WO2000054773A1 - Agonistes dopaminergiques en combinaison avec des donneurs d'oxyde nitrique, compositions et methodes d'utilisation - Google Patents

Agonistes dopaminergiques en combinaison avec des donneurs d'oxyde nitrique, compositions et methodes d'utilisation Download PDF

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Publication number
WO2000054773A1
WO2000054773A1 PCT/US2000/003709 US0003709W WO0054773A1 WO 2000054773 A1 WO2000054773 A1 WO 2000054773A1 US 0003709 W US0003709 W US 0003709W WO 0054773 A1 WO0054773 A1 WO 0054773A1
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nitric oxide
composition
compound
group
arginine
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PCT/US2000/003709
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English (en)
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David S. Garvey
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Nitromed, Inc.
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Priority to AU34903/00A priority Critical patent/AU3490300A/en
Publication of WO2000054773A1 publication Critical patent/WO2000054773A1/fr

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine

Definitions

  • the present invention describes the combination of dopamine agonists and nitric oxide donors (i.e. compounds that donate, transfer or release nitric oxide, elevate endogenous levels of endothelium-derived relaxing factor, stimulate endogenous synthesis of nitric oxide or are substrates for nitric oxide synthase) and novel compositions comprising at least one dopamine agonist and at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase, and /or at least one therapeutic agent, such as a vasoactive agent, an antimetic agent, and mixtures thereof.
  • nitric oxide donors i.e. compounds that donate, transfer or release nitric oxide, elevate endogenous levels of endothelium-derived relaxing factor, stimulate endogenous synthesis of nitric oxide or are substrates for nitric oxide
  • the dopamine agonist is preferably apomorphine.
  • the present invention also provides methods for treating or preventing sexual dysfunctions in males and females, for enhancing sexual responses in males and females, and for treating or preventing neurodegenerative diseases, mitochondrial diseases, spinal cord injury, central or psychostimulant addiction, senile dementia, circulatory disorders, cardiovascular disorders, hyperprolactinaemia or myopia.
  • the compounds and /or compositions of the present invention can be provided in the form of a pharmaceutical kit.
  • Adequate sexual function is a complex interaction of hormonal events and psychosocial relationships. There are four stages to sexual response as described in the International Journal of Gynecology & Obstetrics, 51(3):265-277 (1995). The first stage of sexual response is desire. The second stage of sexual response is arousal. Both physical and emotional stimulation may lead to breast and genital vasodilation and clitoral engorgement (vasocongestion). In the female, dilation and engorgement of the blood vessels in the labia and tissue surrounding the vagina produce the "orgasmic platform," an area at the distal third of the vagina where blood becomes sequestered.
  • sexual dysfunction can include, for example, sexual pain disorders, sexual desire disorders, sexual arousal dysfunction, orgasmic dysfunction, dyspareunia, and vaginismus.
  • sexual dysfunction can be caused, for example, by pregnancy, menopause, cancer, pelvic surgery, chronic medical illness or medications.
  • Papaverine now widely used to treat impotence is generally effective in cases where the dysfunction is psychogenic or neurogenic and where severe atherosclerosis is not involved. Injection of papaverine, a smooth muscle relaxant, or phenoxybenzamine, a non-specific antagonist and hypotensive, into corpus cavernosum has been found to cause an erection sufficient for vaginal penetration, however, these treatments are not without the serious and often painful side effect of priapism.
  • prostaglandin E ⁇ (PGE j ) has been administered to the penis or by intracavernosal injection.
  • PGE j prostaglandin E ⁇
  • a major side effect frequently associated with intracorpral or transurethral delivered PGE X is penile pain and burning.
  • priapism, infection, penile corporal fibrosis, fibrotic nodules, hypotension, bruising and hematomas may occur. Swelling and ulceration of the penile skin at the site of injection have also been reported.
  • Nitric oxide has been shown to mediate a number of actions including the bactericidal and tumoricidal actions of macrophages and blood vessel relaxation of endothelial cells. NO and NO donors have also been implicated as mediators of nonvascular smooth muscle relaxation. As described herein, this effect includes the dilation of the corpus cavernosum smooth muscle, an event involved in the sexual response process in both males and females. However, the effects of dopamine agonists in combination with nitric oxide donors have not been previously investigated.
  • compositions comprising at least one dopamine agonist and at least one compound that donates, transfers or releases nitrogen monoxide as a charged species, i.e., nitrosonium (NO + ) or nitroxyl (NO-), or as the neutral species, nitric oxide (NO*), and /or stimulates endogenous production of nitric oxide or EDRF in vivo and /or is a substrate for nitric oxide synthase.
  • the present invention also provides for such compositions in a pharmaceutically acceptable carrier.
  • compositions comprising at least one dopamine agonist, at least one compound that donates, transfers or releases nitrogen monoxide as a charged species, i.e., nitrosonium (NO + ) or nitroxyl (NO-), or as the neutral species, nitric oxide (NO * ), and/or stimulates endogenous production of nitric oxide or EDRF in vivo and/or is a substrate for nitric oxide synthase, and at least one therapeutic agent.
  • the invention also provides for such compositions in a pharmaceutically acceptable carrier.
  • Yet another embodiment of the present invention provides methods for treating and /or preventing sexual dysfunctions and /or enhancing sexual responses in patients, including males and females, by administering to a patient in need thereof a therapeutically effective amount of at least one dopamine agonist and with at least one compound that donates, transfers or releases nitric oxide as a charged species, i.e., nitrosonium (NO + ) or nitroxyl (NO-), or as the neutral species, nitric oxide (NO*), and/or stimulates endogenous production of nitric oxide or EDRF in vivo and /or is a substrate for nitric oxide synthase.
  • the methods can further comprise administering a therapeutically effective amount of at least one therapeutic agent.
  • the dopamine agonist, nitric oxide donor and therapeutic agent can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.
  • the present invention also describes methods to treat neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease, mitochondrial diseases, spinal cord injuries with resultant loss of memory and sensory function and concomitant loss of muscular control, central or psychostimulant addictions, senile dementia, circulatory disorders, cardiovascular disoders, hyperprolactinaemia and myopia by administering to a patient in need thereof at least one dopamine agonist and at least one compound that donates, transfers or releases nitric oxide as a charged species or as a neutral species and /or stimulates endogenous production of nitric oxide or EDRF in vivo and/or is a substrate for nitric oxide synthase.
  • the methods may further comprise administering at least one therapeutic agent.
  • the dopamine agonist, nitric oxide donor and therapeutic agent can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.
  • “Patient” refers to animals, preferably mammals, more preferably humans.
  • Dopamine agonists refer to agents which enhance endogenous brain dopamanergic neurotransmission. Such agents include, but are not limited to, inhibitors of metabolic inactivation of dopamine as well as inhibitors of transporters involved in dopamine reuptake into nerve terminals.
  • Transdermal refers to the delivery of a compound by passage through the skin and into the blood stream.
  • Transmucosal refers to delivery of a compound by passage of the compound through the mucosal tissue and into the blood stream.
  • Transurethral or “intraurethral” refers to delivery of a drug into the urethra, such that the drug contacts and passes through the wall of the urethra and enters into the blood stream.
  • “Penetration enhancement” or “permeation enhancement” refers to an increase in the permeability of the skin or mucosal tissue to a selected pharmacologically active compound such that the rate at which the compound permeates through the skin or mucosal tissue is increased.
  • “Carriers” or “vehicles” refers to carrier materials suitable for compound administration and include any such material known in the art such as, for example, any liquid, gel, solvent, liquid diluent, solubilizer, or the like, which is non-toxic and which does not interact with any components of the composition in a deleterious manner.
  • Nitric oxide adduct or “NO adduct” refers to compounds and functional groups which, under physiological conditions, can donate, release and /or directly or indirectly transfer any of the three redox forms of nitrogen monoxide (NO + , NO " , NO*), such that the biological activity of the nitrogen monoxide species is expressed at the intended site of action.
  • Nitric oxide releasing or “nitric oxide donating” refers to methods of donating, releasing and /or directly or indirectly transferring any of the three redox forms of nitrogen monoxide (NO + , NO-, NO*), such that the biological activity of the nitrogen monoxide species is expressed at the intended site of action.
  • Nitric oxide donor or “NO donor” refers to compounds that donate, release and /or directly or indirectly transfer a nitrogen monoxide species, and /or stimulate the endogenous production of nitric oxide or endothelium-derived relaxing factor (EDRF) in vivo and /or elevate endogenous levels of nitric oxide or EDRF in vivo.
  • NO donor also includes compounds that are substrates for nitric oxide synthase.
  • Alkyl refers to a lower alkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, a bridged cycloalkyl group, a cycloalkyl group or a heterocyclic ring, as defined herein.
  • Lower alkyl refers to branched or straight chain acyclic alkyl group comprising one to about ten carbon atoms (preferably one to about eight carbon atoms, more preferably one to about six carbon atoms).
  • Exemplary lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, iso-amyl, hexyl, octyl, and the like.
  • Haloalkyl refers to a lower alkyl group, an alkenyl group, an alkynyl group, a bridged cycloalkyl group, a cycloalkyl group or a heterocyclic ring, as defined herein, to which is appended one or more halogens, as defined herein.
  • exemplary haloalkyl groups include trifluoromethyl, chloromethyl, 2- bromobutyl, l-bromo-2-chloro-pentyl, and the like.
  • alkenyl refers to a branched or straight chain C 2 -C 10 hydrocarbon (preferably a C 2 -C 8 hydrocarbon, more preferably a C 2 -C 6 hydrocarbon) which can comprise one or more carbon-carbon double bonds.
  • alkenyl groups include propylenyl, buten-1-yl, isobutenyl, penten-1-yl, 2,2-methylbuten-l-yl, 3- methylbuten-1-yl, hexan-1-yl, hepten-1-yl, octen-1-yl, and the like.
  • Alkynyl refers to an unsaturated acyclic C 2 -C 10 hydrocarbon (preferably a C 2 -C 8 hydrocarbon, more preferably a C 2 -C 6 hydrocarbon) which can comprise one or more carbon-carbon triple bonds.
  • exemplary alkynyl groups include ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyl-1-yl, pentyl-2-yl, 3-methylbutyn-l-yl, hexyl-1-yl, hexyl-2-yl, hexyl-3-yl, 3,3-dimethyl-butyn-l-yl, and the like.
  • Bridged cycloalkyl refers to two or more cycloalkyl groups, heterocyclic groups, or a combination thereof fused via adjacent or non-adjacent atoms. Bridged cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, carboxyl, alkylcarboxylic acid, aryl, amidyl, ester, alkylcarboxylic ester, carboxamido, alkylcarboxamido, oxo and nitro.
  • Exemplary bridged cycloalkyl groups include adamantyl, decahydronapthyl, quinuclidyl, 2,6- dioxabicyclo[3.3.0]octane, 7-oxabycyclo[2.2.1]heptyl, 8-azabicyclo[3,2,l]oct-2-enyl and the like.
  • Cycloalkyl refers to a saturated or unsaturated cyclic hydrocarbon comprising from about 3 to about 8 carbon atoms. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, aryl, amidyl, ester, hydroxy, halo, carboxyl, alkylcarboxylic acid, alkylcarboxylic ester, carboxamido, alkylcarboxamido, oxo and nitro.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohepta,l,3-dienyl, and the like.
  • Heterocyclic ring or group refers to a saturated, unsaturated, cyclic or aromatic or polycyclic hydrocarbon group having about 3 to about 12 carbon atoms (preferably about 4 to about 6 carbon atoms) where 1 to about 4 carbon atoms are replaced by one or more nitrogen, oxygen and /or sulfur atoms. Sulfur maybe in the thio, sulfinyl or sulfonyl oxidation state.
  • heterocyclic ring or group can be fused to an aromatic hydrocarbon group.
  • Heterocyclic groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, hydroxy, oxo, thial, halo, carboxyl, carboxylic ester, alkylcarboxylic acid, alkylcarboxylic ester, aryl, arylcarboxylic acid, arylcarboxylic ester, amidyl, ester, carboxamido, alkylcarboxamido, arylcarboxamido, sulfonic acid, sulfonic ester, sulfonamido and nitro.
  • heterocyclic groups include pyrrolyl, 3-pyrrolinyl,4,5,6-trihydro-2H-pyranyl, pyridinyl, 1,4- dihydropyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrhydrofuranyl, tetrazolyl, 2- pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, oxazolindinyl 1,3-dioxolanyl, 2,6- dioxabicyclo[3,3,0]octanyl, 2-imidazonlinyl, imidazolindinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl
  • Heterocyclic compounds refer to mono- and polycyclic compounds comprising at least one aryl or heterocyclic ring.
  • Aryl refers to a monocyclic, bicyclic, carbocyclic or heterocyclic ring system comprising one or two aromatic rings.
  • Exemplary aryl groups include phenyl, pyridyl, napthyl, quinoyl, tetrahydronaphthyl, furanyl, indanyl, indenyl, indoyl, and the like.
  • Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, hydroxy, carboxyl, carboxylic ester, alkylcarboxylic acid, alkylcarboxylic ester, aryl, arylcarboxylic acid, arylcarboxylic ester, alkylcarbonyl, arylcarbonyl, amidyl, ester, carboxamido, alkylcarboxamido, carbomyl, sulfonic acid, sulfonic ester, sulfonamido and nitro.
  • Exemplary substituted aryl groups include tetrafluorophenyl, pentafluorophenyl, sulfonamide, alkylsulfonyl, arylsulfon
  • Alkylaryl refers to an alkyl group, as defined herein, to which is appended an aryl group, as defined herein.
  • exemplary alkylaryl groups include benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl, fluorophenylethyl, and the like.
  • Arylalkyl refers to an aryl radical, as defined herein, attached to an alkyl radical, as defined herein.
  • Cycloalkylalkyl refers to a cycloalkyl radical, as defined herein, attached to an alkyl radical, as defined herein.
  • Heterocyclicalkyl refers to a heterocyclic ring radical, as defined herein, attached to an alkyl radical, as defined herein.
  • Cycloalkenyl refers to an unsaturated cyclic hydrocarbon having about 3 to about 10 carbon atoms (preferably about 3 to about 8 carbon atoms, more preferably about 3 to about 6 carbon atoms) comprising one or more carbon- carbon double bonds.
  • Arylheterocyclic ring refers to a bi- or tricyclic ring comprised of an aryl ring, as defined herein, appended via two adjacent carbon atoms of the aryl ring to a heterocyclic ring, as defined herein.
  • exemplary arylheterocyclic rings include dihydroindole, 1, 2,3,4- tetra-hydroquinoline, and the like.
  • Alkoxy refers to R 50 O-, wherein R 50 is an alkyl group, as defined herein.
  • exemplary alkoxy groups include methoxy, ethoxy, t-butoxy, cyclopentyloxy, and the like.
  • Arylalkoxy or alkoxyaryl refers to an alkoxy group, as defined herein, to which is appended an aryl group, as defined herein.
  • exemplary arylalkoxy groups include benzyloxy, phenylethoxy, chlorophenylethoxy, and the like.
  • Alkoxyalkyl refers to an alkoxy group, as defined herein, appended to an alkyl group, as defined herein.
  • exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, isopropoxymethyl, and the like.
  • Alkoxyhaloalkyl refers to an alkoxy group, as defined herein, appended to a haloalkyl group, as defined herein.
  • exemplary alkoxyhaloalkyl groups include 4- methoxy-2-chlorobutyl and the like.
  • Cycloalkoxy refers to R 54 0-, wherein R 54 is a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • exemplary cycloalkoxy groups include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Haloalkoxy refers to a haloalkyl group, as defined herein, to which is appended an alkoxy group, as defined herein.
  • exemplary haloalkyl groups include 1,1,1-trichloroethoxy, 2-bromobutoxy, and the like.
  • Hydroxy refers to -OH.
  • Oxy refers to -O " R 77 + wherein R 77 is an organic or inorganic cation.
  • Organic cation refers to a positively charged organic ion.
  • exemplary organic cations include alkyl substituted ammonium cations, and the like.
  • Inorganic cation refers to a positively charged metal ion.
  • Exemplary inorganic cations include metal cations such as for example, sodium, potassium, calcium, and the like.
  • Hydroalkyl refers to a hydroxy group, as defined herein, appended to an alkyl group, as defined herein.
  • Amino refers to -NH 2 .
  • Nirate refers to -0-N0 2 .
  • Nirite refers to -O-NO.
  • Thionitrate refers to -S-N0 2 .
  • Niro refers to the group -N0 2 and “nitrosated” refers to compounds that have been substituted therewith.
  • Niroso refers to the group -NO and “nitrosylated” refers to compounds that have been substituted therewith.
  • Halogen or “halo” refers to iodine (I), bromine (Br), chlorine (Cl), and /or fluorine (F).
  • Alkylamino refers to R 50 NH-, wherein R 50 is an alkyl group, as defined herein.
  • exemplary alkylamino groups include methylamino, ethylamino, butylamino, cyclohexylamino, and the like.
  • Arylamino refers to R 55 NH-, wherein R 55 is an aryl group, as defined herein.
  • Dialkylamino refers to R 50 R 52 N-, wherein R 50 and R 52 are each independently an alkyl group, as defined herein.
  • Exemplary dialkylamino groups include dimethylamino, diethylamino, methyl propargylamino, and the like.
  • Diarylamino refers to R 55 R 60 N-, wherein R 55 and R 60 are each independently an aryl group, as defined herein.
  • Alkylarylamino refers to R 50 R 55 N-, wherein R 50 is an alkyl group, as defined herein, and R 55 is an aryl group, as defined herein.
  • Aminoalkyl refers to an amino group, an alkylamino group, a dialkylamino group, an arylamino group, a diarylamino group, an alkylarylamino group or a heterocyclic ring, as defined herein, to which is appended an alkyl group, as defined herein.
  • Aminoaryl refers to an amino group, an alkylamino group, a dialkylamino group, an arylamino group, a diarylamino group, an alkylarylamino group or a heterocyclic ring, as defined herein, to which is appended an aryl group, as defined herein.
  • Method refers to -C(S)-.
  • Sulfonic acid refers to -S(0) 2 0R 76 , wherein R 76 is a hydrogen, an organic cation or an inorganic cation.
  • Alkylsulfonic acid refers to a sulfonic acid group, as defined herein, appended to an alkyl group, as defined herein.
  • Arylsulfonic acid refers to an sulfonic acid group, as defined herein, appended to an aryl group, as defined herein
  • “Sulfonic ester” refers to -S(0) 2 0R 58 , wherein R 58 is an alkyl group, an aryl group, an alkylaryl group or an aryl heterocyclic ring, as defined herein.
  • “Sulfonamido” refers to -S(0) 2 -N(R 51 )(R 57 ), wherein R 51 and R 57 are each independently a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group, or an arylheterocyclic ring, as defined herein, and R 51 and R 57 when taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • “Alkylsulfonamido” refers to a sulfonamido group, as defined herein, appended to an alkyl group, as defined herein.
  • Arylsulfonamido refers to a sulfonamido group, as defined herein, appended to an aryl group, as defined herein.
  • Alkylthio refers to R 50 S-, wherein R 50 is an alkyl group, as defined herein.
  • Arylthio refers to R S5 S-, wherein R 55 is an aryl group, as defined herein.
  • Cycloalkylthio refers to R 54 S-, wherein R 54 is a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • exemplary cycloalkylthio groups include cyclopropylthio, cyclopentylthio, cyclohexylthio, and the like.
  • Alkylsulfinyl refers to R 50 -S(O)-, wherein R 50 is an alkyl group, as defined herein.
  • Alkylsulfonyl refers to R 50 -S(O) 2 -, wherein R so is an alkyl group, as defined herein.
  • Arylsulfinyl refers to R 55 -S(0)-, wherein R 55 is an aryl group, as defined herein.
  • Arylsulfonyl refers to R 55 -S(0) 2 -, wherein R 55 is an aryl group, as defined herein.
  • “Amidyl” refers to R 51 C(0)N(R 57 )- wherein R 51 and R 57 are each independently a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group, or an arylheterocyclic ring, as defined herein.
  • Ester refers to R 51 C(0)0- wherein R 51 is a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group, or an arylheterocyclic ring, as defined herein.
  • Carbamoyl refers to -0-C(0)N(R 51 )(R 57 ), wherein R 51 and R 57 are each independently a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group or an arylheterocyclic ring, as defined herein, or R 51 and R 57 taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • “Carbamate” refers to R 51 0-C(0)N(R 57 ), wherein R 51 and R 57 are each independently a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group or an arylheterocyclic ring, as defined herein, or R 51 and R 57 taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • “Carboxyl” refers to -C(0)0R 76 , wherein R 76 is a hydrogen, an organic cation or an inorganic cation, as defined herein.
  • Carbonyl refers to -C(O)-.
  • Alkylcarbonyl or “alkanoyl” refers to R 50 -C(O)-, wherein R 50 is an alkyl group, as defined herein.
  • Arylcarbonyl or “aroyl” refers to R 55 -C(0)-, wherein R 55 is an aryl group, as defined herein.
  • Carboxylic ester refers to -C(0)0R 58 , wherein R 58 is an alkyl group, an aryl group, an alkylaryl group or an aryl heterocyclic ring, as defined herein.
  • Alkylcarboxylic acid and “alkylcarboxyl” refer to an alkyl group, as defined herein, appended to a carboxyl group, as defined herein.
  • Alkylcarboxylic ester refers to an alkyl group, as defined herein, appended to a carboxylic ester group, as defined herein.
  • Arylcarboxylic acid refers to an aryl group, as defined herein, appended to a carboxyl group, as defined herein.
  • Arylcarboxylic ester and “arylcarboxyl” refer to an aryl group, as defined herein, appended to a carboxylic ester group, as defined herein.
  • Carboxamido refers to -C(0)N(R 51 )(R 57 ), wherein R 51 and R 57 are each independently a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group or an arylheterocyclic ring, as defined herein, and R 51 and R 57 when taken together with the nitrogen to which they are attached form a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • Alkylcarboxamido refers to an alkyl group, as defined herein, appended to a carboxamido group, as defined herein.
  • Arylcarboxamido refers to an aryl group, as defined herein, appended to a carboxamido group, as defined herein.
  • Rea refers to -N(R 59 )-C(0)N(R 51 )(R 57 ) wherein R 51 , R 57 , and R 59 are each independently a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group, or an arylheterocyclic ring, as defined herein, or R 51 and R 57 taken together with the nitrogen to which they are attached form a heterocyclic ring, as defined herein.
  • Phosphoryl refers to -P(R 70 )(R 71 )(R 72 ), wherein R 70 is a lone pair of electrons, sulfur or oxygen, and R 71 and R 72 are each independently a covalent bond, a hydrogen, a lower alkyl, an alkoxy, an alkylamino, a hydroxy or an aryl, as defined herein.
  • sexual dysfunction generally includes any sexual dysfunction in a patient, including an animal, preferably a mammal, more preferably a human.
  • the patient can be male or female.
  • sexual dysfunctions can include, for example, sexual desire disorders, sexual arousal disorders, orgasmic disorders and sexual pain disorders.
  • Female sexual dysfunction refers to any female sexual dysfunction including, for example, sexual desire disorders, sexual arousal dysfunctions, orgasmic dysfunctions, sexual pain disorders, dyspareunia, and vaginismus.
  • the female can be pre-menopausal or menopausal.
  • Male sexual dysfunction refers to any male sexual dysfunctions including, for example, male erectile dysfunction and impotence.
  • the present invention is directed to the treatment and /or prevention of sexual dysfunctions in patients, including males and females, by administering the compounds and/ or compositions described herein.
  • the present invention is also directed to improving and /or enhancing sexual responses in a patient, including males and females, by administering the compounds and /or compositions described herein.
  • the novel compositions and methods of the present invention are described in more detail herein.
  • the dopamine D2 receptors in the mid-brain region of a patient can be stimulated to a degree sufficient to cause sexual response by the administration of dopamine agonists.
  • Dopamine agonists or agents that enhance brain dopamanergic neurotransmission that can be used in the present invention include, for example, apomorphine, amineptine, N-n-propyl-norapomorphine, bromocriptine, p-chlorophenylalanine, p-chloromethylamphetamine, D- amphetamine, amatidine, benserazide, botiacrine, bupropion, cabergoline, carmoxirole, clozapine, desocriptine, dihydroergotamine, dihydroergocryptine, dihydroergocristine, ⁇ -dihydroergocryptine, dopexamine, dopamine, docarpamine, domperidone, eticlopride,
  • Preferred dopamine agonists for the treatment and/or prevention of sexual dysfunctions are apomorphine, N-n-propyl-norapomorphine, bromocriptine, cabergoline, lisuride, metergoline, naxagolide, pergolide, piribedil, quinagolide, ropinirole, terguride and unergol; more preferably apomorphine, N-n-propyl-norapomorphine, and bromocriptine.
  • Apomorphine a short acting dopamine mixed D1/D2 receptor agonist, is the most preferred dopamine agonist.
  • Apomorphine ((R)-5,6,6 ⁇ ,7-tetrahydro-6- methyl-4H-dibenzo-[de,g] quinoline-10,ll-diol) is represented by formula (I):
  • Apomorphine may exist as a free base or its acid salt.
  • apomorphine refers to and includes the free base form of apomorphine as well as pharmacologically acceptable acid salts thereof.
  • the preferred form is apomorphine hydrochloride, however, other pharmacologically acceptable forms can also be utilized.
  • other acceptable acid salts include, but are not limited to, hydrobromide, hydroiodide, bisulfate, phosphate, acid phosphate, lactate, citrate, tartarate, salicylate, succinate, maleate, gluconate and the like.
  • the present invention also encompasses the use of agents that are able to enhance endogenous brain dopamanergic neurotransmission to a degree sufficient to cause a sexual response.
  • agents include, but are not limited to, inhibitors of metabolic inactivation of dopamine as well as inhibitors of transporters involved in dopamine reuptake into nerve terminals, serotonin receptor agonists (such as, for example, l-(2,5-dimethoxy-4-iodophenyl)-l- aminopropane, 5-methoxytryptamine, ⁇ -methyl-5-trylptamine, 2-methyl-5- hydroxytryptamine, N-acetyl-5-hydroxytryptamine, buspirone, sumatriptin and the like), oxytocinergic analogues (such as, for example, isotonic, carbetocin, lysine-conoprressin deaminooxytocin, mesotocin, antocin, glumitocin
  • Sources of information for the above compounds include Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Ed.), McGraw-Hill, Inc. (1996), The Physician's Desk Reference (49th Ed.), Medical Economics (1995), Drug Facts and Comparisons (1993 Ed), Facts and Comparisons (1993), Merck Index on CD-ROM, Twelfth Edition, Version 12:1, (1996), STN Express, file phar and file registry, the disclosures of each of which are incorporated herein by reference in their entirety.
  • a principal aspect of the present invention relates to novel compositions comprising at least one dopamine agonist, nitric oxide and /or at least one compound that donates, transfers or releases nitric oxide and /or stimulates endogenous production of nitric oxide or EDRF in vivo and /or is a substrate for nitric oxide synthase, and /or otherwise directly or indirectly deliver or transfer nitric oxide to a site of its activity, such as on a cell membrane, in vivo.
  • nitric oxide encompasses uncharged nitric oxide (NO * ) and charged nitrogen monoxide species, preferably charged nitrogen monoxide species, such as nitrosonium ion (NO + ) and nitroxyl ion (NO-).
  • NO* is a highly reactive short-lived species that is potentially toxic to cells. This is critical because the pharmacological efficacy of NO depends upon the form in which it is delivered.
  • nitrosonium (NO + ) does not react with 0 2 or 0 2 species, and functionalities capable of transferring and /or releasing NO + and NO- are also resistant to decomposition in the presence of many redox metals.
  • nitric oxide and compounds that release nitric oxide i.e., compounds that release nitric oxide or otherwise directly or indirectly deliver or transfer nitric oxide to a site of its activity, such as on a cell membrane, and /or elevate or stimulate production of endogenous nitric oxide or EDRF in vivo and /or is a substrate for nitric oxide synthase
  • nitric oxide encompasses uncharged nitric oxide (NO*) and charged nitrogen monoxide species, preferably charged nitrogen monoxide species, such as nitrosonium ion (NO + ) and nitroxyl ion (NO-).
  • the reactive form of nitric oxide can be provided by gaseous nitric oxide.
  • the nitrogen monoxide releasing, delivering or transferring compounds include any and all such compounds which provide nitrogen monoxide to its intended, site of action in a form active for its intended purpose.
  • NO adducts encompasses any nitrogen monoxide releasing, delivering or transferring compounds, including, for example, S-nitrosothiols, nitrites, nitrates, S-nitrothiols, sydnonimines, 2-hydroxy-2-nitrosohydrazines (NONOates), (E)-alkyl-2-[(E)- hydroxyimino]-5-nitro-3-hexene amines or amides, nitrosoamines, furoxans as well as substrates for the endogenous enzymes which synthesize nitric oxide.
  • the "NO adducts" can be mono-nitrosylated, poly-nitrosylated, mono-nitrosated and /or poly-nitrosated or a combination thereof at a variety of naturally susceptible or artificially provided binding sites for biologically active forms of nitrogen monoxide.
  • One group of NO adducts is the S-nitrosothiols, which are compounds that include at least one -S-NO group.
  • These compounds include S-nitroso- polypeptides (the term "polypeptide” includes proteins and polyamino acids that do not possess an ascertained biological function, and derivatives thereof); S- nitrosylated amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof); S-nitrosylated sugars; S-nitrosylated, modified and unmodified, oligonucleotides (preferably of at least 5, and more preferably 5-200 nucleotides); straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted S-nitrosylated hydrocarbons; and S-nitroso heterocyclic compounds.
  • polypeptide includes proteins and polyamino acids that do not possess an ascertained biological function, and derivatives thereof
  • S-nitrosylated amino acids including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof
  • S-nitrosylated sugars S-nitros
  • S-nitroso amino acids where the nitroso group is linked to a sulfur group of a sulfur-containing amino acid or derivative thereof.
  • Such compounds include, for example, S-nitroso-N- acetylcysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicillamine, S-nitroso- homocysteine, S-nitroso-cysteine and S-nitroso-glutathione.
  • Suitable S-nitrosylated proteins include thiol-containing proteins (where the NO group is attached to one or more sulfur groups on an amino acid or amino acid derivative thereof) from various functional classes including enzymes, such as tissue-type plasminogen activator (TPA) and cathepsin B; transport proteins, such as lipoproteins; heme proteins, such as hemoglobin and serum albumin; and biologically protective proteins, such as immunoglobulins, antibodies and cytokines.
  • TPA tissue-type plasminogen activator
  • cathepsin B transport proteins, such as lipoproteins; heme proteins, such as hemoglobin and serum albumin; and biologically protective proteins, such as immunoglobulins, antibodies and cytokines.
  • nitrosylated proteins are described in WO 93/09806, the disclosure of which is incorporated by reference herein in its entirety. Examples include polynitrosylated albumin where one or more thiol or other nucleophilic centers in the protein are modified.
  • S-nitrosothiols include:
  • R e and R f are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, a cycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, a sulfonic ester, an alkylsulf
  • R e and R f are a heterocyclic ring or R e and R f when taken together with the carbon atoms to which they are attached are a heterocyclic ring, then R; can be a substituent on any disubstituted nitrogen contained within the radical wherein R ; is as defined herein.
  • Nitrosothiols can be prepared by various methods of synthesis. In general, the thiol precursor is prepared first, then converted to the S-nitrosothiol derivative by nitrosation of the thiol group with NaN0 2 under acidic conditions (pH is about 2.5) which yields the S-nitroso derivative. Acids which can be used for this purpose include aqueous sulfuric, acetic and hydrochloric acids.
  • the thiol precursor can also be nitrosylated by reaction with an organic nitrite such as tert-butyl nitrite, or a nitrosonium salt such as nitrosonium tetraflurorborate in an inert solvent.
  • NO adduct is a compound that donates, transfers or releases nitric oxide, include compounds comprising at least one ON-O-, ON-N- or ON-C- group.
  • the compounds that include at least one ON-O-, ON-N- or ON-C- group are preferably ON-O-, ON-N- or ON-C-polypeptides (the term "polypeptide” includes proteins and polyamino acids that do not possess an ascertained biological function, and derivatives thereof); ON-O, ON-N- or ON-C-amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures); ON-O-, ON-N- or ON-C-sugars; ON-O-, ON-N- or ON-C- modified or unmodified oligonucleotides (comprising at least 5 nucleotides, preferably 5-200 nucleotides); ON-O-, ON-N- or ON-C- straight or branched, saturated or unsatur
  • NO adducts for use in the present invention include nitrates that donate, transfer or release nitric oxide, such as compounds comprising at least one 0 2 N-0-, 0 2 N-N-, 0 2 N-S- or 0 2 N-C- group.
  • Preferred among these compounds are 0 2 N-0-, 0 2 N-N-, 0 2 N-S- or 0 2 N-C- polypeptides (the term "polypeptide” includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof); 0 2 N-0-, 0 2 N-N-, 0 2 N-S- or 0 2 N-C- amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures); 0 2 N-0-, 0 2 N-N-, 0 2 N-S- or 0 2 N-C-sugars; 0 2 N-0-, 0 2 N-N-, 0 2 N-S- or 0 2 N-C- modified and unmodified oligonucleotides (comprising at least 5 nucleotides, preferably 5-200 nucleotides); 0 2 N-0-, 0 2 N-N-, 0 2 N-S- or 0 2 N
  • Preferred examples of compounds comprising at least one 0 2 N-0-, 0 2 N-N-, 0 2 N-S- or 0 2 N- C- group include isosorbide dinitrate, isosorbide mononitrate, clonitrate, erythrityltetranitrate, mannitol hexanitrate, nitroglycerin, pentaerythritoltetranitrate, pentrinitrol and propatylnitrate.
  • R 1 R 2 -N(0- M + )-NO Another group of NO adducts are N-oxo-N-nitrosoamines that donate, transfer or release nitric oxide and are represented by the formula: R 1 R 2 -N(0- M + )-NO, where R 1 and R 2 are each independently a polypeptide, an amino acid, a sugar, a modified or unmodified oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group, and M + is as defined herein.
  • R 1 -(S)-N0 2 Another group of NO adducts are thionitrates that donate, transfer or release nitric oxide and are represented by the formula: R 1 -(S)-N0 2 , where R 1 is a polypeptide, an amino acid, a sugar, a modified or unmodified oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group.
  • R 1 is a polypeptide or hydrocarbon with a pair or pairs of thiols that are sufficiently structurally proximate, i.e., vicinal, that the pair of thiols will be reduced to a disulfide.
  • Compounds which form disulfide species release nitroxyl ion (NO-) and uncharged nitric oxide (NO * ).
  • the present invention is also directed to compounds that stimulate endogenous NO or elevate levels of endogenous endothelium-derived relaxing factor (EDRF) in vivo or are substrates for the enzyme, nitric oxide synthase.
  • Such compounds include, for example, L-arginine, L-homoarginine, and N- hydroxy-L-arginine, including their nitrosated and nitrosylated analogs (e.g., nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, nitrosated L-homoarginine and nitrosylated L-homoarginine), precursors of L-arginine and/or physiologically acceptable salts thereof, including, for example, citrulline, ornithine, glutamine, lysine, polypeptides comprising at least one of these amino acids, inhibitors of the enzyme arginase
  • EDRF is a vascular relaxing factor secreted by the endothelium, and has been identified as nitric oxide (NO) or a closely related derivative thereof (Palmer et al, Nature, 327:524-526 (1987); Ignarro et al, Proc. Natl. Acad. Sci. USA, 84:9265-9269 (1987)).
  • NO nitric oxide
  • the present invention is also based on the discovery that the administration of at least one dopamine agonist, at least one therapeutic agent and at least one nitric oxide donor described herein, are effective for treating or preventing sexual dysfunctions or enhancing sexual responses in patients, including males and females.
  • the therapeutic agents of the present invention include, but are not limited to vasoactive agents and antiemetic agents.
  • the patient can be administered a therapeutically effective amount of at least dopamine agonist, and at least one compound that donates, transfers or releases nitric oxide, or elevates levels of endogenous EDRF or nitric oxide, or is a substrate for nitric oxide synthase.
  • the patient can be administered a therapeutically effective amount of at least one dopamine agonist, and at least one therapeutic agent, and, optionally, at least one compound that donates, transfers or releases nitric oxide, or elevates levels of endogenous EDRF or nitric oxide, or is a substrate for nitric oxide synthase.
  • the compounds can be administered separately or as components of the same composition.
  • vasoactive agent is any therapeutic agent capable of relaxing vascular smooth muscle.
  • Suitable vasoactive agents include, but are not limited to, potassium channel activators (such as, for example, nicorandil, pinacidil, cromakalim, minoxidil, aprilkalim, loprazolam and the like); calcium channel blockers (such as, for example, nifedipine, verastrial, diltiazem, gallopamil, niludipine, nimodipins, nicardipine, and the like); ⁇ -blockers (such as, for example, butixamine, dichloroisoproterenol, propanolol, alprenolol, bunolol, nadolol, oxprenolol, perbutolol, pinodolol, sotalol, timolol, metoprolol, atenolol, acebutolo
  • prostaglandins such as, for example, carboprost tromethamine, dinoprost tromethamine, dinoprostone, gemeprost, metenoprost, sulprostone, triprost, isoprostanes, and the like
  • opioid antagonists such as, for example, naltrexone, naloxone, and the like
  • endothelin antagonists such as, for example, bosentan, sulfonamide endothelin antagonists, BQ-123, SQ 28608, and the like
  • dopamine agonist such as, for example, apomorphine, N-n-propyl-norapomorphine or bromocriptine
  • nitric oxide donor such as L-arginine
  • apomorphine and NO donors with the ⁇ -blockers, phentolamine or yohimbine.
  • the apomorphine is preferably in the form of apomorphine hydrochloride.
  • the NO donor is preferably L-arginine in the form of L-arginine glutamate or a combination of L-arginine free base and L-glutamic acid.
  • Phentolamine is preferably in the form of phentolamine hydrochloride or phentolamine mesylate, more preferably phentolamine mesylate.
  • Yohimbine is preferably in the form of yohimbine hydrochloride, yohimbine tartarate, yohimbe bark powder or yohimbe bark extract, more preferably yohimbine hydrochloride or yohimbine tartarate.
  • Antiemetic agent is any agent capable of controlling and /or preventing nausea and vomiting.
  • Antiemetic agents include, but are not limited to, antidopaminergic agents (such as, for example, metoclopramide, phenothiazines, such as, for example chlorpromazine, prochlorperazine, pipamazine, thiethylperazine, oxypendyl hydrochloride, and the like), serotonin or 5- hydroxytryp famine antagonists (such as, for example, domperidone, odansteron (ZOFRAN®), and the like), histamine antagonists (such as, for example, buclizine hydrochloride, cyclizine hydrochloride, dimenhydrinate, and the like), parasympathetic depressants (such as, for example, scopolamine, and the like), metopimazine, trimethobenzamide, benzquinamine hydrochloride, diphenidol hydrochloride
  • Patent Nos. 5,562,917, 5,624,677, 5,770,606, 5,773,020, 5,888,534, 5,939,094, 5,945,117, 5,994,363, 5,985,889 and WO 98/31368, WO 99/38467 and WO 99/62502 describe the treatment of sexual impotence in humans by administering apomorphine;
  • U. S. Patent Nos. 6,011,043, 6,001,845 and WO 99/65475 describe methods for treating sexual dysfunction using a combination of apomorphine and phentolamine.
  • the disclosure of each of these patents, applications and publications is incorporated by reference herein in their entirety.
  • Another embodiment of the present invention provides methods to treat neurodegenerative diseases (such as, for example, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and the like) (U.S. Patent No. 4,970,200; Merello et al, Mov. Disord., 14(l):45-49 (1999)); mitochondrial diseases (such as, for example, Kearns-Sayre Syndrome, Merff
  • Neurol, 28 (suppl, l):15-23 (1988)); circulatory disorders; cardiovascular disorders (such as, for example, acute and chronic congestive heart failure, chronic cerebrovascular disease, and the like); hyperprolactinaemia (such as, for example, prolactin release inhibitors, lactation suppressant agents, and the like) (Muller et al, Drugs, 25(4):399-432 (1983) and myopia (Czepita, Klin Oczna., 101(2):145-147 (1999)) by administering to a patient in need thereof a therapeutically effective amount of the compounds and/or compositions described herein.
  • cardiovascular disorders such as, for example, acute and chronic congestive heart failure, chronic cerebrovascular disease, and the like
  • hyperprolactinaemia such as, for example, prolactin release inhibitors, lactation suppressant agents, and the like
  • myopia Czepita, Klin Oczna., 101(2):145-147 (1999)
  • These methods may further comprise administering at least one therapeutic agent, preferably a vasoactive agent, such as an ergot alkaloid, as described herein.
  • a therapeutic agent preferably a vasoactive agent, such as an ergot alkaloid
  • the patient can be administered a therapeutically effective amount of at least one dopamine agonist and at least one compound that donates, transfers or releases nitric oxide, or elevates levels of endogenous EDRF or nitric oxide or is a substrate for nitric oxide synthase.
  • the patient can be administered a therapeutically effective amount of at least one dopamine agonist, at least one therapeutic agent, and at least one compound that donates, transfers or releases nitric oxide, or elevates levels of endogenous EDRF or nitric oxide, or is a substrate for nitric oxide synthase.
  • the dopamine agonists, nitric oxide donors and /or therapeutic agents can be administered separately or in the form of a composition.
  • the compounds and compositions of the present invention can also be administered in combination with other medications used for the treatment of these disorders.
  • compositions of the present invention When administered in vivo, the compositions of the present invention may be administered with pharmaceutically acceptable carriers and in dosages described herein.
  • the compositions of the present invention When administered as a mixture of at least one dopamine agonist and at least one nitric oxide donor, they can also be used in combination with one or more additional compounds (e.g., therapeutic agents).
  • additional compounds e.g., therapeutic agents.
  • the nitric oxide donor (s) and /or therapeutic agent can be administered simultaneously with, subsequently to, or prior to administration of the dopamine agonist(s) and /or other additional compound(s) to prevent or treat the diseases described herein.
  • the compounds and compositions of the present invention can be administered by any available and effective delivery system including, but not limited to, orally, bucally, parenterally, by inhalation spray, by topical application, by injection into the corpus cavernosum tissue, by transurethral drug delivery, transdermally, vaginally, or rectally (e.g., by the use of suppositories) in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles, as desired.
  • Parenteral includes subcutaneous injections, intravenous injections, intramuscular injections, intrasternal injections, and infusion techniques. Parenteral also includes injection into the corpus cavernosum tissue, which can be conducted using any effective injection system including, but not limited to, conventional syringe-and-needle systems or needleless injection devices.
  • Transdermal drug administration involves the delivery of pharmaceutical agents via percutaneous passage of the drug into the systemic circulation of the patient.
  • Topical administration which is well known to one skilled in the art, involves the delivery of pharmaceutical agents via percutaneous passage of the drug into the systemic circulation of the patient.
  • Topical administration includes vaginal administration, vulval administration, penile administration and rectal administration.
  • Topical administration can also involve transdermal patches or iontophoresis devices. Other components can be incorporated into the transdermal patches as well.
  • compositions and /or transdermal patches can be formulated with one or more preservatives or bacteriostatic agents including, but not limited to, methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chloride, and the like.
  • Topical administration also includes administering the compounds and compositions to the eyes, particularly for the treatment of glaucoma.
  • Dosage forms for topical administration of the compounds and compositions of the present invention preferably include creams, sprays, lotions, gels, ointments, emulsions, coatings for condoms, liposomes, foams, and the like.
  • Administration of the cream, spray, lotion, gel, ointment, emulsion, coating, liposome, or foam can be accompanied by the use of an applicator or by transurethral drug delivery using a syringe with or without a needle or penile insert or device, or by clitoral, vulval or vaginal delivery, and is within the skill of the art.
  • a lubricant and/or a local anesthetic for desensitization can also be included in the formulation or provided for use as needed.
  • Lubricants include, for example, K-Y jelly (available from Johnson & Johnson) or a lidocaine jelly, such as XYLOCAINE® 2% jelly (available from Astra Pharmaceutical Products).
  • Local anesthetics include, for example, novocaine, procaine, tetracaine, benzocaine and the like.
  • Solid dosage forms for oral administration can include capsules, tablets, effervescent tablets, chewable tablets, pills, powders, effervescent powders, sachets, granules and gels.
  • the active compounds can be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms can also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms can also comprise buffering agents.
  • Soft gelatin capsules can be prepared to contain a mixture of the active compounds or compositions of the present invention and vegetable oil.
  • Hard gelatin capsules can contain granules of the active compound in combination with a solid, pulverulent carrier such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives of gelatin.
  • Tablets and pills can be prepared with enteric coatings.
  • Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
  • Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • Suppositories for vaginal or rectal administration of the compounds and compositions of the invention can be prepared by mixing the compounds or compositions with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at room temperature but liquid at body temperature, such that they will melt and release the drug.
  • a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at room temperature but liquid at body temperature, such that they will melt and release the drug.
  • sterile injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing agents, wetting agents and/or suspending agents.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution.
  • Sterile fixed oils are also conventionally used as a solvent or suspending medium.
  • compositions of the present invention will typically be administered in a pharmaceutical composition containing one or more carriers or excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral application which do not deleteriously react with the active compounds.
  • carriers or excipients i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral application which do not deleteriously react with the active compounds.
  • Examples of pharmaceutically acceptable carriers include, for example, water, salt solutions, alcohol, silicone, waxes, petroleum jelly, vegetable oils, polyethylene glycols, propylene glycol, liposomes, sugars, gelatin, lactose, amylose, magnesium stearate, talc, surfactants, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, and the like.
  • compositions can also include one or more permeation enhancers including, for example, dimethylsulfoxide (DMSO), dimethyl formamide (DMF), N,N-dimethylacetamide (DMA), decylmethylsulfoxide (C10MSO), polyethylene glycol monolaurate (PEGML), glyceral monolaurate, lecithin, 1 -substituted azacycloheptan-2-ones, particularly l-N-dodecylcyclazacylcoheptan-2-ones (available under the trademark AzoneTM from Nelson Research & Development Co., Irvine, CA), alcohols and the like.
  • permeation enhancers including, for example, dimethylsulfoxide (DMSO), dimethyl formamide (DMF), N,N-dimethylacetamide (DMA), decylmethylsulfoxide (C10MSO), polyethylene glycol monolaurate (PEGML), glyceral monolaurate, lecithin,
  • the pharmaceutical preparations can be sterilized and if desired, mixed with auxiliary agents which do not deleteriously react with the active compounds, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and /or aromatic substances, and the like.
  • auxiliary agents which do not deleteriously react with the active compounds
  • auxiliary agents which do not deleteriously react with the active compounds, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and /or aromatic substances, and the like.
  • auxiliary agents which do not deleteriously react with the active compounds
  • lubricants e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osm
  • the composition can also contain minor amounts of wetting agents, emulsifying agents and/or pH buffering agents.
  • the composition can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder.
  • the composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like.
  • Various delivery systems are known and can be used to administer the compounds or compositions of the present invention, including, for example, encapsulation in liposomes, microbubbles, emulsions, microparticles, microcapsules and the like.
  • the required dosage can be administered as a single unit or in a sustained release form.
  • the bioavailabilty of the compositions can be enhanced by micronization of the formulations using conventional techniques such as grinding, milling, spray drying and the like in the presence of suitable excipients or agents such as phospholipids or surfactants.
  • suitable excipients or agents such as phospholipids or surfactants.
  • the bioavailability and absorption of the dopamine agonists can be increased by the addition of tabletting excipients, such as, for example ⁇ -cyclodextrin, a ⁇ -cyclodextrin derivative, such as for example, hydroxypropyl- ⁇ -cyclodextrin (HPBCD), and the like.
  • compositions of the present invention can be formulated as pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts include, for example, alkali metal salts and addition salts of free acids or free bases.
  • the nature of the salt is not critical, provided that it is pharmaceutically- acceptable.
  • Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitric (nitrate salt), nitrous (nitrite salt), carbonic, sulfuric and phosphoric acid and the like.
  • organic acids include, but are not limited to, aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids, such as, for example, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p- hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2- hydroxyethanesuifonic, sulfanilic, stearic, algenic, ⁇ -hydroxybutyric, cyclohexylaminosulfonic, galactaric
  • Suitable pharmaceutically-acceptable base addition salts include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from primary, secondary and tertiary amines, cyclic amines, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine and the like. All of these salts may be prepared by conventional means from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.
  • “Therapeutically effective amount” refers to the amount of the dopamine agonist, nitric oxide donor and /or therapeutic agent which is effective to achieve its intended purpose. While individual patient needs may vary, determination of optimal ranges for effective amounts of each nitric oxide adduct is within the skill of the art.
  • the dosage regimen for treating a condition with the compounds and /or compositions of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient, the severity of the dysfunction, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound used, whether a drug delivery system is used, and whether the compound is administered as part of a drug combination and can be adjusted by one skilled in the art.
  • the dosage regimen actually employed may vary widely and therefore may deviate from the preferred dosage regimen set forth herein.
  • the amount of a given dopamine agonist which will be effective in the treatment of a particular dysfunction or condition will depend on the nature of the dysfunction or condition, and can be determined by standard clinical techniques, including reference to Goodman and Gilman, supra; The Physician's Desk Reference, supra; Medical Economics Company, Inc., Oradell, N.J., 1995; and Drug Facts and Comparisons, Inc., St. Louis, MO, 1993.
  • the precise dose to be used in the formulation will also depend on the route of administration, and the seriousness of the dysfunction or disorder, and should be decided by the physician and the patient's circumstances.
  • Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems and are in the same ranges or less than as described for the commercially available compounds in the Physician's Desk Reference, supra.
  • Particularly preferred methods of administration of the dopamine agonist may be extrapolated from dose-response curves derived from in vitro or animal model test systems and are in the same ranges or less than as described for the commercially available compounds in the Physician's Desk Reference, supra.
  • apomorphine are buccal or sublingual prior to sexual activity and in an amount of about 2 mg to about 12 mg to maintain a plasma level of no more than about 5.5 ng/ml.
  • the sublingual administration takes place over a time period in the range of about 2 to about 10 minutes or longer in the range of about 15 to about 20 minutes. These methods of administration are described in further detail in U.S. Patent Nos. 5,770,606, 5,624,677, 5,945,117, and 5,985,889 and in WO 99/38467 and WO 99/62502.
  • the sublingual dose can also be administered in a dose escalation regiment as described in U. S. Patent No. 5,994,363.
  • the dopamine agonist can be administered in a fast-acting form designed to disperse the compound rapidly in the oral cavity.
  • the dopamine agonist may be used in an amount of about 0.05 to about 50 mg. This method of administration is described in detail in WO 98/31368.
  • the dopamine agonist can also be administered transdermally in the form of a water soluble gel or as a patch as described in U.S. Patent No. 5,562,917 and 5,939,094 respectively.
  • Another mode of administration of the dopamine agonist is via intranasal administration as described in U.S. Patent No. 5,756,483.
  • the disclosure of each of these patents, applications and publications is incorporated by reference herein in their entirety.
  • the doses of nitric oxide donors in the pharmaceutical composition can be in amounts of about 0.001 mg to about 30 g and the actual amount administered will be dependent on the specific nitric oxide donor compound.
  • L-arginine when L-arginine is the nitric oxide donor, L-arginine can be administered orally at least one hour prior to sexual activity in an amount of about 0.25 grams to about 10 grams (equivalent to about 0.5 grams to about 20 grams of L-arginine glutamate), preferably about 2 grams to about 4 grams (equivalent to about 4 grams to about 8 grams of L-arginine glutamate); more preferably about 2.5 grams to about 3.5 grams (equivalent to about 5 grams to about 7 grams of L-arginine glutamate); most preferably about 3 grams (equivalent to 6 grams of L-arginine glutamate).
  • the ⁇ -antagonist such as phentolamine
  • the ⁇ -antagonist such as yohimbine
  • the yohimbine can also be administered in the form of its pharmaceutical salt, yohimbine tartarate, or yohimbe bark powder or extract that has been standardized to deliver up to about 18 mg of yohimbine.
  • the present invention also provides pharmaceutical kits comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compounds and /or compositions of the present invention, including, at least one dopamine agonist, one or more NO donors, and one or more therapeutic agents described herein.
  • kits can also include, for example, other compounds and/or compositions (e.g., permeation enhancers, lubricants, and the like), a device(s) for administering the compounds and/or compositions, and written instructions in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which instructions can also reflects approval by the agency of manufacture, use or sale for human administration.
  • other compounds and/or compositions e.g., permeation enhancers, lubricants, and the like
  • a device(s) for administering the compounds and/or compositions e.g., permeation enhancers, lubricants, and the like
  • written instructions in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which instructions can also reflects approval by the agency of manufacture, use or sale for human administration.

Abstract

La présente invention concerne de nouvelles compositions contenant au moins un agoniste dopaminergique combiné avec au moins un donneur d'oxyde nitrique (c'est-à-dire des composés qui donnent, transfèrent ou libèrent de l'oxyde nitrique, élèvent les niveaux endogènes du facteur relaxant dérivé de l'endothélium, stimulent la synthèse endogène de l'oxyde nitrique ou sont des substrats de synthase d'oxyde nitrique). Les nouvelles compositions peuvent comprendre facultativement au moins un agent thérapeutique, tel qu'un agent vasoactif, un agent antimétique et des mélanges de ceux-ci. L'agoniste dopaminergique est de préférence de l'apomorphine. La présente invention concerne également des méthodes de traitement et/ou de prévention de dysfonctionnements sexuels et/ou d'amélioration des réactions sexuelles chez des patients. Dans d'autres modes de réalisation, la présente invention concerne des méthodes de traitement ou de prévention de maladies neurodégénératives, de maladies mitochondriales, de lésions de la moelle épinière, de l'accoutumance centrale ou psychotonique, de la démence sénile, de troubles circulatoires, de troubles cardio-vasculaires, de l'hyperprolactinémie ou de la myopie. Les composés et/ou les compositions de la présente invention peuvent aussi se présenter sous la forme d'un kit pharmaceutique.
PCT/US2000/003709 1999-03-12 2000-03-10 Agonistes dopaminergiques en combinaison avec des donneurs d'oxyde nitrique, compositions et methodes d'utilisation WO2000054773A1 (fr)

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US60/123,920 1999-03-12

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WO2001013902A2 (fr) * 1999-08-19 2001-03-01 Boehringer Ingelheim Pharma Kg Combinaison d'agents actifs comprenant de la clonidine
WO2001081343A2 (fr) * 2000-04-21 2001-11-01 Pharmacia & Upjohn Company Composes permettant de traiter la fibromyalgie et le syndrome de fatigue chronique
EP1284141A2 (fr) * 2001-08-15 2003-02-19 Pfizer Products Inc. Combinaisons pharmaceutiques pour le traitement de maladies neurodégénératives comprenant des inhibiteurs de la synthase d'oxyde nitrique neuronale
WO2003000642A3 (fr) * 2001-06-21 2003-03-27 Nicox Sa Medicaments contre les douleurs chroniques
US6677374B2 (en) 1996-06-04 2004-01-13 Queen's University At Kingston Nitrate esters and methods of making same
EP1383502A2 (fr) * 2001-03-06 2004-01-28 Cellegy Pharmaceuticals, Inc Composes et procedes pour le traitement de desordres urogenitaux
WO2004028634A1 (fr) * 2002-09-25 2004-04-08 The Board Of Trustees Of The University Of Illinois Methode et composition de traitement de la maladie d'alzheimer et de demences d'origine vasculaire
WO2004054965A1 (fr) * 2002-12-17 2004-07-01 Nicox S.A. Medicaments contre la douleur chronique
EP1463440A2 (fr) * 2001-12-06 2004-10-06 Duke University Prevention de la necrose des lambeaux en chirurgie plastique
US6872739B1 (en) 1999-06-04 2005-03-29 Vereniging Voor Christelijk Wetenshappelikjk Onderwijs Use of riluzole for the treatment of multiple sclerosis
WO2006034902A1 (fr) * 2004-09-29 2006-04-06 Polichem S.A. Compositions pharmaceutiques d'alpha-dihydroergocryptine pour application transdermique et/ou transmuqueuse
EP1731146A1 (fr) * 2004-03-05 2006-12-13 Morishige, Fumie Pr vention de et mesure contre la maladie mitochondriale
EP1737429A1 (fr) * 2004-04-19 2007-01-03 Strategic Science & Technologies, LLC Distribution transdermique de substances benefiques effectuee par un environnement biophysique hostile
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US7914814B2 (en) 1997-09-17 2011-03-29 Strategic Science & Technologies, Llc Topical delivery of arginine of cause beneficial effects
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WO2017219080A1 (fr) * 2016-06-21 2017-12-28 The University Of Newcastle Traitement de la myopie
US10022320B2 (en) 2014-03-13 2018-07-17 Neuroderm, Ltd. Dopa decarboxylase inhibitor compositions
CN105434439B (zh) * 2015-11-11 2018-07-24 温州医科大学 一种多巴胺d2受体的部分激动剂在制备抑制近视药物上的应用及其使用方法
US10258585B2 (en) 2014-03-13 2019-04-16 Neuroderm, Ltd. DOPA decarboxylase inhibitor compositions
EP3616723A4 (fr) * 2018-07-18 2020-03-25 Wenzhou Medical University Procédé de traitement de la myopie et son application dans la préparation d'un médicament
US11213502B1 (en) 2020-11-17 2022-01-04 Neuroderm, Ltd. Method for treatment of parkinson's disease
US11331293B1 (en) 2020-11-17 2022-05-17 Neuroderm, Ltd. Method for treatment of Parkinson's disease
US11684624B2 (en) 2009-06-24 2023-06-27 Strategic Science & Technologies, Llc Treatment of erectile dysfunction and other indications
US11844754B2 (en) 2020-11-17 2023-12-19 Neuroderm, Ltd. Methods for treatment of Parkinson's disease

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US6916835B2 (en) 1996-06-04 2005-07-12 Queen's Uninversity At Kingston Nitrate esters and their use for neurological conditions
US6677374B2 (en) 1996-06-04 2004-01-13 Queen's University At Kingston Nitrate esters and methods of making same
US8603519B2 (en) 1997-09-17 2013-12-10 Strategic Science & Technologies, Llc Topical delivery of L-arginine to cause beneficial effects
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US6872739B1 (en) 1999-06-04 2005-03-29 Vereniging Voor Christelijk Wetenshappelikjk Onderwijs Use of riluzole for the treatment of multiple sclerosis
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WO2001013903A2 (fr) * 1999-08-19 2001-03-01 Boehringer Ingelheim Pharma Kg Traitement therapeutique du syndrome des jambes sans repos
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