WO1997011698A1 - ALPHA 1b ADRENERGIC RECEPTOR ANTAGONISTS - Google Patents
ALPHA 1b ADRENERGIC RECEPTOR ANTAGONISTS Download PDFInfo
- Publication number
- WO1997011698A1 WO1997011698A1 PCT/US1996/015223 US9615223W WO9711698A1 WO 1997011698 A1 WO1997011698 A1 WO 1997011698A1 US 9615223 W US9615223 W US 9615223W WO 9711698 A1 WO9711698 A1 WO 9711698A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- adrenergic receptor
- compound
- human alpha
- alkyl
- alpha
- Prior art date
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- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229950002757 teoclate Drugs 0.000 description 1
- PAPIFWXLMZMQIW-SNVBAGLBSA-N tert-butyl (2r)-2-(tert-butylcarbamoyl)piperazine-1-carboxylate Chemical compound CC(C)(C)NC(=O)[C@H]1CNCCN1C(=O)OC(C)(C)C PAPIFWXLMZMQIW-SNVBAGLBSA-N 0.000 description 1
- DJVAEULYGOINHI-MRXNPFEDSA-N tert-butyl (2r)-4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-2-(tert-butylcarbamoyl)piperazine-1-carboxylate Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)NC(C)(C)C)C1 DJVAEULYGOINHI-MRXNPFEDSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetraline Natural products C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000001149 thermolysis Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 239000003451 thiazide diuretic agent Substances 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
-
- 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
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Definitions
- This invention relates to certain novel compounds and derivatives thereof, their synthesis, and their use as selective alpha 1 adrenoceptor antagonists, especially alpha lb selective antagonists. More particularly, the compounds of the present invention are useful for treating hypertension.
- Human adrenergic receptors are integral membrane proteins which have been classified into two broad classes, the alpha and the beta adrenergic receptors. Both types mediate the action of the peripheral sympathetic nervous system upon binding of catecholamines, norepinephrine and epinephrine.
- Norepinephrine is produced by adrenergic nerve endings, while epinephrine is produced by the adrenal medulla.
- the binding affinity of adrenergic receptors for these compounds forms one basis of the classification: alpha receptors bind norepinephrine more strongly than epinephrine and much more strongly than the synthetic compound isoproterenol.
- the binding affinity of these hormones is reversed for the beta receptors.
- the functional responses such as smooth muscle contraction, induced by alpha receptor activation are opposed to responses induced by beta receptor binding.
- alpha and beta receptors were further subdivided into oci , ot2, Bl , and ⁇ 2 subtypes. Functional differences between ⁇ i and o 2 receptors have been recognized, and compounds which exhibit selective binding between these two subtypes have been developed. Blockade of cq receptors inhibits vasoconstriction induced by endogenous catecholamines; - 2 -
- vasodilation may occur in both arteriolar resistance vessels and veins. The result is a fall in blood pressure because of decreased vascular resistance.
- c 2 adrenergic receptors play an important role in regulation of the activity of the sympathetic nervous system, both peripherally and centrally. Blockade of C adrenergic receptors with selective antagonists increase sympathetic outflow and potentiate the release of norepinephrine from nerve endings, leading to activation of cq and ⁇ i receptors in the heart and peripheral vasculature with a consequent rise in blood pressure [B. Hoffman and R.J.
- Hypertension or high blood pressure, is a major public health concern in developed countries, it being common, asymptomatic, readily detectible and often leading to lethal complications if left untreated. Patients with hypertension die prematurely; the most common cause of death is heart disease, with stroke and renal failure also frequent. [Harrison's Principles of Internal Medicine (12th ed., 1991)].
- Two selective cq adrenergic receptor antagonists useful as antihypertensives are prazosin (i.e., l -(4-amino-6,7-dimethoxy-2-quinazolinyl-4-(2- furanylcarbonyl)piperazine) and terazosin (i.e., l-(4-amino-6,7- dimethoxy-2-quinazolinyl-4-(2-tetrahydrofuroyl)piperazine).
- prazosin i.e., l -(4-amino-6,7-dimethoxy-2-quinazolinyl-4-(2- furanylcarbonyl)piperazine
- terazosin i.e., l-(4-amino-6,7- dimethoxy-2-quinazolinyl-4-(2-tetrahydrofuroyl)piperazine
- non-selective alpha-adrenergic blockers such as phenoxybenzamine and phentolamine
- phenoxybenzamine and phentolamine are limited by their ⁇ 2 adrenergic receptor mediated induction of increased plasma catecholamine concentration and the attendant physiological sequelae (increased heart rate and smooth muscle contraction).
- Benign prostatic hype ⁇ lasia also known as benign prostatic hypertrophy or BPH
- BPH benign prostatic hypertrophy
- the symptoms of the condition include, but are not limited to, increased difficulty in urination and sexual dysfunction. These symptoms are induced by enlargement, or hype ⁇ lasia, of the prostate gland. As the prostate increases in size, it impinges on free ⁇ flow of fluids through the male urethra.
- the increased noradrenergic innervation of the enlarged prostate leads to an increased adrenergic tone of the bladder neck and urethra, further restricting the flow of urine through the urethra.
- the ⁇ i adrenergic receptor that mediates human prostatic smooth muscle contraction in human prostate has the pharmacological properties of the cloned human ⁇ ic subtype [Forray, C. et al., Mol. Pharmacol., 45, 703-708 (1994)].
- rat tissues have been used to screen for potential adrenergic receptor antagonists.
- compounds which appear active in animal tissue may not be active or sufficiently selective in humans. This results in substantial wastage of time and effort, particularly where high volume compound screening programs are employed.
- compounds, which might be highly effective in humans would be missed because of their absence of appreciable affinity for the heterologous animal receptors.
- even single amino acid changes between the sequence of biologically active proteins in one species may give rise to substantial pharmacological differences.
- the instant patent disclosure describes novel compounds which selectively bind to the human ⁇ ib receptor. These compounds are further tested for binding to other human alpha 1 receptor subtypes, as well as counterscreened against other types of receptors, thus defining the specificity of the compounds of the present invention for the human ⁇ ib adrenergic receptor. Because of their ability to selectively antagonize ⁇ ib adrenergic receptors, the compounds of this invention are useful for reducing blood pressure without causing ancillary effects due to binding to the ⁇ ia and ⁇ i c receptor subtypes (e.g., inducing relaxation of urethral smooth muscle).
- ⁇ i-AR ⁇ i adrenergic receptor
- This new naming system reflects the correspondence between the proteins encoded by the ⁇ ia and ⁇ ib genes (new IUPHAR nomenclature) and the receptors characterized by traditional pharmacological means as ⁇ iA and ⁇ iB, respectively, in the literature. Recombinant receptors and receptors characterized pharmacologically in tissues are distinguished by lowercase and uppercase subscripts, respectively.
- the present invention provides compounds for the treatment of hypertension.
- the compounds selectively antagonize the human alpha 1 adrenergic receptors.
- the compounds of the present invention selectively bind to the alpha lb adrenergic receptor at submicromolar concentrations while exhibiting at least five fold lower affinity for the alpha ld and alpha la human adrenergic receptors and many other G-protein coupled receptors (e.g., serotonin).
- the compounds of the present invention have the structure:
- A is selected from CR3R8, N-R3/0, S or S02;
- Rl and R2 are each independently selected from hydrogen, CN, C(0)R 4 , CH20R4, CH2NR4R5, CONR 4 R5, CO2R 4 or SO2R 4 , provided that Rl and R2 are not both hydrogen;
- R is selected from hydrogen, CN, OR6, NR6R , C(0)R 4 , CO2R 4 , CONR 4 R5, Het or (CH2)mAr where Ar is unsubstituted, mono-, di- or tri-substituted Ar and where the substituents on Ar are independently selected from OR 4 , NR R5, halogen, Cl-8 alkyl, CF3, nitro or CN;
- R 4 and R5 are each independently selected from hydrogen, CH2CF3, Ci-g alkyl, C3-8 cycloalkyl, Het or (CH2)mAr, where Ar is unsubstituted, mono-, di- or tri-substituted Ar and where the substituents on Ar are independently selected from OR6, halogen, NR6R7, Cl-8 alkyl, CF3 or C3-8 cycloalkyl;
- R6 and R7 are each independently selected from hydrogen, CH2CF3, Ci-8 alkyl or C3-8 cycloalkyl;
- R8 is selected from hydrogen, Cl- alkyl, CF3, C3-8 cycloalkyl, Het or (CH2)mAr where Ar is unsubstituted, mono-, di- or tri-substituted Ar and where the substituents on Ar are independently selected from OR 4 , NR 4 R5, halogen, Cl -8 alkyl, CF3, nitro or CN; Ar is selected from phenyl, naphthyl, furanyl, thiazolyl, pyrrolyl, thienyl, 2-, 3- or 4-pyridyl, or chromanyl;
- Het is an unsubstituted, mono- or di-substituted heterocyclic ring selected from tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl or mo ⁇ holinyl, where the substituents on Het are independently selected from hydroxyl, Cl-8 alkyl, CF3, halogen, CN, nitro, Cl-4 alkoxy, amino or C ⁇ 2-Cl-4 alkyl;
- n is an integer of from one to three; and the pharmaceutically acceptable salts thereof.
- Rl and R2 are each independently selected from CN, C(0)R 4 , CH2OR 4 , CH2NR 4 R5, CONR 4 R5, CO2R 4 or SO2R 4 ;
- R 4 is selected from hydrogen, CH2CF3, Cl-6 alkyl, C3-6 cycloalkyl, Het or (CH2)mAr where Ar is unsubstituted, mono-, di- or tri ⁇ substituted Ar and the substituents on Ar are independently selected from OR6, halogen, NR 6 R 7 , Cl-5 alkyl, CF3 or C3-8 cycloalkyl; and
- R5 is selected from hydrogen, CH2CF3, Cl-8 alkyl or C3-8 cycloalkyl; where all other variables are as defined above; and the pharmaceutically acceptable salts thereof.
- A is selected from CR 3 R8 0 r N-R3;
- Rl and R2 are each independently selected from CN, CONR 4 R5 or CO2R 4 ;
- R3 is selected from hydrogen, C(0)R 4 or CO2R 4 ;
- R 4 is selected from Cl-6 alkyl, C3-6 cycloalkyl, tetrahydrofuranyl or (CH2)mAr where Ar is unsubstituted, mono-, di- or tri-substituted Ar and the substituents on Ar are independently selected from OR6, halogen, Cl -4 alkyl or C3-8 cycloalkyl;
- R5 is selected from hydrogen, Cl-6 alkyl or C3-6 cycloalkyl
- Ar is selected from phenyl, furanyl or chromanyl
- n is an integer of from zero to two; where all other variables are as defined above; and the pharmaceutically acceptable salts thereof.
- R 4 is selected from Cl-4 alkyl, benzyl, furanyl, tetrahydrofuranyl or 4-oxo-chromene;
- R5 is selected from hydrogen, Cl-4 alkyl or C3-6 cycloalkyl; and where all other variables are as defined above; and the pharmaceutically acceptable salts thereof.
- Illustrative of the invention is the compound of the formula where all other variables are as defined above; and the pharmaceutically acceptable salts thereof.
- Exemplifying the invention is the compound selected from (S)-l-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-
- A is selected from CR R8 or N-R3; where all other variables are as defined above; and the pharmaceutically acceptable salts thereof.
- R is selected from hydrogen, C(0)R 4 or CO2R 4 ;
- Ar is selected from phenyl, furanyl or chromanyl
- Het is tetrahydrofuranyl; where all other variables are as defined above; and the pharmaceutically acceptable salts thereof.
- An example of the invention is a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described above and a pharmaceutically acceptable carrier.
- Another example of the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier.
- Another illustration of the invention is a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
- FIG. 1 Further illustrating the invention is a method of treating hypertension in a subject in need thereof which comprises administering to the subject a therepeutically effective amount of any of the compounds or pharmaceutical compositions described above.
- a method of lowering blood pressure in a subject in need thereof which comprises administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical composition described above.
- More specifically illustrating the invention is a method of treating a disease which is susceptible to treatment by selective antagonism of the alpha lb receptor which comprises administering to a subject in need thereof an amount of any of the compounds or pharmacuetical compositions described above effective to treat the disease.
- Diseases which are susceptible to treatment by selective antagonism of the alpha lb receptor include, but are not limited to, hypertension, high intraocular pressure, congestive heart failure and cardiac arrhythmia.
- More particularly exemplifying the invention is a method of treating hypertension in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound which binds to a human alpha lb adrenergic receptor with a binding affinity greater than five-fold higher than the binding affinity with which the compound binds to a human alpha la adrenergic receptor, a human alpha ld adrenergic receptor, a human alpha 2a adrenergic receptor, a human alpha 2b adrenergic receptor and a human alpha 2c adrenergic receptor.
- the compound utilized in the method of treating hypertension binds to the human alpha lb adrenergic receptor with a binding affinity at least twenty-fold higher than the binding affinity with which the compound binds to the human alpha la adrenergic receptor, the human alpha ld adrenergic receptor, and the human alpha 2a, alpha 2b and alpha 2c adrenergic receptors.
- the compound utilized in the method of treating hypertension binds to the human alpha lb adrenergic receptor with a binding affinity: at least 100-fold higher than the binding affinity with which the compound binds to the human alpha la adrenergic receptor, at least 25-fold higher than the binding affinity with which the compound binds to the human alpha 1 d adrenergic receptor, and at least 100-fold higher than the binding affinity with which the compoimd binds to the human alpha 2a, alpha 2b and alpha 2c adrenergic receptors.
- the compound utilized in the method of treating hypertension binds to the human alpha lb adrenergic receptor with a binding affinity: at least 500-fold higher than the binding affinity with which the compound binds to the human alpha la adrenergic receptor, at least 25-fold higher than the binding affinity with which the compound binds to the human alpha ld adrenergic receptor and at least 500-fold higher than the binding affinity with which the compound binds to the human alpha 2a, alpha 2b and alpha 2c adrenergic receptors.
- Another example of the invention is a drug which is useful for treating and/or preventing hypertension in a mammal in need thereof, the effective ingredient of the said drug being any of the compounds descibed above. More specifically exemplifying the invention is a drug which is useful for lowering blood pressure in a mammal in need thereof, the effective ingredient of the said drug being any of the compounds described above.
- Representative compounds of the present invention exhibited high selectivity for the human alpha lb adrenergic receptor.
- selectivity for lowering blood pressure without, for example, substantially affecting urethral pressure.
- Representative compounds of this invention displayed submicromolar affinity for the human alpha 1 b adrenergic receptor subtype while displaying at least five-fold lower affinity for the human alpha ld and alpha la adrenergic receptor subtypes, human alpha 2a, alpha 2b and alpha 2c adrenergic receptor subtypes and many other G- protein coupled human receptors (e.g., serotonin).
- Particular representative compounds of this invention exhibited nanomolar affinity for the human alpha lb adrenergic receptor subtype while displaying at least 20-fold lower affinity for the human alpha ld and alpha la adrenergic receptor subtypes and the human alpha 2a, alpha 2b and alpha 2c adrenergic receptor subtypes and many other G-protein coupled human receptors (e.g., serotonin).
- Preferred compounds of this invention exhibited Ki's for the human alpha 1 b adrenergic receptor which were more than 25-fold lower than for the human alpha ld receptor, and more than 100-fold lower than for the human alpha la, alpha 2a, alpha 2b and alpha 2c adrenergic receptors, while exhibiting selectivity for the human alpha lb adrenergic receptor over other human G-protein coupled receptors tested (e.g., serotonin).
- Ki's for the human alpha 1 b adrenergic receptor which were more than 25-fold lower than for the human alpha ld receptor, and more than 100-fold lower than for the human alpha la, alpha 2a, alpha 2b and alpha 2c adrenergic receptors, while exhibiting selectivity for the human alpha lb adrenergic receptor over other human G-protein coupled receptors tested (e.g., serotonin).
- the most preferred compounds of the instant invention exhibited Ki's for the human alpha lb adrenergic receptor which were more than 25-fold lower than for the human alpha ld receptor and more than 500-fold lower than for the human alpha la, alpha 2a, alpha 2b and alpha 2c adrenergic receptors.
- the compounds of the present invention are administered in dosages effective to antagonize the alpha lb receptor where such treatment is needed, as in hypertension.
- the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts.”
- Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts.
- Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
- suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
- representative pharmaceutically acceptable salts include the following:
- prodrugs of the compounds of this invention include within its scope prodrugs of the compounds of this invention.
- prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H.
- Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu. Where the compounds according to the invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more chiral centers, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymo ⁇ hs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates are also encompassed within the scope of this invention.
- alkyl shall mean straight or branched chain alkanes of one to eight total carbon atoms, or any number within this range (i.e., methyl, ethyl, 1 -propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.).
- alkenyl shall mean straight or branched chain alkenes of two to eight total carbon atoms, or any number within this range.
- aryl refers to unsubstituted, mono- or poly-substituted aromatic groups such as phenyl or naphthyl.
- cycloalkyl shall mean cyclic rings of alkanes of three to eight total carbon atoms (i.e., cydopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
- alkyl or aryl or either of their prefix roots appear in a name of a substituent (e.g., aralkoxyaryloxy) it shall be inte ⁇ reted as including those limitations given above for "alkyl” and "aryl.”
- Designated numbers of carbon atoms e.g., Cl-8 shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
- halogen shall include iodine, bromine, chlorine and fluorine.
- substituted shall be deemed to include multiple degrees of substitution by a named substitutent.
- poly ⁇ substituted as used herein shall include di-, tri-, tetra- and penta- substitution by a named substituent.
- substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.
- heterocyde or heterocyclic ring represents an unsubstituted or substituted stable 5- to 7-membered monocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from N, O or S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
- the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
- heterocyclic groups include, but is not limited to, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazohdinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, mo ⁇ holinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, tetrahydrofuranyl, thiam
- chromenyl refers to the group
- dotted line represents either a single or a double bond.
- subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
- terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.
- compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier.
- these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
- the compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
- the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
- a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water
- a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate
- This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
- the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
- the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
- the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
- enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
- liquid forms in which the novel compositions of the present invention may be inco ⁇ orated for administration orally or by injection indude aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
- Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
- the processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers
- these isomers may be separated by conventional techniques such as preparative chromatography.
- the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
- the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d- tartaric acid and/or (-t-)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base.
- the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
- any of the processes for preparation of the compounds of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991.
- the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
- the specificity of binding of compounds showing affinity for the alpha 1 b receptor is shown by comparing affinity to membranes obtained from tranfected cell lines that express the alpha lb receptor and membranes from cell lines or tissues known to express other types of alpha (e.g., alpha l d, alpha la) or beta adrenergic receptors.
- alpha e.g., alpha l d, alpha la
- beta adrenergic receptors e.g., beta adrenergic receptors.
- Expression of the cloned human alpha ld, alpha lb, and alpha la receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities.
- Antagonism by these compounds of the human alpha lb adrenergic receptor subtype may be functionally demonstrated in anesthetized animals.
- These compounds may be used to decrease blood pressure without exhibiting effects on urethral pressure.
- the ability of compounds of the present invention to specifically bind to the alpha lb receptor makes them useful for the treatment of hypertension.
- the specificity of binding of compounds showing affinity for the alpha lb receptor is compared against the binding affinities to other types of alpha or beta adrenergic receptors.
- the human alpha adrenergic receptor of the lb subtype was recently identified, cloned and expressed as described in PCT International Application Publication Nos. WO94/08040, published 14 April 1994 and WO 94/21660, published 29 September 1994, each of which is hereby inco ⁇ orated by reference.
- the cloned human alpha lb receptor when expressed in mammalian cell lines, is used to discover ligands that bind to the receptor and alter its function. Expression of the cloned human alpha ld, alpha lb, and alpha la receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities.
- Compounds of this invention exhibiting selective human alpha lb adrenergic receptor antagonism may further be defined by counterscreening. This is accomplished according to methods known in the art using other receptors responsible for mediating diverse biological functions. rSee e.g.. PCT International Application Publication No. WO94/10989, published 26 May 1994; U.S. Patent No. 5,403,847, issued April 4, 1995, the contents of which are hereby inco ⁇ orated by reference].
- the present invention also has the objective of providing suitable topical, oral, systemic and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention.
- compositions containing compounds of this invention as the active ingredient for use in the specific antagonism of human alpha lb adrenergic receptors can be administered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic administration.
- the compounds can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions, or by injection.
- intravenous both bolus and infusion
- intraperitoneal subcutaneous
- topical with or without occlusion
- intramuscular form all using forms well known to those of ordinary skill in the pharmaceutical arts.
- An effective but non-toxic amount of the compound desired can be employed as an alpha lb antagonistic agent.
- compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
- compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
- the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
- the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed.
- a physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
- Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
- the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
- carrier suitable pharmaceutical diluents, excipients or carriers
- the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
- suitable binders, lubricants, disintegrating agents and coloring agents can also be inco ⁇ orated into the mixture.
- suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
- Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
- Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
- the liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
- suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
- Other dispersing agents which may be employed include glycerin and the like.
- glycerin for parenteral administration, sterile suspensions and solutions are desired.
- Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
- the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
- Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
- Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
- the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
- Such polymers can include polyvinyl ⁇ pyrrolidone, pyran copolymer, polyhydroxypropylmethacryl- amidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl- eneoxidepolylysine substituted with palmitoyl residues.
- the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
- a drug for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
- Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever specific blockade of the human alpha lb adrenergic receptor is required.
- the daily dosage of the products may be varied over a wide range from 0.01 to 1 ,000 mg per adult human per day.
- the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0 and 100 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
- An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg/kg to about 250 mg/kg of body weight per day.
- the range is from about 0.001 to 100 mg/kg of body weight per day, and especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
- the compounds may be administered on a regimen of 1 to 4 times per day.
- Compounds of this patent disclosure may be used alone at appropriate dosages defined by routine testing in order to obtain optimal antagonism of the human alpha lb adrenergic receptor while minimizing any potential toxicity.
- co-administration or sequential administration of other agents which alleviate the effects of hypetension e.g., ⁇ -adrenergic blocking agent, diuretic, ACE inhibitor
- this includes administration of compounds of this invention and a thiazide diuretic.
- the dosages of the alpha lb adrenergic receptor and diuretic (or ⁇ blocker) are adjusted when combined to achieve desired effects.
- dosages of the diuretic (or ⁇ blocker) and the alpha lb adrenergic receptor antagonist may be independently optimized and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either agent were used alone.
- the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be inte ⁇ reted accordingly.
- Cbz-Cl benzyloxycarbonyl chloride
- DAST diethylaminosulfurtrifluoride
- DEAD diethylazodicarboxylate
- DMF N,N-dimethylformamide
- EDCI l -(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride
- Et3N triethylamine
- EtOAc ethyl acetate
- FABHRMS fast atom bombardment high resolution mass spectroscopy
- FABLRMS fast atom bombardment low resolution mass spectroscopy
- HOBt or HBT 1 -hydroxy benzotriazole hydrate
- i-Pr2NEt diisopropylethylamine
- Ph phenyl
- the compounds of the present invention can be prepared readily according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Unless otherwise indicated, all variables are as defined above.
- Receptor binding data for representative compounds of the present invention in cloned human receptors is shown below in Table 1.
- nyl alpha adrenergic receptor subtype binding
- PCTLC (Si ⁇ 2, 4 mm, 0 - 10 % CH3OH/CH2CI2) provided the title compound.
- iH NMR CDCI3, 300 MHz
- 100 mg of the compound of Example 7 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.
- Representative compounds of the present invention were found to bind to the human alpha lb adrenergic receptor with binding affinities greater than twenty-fold higher than the binding affinities with which they bind to the human alpha ld and alpha la adrenergic receptors.
- the objective of this assay is to eliminate agents which specifically affect binding of [3H] spiperone to cells expressing human dopamine receptors D2, D3 or D4.
- Frozen pellets containing specific dopamine receptor subtypes stably expressed in clonal cell lines are lysed in 2 ml lysing buffer (lOmM Tris-HCl/5mM Mg, pH 7.4). Pellets obtained after centrifuging these membranes (15' at 24,450 rpm) are resuspended in 50mM Tris-HCl pH 7.4 containing EDTA, MgCl[2], KCl, NaCl, CaCl[2] and ascorbate to give a 1 Mg/mL suspension. The assay is initiated by adding 50-75 ⁇ g membranes in a total volume of 500 ⁇ l containing 0.2 nM [3H]-spiperone. Non-specific binding is defined using 10 ⁇ M apomorphine. The assay is terminated after a 2 hour incubation at room temperature by rapid filtration over GF/B filters presoaked in 0.3% PEI, using 50mM Tris-HCl pH 7.4.
- the objective of this assay is to eliminate agents which specifically affect binding to cloned human 5HT l a receptor.
- Mammalian cells expressing cloned human 5HTla receptors are lysed in ice-cold 5 mM Tris-HCl, 2 mM EDTA (pH 7.4) and homogenized with a polytron homogenizer. The homogenate is centrifuged at lOOOXg for 30', and then the supematant is centrifuged again at 38,OOOXg for 30'.
- the binding assay contains 0.25 nM [3H]8- OH-DPAT (8-hy droxy-2-dipropy lamino- 1 ,2,3,4-tetrahydronaphthalene) in 50 mM Tris-HCl, 4 mM CaCl2 and 1 mg/ml ascorbate. Non-specific binding is defined using 10 ⁇ M propranolol.
- the assay is terminated after a 1 hour incubation at room temperature by rapid filtration over GF/C filters EX AMPLE 12
- Taconic Farms Sprague-Dawley male rats, weighing 250- 400 grams are sacrificed by cervical dislocation under anesthesia (methohexital; 50 mg/kg, i.p.). An incision is made into the lower abdomen to remove the ventral lobes of the prostate.
- Each prostate removed from a mongrel dog is cut into 6-8 pieces longitudinally along the urethra opening and stored in ice-cold oxygenated Krebs solution overnight before use if necessary.
- Dog urethra proximal to prostate is cut into approximately 5 mm rings, the rings are then cut open for contractile measurement of circular muscles.
- Human prostate chips from transurethral surgery of benign prostate hyperplasia are also stored ovemight in ice-cold Krebs solution if needed.
- the tissue is placed in a Petri dish containing oxygenated Krebs solution [NaCl, 118 mM; KCl, 4.7 mM; CaCl2, 2.5 mM; KH2PO4, 1.2 mM; MgS04, 1.2 mM; NaHC ⁇ 3, 2.0 mM; dextrose, 11 mM] warmed to 37°C. Excess lipid material and connective tissue are carefully removed.
- Tissue segments are attached to glass tissue holders with 4-0 surgical silk and placed in a 5 ml jacketed tissue bath containing Krebs buffer at 37°C, bubbled with 5% C ⁇ 2/95% 02-
- the tissues are connected to a Statham-Gould force transducer; 1 gram (rat, human) or 1.5 gram (dog) of tension is applied and the tissues are allowed to equilibrate for one hour. Contractions are recorded on a Hewlett-Packard 7700 series strip chart recorder.
- a cumulative concentration response curve to an agonist is generated; the tissues are washed every 10 minutes for one hour. Vehicle or antagonist is added to the bath and allowed to incubate for one hour, then another cumulative concentration response curve to the agonist is generated.
- Benign prostatic hype ⁇ lasia causes a decreased urine flow rate that may be produced by both passive physical obstruction of the prostatic urethra from increased prostate mass as well as active obstruction due to prostatic contraction.
- Alpha adrenergic receptor antagonists such as prazosin and terazosin prevent active prostatic contraction, thus improve urine flow rate and provide symptomatic relief in man.
- these are non-selective alpha 1 receptor antagonists which also have pronounced vascular effects. Because the alpha 1 a receptor subtype has been identified as the predominent subtype in the human prostate, it is now possible to specifically target this receptor to inhibit prostatic contraction without concomitant changes in the vasculature.
- the alpha lb receptor subtype is predominantly responsible for mediating changes in the vasculature
- the following model is used to measure adrenergically mediated changes in intra-urethral pressure and arterial pressure in anesthetized dogs in order to evaluate the efficacy and potency of selective alpha adrenergic receptor antagonists.
- the goals are to: 1) identify the alpha 1 receptor subtypes responsible for prostatic/urethral contraction and vascular responses, and 2) use this model to evaluate novel selective alpha adrenergic antagonists. Novel and standard alpha adrenergic antagonists may be evaluated in this manner.
- the dogs are anesthetized with pentobarbital sodium (35 mg/kg, i.v. plus 4 mg/kg/hr iv infusion).
- An endotracheal tube is inserted and the animal ventilated with room air using a Harvard instruments positive displacement large animal ventilator.
- Catheters PE 240 or 260
- Catheters are placed in the aorta via the femoral artery and vena cava via the femoral veins (2 catheters, one in each vein) for the measurement of arterial pressure and the administration of drugs, respectively.
- a supra-pubic incision ⁇ l/2 inch lateral to the penis is made to expose the urethers, bladder and urethra.
- the urethers are ligated and cannulated so that urine flows freely into beakers.
- the dome of the bladder is retracted to facilitate dissection of the proximal and distal urethra.
- Umbilical tape is passed beneath the urethra at the bladder neck and another piece of umbilical tape is placed under the distal urethra approximately 1 -2 cm distal to the prostate.
- the bladder is incised and a Millar micro-tip pressure transducer is advanced into the urethra.
- the bladder incision is sutured with 2-0 or 3-0 silk (purse-string suture) to hold the transducer.
- Phenylephrine an alpha 1 adrenergic agonist
- Phenylephrine an alpha 1 adrenergic agonist
- phenylephrine dose-response curves are generated in each animal (one control, three or four doses of antagonist or vehicle).
- the relative antagonist potency on phenylephrine induced changes in arterial and intra-urethral pressure are determined by Schild analysis.
- the family of averaged curves are fit simultaneously (using ALLFIT software package) with a four paramenter logistic equation constraining the slope, minimum response, and maximum response to be constant among curves.
- the dose ratios for the antagonist doses (rightward shift in the dose-response curves from control) are calculated as the ratio of the ED50's for the respective curves.
- the Kb dose of antagonist causing a 2-fold rightward shift of the phenylephrine dose-response curve
- the relative selectivity is calculated as the ratio of arterial pressure and intra-urethral pressure Kb's. Effects of the alpha 1 antagonists on baseline arterial pressure are also monitored. Comparison of the relative antagonist potency on changes in arterial pressure and intra-urethral pressure provide insight as to whether the alpha receptor subtype responsible for increasing arterial pressure is also present in urethral smooth muscle. According to this method, one is able to confirm the selectivity of alpha lb adrenergic receptor antagonists that prevent the increase in arterial pressure to phenylephrine without any activity in inter-urethral pressure.
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Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
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JP9513532A JPH11512710A (en) | 1995-09-29 | 1996-09-24 | Alpha 1b adrenergic receptor antagonist |
EP96933093A EP0853479A4 (en) | 1995-09-29 | 1996-09-24 | ALPHA 1b ADRENERGIC RECEPTOR ANTAGONISTS |
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Application Number | Priority Date | Filing Date | Title |
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US450195P | 1995-09-29 | 1995-09-29 | |
US60/004,501 | 1995-09-29 | ||
GB9604288.2 | 1996-02-29 | ||
GBGB9604288.2A GB9604288D0 (en) | 1996-02-29 | 1996-02-29 | Alpha 1b adrenergic receptor antagonists |
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WO1997011698A1 true WO1997011698A1 (en) | 1997-04-03 |
Family
ID=26308827
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PCT/US1996/015223 WO1997011698A1 (en) | 1995-09-29 | 1996-09-24 | ALPHA 1b ADRENERGIC RECEPTOR ANTAGONISTS |
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Country | Link |
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EP (1) | EP0853479A4 (en) |
JP (1) | JPH11512710A (en) |
CA (1) | CA2232138A1 (en) |
WO (1) | WO1997011698A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000067735A3 (en) * | 1999-05-07 | 2001-02-01 | Recordati Chem Pharm | USE OF SELECTIVE ANTAGONISTS OF THE α1b-ADRENERGIC RECEPTOR FOR IMPROVEMENT OF SEXUAL DYSFUNCTION |
US6559153B2 (en) | 2000-08-31 | 2003-05-06 | Syntex (U.S.A.) Llc | Quinazoline derivatives as alpha-1 adrenergic antagonists |
US7678824B2 (en) | 2004-09-14 | 2010-03-16 | The Regents Of The University Of Colorado, A Body Corporate | Methods for treatment with bucindolol based on genetic targeting |
WO2018005552A1 (en) | 2016-06-27 | 2018-01-04 | Achillion Pharmaceuticals, Inc. | Quinazoline and indole compounds to treat medical disorders |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2014079155A1 (en) * | 2012-11-26 | 2014-05-30 | 辽宁贝雷生物制药有限公司 | Use of benzo five-membered nitrogen heterocyclic piperazine or piperidine derivatives |
Citations (1)
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US4495188A (en) * | 1980-11-26 | 1985-01-22 | Sankyo Company Limited | Acylaminoquinazoline derivatives and a pharmaceutical composition containing them |
Family Cites Families (3)
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US4026894A (en) * | 1975-10-14 | 1977-05-31 | Abbott Laboratories | Antihypertensive agents |
US4101548A (en) * | 1977-02-22 | 1978-07-18 | Bristol-Myers Company | 1,2,3-Thiadiazole amides |
GB2171977A (en) * | 1985-03-05 | 1986-09-10 | Emi Plc Thorn | Gripper |
-
1996
- 1996-09-24 JP JP9513532A patent/JPH11512710A/en active Pending
- 1996-09-24 WO PCT/US1996/015223 patent/WO1997011698A1/en not_active Application Discontinuation
- 1996-09-24 EP EP96933093A patent/EP0853479A4/en not_active Withdrawn
- 1996-09-24 CA CA002232138A patent/CA2232138A1/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US4495188A (en) * | 1980-11-26 | 1985-01-22 | Sankyo Company Limited | Acylaminoquinazoline derivatives and a pharmaceutical composition containing them |
Non-Patent Citations (1)
Title |
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See also references of EP0853479A4 * |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000067735A3 (en) * | 1999-05-07 | 2001-02-01 | Recordati Chem Pharm | USE OF SELECTIVE ANTAGONISTS OF THE α1b-ADRENERGIC RECEPTOR FOR IMPROVEMENT OF SEXUAL DYSFUNCTION |
US6303606B1 (en) | 1999-05-07 | 2001-10-16 | Recordati, S.A., Chemical And Pharmaceutical Company | Use of selective antagonists of the α1B-adrenergic receptor for improvement of sexual dysfunction |
JP2002544158A (en) * | 1999-05-07 | 2002-12-24 | レコルダチ エッセ.ア.,ケミカル アンド ファーマシューティカル カンパニー | Use of selective antagonists of α1b-adrenergic receptors for amelioration of sexual dysfunction |
US6953800B2 (en) | 1999-05-07 | 2005-10-11 | Recordati S.A. Chemical | Use of selective antagonists of the α1B-adrenergic receptor for improvement of sexual dysfunction |
KR100696755B1 (en) * | 1999-05-07 | 2007-03-19 | 레코르다티 아일랜드 리미티드 | Use of Selective Antagonists of α1′-Adrenergic Receptors to Improve Sexual Dysfunction |
US6559153B2 (en) | 2000-08-31 | 2003-05-06 | Syntex (U.S.A.) Llc | Quinazoline derivatives as alpha-1 adrenergic antagonists |
US7678824B2 (en) | 2004-09-14 | 2010-03-16 | The Regents Of The University Of Colorado, A Body Corporate | Methods for treatment with bucindolol based on genetic targeting |
US8080578B2 (en) | 2004-09-14 | 2011-12-20 | The Regents Of The University Of Colorado, A Body Corporate | Methods for treatment with bucindolol based on genetic targeting |
US8093286B2 (en) | 2004-09-14 | 2012-01-10 | The Regents Of The University Of Colorado, A Body Corporate | Methods for treatment with bucindolol based on genetic targeting |
US8916603B2 (en) | 2004-09-14 | 2014-12-23 | The Regents Of The University Of Colorado, A Body Corporate | Methods for treatment with bucindolol based on genetic targeting |
WO2018005552A1 (en) | 2016-06-27 | 2018-01-04 | Achillion Pharmaceuticals, Inc. | Quinazoline and indole compounds to treat medical disorders |
US10961252B2 (en) | 2016-06-27 | 2021-03-30 | Achillion Pharmaceuticals, Inc. | Quinazoline and indole compounds to treat medical disorders |
EP3939591A1 (en) | 2016-06-27 | 2022-01-19 | Achillion Pharmaceuticals, Inc. | Quinazoline and indole compounds to treat medical disorders |
US11248000B2 (en) | 2016-06-27 | 2022-02-15 | Achillion Pharmaceuticals, Inc. | Quinazoline and indole compounds to treat medical disorders |
Also Published As
Publication number | Publication date |
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JPH11512710A (en) | 1999-11-02 |
EP0853479A4 (en) | 2001-04-11 |
EP0853479A1 (en) | 1998-07-22 |
CA2232138A1 (en) | 1997-04-03 |
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