances was supersaturated. The sample was stirred for 24 hr, followed by centrifugation. The supernatant was diluted as much as 64-fold to prepare a test solution. Additional solutions were prepared to have concentrations of 0.01 mg/mL, 0.05 mg/mL, 0.10 mg/mL, 0.50 mg/mL and 1.00 mg/mL to ensure linearity, from which the dissolution concentration of the test substance was calculated. The results are shown in Table 5.
Table 5
Figure PCTKR2011006892-appb-T000005
As can be seen from the results in Table 5, the prodrug (dapoxetine, Compound C) had higher solubilities at all pH values 1.2, 4.0, 6.0 and 7.2 than dapoxetine hydrochloride. From these results, it can be predicted that the prodrug will show a smaller difference in in vivo absorption rate than dapoxetine hydrochloride.
<Experimental Example 6> Comparison and Evaluation of Taste of the Prodrug (Dapoxetine Derivative)
The tastes of the prodrug (dapoxetine derivative, Compound C) prepared in Example 3 and dapoxetine hydrochloride were compared and evaluated by sensory tests. An aqueous solution of each of the test substances was prepared to have a concentration of 0.01 M. 0.5 mL portions of the aqueous solution were filled in brown vials. Thereafter, 10 male adults as subjects were allowed to taste the solutions at a 30-minute interval and to respond to questionnaires about taste. The subjects participating in the sensory tests were precluded from knowing what they tasted at first and later. After tasting the first substance, each subject was allowed to drink a glass of water. 30 minutes after drinking, the subject was allowed to taste the second substance. The results are shown in Table 6.
Table 6
Figure PCTKR2011006892-appb-T000006
The results in Table 6 show that the taste of the prodrug (dapoxetine derivative, Compound C) was markedly improved as compared to that of dapoxetine hydrochloride. After having tasted dapoxetine hydrochloride, most of the subjects stated that the bitter taste had lingered in their mouths for 10 minutes or more after tasting. In contrast, after having tasted the prodrug, some of the subjects responded that a slight bitterness had been felt at first but the taste had not remained long.

Claims (13)

  1. A dapoxetine prodrug in which a pro-group Rp is bonded to the tertiary amine group of dapoxetine, represented by Formula 1:
    Figure PCTKR2011006892-appb-I000006
    (1)
  2. The dapoxetine prodrug according to claim 1, wherein the pro-group Rp has a phosphate bond.
  3. The dapoxetine prodrug according to claim 1, wherein the prodrug has a structure in which the pro-group Rp has a zwitter-ionic structure of -(CRaRb)y-O-P(O)(ORc)(O-), represented by Formula 2:
    Figure PCTKR2011006892-appb-I000007
    (2)
    wherein y is an integer from 1 to 4;
    Ra and Rb are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C4 alkoxy group, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C14 aryl group or a substituted or unsubstituted C7-C20 arylalkyl group, or Ra and Rb are attached together to form a C3-C8 substituted or unsubstituted cycloalkyl group;
    Rc is a hydrogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted C7-C20 arylalkyl group, a substituted or unsubstituted five to fourteen-membered ring group, a heterocyclic group containing at least one heteroatom selected from N, O and S, or a pharmaceutically acceptable salt-forming cation;
    provided that when Ra, Rb or Rc is substituted with at least one substituent, the substituent is selected from halogen atoms and hydroxyl, C1-C4 alkoxy, amino and C1-C4 alkylamino groups.
  4. The dapoxetine prodrug according to claim 1, wherein the prodrug has a structure in which the pro-group Rp is -(CRaRb)y-O-P(O)(ORc)(ORd)X-, represented by Formula 3:
    Figure PCTKR2011006892-appb-I000008
    (3)
    wherein y is an integer from 1 to 4;
    Ra and Rb are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C4 alkoxy group, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C14 aryl group or a substituted or unsubstituted C7-C20 arylalkyl group, or Ra and Rb are attached together to form a C3-C8 substituted or unsubstituted cycloalkyl group;
    Rc and Rd are each independently a hydrogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted C7-C20 arylalkyl group, a substituted or unsubstituted five to fourteen-membered ring group, a heterocyclic group containing at least one heteroatom selected from N, O and S, or a pharmaceutically acceptable salt-forming cation;
    provided that when Ra, Rb, Rc or Rd is substituted with at least one substituent, the substituent is selected from halogen atoms and hydroxyl, C1-C4 alkoxy, amino and C1-C4 alkylamino groups; and
    X- is a pharmaceutically acceptable anion.
  5. The dapoxetine prodrug according to claim 1, wherein the prodrug is
    (S)-tert-butyl((dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl) phosphate,
    (S)-benzyl((dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl) phosphate,
    (S)-(dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl hydrogen phosphate,
    (S)-2-(dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)ethyl 2-hydroxyethyl phosphate,
    (S)-3-(dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)propyl 2-hydroxyethyl phosphate,
    sodium salt of (S)-(dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl phosphate,
    calcium salt of (S)-(dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl phosphate chloride,
    (S)-5-amino-5-carboxypentane-1-aminium salt of (S)-(dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl phosphate,
    (S)-1-(4-amino-4-carboxybutyl)guanidinium salt of (S)-(dimethyl(3-(naphthalen-1-yloxy)-1-phenylpropyl)ammonio)methyl phosphate, or
    a mixture thereof.
  6. A method for preparing a dapoxetine prodrug represented by Formula 2, the method comprising reacting dapoxetine with (RcO)2P(O)O(CRaRb)y-halide:
    Figure PCTKR2011006892-appb-I000009
    (2)
    wherein y is an integer from 1 to 4;
    Ra and Rb are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C4 alkoxy group, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C14 aryl group or a substituted or unsubstituted C7-C20 arylalkyl group, or Ra and Rb are attached together to form a C3-C8 substituted or unsubstituted cycloalkyl group;
    Rc is a hydrogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted C7-C20 arylalkyl group, a substituted or unsubstituted five to fourteen-membered ring group, a heterocyclic group containing at least one heteroatom selected from N, O and S, or a pharmaceutically acceptable salt-forming cation;
    provided that when Ra, Rb or Rc is substituted with at least one substituent, the substituent is selected from halogen atoms and hydroxyl, C1-C4 alkoxy, amino and C1-C4 alkylamino groups.
  7. A method for preparing a dapoxetine prodrug represented by Formula 3, the method comprising reacting dapoxetine with (RcO)2P(O)O(CRaRb)y-halide:
    Figure PCTKR2011006892-appb-I000010
    (3)
    wherein y is an integer from 1 to 4;
    Ra and Rb are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C4 alkoxy group, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C14 aryl group or a substituted or unsubstituted C7-C20 arylalkyl group, or Ra and Rb are attached together to form a C3-C8 substituted or unsubstituted cycloalkyl group;
    Rc and Rd are each independently a hydrogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted C7-C20 arylalkyl group, a substituted or unsubstituted five to fourteen-membered ring group, a heterocyclic group containing at least one heteroatom selected from N, O and S, or a pharmaceutically acceptable salt-forming cation;
    provided that when Ra, Rb, Rc or Rd is substituted with at least one substituent, the substituent is selected from halogen atoms and hydroxyl, C1-C4 alkoxy, amino and C1-C4 alkylamino groups; and
    X- is a pharmaceutically acceptable anion.
  8. The method according to claim 6 or 7, wherein the reaction is carried out in acetone, ethyl acetate, 1,4-dioxane, acetonitrile or a mixture thereof at 20 to 100 ℃ and the method further comprises purifying the reaction product by recrystallization.
  9. The method according to claim 6 or 7, wherein further comprising substituting Rc with hydrogen.
  10. The method according to claim 9, wherein Rc is substituted with hydrogen by reacting the reaction product of dapoxetine and the (RcO)(RdO)P(O)O(CRaRb)y-halide or (RcO)2P(O)O(CRaRb)y-halide with trifluoroacetic acid, acetic acid, hydrochloric acid or a mixture thereof in dichloromethane, tetrahydrofuran, methanol, ethanol, isopropanol, 1,4-dioxane or a mixture thereof.
  11. The method according to claim 9, wherein Rc is substituted with hydrogen by hydrogenating the reaction product of dapoxetine and the (RcO)(RdO)P(O)O(CRaRb)y-halide or (RcO)2P(O)O(CRaRb)y-halide in the presence of a platinum- or palladium-containing compound as a metal catalyst in an amount of 0.1 to 100 mol% relative to the moles of the reaction product at a hydrogen pressure of 1 to 10 atm.
  12. The method according to claim 9, further comprising dispersing the reaction product in which Rc is substituted with hydrogen in acetone, diethyl ether, methyl t-butyl ether, ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile, ethanol, isopropyl alcohol or a mixture thereof, stirring the dispersion at 25 to 100 ℃, followed by recrystallization at 0 to 25 ℃.
  13. A pharmaceutical composition for the treatment or prevention of premature ejaculation, the composition comprising the dapoxetine prodrug according to claim 1 as an active ingredient.
PCT/KR2011/006892 2010-09-17 2011-09-16 (s)-n,n-dimethyl-3-(naphthalen-1-yloxy)-1-phenylpropan-1-amine derivatives, pharmaceutical compositions containing the derivatives and manufacturing methods thereof WO2012036529A2 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007148341A2 (en) * 2006-06-22 2007-12-27 Ramot At Tel Aviv University Ltd. Novel serotonin reuptake inhibitors as drugs having peripheral-system-restricted activity
US20090227682A1 (en) * 2008-03-04 2009-09-10 Pharma Pass Ii Llc Xetine compositions

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Publication number Priority date Publication date Assignee Title
WO2007148341A2 (en) * 2006-06-22 2007-12-27 Ramot At Tel Aviv University Ltd. Novel serotonin reuptake inhibitors as drugs having peripheral-system-restricted activity
US20090227682A1 (en) * 2008-03-04 2009-09-10 Pharma Pass Ii Llc Xetine compositions

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STELLA, V. J. ET AL.: 'Prodrug Strategies to Overcome Poor Water Solubility.' ADV. DRUG DELIV. REV. vol. 59, 2007, pages 677 - 694 *

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