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WO2002019213A2 - Procede de traitement de la migraine - Google Patents

Procede de traitement de la migraine Download PDF

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Publication number
WO2002019213A2
WO2002019213A2 PCT/US2001/026740 US0126740W WO0219213A2 WO 2002019213 A2 WO2002019213 A2 WO 2002019213A2 US 0126740 W US0126740 W US 0126740W WO 0219213 A2 WO0219213 A2 WO 0219213A2
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WO
WIPO (PCT)
Prior art keywords
pde5
migraine
pde5 inhibitor
methyl
group
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PCT/US2001/026740
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WO2002019213A3 (fr
Inventor
Hartmut Porst
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Lilly Icos LLC
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Lilly Icos LLC
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Publication date
Application filed by Lilly Icos LLC filed Critical Lilly Icos LLC
Priority to EP01966306A priority Critical patent/EP1313478A2/fr
Priority to AU2001286832A priority patent/AU2001286832A1/en
Priority to CA002419623A priority patent/CA2419623A1/fr
Priority to JP2002523251A priority patent/JP2004507514A/ja
Priority to BR0113644-5A priority patent/BR0113644A/pt
Priority to MXPA03001717A priority patent/MXPA03001717A/es
Publication of WO2002019213A2 publication Critical patent/WO2002019213A2/fr
Publication of WO2002019213A3 publication Critical patent/WO2002019213A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • 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

  • the present invention relates to a treatment for vascular headaches.
  • the present invention relates to the use of Type 5 phosphodiesterase (PDE5) inhibitors to treat mi- graine .
  • PDE5 Type 5 phosphodiesterase
  • Cyclic nucleotide phosphodiesterases that catalyze the hydrolysis of 3' 5 '-cyclic nucleotides, such as cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) , to the corresponding nucleoside 5 ' -monophosphates constitute a complex family of enzymes.
  • PDEs cyclic guanosine monophosphate
  • cAMP cyclic adenosine monophosphate
  • PDEs Multiple families of PDEs have been iden- tified.
  • the nomenclature system includes first a number that indicates the PDE family.
  • nine families (PDEl-9) which are classified by: (i) primary structure; (ii) substrate preference; (iii) response to different modulators; (iv) sensitivity to specific inhibitors; and (v) modes of regulation (Loughney and Ferguson, in Phosphodi - esterase Inhibi tors, Schudt et al . (Eds.), Academic Press: New York, New York (1996) pp. 1-19) .
  • the number indicating the family is followed by a capital letter, indicating a distinct gene, and the capital letter followed by a second number, indicating a specific splice variant or a specific tran- script that utilizes a unique transcription initiation site.
  • PDE1A and PDE1B preferentially hydrolyze cGMP, while PDEIC has been shown to exhibit a high affinity for both cAMP and cGMP.
  • the sole member of the PDE2 family i.e., PDE2A
  • PDE3A and PDE3B are specifically inhibited by cGMP .
  • the PDE4 family effects cAMP hydrolysis and includes four genes, PDE4A, PDE4B, PDE4C, and PDE4D.
  • the sole member of the PDE5 family i.e., PDE5A, binds cGMP at noncatalytic sites and preferentially hydrolyze cGMP .
  • the photo- receptor PDE6 enzymes specifically hydrolyze cGMP (Loughney and Ferguson, supra) .
  • Genes include PDE6A, PDE6B, and PDE6C.
  • the PDE7 family effects cAMP hydrolysis but, in contrast to the PDE4 family, is not inhibited by rolipram (Loughney and Ferguson, supra) .
  • the PDE8 family has been shown to hydrolyze both cAMP and cGMP and is insensitive to inhibitors specific for PDEs 1-5.
  • PDE8 also is referred to as PDE10.
  • the PDE9 family preferentially hydrolyzes cAMP and is not sensitive to inhibition by rolipram, a PDE4-specific inhibitor, or isobutyl methyl xanthine (IBMX) , a nonspecific PDE inhibitor.
  • PDE5 inhibitors vary significantly in chemical structure. Limiting factors on the therapeutic value of various PDE5 inhibitory compounds include ease of administration, potency, and selectivity. It is generally preferred that an inhibitor is effective in low concentrations and can be administered orally. On the other hand, if adverse physiological side effects are to be avoided, it is important that the compound be highly selective in its inhibitory effect on PDE5.
  • Migraine is a common disease, and is the most common cause of severe, recurring headache. In any given year, about 15 to 20% of women and about 7 to 10% of men experience at least one migraine attack. Migraine headaches can be subdivided into classic and common types. Eighty percent of all migraine headaches are the common type .
  • Classic migraine headaches occur in three stages . The symptoms are related to an initial vasoconstriction and subsequent vasodilation of the blood vessels of the head. The initial vasoconstriction, called the prodrome, is quickly followed by vasodilation. A common migraine headache does not include a prodromal phase .
  • the first stage of a classic migraine headache consists chiefly of visual disturbances, including blurred or cloudy vision, scotomas, and/or flashes of light. Vertigo, chills, tremors, unilat- eral numbness, aphasia, photophobia, or pallor also can occur.
  • the patient experiences a severe, throbbing headache, which initially is unilateral. Nausea, vomiting, diarrhea, chills, tremors, and perspiration also can occur at this time.
  • the third stage is a recovery phase. The pain decreases markedly, but the head is tender and exhaustion is present.
  • a common migraine headache includes no prodromal stage (stage 1) , but the actual headache can last longer (more than two hours) than a classic migraine.
  • migraine is mainly a psychosomatic condition
  • the actual attack has been attributed instead to a primarily neurogenic phenomenon with secondary consequences for the blood vessels of the brain and meninges .
  • Migraine is intermittent by nature, and attack frequency can vary from one period to another. The symptoms and severity vary both between and within individuals from occasional mild attacks to frequent severe attacks. Migraine appears to be a hereditary disease.
  • migraine therapy A major obstacle in migraine therapy is a lack of clear guidelines for disease management. A limited number of effective antimigraine drugs have been identified, but their efficacy in a given individual is hard to predict accurately. Thus, migraine therapies often are individualized for each patient .
  • Treatment for migraine includes avoidance of factors that can trigger an attack, treatment of the acute headache, and the use of regular medication to prevent attacks. Many factors have been associated as triggers of individual migraine attacks: fasting, alcohol, oral contraceptives and hormone replacement therapy, caffeine and caffeine withdrawal, stress or release from stress, too little or too much sleep, menstruation, fatigue, change in weather, head trauma, exposure to bright lights, loud noises, smoke, strong scents, and foods, including chocolate, aged cheeses, cured and processed meats that contain nitrites, dairy products, foods containing monosodium glutamate or aspartame, citrus fruits, and others. In general, however, identifying and avoiding migraine triggers is not an effective treatment plan. First, most migraine headaches are not caused by an identifiable trigger.
  • a patient's response to a trigger varies, e.g., fasting may or may not trigger a migraine, which decreases the patient's will to avoid all recognized triggers .
  • many migraine triggers are unavoidable .
  • a wide variety of drugs are available for both prevention of migraine and treatment of an acute attack.
  • Preventative drugs currently available include ⁇ -blockers, such as propranolol, meto- prolol, atenolol, timolol, and nadolol; calcium channel blockers, such as verapamil, nifedipine, nimopidine, and diltiazem; tricyclic antidepres- sants, such as amitriptyline and nortriptyline; anticonvulsants, such as divalproex sodium; 5-HT agonists, such as sumatriptan, naratriptan, riza- triptan, zolmitriptan, and pizotifen; and a mono- amine oxidase inhibitor, such as phenelzine and isocarboxazid .
  • ⁇ -blockers such as propranolol, meto- prolol, atenolol, timolol, and nadolol
  • calcium channel blockers such
  • Adverse effects attributed to treatment with ⁇ -blockers include aggravation of asthma, brachycardia, hypotension, fatigue, depression, and masking of the symptoms of hypoglycemia.
  • Calcium channel blockers can cause hypotension, constipation, and peripheral edema.
  • Tricyclic antidepres- sants can cause sedation, dry mouth, weight gain, tremor, cardiac arrhythmias, aggravation of angle- closure glaucoma, and difficulty in urinating.
  • Divalproex sodium can cause nausea, fatigue, weight gain, hair loss, tremor, liver dysfunction, and neural tube defects in developing embryos.
  • the 5-HT agonists can cause chest and neck pressure, and myo- cardial ischemia.
  • Prompt treatment is intended to decrease the severity of pain, prevent or reduce associated symptoms such as nausea and vomiting, and shorten attack duration.
  • Available drugs include over the counter analgesics, such as acetaminophen, aspirin, ibuprofen, indometh- icin, and naproxen sodium; combinations of over the counter analgesics with caffeine; ergot alkaloids, like ergotamine and dihydroergotamine; and prescrip- tion analgesic/antimigraine preparations, including narcotics (e.g., butalbitol) .
  • narcotics e.g., butalbitol
  • the present invention is directed to a method of treating migraine, both classic and common, and other vascular headaches in mammals.
  • the method comprises administering a pharmaceutically effective amount of an agent that inhibits cyclic guanosine 3 ' 5 ' -monophosphate specific PDE5, i.e., a PDE5 inhibitor, to an individual that suffers from migraine headaches.
  • a PDE5 inhibitor can be administered prior to or after the onset of the migraine.
  • the ability of a PDE5 inhibitor to treat migraine is unexpected in the art because a typical side effect of treatment with a PDE inhibitor, including PDE5 inhibitors, is headache.
  • the amount of PDE5 inhibitor administered to the individual is ⁇ about 0.1 to about 1000 mg daily. More preferably, the amount of PDE5 inhibitor administered is about 1 to about 100 mg daily. Most preferably, the amount of PDE5 inhibitor administered is about 2 to about 20 mg daily.
  • the method comprises administering an effective amount of a first PDE5 inhibitor in combination with a second PDE5 inhibitor or with another known antimigraine agent, preferably an analgesic.
  • Another aspect of the present invention is to administer a pharmaceutically effective amount of a compound having a structure (I) , (II) , or (III) to an individual to treat a migraine or other vascular headaches
  • R 1 is methyl or ethyl
  • R 2 is n- propyl
  • R 3 is ethyl, n-propyl , or allyl
  • R 4 is COCH 2 NR 5 R 6 , CONR 5 R 6 , S0 2 NR 9 R 10 , or 1-methyl -2-imida- zolyl
  • R 5 and R 6 together represent, with the nitrogen atom to which they are attached, a morpholino or 4-N(R 1:L ) -piperazinyl group
  • R 9 and R 10 together represent, with the nitrogen atom to which they are attached, a 4-N (R 12 ) -piperazinyl group
  • R 11 is methyl or acetyl
  • R 12 is hydrogen, methyl, 2-propyl, or 2 -hydroxyethyl ;
  • R 13 is selected from the group consisting of hydrogen, halogen, and R 14 is selected from the group consisting of hydrogen, C 2 . ⁇ alkenyl, C 2 . 6 alkynyl, halo- Ci.galk l, C 3 _ 8 cycloalkyl, C 3 . 8 cycloalkylC 1 .
  • arylC 1 _ 3 alkyl and arylC 1 _ 3 alkyl, wherein aryl is phenyl or phenyl sub- stituted with one to three substituents independently selected from the group consisting of halogen, and methylenedioxy, and hetero- arylC ⁇ alkyl, wherein heteroaryl is thienyl, furyl, or pyridyl, each optionally substituted with one to three substituents independently selected from the group consisting of halogen,
  • R 15 represents an optionally substituted monocyclic aromatic ring selected from the group consisting of benzene, thiophene, furan, and pyri- dine, or an optionally substituted bicyclic ring
  • fused ring A is a 5- or 6-membered ring, saturated or partially or fully unsaturated, and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur, and nitrogen;
  • R 16 represents hydrogen or C ⁇ alkyl, or R 1 and R 3 together represent a 3- or 4-membered alkyl or alkenyl chain component of a 5- or 6-membered ring; and salts and solvates thereof,
  • R 5 is methyl or ethyl
  • R 6 is ethyl or propyl
  • R 7 and R 8 independently, are a straight- chain or branched alkyl chain having up to five carbon atoms, optionally substituted, independently, with up to two hydroxy or methoxy, or
  • R 7 and R 8 together with the nitrogen form piperidinyl, morpholinyl, thiomorpholinyl, or a residue of the formula
  • R 37 is hydrogen, formyl, or straight-chain or branched acyl or alkoxycarbonyl each having up to three carbon atoms, or is a straight-chain or branched alkyl having up to three carbon atoms, optionally substituted, independently, with one or two hydroxy, carboxyl, or straight-chain or branched alkoxy or alkoxycarbonyl , each having up to three carbon atoms, or by groups of the formula - (D) f NR 38 R 39 or -P(O) (OR 42 ) (OR 43 ) , wherein f is. 0 or 1,
  • D is a group of the formula -CO
  • R 38 and R 39 independently, are hydrogen or methyl
  • R 42 and R 43 independently are hydrogen, methyl, or ethyl, or
  • R 37 is cyclopentyl, and the heterocycles mentioned under R 3 and R 4 that are formed together with the nitrogen atom are optionally substituted, independently, with one or two, optionally geminally, hydroxy, formyl, carboxyl, and straight-chain or branched acyl or alkoxycarbonyl each having up to three carbon atoms, or a group of the formula -P(O) (OR 46 ) (OR 47 ) or - (CO j R ⁇ R 50 , wherein R 46 and R 47 , independently, are hydrogen, methyl, or ethyl, j is 0 or 1, and
  • R 49 and R so are hydrogen or methyl and/or the heterocycles mentioned under R 3 and R 4 that are formed together with the nitrogen atom are optionally substituted by straight-chain or branched with up to three carbon atoms, which is optionally substituted, independently, with one or two hydroxy, carboxyl, or a residue of the formula P(0)OR 53 OR 54 , wherein R 53 and R 54 , independently, are hydrogen, methyl ' , or ethyl, and/or the heterocycles mentioned under R 3 and R 4 that are formed together with the nitrogen atom are optionally substituted via N-linked piperidinyl or pyrrolidinyl ,
  • R 9 is hydrogen
  • R 10 is ethoxy or propoxy, and salts, hydrates, N-oxides, and isometric forms thereof.
  • the present invention is directed to a method for treating migraine and other vascular headaches in mammals.
  • the method comprises administering a pharmaceutically effective amount of an agent that inhibits cyclic guanosine 3 ' 5 ' -monophosphate specific PDE5 to an individual in need there- of .
  • a PDE5 inhibitor can be administered alone, in combination with a second PDE5 inhibitor, or in combination with other known antimigraine treatments.
  • treating is defined as reducing or eliminating a clinical symptom of migraine and/or increasing the time between migraine attacks and/or preventing the recurrence of migraine.
  • a "clinical symptom" of migraine includes headache, nausea, vomiting, extreme sensitivity to light and/or sound, vertigo, chills, tremors, pallor, aphasia, unilateral numbness, diarrhea, and visual disturbances.
  • IC S0 is defined as the concentration of a compound that results in 50% enzyme inhibition, in a single dose response experiment.
  • the IC 50 value therefore is a measure of the potency of a compound to inhibit PDEs, including PDE5. Determining the IC 50 value of a compound is readily carried out by a known in vi tro methodology generally described in Cheng et al . , Biochem. Pharmacol ogy, 22, pages 3099-3108 (1973) .
  • inhibitors refers to blocking the enzymatic activity of PDE5 to a sufficient degree to reduce or eliminate a clinical symptom of migraine and/or increase the time between migraine attacks, or to prevent the recurrence of a clinical symptom of migraine.
  • a pharmaceutically effective amount represents an amount of a compound that is capable of inhibiting PDE5, and causes an improvement in a clinical symptom of migraine and/or prevents or reduces recurrence of migraine or a clini- cal symptom thereof.
  • agent or “drug” refers to a chemical compound suitable for pharmaceutical use.
  • PDE5 inhibitor refers to an agent that inhibits cGMP-specific PDE5 activity.
  • a PDE5 inhibitor useful in the present invention is an agent that inhibits cyclic guanosine 3 ' 5 ' -monophosphate specific PDE5 and has an IC 50 value against human recombinant PDE5 of about 10 nM or less.
  • the IC 50 value of the PDE5 inhibitor is about 5 nM or less, more preferably about 3 nM or less, and most preferably about 1 nM or less.
  • Most preferred PDE5 inhibitors are selective PDE5 inhibitors, i.e., compounds that inhibit PDE5, but do not significantly inhibit other PDE enzymes, i.e., PDE1 through PDE4 and PDE6 through PDE9, and particularly
  • the IC 50 value for PDE5 inhibition is about 100 times less than ' the IC 50 value for PDE1-PDE4 and PDE6-PDE9, particularly, PDE6 or PDElc inhibition, more preferably about 500 times less, and most preferably about 1000 'times less.
  • PDE5 inhibitors can be administered sys- temically, e.g., by oral, intravenous, intramuscular, or subcutaneous routes.
  • the PDE5 inhibitor can be administered as an aerosol for pulmonary administration, as a spray for nasal administration, administered intraventricularly or intrathecally into the cerebrospinal fluid, or administered intravenously via continuous infusion pump.
  • the PDE inhibitor also can be administered topically, e.g., via drops (particularly ophthalmic drops) , ointment, patch, or per rectum or vagina, for example, by suppositories or enemas.
  • a first PDE5 inhibitor and a second PDE5 inhibitor and/or another antimigraine treatment can be administered simultaneously or sequentially.
  • PDE5 inhibitors can be administered at doses of about 0.1 to about 1000 mg, preferably about 1 to about 100 mg daily, and most preferably about 2 to about 20 mg, over a 24-hour period.
  • the dosage can be administered as needed, once daily, or in equivalent doses at longer or shorter intervals.
  • Those of ordinary skill in the art can readily optimize effective dosages and administration regimens as determined by good medical practice and the clinical condition of the individual patient.
  • appropriate dosages can be ascertained through use of established assays for determining blood level dosages in conjunction with appropriate dose-response data.
  • the final dosage regimen is determined by the attending physician, considering various factors, for example, the specific activity of the drug, the severity of the condition and the responsiveness of the patient, the age, condition, body weight, sex and diet of the patient, the severity of the clinical symptoms, time of administration, and other clinical factors.
  • the doses of each agent required to exert a therapeutic effect may be less than the dose necessary when a single PDE5 inhibitor is used alone.
  • PDE5 inhibitors useful in the present invention vary significantly in chemical structure and the use of a PDE5 inhibitor in the present method is not dependent on a particular chemical structure.
  • preferred compounds having the ability to inhibit PDE5 include compounds having a structural formula ( I ) :
  • R 1 is methyl or ethyl ;
  • R 2 is n- propyl ;
  • R 3 is ethyl , n-propyl , or allyl ;
  • R 4 is C0CH 2 NR 5 R 6 , CONR 5 R 6 , S0 2 NR 9 R 10 , or 1 -methyl -2 - imidazol - yl ;
  • R 5 and R 6 together represent, with the nitrogen atom to which they are attached, a morpholino or 4- N(R ⁇ :l ) -piperazinyl group;
  • R 9 and R 10 together with the nitrogen atom to which they are attached represent a 4-N(R 12 ) -piperazinyl group;
  • R 11 is methyl or acetyl; and
  • R 12 is hydrogen, methyl, 2-propyl, or 2 -hydroxy- ethyl .
  • sildenafil having the following structural formula:
  • R 13 is selected from the group consisting of hydrogen, halogen, and C h alky!;
  • R 14 is selected from the group consisting of hydrogen, C ⁇ alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, haloCi.galkyl, C 3 _ 8 cycloalkyl , C 3 . 8 cycloalkylC 1 . 3 alkyl, and arylC 1 . 3 alkyl, wherein aryl is phenyl or phenyl substituted with one to three substituents independently selected from the group consisting of halogen, and methylenedioxy, and heteroarylC 1 .
  • heteroaryl is thienyl, furyl, or pyridyl, each optionally substituted with one to three substituents independently selected from the group consisting of halogen, C h alky1 , and Ci.galko y;
  • R 15 represents an optionally substituted monocyclic aromatic ring selected from the group consisting of benzene, thiophene, furan, and pyri- dine, or an optionally substituted bicyclic ring
  • the fused ring A is a 5- or 6-membered ring, saturated or partially or fully unsaturated, and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen;
  • R 16 represents hydrogen or C ⁇ alkyl, or R 14 and R 16 together represent a 3- or 4-membered alkyl or alkenyl chain component of a 5- or 6-membered ring.
  • Preferred compounds of structural formula (II) are those wherein R 13 is hydrogen, halogen, or C- L .g lkyl; R 14 is hydrogen or R 15 is the bicyclic ring
  • R 16 is hydrogen or C h alky1.
  • Preferred compounds of structural formula (II) include: Cis-2,3, 6, 7,12, 12a-hexahydro-2- (4-pyridylmethyl) -6- (3 , 4 -methylenedioxyphenyl) pyrazino [2 ' ,1' :6,l]pyrido- [3 , 4-b] indole-1, 4-dione;
  • Three preferred compounds of structural formula (II) are: (6R,12aR) -2,3,6, 7, 12, 12a-hexahydro-2 -methyl -6- (3,4- methylenedioxyphenyl) pyrazino [2 ' , 1 ' : 6, 1] pyrido [3, 4- b] indole-1, 4-dione; (6R, 12aR) -2, 3, 6, 7, 12, 12a-hexahydro-6- (5-benzofuran- yl) -2-methylpyrazino [2 ' , 1 ' :6, 1] pyrido [3 ,4-b] indole- 1, -dione; and
  • R 5 is methyl or ethyl
  • R s is ethyl or propyl
  • R 7 and R 8 independently, are a straight- chain or branched alkyl chain having up to five carbon atoms, "optionally substituted, independently, with up to two hydroxy or methoxy, or
  • R 7 and R 8 together with the nitrogen form piperidinyl, morpholinyl, thiomorpholinyl, or a residue of the formula
  • R 37 is hydrogen, formyl, or straight -chain or branched acyl or alkoxycarbonyl each having up to three carbon atoms, or is a straight-chain or branched alkyl having up to three carbon atoms, optionally sub- stituted, independently, with one or two hydroxy, carboxyl, or straight-chain or branched alkoxy or alkoxycarbonyl, each having up to three carbon atoms, or by groups of the formula - (D) f NR 38 R 39 or -P(O) (OR 42 ) (OR 43 ) , wherein f is 0 or 1,
  • D is a group of the formula -CO
  • R 38 and R 39 are hydrogen or methyl
  • R 42 and R 43 independently are hydrogen, methyl, or ethyl, or
  • R 37 is cyclopentyl, and the heterocycles mentioned under R 3 and R 4 that are formed together with the nitrogen atom are optionally substituted, independently, with one or two, optionally geminally, hydroxy, formyl , carboxyl, and straight-chain or branched acyl or alkoxycarbonyl each having up to three carbon atoms, or a group of the formula -P(O) (OR 46 ) (OR 47 ) or - (CO) j NR 49 R 50 , wherein R 46 and R 47 , independently, are hydrogen, methyl, or ethyl, j is 0 or 1, and
  • R 49 and R so are hydrogen or methyl and/or the heterocycles mentioned under R 3 and R 4 that are formed together with the nitrogen atom are optionally substituted by straight-chain or branched with up to three carbon atoms, which is optionally substituted, independently, with one or two hydroxy, carboxyl, or a residue of the formula P(0)OR 53 OR 54 , wherein R 53 and R 54 , independently, are hydrogen, methyl, or ethyl, and/or the heterocycles mentioned under R 3 and R 4 that are formed together with the nitrogen atom are optionally substituted via N-linked piperidinyl or pyrrolidinyl, R 9 is hydrogen, and R 10 is ethoxy or propoxy, and salts, hydrates, N-oxides, and isometric forms thereof.
  • a preferred compound of structural formula (III) is 2- [2-ethoxy-5- (4-ethylpiperazin-l-yl-l- sulphonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5, 1- f] [1, 2,4] triazin-4-one, also known as l-[[3-(3,4- dihydro-5-methyl-4-oxo-7-propylimidazo [5, 1-f] -as- triazin-2-yl) -4-ethoxyphenyl] sulphonyl] -4-ethylpip- erazine and vardenafil, having a formula:
  • Still other exemplary PDE5 inhibitors useful in the present method are those disclosed in
  • PDE5 inhibitors useful in the treatment of migraine headache include, but are not limited to: • 3 -ethyl-5- [5- (4-ethylpiperazin-l- ylsulphonyl) -2-n-propoxyphenyl] -2- (pyridin-2- yl) methyl-2, 6-dihydro-7H-pyrazolo [4, 3-d]pyrimidin-7- one;
  • the most preferred PDE5 inhibitors for use ⁇ in the present invention are (a) potent, i.e., have an IC 50 value vs. PDE5 less than 10 nM, (b) selective, i.e., have a IC 50 against human recombinant PDE5 at least 100-fold less than PDE6 or PDElc, and (c) possess desirable physical and biological prop- erties, e.g., a sufficient water solubility, bio- availability, and metabolic stability, for therapeutic use in the treatment of migraine and other vascular headaches.
  • PDE5 inhibitors cause headaches as an adverse side effect. For example, 16% of the patients treated with sildenafil reported headache as an adverse side effect (vs. 4% for a placebo) . With respect to selectivity, a preferred
  • PDE5 inhibitor exhibits a PDE6/PDE5 and a PDElc/PDE5 IC S0 inhibition quotient of at least 200, and can range to 1,000 or greater.
  • the PDE6/PDE5 IC 50 inhibition quotient is the ratio of the IC 50 value of a compound vs. PDE6 to the IC 50 value of the same compound vs. PDE5.
  • the PDElc/PDE5 inhibition quotient is identically defined for PDElc and PDE5.
  • the compound has a PDE6/PDE5 and a PDElc/PDE5 IC 50 inhibition quotient of at least 100 and an IC 50 for human recombinant PDE5 of about 5 nM or less, e.g., about 0.1 to about 5 nM.
  • the PDE5 inhibitors typically are administered in the form of pharmaceutical compositions comprising a pharmaceutically acceptable excipient and at least one active ingredient.
  • These compositions can be ad- ministered by a variety of routes including oral, buccal , sublingual, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal .
  • Many of the compounds employed in the methods of this invention are effective as both injectable and oral compositions.
  • Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • the PDE5 inhibitor in making a composition employed in the present invention, usually is mixed with an excipient, diluted by an excipient, or enclosed within a carrier, which can be in the form of a capsule, sachet, paper, or other container.
  • a carrier which can be in the form of a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier, or medium for the PDE5 inhibitor.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium) , ointments containing, for example, up to 10% by weight of the PDE5 inhibitor, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the PDE5 inhibitor can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the PDE5 inhibitor is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the PDE5 inhibitor is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.
  • compositions used in the invention can be formulated to provide a rapid, sustained, or delayed release of the PDE5 inhibitor after adminis- tration to the patient by employing procedures known in the art .
  • compositions preferably are formulated in a unit dosage form.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of PDE5 inhibitor, and an optional second active agent, calculated to produce the desired therapeutic effect, and, typically, a suitable pharmaceutical excipient .
  • the PDE5 inhibitors generally are effective over a wide dosage range. However, it will be understood that the amount of the PDE5 inhibitor and optional second active agent actually administered is determined by a physician, in the light of the relevant circumstances.
  • yeast transformation vector employed which is derived from the basic ADH2 plasmid described in V. Price et al . , Methods in Enzymology, 185, pages 308-318 (1990) incorporated yeast ADH2 promoter and terminator sequences rather than ADH1 promoter and terminator sequences and the Saccharomyces cerevisiae host was the pro- tease-deficient strain BJ2-54 deposited on August 31, 1998 with the American Type Culture Collection, Manassas, Virginia, under accession number ATCC 74465.
  • Transformed host cells were grown in 2X SC- leu medium, pH 6.2, with trace metals, and vitamins. After 24 hours, YEP medium containing glycerol was added to a final concentration of 2X YEP/3% glycerol. Approximately 24 hours later, cells were harvested, washed, and stored at -70°C.
  • Cell pellets (29 g) were thawed on ice with an equal volume of lysis buffer (25 mM Tris-Cl, pH 8, 5 mM MgCl 2 , 0.25 mM dithiothreitol, 1 mM benzamidine, and 10 ⁇ M ZnS0 4 ) .
  • lysis buffer 25 mM Tris-Cl, pH 8, 5 mM MgCl 2 , 0.25 mM dithiothreitol, 1 mM benzamidine, and 10 ⁇ M ZnS0 4 .
  • Cells were lysed in a microfluidizer with N 2 at 20,000 psi .
  • the lysate was centrifuged and filtered through 0.45 ⁇ U disposable filters.
  • the filtrate was applied to a 150 ml column of Q Sepharose Fast Flow (Pharmacia) .
  • the column was washed with 1.5 volumes of Buffer A (20 mM Bis-Tris Propane, pH 6.8, 1 mM MgCl 2 , 0.25 mM dithiothreitol, 10 ⁇ M. ZnS0 4 ) and eluted with a step gradient of 125 mM NaCl in Buffer A followed by a linear gradient of 125-1000 mM NaCl in Buffer A.
  • Buffer A (20 mM Bis-Tris Propane, pH 6.8, 1 mM MgCl 2 , 0.25 mM dithiothreitol, 10 ⁇ M. ZnS0 4 .
  • Active fractions from the linear gradient were applied to a 180 ml hydroxylapatite column in Buffer B (20 mM Bis-Tris Propane (pH 6.8), 1 mM MgCl 2 , 0.25 mM dithiothreitol, 10 ⁇ M. ZnS0 4 , and 250 mM KC1) . After loading, the column was washed with 2 volumes of Buffer B and eluted with a linear gradient of 0-125 mM potassium phosphate in Buffer B.
  • Active fractions were pooled, precipitated with 60% ammonium sulfate, and resuspended in Buffer C (20 mM Bis-Tris Propane, pH 6.8, 125 mM NaCl, 0.5 mM dithiothreitol, and 10 ⁇ M ZnSO .
  • Buffer C 20 mM Bis-Tris Propane, pH 6.8, 125 mM NaCl, 0.5 mM dithiothreitol, and 10 ⁇ M ZnSO .
  • the pool was applied to a 140 ml column of Sephacryl S-300 HR and eluted with Buffer C. Active fractions were diluted to 50% glycerol and stored at -20°C. The resultant preparations were about 85% pure by SDS-PAGE.
  • Activity of PDE5 can be measured by standard assays in the art. For example, specific activity of any PDE can be determined as follows. PDE assays utilizing a charcoal separation technique are performed essentially as described in Loughney, et al., J. Biol . Chem. , 271 , pages 796-806 (1996). In this assay, PDE5 activity converts [ 32 P] cGMP to [ 32 P] 5 ' GMP in proportion to the amount of PDE5 activity present. The [ 32 P]5'GMP is then quantitatively converted to free [ 32 P] phosphate and un- labeled adenosine by the action of snake venom 5 ' - nucleotidase .
  • the amount of [ 32 P] phosphate liberated is proportional to enzyme activity.
  • the assay is performed at 30°C in a 100 ⁇ L reaction mixture containing (final concentrations) 40 mM Tris-Cl (pH 8.0), 1 ⁇ M ZnS0 4 , 5 mM MgCl 2 , and 0.1 mg/ l bovine serum albumin.
  • PDE5 is present in quantities that yield ⁇ 30% total hydrolysis of substrate (linear assay conditions) .
  • the assay is initiated by addition of substrate (1 mM [ 32 P] cGMP) , and the mixture is incubated for twelve minutes.
  • the first of the assays is performed in a total volume of 200 ⁇ l containing 50 mM Tris pH 7.5 , 3 mM Mg acetate, 1 mM EGTA, 50 /ig/ml snake venom nucleotidase and 50 nM [ 3 H] -cGMP (Amer- sham) .
  • Compounds of the invention are dissolved in DMSO finally present at 2% in the assay.
  • the assays are incubated for 30 minutes at 30°C and stopped by addition of 800 l of 10 mM Tris pH 7.5, 10 mM EDTA, 10 mM theophylline, 0.1 mM adenosine, and 0.1 mM guanosine.
  • the mixtures are loaded on 0.5 ml QAE Sephadex columns, and eluted by 2 ml of 0.1 M formate (pH 7.4).
  • the eluted radioactivity is measured by scintillation counting in Optiphase Hisafe 3.
  • a second, microplate PDE assay uses Multiscreen plates and a vacuum manifold.
  • the assay (100 ⁇ l ) contains 50 mM Tris pH 7.5, 5 mM Mg acetate, 1 mM EGTA and 250 /ig/ml snake venom nucleotidase.
  • the other components of the reaction mixture are as described above.
  • the total volume of the assay is loaded on a QAE Sephadex microcolumn plate by filtration. Free radioactivity is eluted with 200 ⁇ l of water from which 50 ⁇ l aliquots are analyzed by scintillation counting as described above.
  • test compound was injected intravenously (i.v.) at a dosing volume of 1 mL/kg or, in the alterna- tive, test compound was administered orally (p.o.) via gavage at a volume of 2 mL/kg.
  • a 50 mg/kg dose of Evans Blue a fluorescent dye, also was injected intravenously.
  • the Evans Blue complexed with pro- teins in the blood and functioned as a marker for protein extravasation.
  • the left trigeminal ganglion was stimulated for 3 minutes at a current intensity of 1.0 A (5 Hz, 4 msec duration) with a Model 273 potentiostat/galvanostat (EG&G Princeton Applied Research) .
  • the animals were killed and exsanguinated with 40 mL of saline.
  • the top of the skull was removed to facilitate the collection of the dural membranes.
  • the membrane samples were removed from both hemispheres, rinsed with water, and spread flat on microscopic slides. Once dried, the tissues were cover-slipped with a 70% glycerol/water solution.
  • a fluorescence microscope (Zeiss) equipped with a grating monochromator and a spectro- photometer was used to quantify the amount of Evans Blue dye in each sample.
  • An excitation wavelength of approximately 535 n was utilized and the emission intensity at 600 nm was determined.
  • the microscope was equipped with a motorized stage and also interfaced with a personal computer. This facili- tated the computer-controlled movement of the stage with fluorescence measurements at 25 points (500 mm steps) on each dural sample. The mean and standard deviation of the measurements were determined by the computer .
  • the extravasation induced by the electrical stimulation of the trigeminal ganglion was an ipsilateral effect (i.e., occurs only on the side of the dura in which the trigeminal ganglion was stimulated) . This allows the other (unstimulated) half of the dura to be used as a control.
  • Compound (lie) was tested in rats using the dural extravasation model described above. Compound (lie) has an IC 50 versus human recombinant PDE5 of 2.4 nM. The minimum selectivity of compound (He) for PDE5 vs. PDEs 1-4 and 7-10 is 2800-fold.
  • An intravenous 20 mg/kg dose of compound (lie) in rats provides a total plasma level of about 1500 ng/mL of compound (lie) with a half-life (t 12 ) of 3.8 hours. This corresponds to a free concentration of compound (lie) of about 375 nM at maximum concentration (C raax ) . This amount of compound (lie) inhibits of PDE5, but does not inhibit PDEs 1-4 and 7- 10.
  • rat plasma protein extrav- asation (PPE) model for migraine compound (lie) was administered intravenously.
  • a extravasation ratio of about one indicates a complete inhibition of extravasation.
  • a dose of 0.3 ng/kg of compound (lie) exhibited an extravasation ratio of about 2, wherein a control sample (i.e.,. vehicle only) exhibited an extravasa- tion ratio of about 1.8.
  • a control compound, naratriptan inhibits PPE at 0.1 ng/kg in an identical test.
  • This example illustrates that administration of a PDE5 inhibitor is an effective treatment for migraine.
  • the subject required permanent medication during the migraine attacks, in particular a sumatriptan-containing medication.
  • the patient also suffered from mild diabetes and erectile dysfunction.
  • the patient
  • VIAGRA active ingredient is sildenafil
  • Exemplary formulations for use in the method of the invention include, but are not limited to the following:
  • the active ingredient was sieved and blended with the excipients.
  • the resultant mix was compressed into tablets .
  • the polyvinylpyrrolidone, polyethylene glycol, and polysorbate 80 were dissolved in water. The resultant solution was used to granulate the active ingredient. After drying, the granules were screened then extruded at elevated temperatures and pressures. The extrudate was milled and/or screened, then was blended with the microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. The resultant mix was compressed into tablets. Tablets of other strengths may be prepared by altering the ratio of active ingredient to the other excipients.
  • t Opadry white is a proprietary material obtainable from Colorcon Limited, UK, which contains hydroxy- propyl methylcellulose, titanium dioxide, and tri- acetin.
  • the tablets were film coated using the coating suspension in conventional film coating equipment .
  • the active ingredient was sieved and blended with the excipients.
  • the mix was filled into size No. 1 hard gelatin capsules using suitable equipment .

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Abstract

L'invention concerne un procédé de traitement de la migraine au moyen d'un inhibiteur PDE5, seul ou en combinaison avec un second inhibiteur PDE5 et/ou d'autres agents antimigraineux.
PCT/US2001/026740 2000-08-30 2001-08-27 Procede de traitement de la migraine Ceased WO2002019213A2 (fr)

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EP01966306A EP1313478A2 (fr) 2000-08-30 2001-08-27 Traitement de la migraine par des inhibiteurs de pde5
AU2001286832A AU2001286832A1 (en) 2000-08-30 2001-08-27 Method for treatment of migraine using PDE5 inhibitors
CA002419623A CA2419623A1 (fr) 2000-08-30 2001-08-27 Procede de traitement de la migraine
JP2002523251A JP2004507514A (ja) 2000-08-30 2001-08-27 片頭痛の治療法
BR0113644-5A BR0113644A (pt) 2000-08-30 2001-08-27 Usos do inibidor de pde5 no tratamento de enxaqueca
MXPA03001717A MXPA03001717A (es) 2000-08-30 2001-08-27 METODO PARA EL TRATAMIENTO DE LA MIGRAnA.

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WO2004016259A1 (fr) * 2002-08-15 2004-02-26 Pfizer Limited Combinaison synergique d'un ligand alpha-2-delta et d'un inhibiteur de pdev destinee a traiter la douleur
EP1733728A3 (fr) * 2001-07-23 2007-03-21 Bayer HealthCare AG Utilisation d'imidazotriazinones 2-alcoxyphenyl substituées en tant qu'inhibiteurs de la phosphodiestérase
WO2008119057A2 (fr) 2007-03-27 2008-10-02 Omeros Corporation Utilisation d'inhibiteurs pde7 dans le traitement des troubles du
WO2014018222A1 (fr) * 2012-07-27 2014-01-30 Wellesley Pharmaceuticals, Llc Formulation pharmaceutique pour réduire la fréquence de miction et son procédé d'utilisation
US8703184B2 (en) 2010-07-08 2014-04-22 Wellesley Pharmaceuticals, Llc Delayed-release formulation for reducing the frequency of urination and method of use thereof
EP2756756A1 (fr) 2008-04-28 2014-07-23 Zogenix, Inc. Compositions inédites destinées au traitement de la migraine
US9278097B2 (en) 2003-06-06 2016-03-08 Universitatsklinikum Freiburg Prophylaxis and/or treatment of portal hypertension
US9394314B2 (en) 2012-12-21 2016-07-19 Map Pharmaceuticals, Inc. 8′-hydroxy-dihydroergotamine compounds and compositions
US9415048B2 (en) 2010-07-08 2016-08-16 Wellesley Pharmaceuticals, Llc Pharmaceutical formulation for reducing frequency of urination and method of use thereof
US9532959B2 (en) 2010-07-08 2017-01-03 Wellesley Pharmaceuticals, Llc Pharmaceutical formulation for reducing frequency of urination and method of use thereof
US9833451B2 (en) 2007-02-11 2017-12-05 Map Pharmaceuticals, Inc. Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile
US10010514B2 (en) 2010-07-08 2018-07-03 Wellesley Pharmaceuticals, Llc Pharmaceutical formulation for reducing frequency of urination and method of use thereof
US10105330B2 (en) 2012-01-04 2018-10-23 Wellesley Pharmaceuticals, Llc Extended, delayed and immediate release formulation method of manufacturing and use thereof
US10105328B2 (en) 2014-06-06 2018-10-23 Wellesley Pharmaceuticals, Llc Composition for reducing frequency of urination, method of making and use thereof
US10278925B2 (en) 2012-01-04 2019-05-07 Wellesley Pharmaceuticals, Llc Delayed-release formulations, methods of making and use thereof
US10792326B2 (en) 2013-06-28 2020-10-06 Wellesley Pharmaceuticals, Llc Pharmaceutical formulation for bedwetting and method of use thereof
US10799554B2 (en) 2010-07-08 2020-10-13 Wellesley Pharmaceuticals, Llc Pharmaceutical formulation for bedwetting and method of use thereof

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US20130040971A1 (en) * 2011-02-14 2013-02-14 Boehringer Ingelheim International Gmbh 6-cycloalkyl-pyrazolopyrimidinones for the treatment of cns disorders
JP2017114764A (ja) * 2014-04-25 2017-06-29 武田薬品工業株式会社 片頭痛治療剤

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Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1733728A3 (fr) * 2001-07-23 2007-03-21 Bayer HealthCare AG Utilisation d'imidazotriazinones 2-alcoxyphenyl substituées en tant qu'inhibiteurs de la phosphodiestérase
WO2004016259A1 (fr) * 2002-08-15 2004-02-26 Pfizer Limited Combinaison synergique d'un ligand alpha-2-delta et d'un inhibiteur de pdev destinee a traiter la douleur
EA007504B1 (ru) * 2002-08-15 2006-10-27 Пфайзер Инк. Синергическая комбинация лиганда альфа-2-дельта и ингибитора pde5 для применения при лечении боли
US9278097B2 (en) 2003-06-06 2016-03-08 Universitatsklinikum Freiburg Prophylaxis and/or treatment of portal hypertension
US10172853B2 (en) 2007-02-11 2019-01-08 Map Pharmaceuticals, Inc. Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile
US9833451B2 (en) 2007-02-11 2017-12-05 Map Pharmaceuticals, Inc. Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile
WO2008119057A2 (fr) 2007-03-27 2008-10-02 Omeros Corporation Utilisation d'inhibiteurs pde7 dans le traitement des troubles du
EP2756756A1 (fr) 2008-04-28 2014-07-23 Zogenix, Inc. Compositions inédites destinées au traitement de la migraine
EP2829265A2 (fr) 2008-04-28 2015-01-28 Zogenix, Inc. Compositions inédites destinées au traitement de la migraine
EP3000462A1 (fr) 2008-04-28 2016-03-30 Zogenix, Inc. Compositions inédites destinées au traitement de la migraine
US9532959B2 (en) 2010-07-08 2017-01-03 Wellesley Pharmaceuticals, Llc Pharmaceutical formulation for reducing frequency of urination and method of use thereof
US10799554B2 (en) 2010-07-08 2020-10-13 Wellesley Pharmaceuticals, Llc Pharmaceutical formulation for bedwetting and method of use thereof
US8703184B2 (en) 2010-07-08 2014-04-22 Wellesley Pharmaceuticals, Llc Delayed-release formulation for reducing the frequency of urination and method of use thereof
US9415048B2 (en) 2010-07-08 2016-08-16 Wellesley Pharmaceuticals, Llc Pharmaceutical formulation for reducing frequency of urination and method of use thereof
US10010514B2 (en) 2010-07-08 2018-07-03 Wellesley Pharmaceuticals, Llc Pharmaceutical formulation for reducing frequency of urination and method of use thereof
US10278925B2 (en) 2012-01-04 2019-05-07 Wellesley Pharmaceuticals, Llc Delayed-release formulations, methods of making and use thereof
US10105330B2 (en) 2012-01-04 2018-10-23 Wellesley Pharmaceuticals, Llc Extended, delayed and immediate release formulation method of manufacturing and use thereof
US10792261B2 (en) 2012-01-04 2020-10-06 Wellesley Pharmaceuticals, Llc Extended, delayed and immediate release formulation method of manufacturing and use thereof
AU2013293488B2 (en) * 2012-07-27 2018-05-17 David A. Dill Pharmaceutical formulation for reducing frequency of urination and method of use thereof
WO2014018222A1 (fr) * 2012-07-27 2014-01-30 Wellesley Pharmaceuticals, Llc Formulation pharmaceutique pour réduire la fréquence de miction et son procédé d'utilisation
US9394314B2 (en) 2012-12-21 2016-07-19 Map Pharmaceuticals, Inc. 8′-hydroxy-dihydroergotamine compounds and compositions
US10792326B2 (en) 2013-06-28 2020-10-06 Wellesley Pharmaceuticals, Llc Pharmaceutical formulation for bedwetting and method of use thereof
US10130596B2 (en) 2014-06-06 2018-11-20 Wellesley Pharmaceuticals, Llc Composition for reducing frequency of urination, method of making and use thereof
US10105328B2 (en) 2014-06-06 2018-10-23 Wellesley Pharmaceuticals, Llc Composition for reducing frequency of urination, method of making and use thereof

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CN1471397A (zh) 2004-01-28
JP2004507514A (ja) 2004-03-11
WO2002019213A3 (fr) 2002-10-17
AU2001286832A1 (en) 2002-03-13
EP1313478A2 (fr) 2003-05-28
MXPA03001717A (es) 2003-09-22
BR0113644A (pt) 2003-07-29

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