WO1987005602A1 - Substituted 2-aminotetralins - Google Patents
Substituted 2-aminotetralins Download PDFInfo
- Publication number
- WO1987005602A1 WO1987005602A1 PCT/US1987/000491 US8700491W WO8705602A1 WO 1987005602 A1 WO1987005602 A1 WO 1987005602A1 US 8700491 W US8700491 W US 8700491W WO 8705602 A1 WO8705602 A1 WO 8705602A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- group
- methyl
- halogen
- active compound
- Prior art date
Links
Classifications
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
-
- 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
- A61K31/275—Nitriles; Isonitriles
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
-
- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/28—Halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/58—Radicals substituted by nitrogen atoms
Definitions
- the invention relates generally to substituted 2-aminotetralins and to processes for preparing such compounds. More particularly, the invention relates to compounds for therapeutic use, in particular in treating disorders of the central nervous, cardiovascular and endocrine systems.
- the compounds of this invention are als useful for alleviating glaucoma in mammals.
- R 1 and R 2 are saturated alkyl groups and n is 1 or 2, are dopamine receptor agonists (Mc Dermed et al., J. Med. Chem.18, 362 (1975); Feenstra et al., Arch. Pharmacol. 313, 213 (1980).
- R 2 , R 3 and R 4 are each selected from the group consisting of H, and OA;
- A is H or R 5 is selected from the group consisting of alkyl and aromatic residues, e.g. residues comprising from one to about twelve carbon atoms;
- n is 2 or 3 and R 1 is selected from the group consisting of
- R 6 is selected from the group consisting of halogen, hydrocarbyl and hetero atom-substituted hydrocarbyl, comprising from 1 to 12 carbon atoms and wherein said hetero-atoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorus;
- R 7 is R 6 or H and m equals 1, 2 or 3; with the proviso that at least one of R 2 , R 3 and R 4 is H, that at least one of R 2 , R 3 and R 4 is not H, and that R 2 and R 4 are not both OA.
- the compounds are useful as dopamine and, in particular, dopamine D-2 receptor agonists for the treatment of disorders of the central nervous, cardiovascular and endocrine systems .such as Parkinson's disease and related disorders, hypertension and hyperprolactinemia.
- the compounds of this invention are useful in the treatment of glaucoma in mammals.
- Figures 1 and 2 show the effect on pupil diameter and intraocular pressure, respectively, of monkeys that have been treated with 2-(N-n-pro ⁇ yl-N-2-thienylethylamino)-5-hydroxy-tetralin, the unsubstituted compound corresponding to the compounds of the present invention.
- the compounds of this invention are prepared by reacting an alkoxy-substituted 2-(N-n-propylamino)tetralin with a thienylacetic acid substituted with the R 6 or groups of choice as described further in the examples below.
- the resulting compound may be dealkylated to obtain the hydroxy-substituted derivative.
- R 6 is selected from the group consisting of an alkyl radical having from one to four carbon atoms, trifluoromethyl, halogen and phenyl. More preferably, R 6 is selected from the group consisting of methyl, ethyl, chloro and bromo. Preferably, R 7 is H.
- prodrugs of these compounds where A is may be prepared by treating the compound with the desired corresponding acid chloride (See Horn et al. , J. Med. Chem. 25, 993 , 1982) .
- a preferred embodiment of this invention is a method of treatment which comprises inducing a dopaminergic response by administering a therapeutically effective amount of one of the f oregoing compounds to a patient.
- a pharmacologically-eff ective daily dose can be from 0.01 mg./kg. to 100 mg./kg. per day, and preferably f rom about 0.1 mg. /k g. to 25 mg./k g. pe r day, bear ing i n mind, of course, that in selecting the appropriate dosage in any specif ic case, consideration must be given to the patient' s weight, general health, metaboli sm, age and other f actors which influence response to the drug.
- a particularly pref erred dose is 1.0 mg./kg. per day.
- Another embodiment of this invention is the prov ision of pharmaceutical compositions in dosage unit f orm which compr i se f rom about 2 mg. to 500 mg. of a compound of the above f ormula.
- the pharmaceutical composition may be in a form suitable for oral use, for example, as tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
- Compositions intended for oral use may be prepared according to any method know n to the art f or the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide a pharmaceutically elegant and palatable preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets.
- excipients may be, for example, inert diluents, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents, for example maize starch, or alginic acid; binding agents, for example starch, gelatine, or acacia; and lubricating agents, for example magnesium stearate, stearic acids, or talc.
- the tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- Formulations for oral use may also be presented as hard gelatine capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium cabonate, calcium phosphate, or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with an oil medium, for example arachis oil, liquid paraffin, or olive oil.
- an inert solid diluent for example calcium cabonate, calcium phosphate, or kaolin
- an oil medium for example arachis oil, liquid paraffin, or olive oil.
- Aqueous suspensions contain the active compound in admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example of polyoxethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived f rom fatty acids and a hexitol, for example, polyoxyethylene sorbitol monooleate, or condensation product of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, f or example
- the said aqueous suspensions may al so contain one or more preservatives, for example ethyl, n-propyl, or p-hydroxy benzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin, or sodium or cal cium cyclamate.
- preservatives for example ethyl, n-propyl, or p-hydroxy benzoate
- coloring agents for example ethyl, n-propyl, or p-hydroxy benzoate
- one or more coloring agents for example ethyl, n-propyl, or p-hydroxy benzoate
- one or more coloring agents for example ethyl, n-propyl, or p-hydroxy benzoate
- flavoring agents for example ethyl, n-propyl, or p-hydroxy benzoate
- sweetening agents such as sucrose, saccharin, or sodium or cal c
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture w ith a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exempl if ied by those al ready mentioned above. Additional excipients, for exampl e, sweetening, fl avoring, and col oring agents, may al so be present.
- Sy rups and el ixi rs may be formulated with sweetening agents, f or example glycerol, sorbitol or sucrose. Such formulations may al so contain a demulcent, a preservative and flavoring and coloring agents.
- the pharmaceutical compositions may be in the form of a sterile inj ectabl e preparation, f or example as a sterile injectable aqueous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
- the sterile inj ectable preparation may also be a sterile inj ectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 , 3-butane diol .
- the pharmaceutical compositions may be tableted or otherwise formulated so that for every 100 parts by weight of the composition there are present between 5 and 95 parts by weight of the active ingredient and preferably between 25 and 85 parts by weight of the active ingredient.
- the dosage unit form will gnerally contain between about 1 mg. and about 100 mg. of the active ingredient of the formula stated above.
- compositions of this invention can be administered orally or parenterally.
- parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, or intrasternal injection or fusion techniques.
- the method of the present invention comprises administering substituted 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin to the eye of a mammal to reduce intraocular pressure.
- the levo (-) isomers of these substituted compounds are believed to be the more active isomers for use in the method of the present invention.
- Suitable opthalmic carriers are known to those skilled in the art and all such conventional carriers may be employed in the present invention.
- a particular carrier may take the form of a sterile opthalmic ointment, cream, gel, solution, or dispersion and preferably a solution.
- suitable ophthalmic carriers are slow releasing polymers, e.g. "Ocusert” polymers, "Hydron” polymers, etc.
- Stabilizers may also be used as, for example, chelating agents, e.g. EDTA.
- Anti-oxidants may also be used, e.g. sodium bisulfite, sodium thiosulfite, 8-hydroxy quinoline or ascorbic acid.
- Sterility typically will be maintained by conventional opthalmic preservatives, e.g. chlorbutanol, benzalkonium chloride, cetylpyridinium chloride, phenyl mercuric salts, thimerosal, phenethyl alcohol, etc., for aqueous formulations, and used in amounts which are non-toxic and which generally vary from about 0.001 to about 0.1% by weight of the aqueous solution.
- Conventional preservatives for ointments include methyl and propyl parabens.
- Typical, ointment bases include white petrolatum and mineral oil or liquid petrolatum. However, preserved aqueous carriers are preferred.
- Solutions may be manually delivered to the eye in suitable dosage form, e.g., eye drops, or delivered by suitable microdrop or spray apparatus typically affording a metered dose of medicament.
- suitable opthalmic carriers or stabilizers include sterile, substantially isotonic, aqueous solutions containing minor amounts, i.e., less than about 5% by weight hydroxypropylmethylcellulose, poly vinyl alcohol, carboxymethylcellulose, hydroxyethyl cellulose, glycerine, EDTA, sodium bisulfite and ascorbic acid.
- the amount of active compound to be used in the therapeutic treatment of glaucoma will vary with the age of the patient and the severity of the glaucoma. Generally, a dose level of one or two drops of the foregoing aqueous solution 1-4 times daily would be a suitable dosage amount. Generally, the concentration of active compound will vary between about 0.001 and about 5% and preferably between about 0.05 and about 1% (wt./v calculated on the basis of the free base) of said opthalmic composition.
- the opthalmic composition of this invention should have a pH within the range of about 4.0 to 9.0 when intended for topical application. Above and below this pH range the solution may irritate and sting the eye of the user.
- the solutions of the present invention may be maintained between about pH 4.0 and 7.5 with suitable amounts of buffering agents including borate, carbonate, phosphate. Tris (hydroxymethyl aminomethane), acetate and citrate buffers.
- a preferred opthalmic composition is a preserved aqueous solution containing the following ingredients at approximately the indicated concentration.
- Prodrug esters of the compounds of EXAMPLES 1-5 are prepared by reacting the phenols with desired corresponding acid chloride (Horn et al I. Med. Chem. 25. 993, 1982).
- Rabbits were used primarily to screen for undue ocular toxicity of the active compound before conducting experiments in monkeys. Cats were used to localize the site and mechanism of action of the active compound as either ganglionic, prejunctional or postjunctional.
- a racemic mixture of the active compound was dissolved in distilled water (vehicle) on the day of the experiment. Solutions were administered in a masked manner, that is, solutions were prepared by a person that was neither involved in drug administration nor measurement of intraocular pressure (IOP) and pupil diameter (PD). The solution of the active compound was applied unilaterally with the contralateral (fellow) eye receiving vehicle only. Five monkeys were treated bilaterally with vehicle; one to two vehicle-treated monkeys were included each time a different dose of the active compound was used. Doses of active compound tested were: 0.165, 0.5 and 1.65 mg. Horizontal PD was measured utilizing an Optistick.
- the active compound produced dose-related ocular hypotension, miosis and ptosis in monkeys at doses of 0.5 and 1.65 mg topically. Shortly after topical administration there was evidence of ocular irritation in the form of tearing, exudate and hyperemia. Subsequently, there was evidence of clouding of the cornea, miosis and ptosis. After the initial phase of exudation, the hyperemia, ptosis and miosis persisted for hours to days, at 144 hours and beyond, there were also signs of sympathetic suppression to extraocular (ptosis) and intraocular (miosis and hyperemia) structures.
- the active compound also produced dose-related suppression of neuronally mediated contractions of the nictitans with minimal effects on contractions induced bynorepinephrine intra-arterially (i.a.). This test is described in Potter, D.E. and Burke, J.A. (1984), "An In Vivo Model for Discriminating 2 and DA 2 - Adrenoceptor Activity in an Ocular Adnexa; Utility of the Cat Nictitating Membrane Preparation", Curr. Eye Res. 3, 1289-1298.
- the inhibitory effects of the active compound were fully reversible within 106 minutes after the last dose.
- Pretreatment with domperidone i.a. had no effect on contractions elicited by neuronal stimulation and by exogenous norepinephrine but produced a 100 fold shift in the inhibitory index of the active compound on neuronally mediated contractions of the nictitans.
- the chronic response to the active compound in monkeys would also appear to be due to suppression of sympathetic neuronal function and w ould appear to be sl owly reversible.
- the prolonged phase of action is pronounced of a guanethidine-or reserpine-like effect.
- the active compound is a DA 2 agonist that lowers IOP in monkeys. Although it produces moderate ocular irritation at high doses, the compound provides a very prolonged occular hypotensive action.
- EXAMPLE 7 The compounds of EXAMPLES 1 to 6 are formulated into compositions having ingredients and concentrations given in the above Table. When these compositions, which are derivatives of the active compound, are introduced into the eye of a mammal and tested, as was the active compound, the intraocular pressure is reduced. While particular embodiments of the invention have been described it w ill be understood of course that the invention is not l imited thereto since many obvious modifications can be made and it is intended to include w ithin this invention any such modif ications as w ill fall within the scope of the appended claims.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Emergency Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Ophthalmology & Optometry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Compounds represented by general formula (I), where R2, R3 and R4 are each selected from the group consisting of H, and OA; A is H or formula (II); R5 is selected from the group consisting of alkyl and aromatic residues; n is 2 or 3; and R1 is selected from the group consisting of (a), (b), (c) and (d) wherein R6 is selected from the group consisting of halogen, hydrocarbyl and hetero atom-substituted hydrocarbyl, comprising from 1 to 12 carbon atoms and wherein said hetero-atoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorus; R7 is R6 or H and m equals 1, 2 or 3; with the proviso that at least one of R2, R3 and R4 is H, that at least one of R2, R3 and R4 is not H and that R2 and R4 are not both OA; and pharmaceutically-acceptable salts thereof. The compounds are dopamine receptor agonists and useful for the treatment of glaucoma in mammals.
Description
SUBSTITUTED 2-AMINOTETRALINS
Cross Reference to Related Applications
This patent application is a continuation in part of U.S. Patent Application Serial No. 811,768, filed on December 20, 1986, which is a continuation-in-part of U.S. Patent Application Serial No. 640,685, filed on August 13, 1984, now U.S. Patent No.4,564,628, both of which applications were filed in the name of Alan S. Horn and. are hereby incorporated by reference.
Background of the Invention Field of the Invention
The invention relates generally to substituted 2-aminotetralins and to processes for preparing such compounds. More particularly, the invention relates to compounds for therapeutic use, in particular in treating disorders of the central nervous, cardiovascular and endocrine systems. The compounds of this invention are als useful for alleviating glaucoma in mammals.
Background of the Prior Art
It is known that various hydroxylated 2-aminotetralins of the general formula
where R1 and R2 are saturated alkyl groups and n is 1 or 2, are dopamine receptor agonists (Mc Dermed et al., J. Med. Chem.18, 362 (1975); Feenstra et al., Arch. Pharmacol. 313, 213 (1980).
It is also known that certain dopaminergic compounds can lower intraocular pressure in various mammals. For example, it has been suggested that bromocriptine may lower intraocular pressure in man. (See The Lancet,
February 4, 1984, "Bromocriptine Eyedrops Lower Intraocular Pressure without Affecting Prolactin Levels.", by Mekki, et al. at pages 287-288.)
Similarly, bromocriptine, as well as lergotrile and pergolide has been shown to lower the intraocular pressure of rabbits and the latter two compounds also lowered the intraocular pressure of monkeys. (See Potter, D. E. and Burke, J.A. (1982/1983), "Effects of Ergoline Derivatives on Intraocular Pressure and Iris Function in Rabbits and Monkeys", Curr. Eye Res. 2, 281-288 and Potter, D. E., Burke, J.A. and Chang, F.W. (1984), "Ocular Hypotensive Action of Ergoline Derivatives in Rabbits: Effects of Sympathectomy and Domperidone Pretreatment", Curr. Eye Res. 3, 307-314.)
It has also been shown that certain dopamine analogs of the phenylethylamine class, e.g. N-methyl dopamine, N,N-dimethyl-dopamine and N,N-di-n-propyldopamine, may alter ocular function by operating through a variety of mechanisms. However, N-methyl dopamine appeared to function by suppressing aqueous humor formation. (See Potter, D. E. , Burke, J.A. and Chang, F.W. (1984), "Alteration in Ocular Function Induced by Phenylethylamine Analogs of Dopamine", Curr. Eye Res. 3, 851-859.)
F.W. and Potter, D.E. (1984), "Effects of Aminotetralins on Intraocular Pressure and Pupillary Function in Rabbits", J. Auton, Pharmacol. 4, 185-192.)
Summary of the Invention
There has now been discovered certain novel compounds having the structural formula
where R2, R3 and R4 are each selected from the group consisting of H, and OA; A is H or R5 is selected
from the group consisting of alkyl and aromatic residues, e.g. residues comprising from one to about twelve carbon atoms; n is 2 or 3 and R1 is selected from the group consisting of
wherein R6 is selected from the group consisting of halogen, hydrocarbyl and hetero atom-substituted hydrocarbyl, comprising from 1 to 12 carbon atoms and wherein said hetero-atoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and
phosphorus; R7 is R6 or H and m equals 1, 2 or 3; with the proviso that at least one of R2, R3 and R4 is H, that at least one of R2, R3 and R4 is not H, and that R2 and R4 are not both OA.
The compounds are useful as dopamine and, in particular, dopamine D-2 receptor agonists for the treatment of disorders of the central nervous, cardiovascular and endocrine systems .such as Parkinson's disease and related disorders, hypertension and hyperprolactinemia. In particular, the compounds of this invention are useful in the treatment of glaucoma in mammals.
Brief Description of the Drawing Figures
Figures 1 and 2 show the effect on pupil diameter and intraocular pressure, respectively, of monkeys that have been treated with 2-(N-n-proρyl-N-2-thienylethylamino)-5-hydroxy-tetralin, the unsubstituted compound corresponding to the compounds of the present invention.
Detailed Description of the Invention The above compounds may be made by any of the methods disclosed in U.S. Patent Application Serial No. 640,685, cited above.
In particular, the compounds of this invention are prepared by reacting an alkoxy-substituted 2-(N-n-propylamino)tetralin with a thienylacetic acid substituted with the R6 or groups of choice as described
further in the examples below. The resulting compound may be dealkylated to obtain the hydroxy-substituted derivative.
Preferably, R6 is selected from the group consisting of an alkyl radical having from one to four carbon atoms, trifluoromethyl, halogen and phenyl. More preferably, R6 is selected from the group consisting of methyl, ethyl, chloro and bromo. Preferably, R7 is H.
Specific preferred compounds, which are within the scope of the above general formula include:
2-(N-n-propyl-N-2-[thienyl-4-methyl]ethylamino)-5-hydroxytetralin.
2-(N-n-propyl-N-2-[thienyl-3, 4, 5-trimethyl]ethylamino)-5-hydroxytetralin.
2-(N-n-propyl-N-2-[thienyl-5-chloro]ethylamino)-5-hydroxytetralin.
2-(N-n-propyl-N-2-[thienyl-4-bromo-5-methyl]ethylamino)-5-hydroxytetralin.
2-(N-n-propyl-N-2[thienyl-4-methyl-5-ethyl]ethylamino 5-hydroxytetralin.
2-(N-n-propyl-N-2-[benzothienyl]ethylamino)-5-hydroxytetralin.
2-(N-n-propyl-N-3-[benzothienyl]ethylamino)-5-hydrooxytetralin.
The prodrugs of these compounds where A is may
be prepared by treating the compound with the desired corresponding acid chloride (See Horn et al. , J. Med. Chem. 25, 993 , 1982) .
A preferred embodiment of this invention is a method of treatment which comprises inducing a dopaminergic response by administering a therapeutically effective amount of one of the f oregoing compounds to a patient. In general, a pharmacologically-eff ective daily dose can be from 0.01 mg./kg. to 100 mg./kg. per day, and preferably f rom about 0.1 mg. /k g. to 25 mg./k g. pe r day, bear ing i n mind, of course, that in selecting the appropriate dosage in any specif ic case, consideration must be given to the patient' s weight, general health, metaboli sm, age and other f actors which influence response to the drug. A particularly pref erred dose is 1.0 mg./kg. per day.
Another embodiment of this invention is the prov ision of pharmaceutical compositions in dosage unit f orm which compr i se f rom about 2 mg. to 500 mg. of a compound of the above f ormula.
The pharmaceutical composition may be in a form suitable for oral use, for example, as tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method know n to the art f or the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide a pharmaceutically elegant and palatable preparation. Tablets contain the active ingredient in
admixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets. These excipients may be, for example, inert diluents, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents, for example maize starch, or alginic acid; binding agents, for example starch, gelatine, or acacia; and lubricating agents, for example magnesium stearate, stearic acids, or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
Formulations for oral use may also be presented as hard gelatine capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium cabonate, calcium phosphate, or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with an oil medium, for example arachis oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active compound in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example of polyoxethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with
partial esters derived f rom fatty acids and a hexitol, for example, polyoxyethylene sorbitol monooleate, or condensation product of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, f or example polyoxyethylene sorbitan monooleate. The said aqueous suspensions may al so contain one or more preservatives, for example ethyl, n-propyl, or p-hydroxy benzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin, or sodium or cal cium cyclamate.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture w ith a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exempl if ied by those al ready mentioned above. Additional excipients, for exampl e, sweetening, fl avoring, and col oring agents, may al so be present.
Sy rups and el ixi rs may be formulated with sweetening agents, f or example glycerol, sorbitol or sucrose. Such formulations may al so contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile inj ectabl e preparation, f or example as a sterile injectable aqueous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile inj ectable preparation may also be a sterile inj ectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 , 3-butane diol .
The pharmaceutical compositions may be tableted or otherwise formulated so that for every 100 parts by weight of the composition there are present between 5 and 95 parts by weight of the active ingredient and preferably between 25 and 85 parts by weight of the active ingredient. The dosage unit form will gnerally contain between about 1 mg. and about 100 mg. of the active ingredient of the formula stated above.
From the foregoing formulation discussion it is apparent that the compositions of this invention can be administered orally or parenterally. The term parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, or intrasternal injection or fusion techniques.
Even more preferably, the method of the present invention comprises administering substituted 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin to the eye of a mammal to reduce intraocular pressure. Moreover, the levo (-) isomers of these substituted compounds are believed to be the more active isomers for use in the method of the present invention.
Suitable opthalmic carriers are known to those skilled in the art and all such conventional carriers may be employed in the present invention. Thus, a particular carrier may take the form of a sterile opthalmic ointment, cream, gel, solution, or dispersion and preferably a solution. Also including as suitable ophthalmic carriers are slow releasing polymers, e.g. "Ocusert" polymers, "Hydron" polymers, etc. Stabilizers may also be used as, for example, chelating agents, e.g. EDTA. Anti-oxidants may also be used, e.g. sodium bisulfite, sodium thiosulfite, 8-hydroxy quinoline or ascorbic acid. Sterility typically will be maintained by conventional
opthalmic preservatives, e.g. chlorbutanol, benzalkonium chloride, cetylpyridinium chloride, phenyl mercuric salts, thimerosal, phenethyl alcohol, etc., for aqueous formulations, and used in amounts which are non-toxic and which generally vary from about 0.001 to about 0.1% by weight of the aqueous solution. Conventional preservatives for ointments include methyl and propyl parabens. Typical, ointment bases include white petrolatum and mineral oil or liquid petrolatum. However, preserved aqueous carriers are preferred. Solutions may be manually delivered to the eye in suitable dosage form, e.g., eye drops, or delivered by suitable microdrop or spray apparatus typically affording a metered dose of medicament. Examples of suitable opthalmic carriers or stabilizers include sterile, substantially isotonic, aqueous solutions containing minor amounts, i.e., less than about 5% by weight hydroxypropylmethylcellulose, poly vinyl alcohol, carboxymethylcellulose, hydroxyethyl cellulose, glycerine, EDTA, sodium bisulfite and ascorbic acid.
The amount of active compound to be used in the therapeutic treatment of glaucoma will vary with the age of the patient and the severity of the glaucoma. Generally, a dose level of one or two drops of the foregoing aqueous solution 1-4 times daily would be a suitable dosage amount. Generally, the concentration of active compound will vary between about 0.001 and about 5% and preferably between about 0.05 and about 1% (wt./v calculated on the basis of the free base) of said opthalmic composition.
Preferably, the opthalmic composition of this invention should have a pH within the range of about 4.0 to 9.0 when intended for topical application. Above and
below this pH range the solution may irritate and sting the eye of the user. The solutions of the present invention may be maintained between about pH 4.0 and 7.5 with suitable amounts of buffering agents including borate, carbonate, phosphate. Tris (hydroxymethyl aminomethane), acetate and citrate buffers.
A preferred opthalmic composition is a preserved aqueous solution containing the following ingredients at approximately the indicated concentration.
Table
Active compound 0.001 - 1 wt. %
Stabilizer 0.01 - 0.1 wt. %
Preservative 0.005 - 0.5 wt. %
Buffer (sufficient to maintain 0.1 - 0.001 M pH between about 4.0 and 7.5) NaCl qs. ad. (isotonic)
Water qs. ad. 100%
To illustrate the manner in which the invention may be carried out, the following examples are given. It is understood, however, that the examples are for the purpose of illustration and the invention is not be regarded as limited to any of the specific materials or conditions therein.
EXAMPLE 1 Preparation of 2-(N-n-propγl-N-2-[thienyl-4-methyl]ethylamino)-5-hydroxytetralin
A mixture of 2-(N-n-propylamino)-5-methoxytetralin, 4-methyl-2-thienylacetic acid (Clemence et al. Eur. J.
Med. Chem. 9390-396, 1974) and trimethylaminoborohydride in dry xylene was refluxed under an atomosphere of nitrogen as described by Horn et al Pharm. Weekbld. Sci. Ed. 7208-211, 1985. The resulting methoxy intermediate was demethylated using boron tribromide as described in the above article to yield the desired end product.
EXAMPLE 2 Preparation of 2-(N-n-propγl-N-2-[thienyl-3,4,5-trimethγl]ethylamino)-5-hydroxytetralin
The end product was obtained using the above method and 3,4,5-trimethyl-2-thienylacetic acid (Gronwitz and Torbjorn, Acta Chem. Scand. Ser B. , B 29, 818-826, 1975).
EXAMPLE 3 Preparation of 2-(N-n-propyl-N-2-[thienyl-5-chlorolethylamino)-5-hydroxytetrqlin
The end product was obtained using the above method and 5-chloro-2-thienylacetic acid (Ford et al. J. Am. Chem. Soc. 72 2109-2112, 1950).
EXAMPLE 4 Preparation of 2-(N-n-propyl-N-2-[thienyl-4-bromo-5-methyl]ethylamino)-5-hydroxytetralin
The end product was obtained using the above method and 4-bromo-5-methyl-2-thieny lacetic acid (Gronwitz and Torbjorn, Acta Chem. Scand. Ser B., B. 29, 818-826, 1975).
EXAMPLE 5 Preparation of 2-(N-n-propyl-N-2[thienyl-4-methγl-5-ethyl]ethylamino-5-hydroxytetralin
The end product was obtained by using the above method and 4-methyl-5-ethyl-2-thienylacetic acid (Nguyen and Hauptmann, Z. Chem. 13 57-58, 1973).
EXAMPLE 6
Prodrug esters of the compounds of EXAMPLES 1-5 are prepared by reacting the phenols with desired corresponding acid chloride (Horn et al I. Med. Chem. 25. 993, 1982).
The unsubstituted 2-(N-n-propyl-N-2-thienylethylamino)-5-hydroxy-tetralin (active compound) was tested for reducing the intraocular pressure in mammals, as described below.
Male, albino New Zealand rabbits, female Cebus apella monkeys and cats of mixed sexes were used for this test. Rabbits were used primarily to screen for undue ocular toxicity of the active compound before conducting experiments in monkeys. Cats were used to localize the site and mechanism of action of the active compound as either ganglionic, prejunctional or postjunctional.
A racemic mixture of the active compound was dissolved in distilled water (vehicle) on the day of the experiment. Solutions were administered in a masked manner, that is, solutions were prepared by a person that was neither involved in drug administration nor measurement of intraocular pressure (IOP) and pupil diameter (PD). The solution of the active compound was applied unilaterally with the contralateral (fellow) eye receiving vehicle only. Five monkeys were treated bilaterally with vehicle; one to two vehicle-treated monkeys were included each time a different dose of the active compound was used. Doses of active compound tested were: 0.165, 0.5 and 1.65 mg.
Horizontal PD was measured utilizing an Optistick. After taking two baseline (0 time) measurements, aliquots (50 1) of the solution of the active compound and/or vehicle, only, were administered topically. Subwsequently, IOP and PD mesurements were made at 0.5, 1, 2, 3, 4 and 5 hours post drug. Additional readings were taken on subsequent days when it became apparent that the ocular effects of the active compound were protracted. Gross observations were made regarding signs of ocular irritation and systemic effects. The results were reported in Figures 1 and 2.
The active compound produced dose-related ocular hypotension, miosis and ptosis in monkeys at doses of 0.5 and 1.65 mg topically. Shortly after topical administration there was evidence of ocular irritation in the form of tearing, exudate and hyperemia. Subsequently, there was evidence of clouding of the cornea, miosis and ptosis. After the initial phase of exudation, the hyperemia, ptosis and miosis persisted for hours to days, at 144 hours and beyond, there were also signs of sympathetic suppression to extraocular (ptosis) and intraocular (miosis and hyperemia) structures.
The active compound also produced dose-related suppression of neuronally mediated contractions of the nictitans with minimal effects on contractions induced bynorepinephrine intra-arterially (i.a.). This test is described in Potter, D.E. and Burke, J.A. (1984), "An In Vivo Model for Discriminating 2 and DA2- Adrenoceptor Activity in an Ocular Adnexa; Utility of the Cat Nictitating Membrane Preparation", Curr. Eye Res. 3, 1289-1298. The inhibitory effects of the active compound were fully reversible within 106 minutes after the last dose. Pretreatment with domperidone i.a. had no effect on
contractions elicited by neuronal stimulation and by exogenous norepinephrine but produced a 100 fold shift in the inhibitory index of the active compound on neuronally mediated contractions of the nictitans.
These results demonstrate that the active commpound, a DA2 agonist, lowered IOP and reduced miosis and ptosis in monkeys. The IOP and pupillary responses to the active compound responses occurred within several hours and, depending on the dose, persisted for many days. The acute response of the cat nictitans to the active compound i.a. was reversible and antagonized competitively by domperidone. These data would suggest that the acute phase of action is an action on DA2 receptors in the periphery because the relatively selective antagonist, domperidone, penetrates the pial-glial barrier poorly. The chronic response to the active compound in monkeys would also appear to be due to suppression of sympathetic neuronal function and w ould appear to be sl owly reversible. The prolonged phase of action is reminiscent of a guanethidine-or reserpine-like effect.
In summary, the active compound is a DA2 agonist that lowers IOP in monkeys. Although it produces moderate ocular irritation at high doses, the compound provides a very prolonged occular hypotensive action.
EXAMPLE 7 The compounds of EXAMPLES 1 to 6 are formulated into compositions having ingredients and concentrations given in the above Table. When these compositions, which are derivatives of the active compound, are introduced into the eye of a mammal and tested, as was the active compound, the intraocular pressure is reduced.
While particular embodiments of the invention have been described it w ill be understood of course that the invention is not l imited thereto since many obvious modifications can be made and it is intended to include w ithin this invention any such modif ications as w ill fall within the scope of the appended claims.
Claims
1. A compound having the structural formula
where R2, R3 and R4 are each selected from the group consisting of H, and OA; A is H or R5 is selected from the group consisting of alkyl and aromatic residues; n is 2 or 3; and R1 is selected from the group consisting
wherein R6 is selected from the group consisting of halogen, hydrocarbyl and hetero atom-substituted hydrocarbyl, comprising from 1 to 12 carbon atoms and wherein said hetero-atoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorus; R7 is R6 or H and m equals 1, 2 or 3; with the proviso that at least one of R2, R3 and R4 is H, that at least one of R2, R3 and R4 is not H and that R2 and R4 are not both OA; and pharmaceutically-acceptable salts thereof.
2. The compound of Claim 1, where R4 is H and R2 and
R3 are OH.
3. The compound of Claim 1, where R2 is H and R3 and R4 are OH.
4. The compound of Claim 1, where R3 and R4 are H and R2 is OH.
5. The compound of Claim 1, where R2 and R3 are H and R4 is OH.
6. The compound of Claim 1, where n is 2.
8. The compound of Claim 7 wherein R6 is selected from the group consisting of an alkyl radical having from one to four carbon atoms, trifluoromethyl, halogen and phenyl, and R7 is hydrogen.
10. The compound of Claim 9 whrein R6 is methyl and m is 1.
11. The compound of Claim 9 wherein R6 is methyl and m is 3.
12. The compound of Claim 9 wherein R6 is chloro and m is 1.
13. The compound of Claim 9 wherein R6 is selected from the group consisting of bromo and methyl and m is 2.
14. The compound of Claim 9 wherein R6 is selected from the group consisting of methyl and ethyl and m is 2.
15. A method comprising: inducing a dopaminergic response in a patient by administering a pharmacologically-effective amount of a compound of Claim 1.
16. The method of Claim 15, wherein the compound is a compound of Claim 7.
17. The method of Claim 15, wherein the compound is a compound of Claim 8.
18. The method of Claim 15, wherein the compound is a compound of Claim 10.
19. The method of Claim 15, wherein the compound is a compound of Claim 11.
20. The method of Claim 15, wherein the compound is a compound of Claim 12.
21. The method of Claim 15 wherein the compound is a compound of Claim 13.
22. The method of Claim 15 wherein the compound is a compound of Claim 14.
23. A method for reducing the intraocular pressure in mammals which comprises administering an effective amount of a compound of Claim 1.
24. A method according to Claim 23 wherein the compound is a compound of Claim 7.
25. A method according to Claim 23 wherein the compound is a compound of Claim 8.
26. A method according to Claim 23 wherein the compound is a compound of Claim 10.
27. A method according to Claim 23 wherein the compound is a compound of Claim 11.
28. A method according to Claim 23 wherein the compound is a compound of Claim 12.
29. A method according to Claim 23 wherein the compound is a compound of Claim 13.
30. A method according to Claim 23 wherein the compound is a compound of Claim 14.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US839,976 | 1986-03-17 | ||
US06/839,976 US4722933A (en) | 1985-12-20 | 1986-03-17 | Substituted 2-aminotetralins |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1987005602A1 true WO1987005602A1 (en) | 1987-09-24 |
Family
ID=25281135
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1987/000491 WO1987005602A1 (en) | 1986-03-17 | 1987-03-06 | Substituted 2-aminotetralins |
Country Status (6)
Country | Link |
---|---|
US (1) | US4722933A (en) |
EP (1) | EP0259480A4 (en) |
JP (1) | JPH01500033A (en) |
AU (1) | AU597642B2 (en) |
CA (1) | CA1286681C (en) |
WO (1) | WO1987005602A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4924008A (en) * | 1989-05-04 | 1990-05-08 | American Home Products Corporation | Benzobicycloalkane derivatives as anticonvulsant neuroprotective agents |
JPH03504972A (en) * | 1988-06-13 | 1991-10-31 | ディスカバリー・セラピューティックス・インコーポレーテッド | Methods and therapeutic compositions for treating Parkinson's syndrome in mammals |
Families Citing this family (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5268385A (en) * | 1983-01-03 | 1993-12-07 | Whitby Research, Inc. | Method for treating schizophrenia |
US5256661A (en) * | 1983-01-03 | 1993-10-26 | Whitby Research, Inc. | Substituted 2-aminotetralins and pharmaceutical use |
US4882352A (en) * | 1986-07-28 | 1989-11-21 | Nelson Research & Development Co. | Method for treating schizophrenia |
US4943428A (en) * | 1987-07-10 | 1990-07-24 | Wright State University | Stimulation of serotonin-1A receptors in mammals to alleviate motion sickness and emesis induced by chemical agents |
US5288749A (en) * | 1991-12-20 | 1994-02-22 | Abbott Laboratories | Tertiary and secondary amines as alpha-2 antagonists and serotonin uptake inhibitors |
US5364884A (en) * | 1993-01-21 | 1994-11-15 | Baylor College Of Medicine | Arginine compounds as ocular hypotensive agents |
WO1994022495A1 (en) * | 1993-03-31 | 1994-10-13 | The Trustees Of The University Of Pennsylvania | Dopamine d-3 and serotonin (5-ht1a) receptor ligands and imaging agents |
US5629345A (en) * | 1993-07-23 | 1997-05-13 | Vide Pharmaceuticals | Methods and compositions for ATP-sensitive K+ channel inhibition for lowering intraocular pressure |
US5965620A (en) * | 1993-07-23 | 1999-10-12 | Vide Pharmaceuticals | Methods and compositions for ATP-sensitive K+ channel inhibition for lowering intraocular pressure |
US5382596A (en) * | 1993-08-05 | 1995-01-17 | Whitby Research, Inc. | Substituted 2-aminotetralins |
ATE196734T1 (en) * | 1993-08-18 | 2000-10-15 | Alcon Lab Inc | COMPOSITIONS OF ERGOLINE DERIVATIVES FOR THE TREATMENT OF GLAUCOMA |
DE10041479A1 (en) * | 2000-08-24 | 2002-03-14 | Sanol Arznei Schwarz Gmbh | New pharmaceutical composition for the administration of N-0923 |
DE10041478A1 (en) * | 2000-08-24 | 2002-03-14 | Sanol Arznei Schwarz Gmbh | New pharmaceutical composition |
US20040048779A1 (en) * | 2002-05-06 | 2004-03-11 | Erwin Schollmayer | Use of rotigotine for treating the restless leg syndrome |
WO2004028536A1 (en) * | 2002-09-30 | 2004-04-08 | Babizhayev Mark A | Method for topical treatment of eye disease and composition and device for said treatment |
DE10334188B4 (en) * | 2003-07-26 | 2007-07-05 | Schwarz Pharma Ag | Use of rotigotine to treat depression |
DE10334187A1 (en) * | 2003-07-26 | 2005-03-03 | Schwarz Pharma Ag | Substituted 2-aminotetralins for the treatment of depression |
DE10361258A1 (en) * | 2003-12-24 | 2005-07-28 | Schwarz Pharma Ag | Use of substituted 2-aminotetralins for the preventive treatment of Parkinson's disease |
US20050197385A1 (en) * | 2004-02-20 | 2005-09-08 | Schwarz Pharma Ag | Use of rotigotine for treatment or prevention of dopaminergic neuron loss |
DE102004014841B4 (en) * | 2004-03-24 | 2006-07-06 | Schwarz Pharma Ag | Use of rotigotine for the treatment and prevention of Parkinson-Plus syndrome |
EP1987815A1 (en) * | 2007-05-04 | 2008-11-05 | Schwarz Pharma Ag | Oronasopharyngeally deliverable pharmaceutical compositions of dopamine agonists for the prevention and/or treatment of restless limb disorders |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3930022A (en) * | 1972-07-03 | 1975-12-30 | Squibb & Sons Inc | Certain tetrahydronaphthalenes used in the treatment of cardiac arrhythmia |
US4076843A (en) * | 1972-07-03 | 1978-02-28 | E. R. Squibb & Sons, Inc. | 5,6,7,8-Tetrahydronaphthalene hypotensive agents |
US4267373A (en) * | 1972-07-03 | 1981-05-12 | E. R. Squibb & Sons, Inc. | 5,6,7,8-Tetrahydronaphthalene hypotensive agents |
GB1597140A (en) * | 1976-12-07 | 1981-09-03 | Sandoz Ltd | Tetralines |
US4314082A (en) * | 1978-07-14 | 1982-02-02 | American Hospital Supply Corporation | Derivatives of 2-amino-6,7-dihydroxytetrahydro naphthalene (ADTN) |
EP0064964A1 (en) * | 1981-05-08 | 1982-11-17 | Astra Läkemedel Aktiebolag | Therapeutically useful 1-alkyl-2-aminotetralin derivatives |
US4410519A (en) * | 1979-09-14 | 1983-10-18 | Sandoz Ltd. | Tetraline derivatives, their production and pharmaceutical compositions containing them |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4564628A (en) * | 1983-01-03 | 1986-01-14 | Nelson Research & Development Co. | Substituted 2-aminotetralins |
JPS60258146A (en) * | 1984-06-01 | 1985-12-20 | ウイットバイ リサーチ インコーポレイテッド | Substituted 2-aminotetralins and synthesis |
-
1986
- 1986-03-17 US US06/839,976 patent/US4722933A/en not_active Expired - Fee Related
-
1987
- 1987-03-06 EP EP19870902225 patent/EP0259480A4/en not_active Withdrawn
- 1987-03-06 AU AU71694/87A patent/AU597642B2/en not_active Ceased
- 1987-03-06 JP JP62502102A patent/JPH01500033A/en active Pending
- 1987-03-06 WO PCT/US1987/000491 patent/WO1987005602A1/en not_active Application Discontinuation
- 1987-03-16 CA CA000532095A patent/CA1286681C/en not_active Expired - Fee Related
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3930022A (en) * | 1972-07-03 | 1975-12-30 | Squibb & Sons Inc | Certain tetrahydronaphthalenes used in the treatment of cardiac arrhythmia |
US4076843A (en) * | 1972-07-03 | 1978-02-28 | E. R. Squibb & Sons, Inc. | 5,6,7,8-Tetrahydronaphthalene hypotensive agents |
US4267373A (en) * | 1972-07-03 | 1981-05-12 | E. R. Squibb & Sons, Inc. | 5,6,7,8-Tetrahydronaphthalene hypotensive agents |
GB1597140A (en) * | 1976-12-07 | 1981-09-03 | Sandoz Ltd | Tetralines |
US4314082A (en) * | 1978-07-14 | 1982-02-02 | American Hospital Supply Corporation | Derivatives of 2-amino-6,7-dihydroxytetrahydro naphthalene (ADTN) |
US4410519A (en) * | 1979-09-14 | 1983-10-18 | Sandoz Ltd. | Tetraline derivatives, their production and pharmaceutical compositions containing them |
EP0064964A1 (en) * | 1981-05-08 | 1982-11-17 | Astra Läkemedel Aktiebolag | Therapeutically useful 1-alkyl-2-aminotetralin derivatives |
Non-Patent Citations (1)
Title |
---|
See also references of EP0259480A4 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH03504972A (en) * | 1988-06-13 | 1991-10-31 | ディスカバリー・セラピューティックス・インコーポレーテッド | Methods and therapeutic compositions for treating Parkinson's syndrome in mammals |
US4924008A (en) * | 1989-05-04 | 1990-05-08 | American Home Products Corporation | Benzobicycloalkane derivatives as anticonvulsant neuroprotective agents |
Also Published As
Publication number | Publication date |
---|---|
JPH01500033A (en) | 1989-01-12 |
US4722933A (en) | 1988-02-02 |
CA1286681C (en) | 1991-07-23 |
EP0259480A1 (en) | 1988-03-16 |
AU7169487A (en) | 1987-10-09 |
AU597642B2 (en) | 1990-06-07 |
EP0259480A4 (en) | 1988-07-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4722933A (en) | Substituted 2-aminotetralins | |
US5177112A (en) | Substituted 2-aminotetralins | |
US4657925A (en) | Method and compositions for reducing the intraocular pressure of mammals | |
JPWO2002100819A1 (en) | N-arylphenylacetamide derivatives and pharmaceutical compositions containing them | |
US5506257A (en) | Aminocyclohexylamides for antiarrhythmic and anaesthetic uses | |
US4743618A (en) | Substituted 2-aminotetralins | |
GB2068376A (en) | Imidazoline derivative | |
EP0420871A1 (en) | Method and compositions for treatment of parkinsonism syndrome in mammals | |
EP0632806B1 (en) | Aminocyclohexylamides for antiarrhythmic and anaesthetic uses | |
HU201731B (en) | Process for producing substituted benzamides and pharmaceutical compositions comprising such active ingredient | |
US7005448B2 (en) | Aminoalkyl-benzofuran-5-ol compounds for the treatment of glaucoma | |
KR960010454B1 (en) | Cycloalkylamides of (8-beta)-1-alkyl-6-(substituted)ergolines | |
CA2557758C (en) | Medicinal composition for prevention or treatment of overactive bladder accompanying nervous disorder | |
US4851429A (en) | Pharmaceutically useful tricyclic amines derived from 2,3,5,6,7,8-hexahydronaphtho(2,3-B)furan and from 2,3,6,7,8,9-hexahydro-5H-benzocyclohepta(2,3-B)furan | |
JP2844109B2 (en) | Eye disease treatment | |
US5256661A (en) | Substituted 2-aminotetralins and pharmaceutical use | |
EP0254989B1 (en) | Substituted 2-aminotetralins | |
JPH04226992A (en) | 4-alkylamino-6-(c3-5-hydrocarbyl)- thieno(2,3-b)thiopyran-2-sulfonamide- 7,7-dioxide | |
US20070293475A1 (en) | Aryl and heteroaryl tetrahydrobenzazepine derivatives and their use for treating glaucoma | |
US5955468A (en) | Benzo G!quinolines for use in prevention or delay of progressive atrophy of the optic nerve | |
US9968566B2 (en) | Pharmaceutical composition for prophylaxis and/or treatment of corneal and conjunctival diseases or presbyopia containing stilbene compound as active ingredient | |
EP0131595A1 (en) | Carbostyriloximinopropanolamines useful as medicaments and preparation method thereof | |
JP2004530647A (en) | Ophthalmic composition for treatment of high intraocular pressure | |
JP2012250947A (en) | Combination of adenosine derivative and beta-receptor blocker | |
JP2003505499A (en) | 2-aminotetralin derivatives for the treatment of glaucoma |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU JP |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE FR GB IT LU NL SE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1987902225 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1987902225 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1987902225 Country of ref document: EP |