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WO1996038143A1 - Utilisation d'agents agonistes du recepteur adrenergique alpha-1c-selectif dans le traitement de l'incontinence urinaire - Google Patents

Utilisation d'agents agonistes du recepteur adrenergique alpha-1c-selectif dans le traitement de l'incontinence urinaire Download PDF

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Publication number
WO1996038143A1
WO1996038143A1 PCT/US1996/007979 US9607979W WO9638143A1 WO 1996038143 A1 WO1996038143 A1 WO 1996038143A1 US 9607979 W US9607979 W US 9607979W WO 9638143 A1 WO9638143 A1 WO 9638143A1
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WIPO (PCT)
Prior art keywords
human
adrenoceptor
activates
selective agonist
fold
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PCT/US1996/007979
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English (en)
Inventor
Douglas A. Craig
Carlos C. Forray
Charles Gluchowski
Theresa A. Branchek
Original Assignee
Synaptic Pharmaceutical Corporation
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Publication date
Priority claimed from US08/459,410 external-priority patent/US5610174A/en
Application filed by Synaptic Pharmaceutical Corporation filed Critical Synaptic Pharmaceutical Corporation
Priority to EP96917858A priority Critical patent/EP0835107A1/fr
Priority to AU60035/96A priority patent/AU6003596A/en
Priority to JP8536635A priority patent/JPH11507024A/ja
Publication of WO1996038143A1 publication Critical patent/WO1996038143A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • 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
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • n ⁇ y ⁇ c is an unambiguous description of this unique receptor subtype.
  • Incontinence is a condition characterized by the involuntary loss of urine. It can be divided generally into two types, the first involving an unstable bladder as the underlying cause, and the second involving an insufficiency in bladder outlet closing pressure despite the presence of a stable bladder.
  • the condition may arise from a variety of different pathological, anatomical or neurological factors (Lundberg, 1989) . While the prevalence in females is two fold higher, it also affects males (Lundberg, 1989) . The greatest incidence is seen in postmenopausal women. It is estimated that at least 10 million Americans suffer from urinary incontinence (Sand et al. , 1990). Incontinence can be treated by surgical and nonsurgical methods.
  • Conservative approaches include physiotherapy (Kegel exercises) and functional electrical stimulation which aim to strengthen the peri-urethral musculature (Walters et al., 1992) .
  • Periurethral injection of polytetraflurorethylene is a more invasive procedure intended to augment the urethral support (Sand et al, 1990) .
  • the most radical treatment for stress incontinence is surgery, involving a variety of techniques which seek to improve the alignment of the bladder, urethra, and surrounding structures.
  • a variety of pharmaceutical agents have been employed with varying success to treat urinary incontinence.
  • Drugs useful in reducing the contractility of the bladder include anticholinergics, /3-blockers, calcium channel blockers, and tricyclic antidepressants.
  • Estrogen has been used with some success in increasing bladder outlet resistance, particularly in postmenopausal women. Its actions have been attributed to a "mucosal seal effect" resulting from urethral mucosal cell proliferation (Wein, 1987) , although there is now some suggestion that it may also contribute to a restoration of ⁇ -adrenoceptor expression in the urethra (Wein, 1987) .
  • the most commonly employed agents for increasing bladder outlet resistance are the a-adrenoceptor agonists. These activate ⁇ -adrenoceptors located on the smooth muscle cells of the proximal urethra and bladder neck (Sourander, 1990; Wein, 1987), resulting in contraction and increased closing pressure.
  • the compounds currently employed for this therapy include the non-selective adrenoceptor agents phenylpropanolamine, ephedrine, and phenylephrine (Wein, 1987; Lundberg, 1989) .
  • the actions of these drugs are attributable, in part, to direct activation of adrenoceptors and in part to their ability to displace endogenous norepinephrine from sympathetic neurons following uptake into the nerve terminal, a so-called indirect sympathomimetic action (jAndersson and Sj ⁇ gren, 1982) .
  • Their lack of selectivity (see Table 3 hereinafter) among the adrenoceptor subtypes and the indirect action of these compounds results in their activating ⁇ -, a 2 -, and ⁇ -adrenoceptors in the CNS and in the periphery.
  • any desired therapeutic effect of these agents may be accompanied by a constellation of undesirable side effects.
  • midodrine a prodrug which is converted in vivo to the active phenylethylamine ST-1059.
  • the clinical efficacy of midodrine has not been demonstrated conclusively (Andersson and Sj ⁇ gren, 1982) .
  • its effects may be limited by cross- reactivity with other adrenoceptors (see Table 3) which may limit the maximum achievable dose.
  • Table 3 A better understanding of the subtypes of a-adrenoceptors and their involvement in various physiological processes will facilitate the development of more efficacious drugs for the treatment of incontinence.
  • the -adrenoceptors are specific neuroreceptor proteins located in the peripheral and central nervous systems and on tissues throughout the body.
  • the receptors are important switches for controlling many physiological functions and, thus, represent important targets for drug development.
  • Drugs which interact at these receptors comprise two main classes: agonists, which mimic the endogenous ligands (norepinephrine and epinephrine) in their ability to activate the receptor; and antagonists, which serve to block the actions of the endogenous ligands.
  • Many a-adrenoceptor drugs of both classes have been developed over the past 40 years.
  • Examples in addition to those indicated above, which owe at least part of their action to stimulation of alpha adrenoceptors, include clonidine (agonist; treatment of hypertension) , prazosin (antagonist; hypertension) , oxymetazoline (agonist, nasal decongestion) , and methoxamine (treatment of episodes supraventricular tachycardia) . While many of these drugs are effective, they also produce undesirable side effects at therapeutic doses (e.g., clonidine produces dry mouth, sedation and orthostatic hypotension in addition to its an ihypertensive effect) .
  • a_ adrenoceptor subtypes In addition to the cloned -adrenoceptors, several putative a_ adrenoceptor subtypes have been recently described based upon functional studies in a variety of mammalian tissues. These receptors, which have not been cloned, are described as ⁇ 1H , a__ and o ⁇ __ (Murmamatsu, 1995) or "atypical a_" (Abel, 1995) adrenoceptors. The precise role of each of the subtypes in various physiological responses is only beginning to be understood, but it is clear that distinct subtypes do mediate distinct physiological responses to agonists and antagonists.
  • This invention relates to the discovery that ⁇ ⁇ c -agonists are useful for the treatment of urinary incontinence with the potential for decreased side effects.
  • agonists exhibiting significant binding and functional selectivity for the ⁇ ⁇ c -adrenoceptor over other ot x -adrenoceptors, ot 2 -adrenoceptors, ⁇ -adrenoceptors, as well as histamine receptors and serotonin (5-HT) receptors, are contemplated to be more effective agents, relative to currently available therapies, for the treatment of urinary incontinence.
  • the present invention provides a method of treating urinary incontinence in a subject which comprises administering to the subject a therapeutically effective amount of an a lc selective agonist which activates a human ⁇ lc adrenoceptor at least ten-fold more than it activates a human ⁇ 1A adrenoceptor and a human ⁇ 1B adrenoceptor.
  • the present invention further provides a method of inducing contraction of urethra and bladder neck tissues which comprises contacting the urethra and bladder neck tissues with an effective contraction-inducing amount of an ⁇ ⁇ c selective agonist which activates a human ⁇ ⁇ c adrenoceptor at least ten-fold more than it activates a human ⁇ 1A adrenoceptor and a human ⁇ 1B adrenoceptor.
  • the invention includes compounds for the treatment of urinary incontinence and for use in inducing contraction of urethra and bladder neck tissues.
  • Figures 1A, IB, and C show correlation of antagonist pK B values determined in functional studies of human urethra versus pK x values measured in binding experiments using cloned human ⁇ 1A -adrenoceptors (A) , o; 1B -adrenoceptors (B) , and ⁇ lc -adrenoceptors (C) .
  • the slopes and correlation coefficients (r) for the linear regression analysis are presented in each figure.
  • Figures 2A. 2B. and 2_C show correlation of antagonist pK B values determined in functional studies of female rabbit urethra versus pK x values measured in binding experiments using cloned human ⁇ 1A -adrenoceptors (A) , ⁇ 1B -adrenoceptors (B) , and ⁇ lc -adrenoceptors (C) .
  • the slopes and correlation coefficients (r) for the linear regression analysis are presented in each figure.
  • Figures 3A, 3B, and 3_C show correlation of antagonist pK B values determined in functional studies of male rabbit urethra versus pKj values measured in binding experiments using cloned human ⁇ 1A -adrenoceptors (A) , ot 1B -adrenoceptors
  • Figures 4A, 4B, and __ show correlation of antagonist pK B values determined in functional studies of female dog urethra versus pK j values measured in binding experiments using cloned human ⁇ 1A -adrenoceptors (A) , ⁇ 1B -adrenoceptors (B) , and ⁇ ⁇ c -adrenoceptors (C) .
  • the slopes and correlation coefficients (r) for the linear regression analysis are presented in each figure.
  • FIGS 5_B, and 5_C show correlation of antagonist pK B values determined in functional studies of male dog urethra versus pK x values measured in binding experiments using cloned human ⁇ 1A -adrenoceptors (A) , ⁇ 1B -adrenoceptors (B) , and ⁇ ⁇ c -adrenoceptors (C) .
  • the slopes and correlation coefficients (r) for the linear regression analysis are presented in each figure.
  • Figure 6 shows the chemical structures of SK&F 102652, A- 61603, SDZ NVI 085, Prazosin, 5-Methyl urapidil, Abanoquil, Compound 1, and ST-1059.
  • Receptor Activation describes the process in which the binding of a compound to the receptor when it is on the surface of a cell leads to a metabolic response within the cell.
  • metabolic responses include, but are not limited to, activation of adenylyl cyclase, activation of guanylyl cyclase, hydrolysis of inositol phospholipids, movement of ions across the cell membrane, or contraction in a tissue in the cells of which the receptor is expressed.
  • Potency means the concentration of an agonist which elicits half of its maximum activation (expressed as EC 50 or the negative log of the EC 50 , i.e., pEC 50 ) .
  • Intrinsic Activity means the magnitude of the maximum activation in a cell or tissue which a particular agonist is capable of eliciting, relative to the maximum activation elicited by a reference full agonist and is expressed as values ranging between unity for full agonists (e.g., norepinephrine in the case of a- adrenoceptors) and zero for antagonists.
  • full agonists e.g., norepinephrine in the case of a- adrenoceptors
  • antagonists e.g., norepinephrine in the case of a- adrenoceptors
  • Selectivity of Receptor Activation refers to the ability of an agonist to selectively activate one receptor relative to another receptor. Such selectivity may reflect either (a) the agonist's ability to activate one receptor at a much lower concentration than that required to activate another receptor (i.e., a potency difference) or (b) the agonist's ability to activate one receptor to a much greater degree than another receptor, independent of concentration, (i.e., an intrinsic activity difference) or (c) a combination of both.
  • statements of the form activates a human ⁇ lc - adrenoceptor at least ten-fold more than it activates any of the following (receptors) " mean and include any such difference whether it is by virtue of a difference in potency, or a difference in intrinsic activity, or both.
  • the present invention provides a method of treating urinary incontinence in a subject which comprises administering to the subject a therapeutically effective amount of an ⁇ ! lc selective agonist which activates a human ⁇ ⁇ c adrenoceptor at least ten-fold more than it activates a human ⁇ 1A adrenoceptor and a human ⁇ 1B adrenoceptor.
  • the invention further provides a method of treating urinary incontinence in a subject which comprises administering to the subject a therapeutically effective amount of an ⁇ ⁇ c selective agonist which activates a human ⁇ ⁇ c adrenoceptor at least 50-fold more than it activates a human ⁇ 1A adrenoceptor and a human ⁇ 1B adrenoceptor.
  • the invention provides a method of treating urinary incontinence in a subject which comprises administering to the subject a therapeutically effective amount of an ⁇ ⁇ c selective agonist which activates a human a ⁇ c adrenoceptor at least 100-fold more than it activates a human ⁇ 1A adrenoceptor and a human ⁇ 1B adrenoceptor.
  • the invention provides a method of treating urinary incontinence in a subject which comprises administering to the subject a therapeutically effective amount of an ⁇ lc selective agonist which activates a human ⁇ ⁇ c adrenoceptor at least 200-fold more than it activates a human ⁇ 1A adrenoceptor and a human ⁇ 1B adrenoceptor.
  • the ⁇ lc selective agonist used to practice the method of treating urinary incontinence further has the characteristic that it does not antagonize a human a 1A adrenoceptor and a human ⁇ 1B adrenoceptor.
  • the ⁇ c selective agonist used to practice the method of treating urinary incontinence activates the human ⁇ lc adrenoceptor at least ten-fold more than it activates any human a 2 adrenoceptor and any ⁇ adrenoceptor.
  • a 2 adrenoceptors include the ⁇ 2A , ⁇ 2B , and of 2C receptors.
  • the invention also provides that the ⁇ ⁇ c selective agonist used to practice the method of treating urinary incontinence further has the characteristic that it does not antagonize any human 2 adrenoceptor and any ⁇ adrenoceptor.
  • a 2 adrenoceptors include the ⁇ 2A , Q; 2B , and ⁇ 2C receptors.
  • the ⁇ ⁇ c selective agonist used to practice the method of treating urinary incontinence activates the human ⁇ ⁇ c adrenoceptor at least ten-fold more than it activates a human histamine K_ or H 2 receptor.
  • the invention further provides that the ⁇ lc selective agonist used to practice the method of treating urinary incontinence activates the human ⁇ ⁇ c adrenoceptor at least ten-fold more than it activates a human dopamine D lf D 2 , D 3 , or D 5 receptor.
  • the invention also provides that the a ⁇ c selective agonist used to practice the method of treating urinary incontinence activates the human ⁇ ⁇ c adrenoceptor at least ten-fold more than it activates a human serotonin 5-HT 1A/ 5-HT 1Do , 5-HT 1D3 , 5-HT 1E , 5-HT 1F , 5-HT 2 , or 5-HT 7 receptor.
  • the present invention further provides a method of inducing contraction of urethra and bladder neck tissues which comprises contacting the urethra and bladder neck tissues with an effective contraction-inducing amount of an ⁇ lc selective agonist which activates a human ⁇ lc adrenoceptor at least ten-fold more than it activates a human ⁇ 1A adrenoceptor and a human a__ adrenoceptor.
  • the invention further provides a method of inducing contraction of urethra and bladder neck tissues which comprises contacting the urethra and bladder neck tissues with an effective contraction-inducing amount of an lc selective agonist which activates a human ⁇ ⁇ c adrenoceptor at least 50-fold more than it activates a human lh adrenoceptor and a human ⁇ 1B adrenoceptor.
  • the invention provides a method of inducing contraction of urethra and bladder neck tissues which comprises contacting the urethra and bladder neck tissues with an effective contraction-inducing amount of an o; lc selective agonist which activates a human ⁇ ⁇ c adrenoceptor at least 100-fold more than it activates a human ⁇ 1A adrenoceptor and a human ⁇ 1B adrenoceptor.
  • the invention also provides a method of inducing contraction of urethra and bladder neck tissues which comprises contacting the urethra and bladder neck tissues with an effective contraction-inducing amount of an ⁇ , selective agonist which activates a human ⁇ ⁇ c adrenoceptor at least 200-fold more than it activates a human ⁇ 1A adrenoceptor and a human ⁇ 1B adrenoceptor.
  • the ⁇ lc selective agonist used to practice the method of inducing contraction of urethra and bladder neck tissues further has the characteristic that it does not antagonize a human ⁇ 1A adrenoceptor and a human ⁇ 1B adrenoceptor.
  • the ⁇ lc selective agonist used to practice the method of inducing contraction of urethra and bladder neck tissues activates the human ⁇ lc adrenoceptor at least ten-fold more than it activates any human a 2 adrenoceptor and any ⁇ adrenoceptor.
  • 2 adrenoceptors include the ⁇ 2A , c ⁇ 2B , and ⁇ 2C receptors
  • the invention also provides that the ⁇ lc selective agonist used to practice the method of inducing contraction of urethra and bladder neck tissues further has the characteristic that it does not antagonize any human ⁇ 2 adrenoceptor and any ⁇ adrenoceptor.
  • 2 adrenoceptors include the ⁇ 2A , ⁇ 2B , and a 2C receptors
  • the ⁇ ⁇ c selective agonist used to practice the method of inducing contraction of urethra and bladder neck tissues activates the human ⁇ ⁇ c adrenoceptor at least ten-fold more than it activates a human histamine H-* or H 2 receptor.
  • the invention further provides that the ⁇ ⁇ c selective agonist used to practice the method of inducing contraction of urethra and bladder neck tissues activates the human ⁇ ⁇ c adrenoceptor at least ten-fold more than it activates a human dopamine D 1# D 2 , D 3 , or D 5 receptor.
  • the invention also provides that the ⁇ c selective agonist used to practice the method of inducing contraction of urethra and bladder neck tissues activates the human ⁇ ⁇ c adrenoceptor at least ten-fold more than it activates a human serotonin 5-HT 1A , 5-HT 1D ⁇ , 5 - ⁇ .T__ ⁇ , 5-HT 1E , 5-HT 1F , 5-HT 2 , or 5-HT-, receptor.
  • n is an integer from 1 to 6;
  • R is H or C ⁇ Cg alkyl;
  • R_ is C_-C 6 alkyl, phenyl, naphthyl, substituted phenyl or naphthyl where the substituent is a halogen, or a alkyl or alkoxy group;
  • the heterocyclic group is piperidine, morpholine, piperazine, pyrrolidine, hexamethylene, or thiomorpholine, the heterocyclic group being bonded through the nitrogen atom thereof to the (CH 2 ) n group; the amino group, where R 2 is H, C- L -Cg alkyl, benzyl, or benzyhydryl and where R 3 is H;
  • Ci-Cio alkyl C 2 -C 10 alkenyl; C 3 ⁇ C 10 cycloalkyl or cycloalkenyl .
  • the present invention also provides that the compound has the structure:
  • the invention further provides that the compound has the structure:
  • m is an integer from 0 to 2; where each of R l t R 2 , R 3 and R 7 is independently H; OH; C ⁇ -C.* alkyl or alkoxy; halo; amino; acetamido or NHS0 2 R with R being H or C-.-C 6 alkyl; where R_ and R 2 or R 2 and R 3 or R 3 and R 7 taken together constitute a methylenedioxy, ethylenedioxy, benzimidazole or indole ring; where each of R 4 and R 5 are independently H or taken together has the following formula:
  • R 6 is H or C_-C 6 alkyl; or a pharmaceutically acceptable salt thereof.
  • the invention also provides that the compound has the structure:
  • the invention further provides that the compound has the structure:
  • each of R_ and R 2 is independently H or C 1 -C 4 alkyl; where R 3 is OH or C 1 -C 4 alkoxy; and R 4 is C 1 -C 4 alkylthio, alkylsulfoxide or alkylsulfone; Cl; Br; I or CF 3 ; where X is 0, S, SO, S0 2 , NH, NR-. or NCtO ⁇ ; in free base or acid addition salt form.
  • the invention further provides that the compound has the structure:
  • the invention specifically provides that the compound has the structure:
  • This invention is also directed to optical isomers of the compounds described above.
  • the invention also provides for the (-) and (+) enantiomers of all compounds of the subject application described herein.
  • Included in this invention are pharmaceutically acceptable salts and complexes of all of the compounds described herein.
  • the salts include but are not limited to the following acids and bases. The following inorganic acids; hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid.
  • the organic acids acetic acid, trifluoroacetic acid, formic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzoic acid, glycolic acid, lactic acid and mandelic acid.
  • the following inorganic bases ammonia, hydroxyethylamine and hydrazine.
  • the following organic bases methylamine, ethylamine, propylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, ethylenediamine, hydroxyethylamine, morpholine, piperazine and guanidine.
  • This invention further provides for the hydrates, isomorphs and polymorphs of all of the compounds described herein.
  • the present invention therefore provides a method of treating urinary incontinence, which comprises administering a quantity of any of the ⁇ ⁇ c receptor agonists defined herein in a quantity effective against urinary incontinence.
  • the drug may be administered to a patient afflicted with urinary incontinence by any conventional route of admin ⁇ istration, including, but not limited to, intravenous, intramuscular, oral, subcutaneous, intratumoral, intra- dermal, and parenteral.
  • the quantity effective against urinary incontinence is between 0.001 mg and 10.0 mg per kg of subject body weight.
  • the method of treating urinary incontinence disclosed in the present invention may also be carried out using a pharmaceutical composition comprising any of the ⁇ ⁇ c receptor agonists as defined herein and a pharmaceutically acceptable carrier.
  • the composition may contain between 0.05 mg and 500 mg of an ⁇ ⁇ c receptor agonist, and may be constituted into any form suitable for the mode of administration selected.
  • compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions.
  • forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.
  • the drug may otherwise be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium.
  • Carriers are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
  • the drug may also be formulated as a transdermal patch.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular ⁇ ⁇ c receptor agonist in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration.
  • terapéuticaally effective amount refers to that amount of pharmaceutical agent that elicits in a tissue, system, animal or human, the biological or medicinal response that is being sought by a researcher, veterinarian, medical doctor or other clinician, which response includes alleviation of the symptoms of the disease being treated.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • the binding and functional properties of compounds at the different human receptors were determined in vi tro using cultured cell lines that selectively express the receptor of interest. These cell lines were prepared by transfecting the cloned cDNA or cloned genomic DNA or constructs containing both genomic DNA and cDNA encoding the human a-adrenoceptors as further described in detail in Example 10 hereinbelow.
  • Transient transfections of COS-7 cells with various plasmids were performed using the DEAE-Dextran method. which is well-known to those skilled in the art. Briefly, a plasmid comprising an expression vector for the receptor of interest was added to monolayers of COS-7 cells bathed in a DEAE-Dextran solution. In order to enhance the efficiency of transfection, dimethyl sulfoxide was typically also added, according to the method of Lopata (Lopata, et al., 1984) . Cells were then grown under controlled conditions and used in experiments after about 72 hours.
  • Stable cell lines were obtained using means which are well-known in the art. For example, a suitable host cell was typically cotransfected, using the calcium phosphate technique, with a plasmid comprising an expression vector for the receptor of interest and a plasmid comprising a gene which allows selection of successfully transfected cells. Cells were then grown in a controlled environment, and selected for expression of the receptor in interest. By continuing to grow and select cells, stable cell lines were obtained expressing the receptors described and used herein.
  • the binding of a test compound to a receptor of interest was generally evaluated by competitive binding assays using membrane preparations derived from cells which expressed the receptor. First, conditions were determined which allowed measurement of the specific binding of a compound known to bind to the receptor. Then, the binding of the known compound to the receptor in membrane preparations was evaluated in the presence of several different concentrations of the test compound. Binding of the test compound to the receptor resulted in a reduction in the amount of the known compound which was abound to the receptor. A test compound having a ' high affinity for the receptor of interest would displace a given fraction of the bound known compound at a concentration lower than the concentration which would be required if the test compound had a low affinity for the receptor of interest.
  • the data shown in the Table 2 indicate that it is the ⁇ : - adrenoceptor which is responsible for mediating the contractile response to adrenoceptor agonists in the urethra of mammals, particularly humans.
  • This in vitro property is recognized in the art as correlating with efficacy in treating urinary incontinence in vivo.
  • Phenylephrine, prazosin, 5-methylurapidil, and BMY 7378 were obtained from Research Biochemicals, Inc. Other compounds were prepared according to the examples which follow.
  • CD 3 0D ⁇ 1.78 (m, 2H) , 1.90 (m, 1H) , 2.04 (m, 1H) , 2.93
  • reaction mixture was then diluted with EtOAc and washed with IN aqueous HCl. Organic layer was dried over Na 2 S0 4 and concentrated in vacuo, yielding an oil which corresponds to the amide.
  • the oily residue was redissolved in 20 ml of THF, and NaH (0.35 g, 8.8 mmol) and tetrabutylammonium iodide (0.25 g, 0.67 mmol) were added into the solution at 0 °C.
  • the reaction mixture was stirred for 12 h at 25 °C. It was diluted with EtOAc and washed with brine.
  • reaction mixture was quenched with ice, diluted with EtOAc and filtered through Celite.
  • organic layer was dried over Na 2 S0 4 and concentrated in vacuo, yielding an oily residue which was subjected to column chromatography (5% MeOH-EtOAc) to yield 0.19 g (75%) of the desired product.
  • the construct involved the ligation of partial overlapping human lymphocyte genomic and hippocampal cDNA clones: 5' sequences were contained on a 1.2 kb Smal-Xhol genomic fragment (the vector-derived BamHI site was used for subcloning instead of the internal insert-derived Smal site) and 3' sequences were contained on an 1.3 kb Xhol- Clal cDNA fragment (the Clal site was from the vector polylinker)- .
  • Stable cell lines were obtained by cotransfection with the plasmid ⁇ lA/EXJ (expression vector containing the ⁇ lA receptor gene) and the plasmid pGCcos3neo (plasmid containing the aminoglycoside transferase gene) into LM ( tkJ , CHO, and NIH3T3 cells, using calcium phosphate technique.
  • the cells were grown, in a controlled environment (37°C.
  • Human ⁇ 1P Adrenoceptor Human ⁇ 1P Adrenoceptor.
  • the entire coding region of the ⁇ -lB receptor (1563 bp) , including 200 basepairs and 5' untranslated sequence (5' UT) and 600 bp of 3' untranslated sequence (3' UT) , was cloned into the EcoRI site of pCEXV-3 eukaryotic expression vector.
  • the construct involved ligating the full-length containing EcoRI brainstem cDNA fragment from ⁇ ZapII into the expression vector. Stable cell lines were obtained as described above.
  • Human ⁇ 1? Adrenoceptor The entire coding region of the ⁇ lC receptor (1401 bp) , including 400 basepairs of 5' untranslated sequence (5' UT) and 200 bp of 3' untranslated sequence (3' UT) , was cloned into the Kpnl site of the polylinker-modified pCEXV-3-derived eukaryotic expression vector, EXJ.RH.
  • the construct involved ligating three partial overlapping fragments: a 5' 0.6kb Hindi genomic clone, a central 1.8 EcoRI hippocampal cDNA clone, and a 3' 0.6Kb PstI genomic clone.
  • the hippocampal cDNA fragment overlaps with the 5' and 3' genomic clones so that the Hindi and PstI sites at the 5' and 3' ends of the cDNA clone, respectively, were utilized for ligation.
  • This full- length clone was cloned into the Kpnl site of the expression vector, using the 5' and 3' Kpnl sites of the fragment, derived from vector (i.e., pBluescript) and 3 ' - untranslated sequences, respectively.
  • Stable cell lines were obtained as described above. Radioligand Binding Assays.
  • Binding of the ⁇ l antagonist [ 3 H]prazosin (0.5 nM, specific activity: about 76.2 Ci/mmol) to membrane preparations of LM(tk-) cells was done in a final volume of 0.25 ml and incubated at 37°C for 20 min. Nonspecific binding was defined as that binding which remained in the presence of 10 ⁇ M phentolamine (a concentration at least 100-fold greater than the affinity of phentolamine at any human a- adrenoceptors) . The reaction was stopped by filtration through GF/B filters using a cell harvester.
  • LM(tk-) cell lines stably transfected with the genes encoding the 0! 2A , ⁇ 2B , and ⁇ 2C receptors were used.
  • Cell lysates were prepared as described above (see Radioligand Binding Assays) , and suspended in 25mM glycylglycine buffer (pH 7.6 at room temperature) .
  • Equilibrium competition binding assays were performed using [ 3 H] rauwolscine (0.5nM) , and nonspecific binding was determined by incubation with lO ⁇ M phentolamine. The bound radioligand was separated by filtration through GF/B filters using a cell harvester.
  • Human Histamine H- Receptor The coding sequence of the human histamine H_ receptor, homologous to the bovine H- . receptor, was obtained from a human hippocampal cDNA library, and was cloned into the eukaryotic expression vector pCEXV-3.
  • the plasmid DNA for the H-. receptor is designated pcEXV-Hl, and was deposited on November 6, 1992 under ATCC Accession No. 75346. This construct was transfected into C0S-7 cells by the DEAE-dextran method. Cells were harvested after 72 hours and lysed by sonication in 5mM Tris-HCl, 5mM EDTA, pH 7.5.
  • the cell lysates were centrifuged at 1000 rpm for 5 min at 4°C, and the supernatant was centrifuged at 30,000 x g for 20 min. at 4°C.
  • the pellet was suspended in 37.8 mM NaHP0 4 , 12.2 mM KH 2 P0 4 , pH 7.5.
  • the binding of the histamine H, antagonist [ 3 H]mepyramine was done in a final volume of 0.25 ml and incubated at room temperature for 60 min. Nonspecific binding was determined in the presence of 10 ⁇ M mepyramine.
  • the bound radioligand was separated by filtration through GF/B filters using a cell harvester.
  • Human Histamine H-, Receptor The coding sequence of the human H 2 receptor was obtained from a human placenta genomic library, and cloned into the cloning site of PCEXV-3 eukaryotic expression vector.
  • the plasmid DNA for the H 2 receptor is designated pcEXV-H2, and was deposited on November 6, 1992 under ATCC Accession No. 75345. This construct was transfected into C0S-7 cells by the DEAE-dextran method. Cells were harvested after 72 hours and lysed by sonication in 5mM Tris-HCl, 5mM EDTA, pH 7.5.
  • the cell lysates were centrifuged at 1000 rpm for 5 min at 4°C, and the supernatant was centrifuged at 30,000 x g for 20 min at 4 °C.
  • the pellet was suspended in 37.8 mM NaHP0 4 , 12.2 mM K2P0 4 , pH 7.5.
  • the binding of the histamine H 2 antagonist [ 3 H] tiotidine was done in a final volume of 0.25 ml and incubated at room temperature for 60 min. Nonspecific binding was determined in the presence of 10 ⁇ M histamine.
  • the bound radioligand was separated by filtration through GF/B filters using a cell harvester.
  • 5-HT 1D ⁇ , 5-HT 1D3 , 5-HT 1E , 5-HT 1F , and 5-HT 7 Receptors The cell lysates of LM(tk-) clonal cell line stably transfected with the genes encoding each of these 5-HT receptor-subtypes were prepared as described above.
  • the cell line for the 5-HT 1E receptor designated 5-HT 1E -7, was deposited on November 6, 1991, and accorded ATCC Accession No. CRL 10913.
  • the cell line for the 5-HT 1F receptor designated L-5-HT 1F , was deposited on December 27, 1991, and accorded ATCC Accession No. CRL 10957.
  • the cell line for the 5-HT-, receptor designated as L-5-HT-4B, was deposited on October 20, 1992, and accorded ATCC Accession No. CRL 11166.
  • Human 5-HT-, Receptor The coding sequence of the human 5-HT 2 receptor was obtained from a human brain cortex cDNA library, and cloned into the cloning site of pCEXV-3 eukaryotic expression vector. This construct was transfected into C0S-7 cells by the DEAE-dextran method. Cells were harvested after 72 hours and lysed by sonication in 5mM Tris-HCl, 5mM EDTA, pH 7.5. This cell line was deposited with the ATCC on October 31, 1989, designated as L-NGC-5-HT 2 , and was accorded ATCC Accession No. CRL 10287.
  • the cell lysates were centrifuged at 1000 rpm for 5 minutes at 4°C, and the supernatant was centrifuged at 30,000 x g for 20 minutes at 4°C.
  • the pellet was suspended in 50mM Tris-HCl buffer (pH 7.7 at room temperature) containing 10 mM MgS0 4 , 0.5mM EDTA, and 0.1% ascorbate.
  • the affinity of compounds at 5-HT 2 receptors were determined in equilibrium competition binding assays using [ 3 H] ketanserin (InM) . Nonspecific binding was defined by the addition of lO ⁇ M mianserin.
  • the bound radioligand was separated by filtration through GF/B filters using a cell harvester.
  • 5-HT 1 ⁇ receptor The cell line for the 5-HT 1A receptor, designated 5-HT1A-3, was deposited on May 11, 1995, and accorded ATCC Accession No. CRL 11889.
  • Radioligand binding assays were performed as described above for the 5-HT 2 receptor, except that [ 3 H] -8-0H-DPAT was used as the radioligand and nonspecific binding was determined by the addition of lO ⁇ M mianserin.
  • Human Dopamine D-, Receptors The affinity of compounds at the D2 receptor were determined using membrane preparations from C0S-7 cells transfected with the gene encoding the human D 2 receptor.
  • the coding region for the human D2 receptor was obtained from a human striatum cDNA library, and cloned into the cloning site of PCDNA 1 eukariotic expression vector.
  • the plasmid DNA for the D 2 receptor is designated pcEXV-D2, and was deposited on November 6, 1992 under ATCC Accession No. 75344. This construct was transfected into C0S-7 cells by the DEAE- dextran method.
  • Cells were harvested after 72 hours and lysed by sonication in 5mM Tris-HCl, 5mM EDTA, pH 7.5. The cell lysates were centrifuged at 1000 rpm for 5 minutes at 4°C, and the supernatant was centrifuged at 30,000 x g for 20 minutes at 4°C. The pellet was suspended in 50 mM Tris-HCl (pH 7.4) containing ImM EDTA, 5mM KC1, 1.5mM CaCl 2 , 4mM MgCl 2 , and 0.1% ascorbic acid. The cell lysates were incubated with [ 3 H] spiperone (2nM) , using lO ⁇ M (+)Butaclamol to determine nonspecific binding.
  • Dopamine receptors were prepared by known methods .
  • D-_ Dearry et al. , Nature, 347, 72, (1990) , deposited with the European Molecular Biological Laboratory (EMBL) Genbank as X55760
  • D 3 Sokoloff, P. et al . , Nature, 347, 146 (1990) , deposited with the European Molecular Biological Laboratory (EMBL) Genbank as X53944
  • D c Sunahara, R.K., et al . , Nature, 350, 614 (1991) , deposited with EMBL Genbank as X58454-HU HD 5DR
  • test compounds ⁇ -i-Adrenoceptor-Mediated Phosphoinositide Accumulation in Cultured Cell Lines.
  • the agonist activity of test compounds was assayed by measuring their ability to generate phosphoinositide production in cells stably transfected with each of the three cloned human a. - adrenoceptor subtypes. Cells were plated in 96-well plates and grown to confluence.
  • the growth medium was changed to 100 ⁇ l of medium containing 1% serum and 0.5 ⁇ Ci [ 3 H]myo-inositol, and the plates were incubated overnight in a C0 2 incubator (5% C0 2 at 37°C) .
  • the medium was removed and replaced by 200 ⁇ l of PBS containing 10 mM LiCl, and the cells were equilibrated with the new medium for 20 min. During this interval cells were also equilibrated with the antagonist, added as 10 ⁇ l aliquot of a 20-fold concentrated solution in PBS.
  • IP inositol-phosphate
  • the content of the wells was transferred to a Multiscreen HV filter plate (Millipore) containing Dowex AG1-X8 (200-400 mesh, formate form) .
  • the filter plates were prepared adding 200 ⁇ l of Dowex AG1-X8 suspension (50% v/v, water:resin) to each well.
  • the filter plates were placed on a vacuum manifold to wash or elute the resin bed.
  • Each well was washed 2 times with 200 ⁇ l of water, followed by 2 x 200 ⁇ l of 5mM sodium tetraborate/60 mM ammonium formate.
  • the filter plates were prepared adding 200 ⁇ l of Dowex AG1-X8 suspension (50% v/v, water:resin) to each well.
  • the filter plates were placed on a vacuum manifold to wash or elute the resin bed.
  • Each well was washed 2 times with 200 ⁇ l of water, followed by 2 x 200 ⁇ l of 5mM sodium tetrabor
  • IPs were eluted into empty 96-well plates with 200 ⁇ l of 1.2 M ammonium formate/0.1 formic acid. The content of the wells was added to 3 mis of scintillation cocktail, and the radioactivity was determined by liquid scintillation counting.
  • test compounds ⁇ -,-Adrenoceptor-Mediated Inhibition of Forskolin- Stimulated Adenylyl Cyclase.
  • the agonist activity of test compounds was assayed by measuring their ability to inhibit adenylyl cyclase in cells stably transfected with each of the three 'cloned human a 2 -adrenoceptors .
  • LM(tk-) cells expressing the ot 2A - or the ⁇ 2C - , as well as Yl cells expressing the ⁇ 2B -adrenoceptor were used.
  • the cell line for the ⁇ 2B -adrenoceptor, designated as Ya2B-2 was deposited on May 11, 1995, and accorded ATCC Accession
  • a pharmacological profile of the receptor which mediates the contractile response to ⁇ -agonists in the urethra of male humans, and male and female dogs and rabbits was determined.
  • similar studies were done using bladder neck tissue from female dogs. In order to identify the specific receptor subtype in each tissue, the pharmacological profile was compared to the profiles for these same drugs at the cloned human ⁇ 1A , ⁇ 1B , or ⁇ ⁇ c subtypes.
  • Tissue samples from the proximal urethra of male humans and male and female rabbits, as well as tissue samples from both the proximal urethra and bladder neck of male and female dogs were cut into transverse strips (3x10mm) and suspended under 0.5g tension in Krebs' physiological buffer at 37°C.
  • concentration-effect curves to the non-selective agonist phenylepherine were constructed in the absence and in the presence of increasing concentrations of the antagonist. Up to four sequential curves were constructed in each tissue. Antagonists were allowed to equilibrate for lh before each concentration-effect curve, and the drugs were completely washed out in between successive curves.
  • pK B log ( (CR- 1) / [Antagonist] ) , where CR is defined as the ratio of the agonist EC 50 in the presence of the antagonist to that in the absence of the antagonist.
  • the ⁇ ⁇ c -selective agonists A-61603 and SK&F 102652 were used to characterize the receptor subtype in the female dog urethra, and to compare the receptor profiles in the urethra with that in the bladder neck.
  • two concentration effect curves were constructed on each tissue, one in the absence and the second in the presence of prazosin.
  • the pK B values derived for prazosin using A-61603 and SK&F 102652 as the agonists were compared to the pK B obtained for prazosin using phenylephrine as the agonist, to verify that each agonist interacted with a common a_- adrenoceptor site.
  • pEC 50 values for agonists were calculated by logistic curve fitting.
  • the antagonist effects of the test compounds were measured using the dose-ratio method, by comparing the shift in pEC 50 for isoprenaline.
  • Table 2 shows the pK ⁇ values determined from binding assays for various antagonists at the cloned human a_ - adrenoceptor subtypes and the corresponding pK B values determined from contractile studies in urethral and bladder neck tissues obtained from human, dog, and rabbit.
  • Figures 1-5 illustrate the data from Table 2 in a graphical format.
  • the pK B value for each antagonist (abcissa) is plotted against the pK x values determined for each of the three cloned human ⁇ -adrenoceptor subtypes (ordinate) .
  • the slopes and correlation coefficients (r) for the linear regression analysis are presented in each figure.
  • the antagonist data derived from the functional experiments correlates best with the ⁇ ⁇ c -subtype.
  • Table 3 shows the pK ⁇ , pEC 50 , and intrinsic activity at the cloned ⁇ - and ⁇ 2 -subtypes for the various agonists.
  • A-61603 and SK&F 102652 each fully stimulate inositol phosphate production in cells transfected with the human ⁇ lc -adrenoceptor, but are virtually inactive at the ⁇ 1A - and ⁇ 1B -subtypes.
  • Table 3 also indicates that while both A-61603 and SK&F 102652 are selective among the ⁇ -adrenoceptors, these compounds also possess significant activity at ⁇ 2 -adrenoceptors .
  • the cross-reactivity binding profiles of these drugs and other agonists are shown in Table 4.
  • Antagonist affinities pK ⁇ versus 3 H-prazosin binding
  • antagonist affinities determined from contractile studies (pK B versus phenylephrine-induced contraction) in urethra and bladder neck (BN) tissue from mammalian species.
  • Prazosin 9 . 5 9 . 3 9 . 2 9.5 7.8 7.8 8.2 8.0
  • Alpha-1A-adrenoceptor subtype mediates contraction of the rat urethra. J Auton Pharmacol , 14, 375-381.

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Abstract

Cette invention se rapporte à un procédé pour traiter l'incontinence urinaire chez un sujet, procédé qui consiste à administrer à ce sujet une quantité thérapeutiquement efficace d'un agent agoniste α1C sélectif qui active un récepteur α1C-adrénergique humain au moins dix fois plus qu'il n'active un récepteur α1A adrénergique humain et un récepteur α1B adrénergique humain. Cette invention se rapporte en outre à un procédé pour provoquer une contraction de tissus de l'urètre et du col vesical, ce procédé consistant à mettre en contact ces tissus de l'urètre et du col vesical avec une quantité d'un agent agoniste α1C-sélectif propre à produire une contraction, cet agent agoniste activant à un récepteur α1C-adrénergique humain au moins dix fois plus qu'il n'active un récepteur α1A adrénergique humain et un récepteur α1B adrénergique humain. Cette invention se rapporte également à des composés pour traiter l'incontinence urinaire et pour servir à provoquer une contraction des tissus de l'urètre et du col vesical.
PCT/US1996/007979 1995-06-02 1996-05-30 Utilisation d'agents agonistes du recepteur adrenergique alpha-1c-selectif dans le traitement de l'incontinence urinaire WO1996038143A1 (fr)

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EP96917858A EP0835107A1 (fr) 1995-06-02 1996-05-30 Utilisation d'agents agonistes du recepteur adrenergique alpha-1c-selectif dans le traitement de l'incontinence urinaire
AU60035/96A AU6003596A (en) 1995-06-02 1996-05-30 The use of alpha-1c-selective adrenoceptor agonists for the treatment of urinary incontinence
JP8536635A JPH11507024A (ja) 1995-06-02 1996-05-30 尿失禁の治療のためのアルファ−１ｃ−選択的アドレナリン受容体作動薬の使用

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0887346A3 (fr) * 1997-06-23 1999-05-06 F. Hoffmann-La Roche Ag Dérivés de phenyl- et aminophenyl-alkylsulfonamide et -urée, leur préparation et leur utilisation comme agonsiste de adrénocepteur alpha1A/1L
WO2001060352A1 (fr) * 2000-02-17 2001-08-23 Abbott Laboratories Agonistes du recepteur alpha 1a adrenergique presentant un antagonisme alpha 1b et alpha 1d utilises dans le traitement de l'incontinence d'urine a l'effort
US6323231B1 (en) 2000-02-17 2001-11-27 Abbott Laboratories Use of α1A adrenoceptor agonists with α1B and α1D antagonism for the treatment of stress urinary incontinence
WO2002060421A3 (fr) * 2001-02-01 2002-12-19 Boehringer Ingelheim Pharma Utilisation de 2-amino-1(4-hydroxy-2-methanesulphonamidophenyl)ethanol pour le traitement de l'incontinence d'urine
US6503935B1 (en) 1998-08-07 2003-01-07 Abbott Laboratories Imidazoles and related compounds as α1A agonists
CN105622434A (zh) * 2015-12-31 2016-06-01 天津英吉诺科技有限公司 1-(2,5-二甲氧基苯基)-2-氨基乙醇的制备方法

Families Citing this family (1)

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JPWO2015152196A1 (ja) * 2014-03-31 2017-04-13 東レ株式会社 イミダゾリン誘導体及びその医薬用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 110, No. 17, issued 24 April 1989, KYNCL et al., "Novel Adrenergic Compounds. I. Receptor Interactions of Abbott-54741 Ä(5,6-Dihydroxy-1,2,3,4-Tetrahydro-1-Naphthyl)ImidazolineÜ an alpha-Adrenergic Agonist", page 70, Abstract No. 110:147673v; & J. CARDIOVASC. PHARMACOL. *
CHEMICAL ABSTRACTS, Volume 117, No. 1, issued 06 July 1992, KONTANI et al., "Effects of Adrenergic Agonists on an Experimental Urinary Incontinence Model in Anesthetized Rabbits", page 580, Abstract No. 117:576b; & JPN. J. PHARMACOL. *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0887346A3 (fr) * 1997-06-23 1999-05-06 F. Hoffmann-La Roche Ag Dérivés de phenyl- et aminophenyl-alkylsulfonamide et -urée, leur préparation et leur utilisation comme agonsiste de adrénocepteur alpha1A/1L
US5952362A (en) * 1997-06-23 1999-09-14 Syntex (U.S.A) Inc. 2-imidazoline, 2-oxazoline, 2-thiazoline, and 4-imidazole derivatives of methylphenyl, methoxyphenyl, and aminophenyl alkylsulfonamides and ureas and their use
US6057349A (en) * 1997-06-23 2000-05-02 F. Hoffman La Roche Ag 2-imidazoline, 2-oxazoline, 2-thiazoline, and 4-imidazole derivatives of methylphenyl, methoxphenyl, and aminophenyl alkylsulfonamides and ureas and their use
US6503935B1 (en) 1998-08-07 2003-01-07 Abbott Laboratories Imidazoles and related compounds as α1A agonists
WO2001060352A1 (fr) * 2000-02-17 2001-08-23 Abbott Laboratories Agonistes du recepteur alpha 1a adrenergique presentant un antagonisme alpha 1b et alpha 1d utilises dans le traitement de l'incontinence d'urine a l'effort
US6323231B1 (en) 2000-02-17 2001-11-27 Abbott Laboratories Use of α1A adrenoceptor agonists with α1B and α1D antagonism for the treatment of stress urinary incontinence
WO2002060421A3 (fr) * 2001-02-01 2002-12-19 Boehringer Ingelheim Pharma Utilisation de 2-amino-1(4-hydroxy-2-methanesulphonamidophenyl)ethanol pour le traitement de l'incontinence d'urine
CN105622434A (zh) * 2015-12-31 2016-06-01 天津英吉诺科技有限公司 1-(2,5-二甲氧基苯基)-2-氨基乙醇的制备方法
CN105622434B (zh) * 2015-12-31 2018-03-13 天津英吉诺科技有限公司 1‑(2,5‑二甲氧基苯基)‑2‑氨基乙醇的制备方法

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