Claims
- 1. A pharmaceutical composition suitable for use in the treatment of anxiety, psychosis, glaucoma, and for stimulating gastric motility comprising a pharmaceutically acceptable carrier in admixture with a compound of the formula ##STR7## wherein A is H.sub.2, O, (H)(OH), (OH).sub.2 or N--OH; B is H.sub.2, (H)(CH.sub.3), (H)(CH.sub.2 NR.sub.3 R.sub.4) or CH.sub.2 wherein R.sub.3 and R.sub.4 are C.sub.2-4 alkyl or are combined to give tetramethylene, pentamethylene or --CH.sub.2 CH.sub.2 --O--CH.sub.2 CH.sub.2 ; R.sub.1 is ##STR8## wherein Z is NR.sub.9, O or S; R.sub.5, R.sub.6 and R.sub.8 are each hydrogen, halogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxy; R.sub.7 is hydrogen, amino, (C.sub.1-4 alkyl)amino, (C.sub.1-4 alkyl).sub.2 amino, alkoxy, or nitro; R.sub.9 is hydrogen, C.sub.1-4 alkyl or phenyl (C.sub.1-2 alkyl); R.sub.10 is hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxyl, cyano or --CONH.sub.2 ; R.sub.11 is hydrogen, halogen, C.sub.1-4 alkyl or phenyl; the wavy line indicates that the configuration of the oxygen substituent on the ring can be endo or exo; and the pharmaceutically acceptable acid addition and quarternary ammonium salts of the aforesaid compounds.
- 2. A pharmaceutical composition according to claim 1 wherein said compound is endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one.
- 3. A method for the treatment of anxiety comprising administering to a patient in need thereof of an effective amount of a compound of the formula ##STR9## wherein A is H.sub.2, O, (H)(OH), (OH).sub.2 or N--OH; B is H.sub.2, (H)(CH.sub.3), (H)(CH.sub.2 NR.sub.3 R.sub.4) or CH.sub.2 wherein R.sub.3 and R.sub.4 are C.sub.2-4 alkyl or are combined to give tetramethylene, pentamethylene or --CH.sub.2 CH.sub.2 --O--CH.sub.2 CH.sub.2 --; R.sub.1 is ##STR10## wherein Z is NR.sub.9, O or S; R.sub.5, R.sub.6 and R.sub.8 are each hydrogen, halogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxy; R.sub.7 is hydrogen, amino, (C.sub.1-4 alkyl)amino, (C.sub.1-4 alkyl).sub.2 amino, alkoxy or nitro; R.sub.9 is hydrogen, C.sub.1-4 alkyl or phenyl (C.sub.1-2 alkyl); R.sub.10 is hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, cyano or --CONH.sub.2 ; R.sub.11 is hydrogen, halogen, C.sub.1-4 alkyl or phenyl; the wavy line indicates that the configuration of the oxygen substituent on the ring can be endo or exo; and the pharmaceutically acceptable acid addition and quarternary ammonium salts of the aforesaid compounds.
- 4. A method according to claim 3 wherein said compound is endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one.
- 5. A method for the treatment of psychosis comprising administering to a patient in need thereof an effective amount of a compound of the formula ##STR11## wherein A is H.sub.2, O, (H)(OH), (OH).sub.2 or N--OH; B is H.sub.2, (H)(CH.sub.3), (H)(CH.sub.2 NR.sub.3 R.sub.4) or CH.sub.2 wherein R.sub.3 and R.sub.4 are C.sub.2-4 alkyl or are combined to give tetramethylene, pentamethylene or --CH.sub.2 CH.sub.2 --O--CH.sub.2 CH.sub.2 --; R.sub.1 is ##STR12## wherein Z is NR.sub.9, O or S; R.sub.5, R.sub.6 and R.sub.8 are each hydrogen, halogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxy; R.sub.7 is hydrogen, amino, (C.sub.1-4 alkyl)amino, (C.sub.1-4 alkyl).sub.2 amino, alkoxy or nitro; R.sub.9 is hydrogen, C.sub.1-4 alkyl or phenyl (C.sub.1-2 alkyl); R.sub.10 is hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, cyano or --CONH.sub.2 ; R.sub.11 is hydrogen, halogen, C.sub.1-4 alkyl or phenyl; the wavy line indicates that the configuration of the oxygen substituent on the ring can be endo or exo; and the pharmaceutically acceptable acid addition and quarternary ammonium salts of the aforesaid compounds.
- 6. A method according to claim 5 wherein said compound is endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one.
- 7. A method for stimulating gastric motility comprising administering to a patient in need thereof an effective amount of a compound of the formula: ##STR13## wherein A is H.sub.2, O, (H)(OH), (OH).sub.2 or N--OH; B is H.sub.2, (H)(CH.sub.3), (H)(CH.sub.2 NH.sub.3 R.sub.4) or CH.sub.2 wherein R.sub.3 and R.sub.4 are C.sub.2-4 alkyl or are combined to give tetramethylene, pentamethylene or --CH.sub.2 CH.sub.2 --O--CH.sub.2 CH.sub.2 --; R.sub.1 is ##STR14## wherein Z is NR.sub.9, O or S; R.sub.5, R.sub.6 and R.sub.8 are each hydrogen, halogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxy; R.sub.7 is hydrogen, amino, (C.sub.1-4 alkyl)amino, (C.sub.1-4 alkyl).sub.2 amino, alkoxy or nitro; R.sub.9 is hydrogen, C.sub.1-4 alkyl or phenyl (C.sub.1-2 alkyl); R.sub.10 is hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, cyano or --CONH.sub.2 ; R.sub.11 is hydrogen, halogen, C.sub.1-4 alkyl or phenyl; the wavy line indicates that the configuration of the oxygen substituent on the ring can be endo or exo; and the pharmaceutically acceptable acid addition and quarternary ammonium salts of the aforesaid compounds.
- 8. A method according to claim 7 wherein said compound is endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one.
- 9. A method for the treatment of glaucoma comprising administering to a patient in need thereof an effective amount of a compound of the formula: ##STR15## wherein A is H.sub.2, O, (H)(OH), (OH).sub.2 or N--OH; B is H.sub.2, (H)(CH.sub.3), (H)(CH.sub.2 NR.sub.3 R.sub.4) or CH.sub.2 wherein R.sub.3 and R.sub.4 are C.sub.2-4 alkyl or are combined to give tetramethylene, pentamethylene or --CH.sub.2 CH.sub.2 --O--CH.sub.2 CH.sub.2 --; R.sub.1 is ##STR16## wherein Z is NR.sub.9, O or S; R.sub.5, R.sub.6 and R.sub.8 are each hydrogen, halogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxy; R.sub.7 is hydrogen, amino, (C.sub.1-4 alkyl)amino, (C.sub.1-4 alkyl).sub.2 amino, alkoxy or nitro; R.sub.9 is hydrogen, C.sub.1-4 alkyl or phenyl (C.sub.1-2 alkyl); R.sub.10 is hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, cyano or --CONH.sub.2 ; R.sub.11 is hydrogen, halogen, C.sub.1.varies.4 alkyl or phenyl; the wavy line indicates that the configuration of the oxygen substituent on the ring can be endo or exo; and the pharmaceutically acceptable acid addition and quarternary ammonium salts of the aforesaid compounds.
- 10. A method according to claim 9 wherein said compound is endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one.
- 11. A pharmaceutical composition according to claim 1 wherein said compound is endo-8-(3-indolylcarbonyl-oxy)-2,6-methanooctahydro-2H-quinolizin-3-ol.
- 12. A method according to claim 3 wherein said compound is endo-8-(3-indolylcarbonyl-oxy)-2,6-methanooctahydro-2H-quinolizin-3-ol.
- 13. A method according to claim 5 wherein said compound is endo-8-(3-indolylcarbonyl-oxy)-2,6-methanooctahydro-2H-quinolizin-3-ol.
- 14. A method according to claim 7 wherein said compound is endo-8-(3-indolylcarbonyl-oxy)-2,6-methanooctahydro-2H-quinolizin-3-ol.
- 15. A method according to claim 9 wherein said compound is endo-8-(3-indolylcarbonyl-oxy)-2,6-methanooctahydro-2H-quinolizin-3-ol.
Priority Claims (5)
| Number |
Date |
Country |
Kind |
| 88 400415 |
Feb 1988 |
FRX |
|
| 88 400418 |
Feb 1988 |
FRX |
|
| 88 400416 |
Feb 1988 |
FRX |
|
| 88 400417 |
Feb 1988 |
FRX |
|
| 89 100392 |
Jan 1989 |
FRX |
|
CROSS-REFERENCE TO RELATED APPLICATION
This is a continuation of application Ser. No. 313,119, filed Feb. 21, 1989, abandoned.
The present invention relates to the use of quinolizine and quinolizinone derivatives in the manufacture of a medicament for the treatment of anxiety, psychosis, glaucoma, and to stimulate gastric motility. The invention also relates to certain novel derivatives of quinolizine and quinolizinone which are useful for the purposes indicated above and which are also useful for the treatment of migraine and the treatment of nausea and vomiting.
In accordance with the present invention, it has been discovered that anxiety, glaucoma, and psychosis can be treated and that gastric motility can be stimulated, in a patient in need thereof, by the administration of an effective amount of a compound of the formula: ##STR1## wherein A is H.sub.2, O, (H)(OH), (OH).sub.2 or N-OH; B is H.sub.2, (H)(CH.sub.3), (H)(CH.sub.2 NR.sub.3 R.sub.4) or CH.sub.2 wherein R.sub.3 and R.sub.4 are C.sub.2-4 alkyl or are combined to give tetramethylene, pentamethylene or --CH.sub.2 CH.sub.2 --O--CH.sub.2 CH.sub.2 --; R.sub.1 is ##STR2## wherein Z is NR.sub.9, O or S; R.sub.5, R.sub.6, and R.sub.8 are each hydrogen, halogen, C.sub.1-3 alkyl or C.sub.1-3 alkoxy; R.sub.7 is hydrogen, amino, (C.sub.1-4 alkyl)amino, (C.sub.1-4 alkyl).sub.2 amino, alkoxy or nitro; R.sub.9 is hydrogen, C.sub.1-4 alkyl or phenyl (C.sub.1-2 alkyl); R.sub.10 is hydrogen, halogen C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, cyano or --CONH.sub.2 ; indicates that the configuration of the oxygen substituent on the ring can be endo or exo; and the pharmaceutically acceptable acid addition and quaternary ammonium salts of the aforesaid compounds.
A novel group of compounds, according to the present invention are compounds of the following formula: ##STR3## wherein R.sub.1 ' is ##STR4## and A, B, R.sub.9 and R.sub.10 are defined as above.
Examples of the C.sub.1-4 alkyl groups referred to above are methyl, ethyl, propyl, isopropyl and butyl. Examples of the C.sub.1-4 alkoxy groups are methoxy, ethoxy, propoxy and butoxy. The halogens referred to above can be fluorine, chlorine or bromine. When the wavy line in the general structural formula is changed to a solid line, this indicates that the configuration of the compounds is endo. Such endo-compounds can also be referred to as trans. Similarly, exo-compounds can also be referred to as cis. Any hydrates of the present compounds are considered as equivalent to the compounds themselves and this would include compounds in which the carbonyl (i.e., A is O) exists as (OH).sub.2.
A preferred group of compounds for use in the present invention are those wherein the ester is attached to the polycyclic ring in the endo-configuration. A further preferred group are those having the endo-configuration wherein A is .dbd.O and .dbd.(OH).sub.2. In a still further preferred group, B is additionally .dbd.H.sub.2.
The pharmaceutically acceptable acid addition salts referred to above can be non-toxic salts with suitable acids such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acids; or with organic acids such as organic carboxylic acids, for example, acetic, propionic, glycolic, maleic, hydroxymaleic, malic tartaric, citric, salicyclic, 2-acetyloxybenzoic, nicotinic or isonicotinic; or organic sulfonic acids, for example methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, 4-toluenesulfonic or 2-naphthalensulfonic. Quaternary ammonium salts are formed with alkyl halides such as methyl chloride, methyl bromide or ethyl bromide; or with sulfate esters such as methyl 4-toluenesulfonate or methyl 2-naphthalenesulfonate.
Some specific examples of compounds encompassed by the present invention are the following:
The compounds of the present invention can be prepared by reacting an alcohol or a reactive derivatives thereof, said alcohol having the formula: ##STR5## wherein A' is O or H.sub.2, with a reactive equivalent of an acid of the formula:
When the --OH group in the starting alcohol is axial (endo), it can also be converted to the corresponding ester by reaction with the appropriate acid chloride or bromide with the reaction being carried out in the presence of an equivalent of a suitable tertiary base such as 4-dimethylaminopyridine in a high boiling inert solvent such as xylene. In this case, however, long heating (24-84 hours) at a temperature at or above 140.degree. C. is necessary so that the procedure would not be suitable for use with acid halides that are not stable under the indicated conditions. Thus, it was necessary to use an alternative for the preparation of such compounds. In this procedure, an appropriate acid chloride or bromide or a glyoxylyl chloride or bromide, in a nitroparaffin solvent, is reacted with a solution of a super acid salt of the alcohol and an equivalent amount of a heavy metal salt of the same super acid. The glyoxylyl chloride can be used in the process as indicated because it decarbonylates readily under the conditions used. The reaction itself can be carried out over a period of 1-24 hours at temperatures ranging from -80.degree. C. to ambient temperatures (about 23.degree. C.). Examples of suitable super acids with M=H are MBF.sub.4, MAsF.sub.6, MSbF.sub.6, MPF.sub.6, MTaF.sub.6 or MNbF.sub.6 with examples of suitable heavy metals (M) being silver and thallium. Examples of nitroparaffin solvents are nitromethane, nitroethane, 1-nitropropane and 2-nitropropane.
Actually, where the group R.sub.1 contains a primary or secondary amino group, it is usually protected during the above reaction, with a benzyl group being commonly used to protect a secondary amine and a benzyloxycarbonyl group being used to protect a primary amine. In either case, the protecting group in the product is removed by conventional procedures, for example by hydrogenation with hydrogen and a palladium catalyst.
Various procedures can be used to convert those compounds wherein A is O and whose preparation is described below, to other different bridged derivatives of the present invention by standard methods. Thus, the ketone group in the polycyclic system can be reduced to the corresponding alcohol using an alkali metal (sodium or potassium) borohydride in a lower alkanol such as methanol or ethanol.
The ketone group can also be reduced completely to a methylene group by a two step procedure. In the first step, the ketone is reacted with ethylene dithiol or trimethylene dithiol in the presence of a strong acid such as hydrochloric acid or BF.sub.3 to give the corresponding dithioketal. The reaction is carried out in a suitable polar solvent such as nitromethane or acetic acid. The dithioketal is then reduced with hydrazine in the presence of Raney nickel in a lower alkanol solvent such a 2-propanol at elevated temperatures (60.degree.-100.degree. C.). Actually this same procedure can be used to reduce the original starting alcohol, hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-one, to 8-hydroxy-2,6-methanooctahydro-2H-quinolizine which can itself be reacted with acid derivatives as described earlier to give the corresponding esters.
Compounds containing other B-groups (i.e. aminomethyl, methylene or methyl groups) can be obtained from products in which A is O and B is H.sub.2 by a Mannich reactions using formaldehyde and a secondary amine such as dimethylamine, diethylamine, piperidine or pyrrolidine. This reaction gives the corresponding aminomethyl compound and, when B is dimethylaminomethyl, the amino moiety is eliminated on heating at 90.degree.-110.degree. C. in an inert solvent such as toluene to give the corresponding methylene compound (B is .dbd.CH.sub.2). This exocyclic methylene compound can be isolated by standard methods and transformed into a methyl group by hydrogenation, for example, by using hydrogen and platinum oxide.
To obtain those compounds in which A is hydroxyimino (N--OH), the ketone referred to above can be reacted with hydroxylamine hydrochloride by standard procedures.
The alcohol used as a reactant in the above procedure can be obtained from known alkyl (C.sub.1-4) 3-cyclopentene-1-carboxylates by a multi-step procedure. Specifically, the double bond in the indicated cyclopentene is oxidized to a 1,2-diol using N-methylmorpholine N-oxide in the presence of osmium tetroxide catalyst. The diol is then cleaved to the corresponding dialdehyde using sodium metaperiodate. A Robinson-Schopf cyclization of the dialdehyde with a lower alkyl glycine ester and acetone-dicarboxylic acid, preferably at pH.sub.4, gives a pseudopelletierine derivative of the following type: ##STR6##
The ketone group is reduced to an alcohol using sodium borohydride and the product is reacted with dihydropyran to protect the --OH group as a tetrahydropyranyl ether. Dieckmann cyclization of the diester using a strong base (e.g. potassium t-butoxide) followed by aqueous acid hydrolysis and decarboxylation gives the desired alcohol. The resulting alcohols can exist in two conformations--axial and equatorial. The main product obtained by the above procedure is the axial alcohol and it can be separated from the equatorial isomer by crystallization of the camphorsulfonate or tetrafluoroborate salt.
The compounds represented by Formula I are 5-HT M-receptor antagonists. The 5-HT M-receptor is also known as the 5HT-.sub.3 receptor to those skilled in the art. The compounds are useful in the treatment of anxiety, glaucoma, and psychosis and in the manufacture of a medicaments, therefor. The compounds are also useful for increasing gastric motility and in the manufacture of medicaments, therefor.
The activity of the compounds against 5-HT can be assessed by determining their pA.sub.2 values in the isolated rabbit heart as described by J. R. Fozard et al., Eur. J. Pharmacol., 59, 195-210 (1979). In the method described, the molar concentration of antagonist which reduces the effects of twice the ED.sub.50 of 5-HT to that of the ED.sub.50 in the absence of antagonist is determined. The pA.sub.2 value is the negative logarithm of said molar concentrations. In general terms, the higher the pA.sub.2 value the more potent is the compound. When tested in this way, the present compounds show pA.sub.2 's generally in the range of about 8 to 10.
The activity of these compounds against 5-HT can be assessed in vivo by measurement of the effect of the compound on the Von Bezold-Jarisch Reflex induced by 5-HT injected intravenously into the rat (see Paintal A.S., Physiol. Rev. 53, 159-227, 1973; J. R. Fozard, Naunyn-Schmiedeberg's Arch. Pharmacol., 326, 1984, 36-44). The transient cardiac slowing arises from an increased afferent vagus activity arising from stimulation by 5-HT of sensory afferent fibers in and around the heart. When tested against the Von Bezold-Jarisch Reflex induced by 5-HT, compounds endo-8-(3,5-dimethylbenzoyloxy)hexahydro-2,6-methano-2H-quinolizin-3(4H)-one hydrochloride and endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one hydrochloride suppressed the response dose-dependently at doses of 0.01-0.1 mg/kg given intravenously or 0.25-1 mg/kg given orally.
The present compounds appear to be highly selective in their action against the 5-HT M-receptor. Their potency against other 5-HT receptors and other spasmogens, in particular carbachol, phenylephrine, histamine and calcium, is known to be at least three orders lower that that against 5-HT M-receptors.
As used in this application:
(a) the phrase "gastric motility", refers to the rate at which the stomach empties its contents into the duodenum.
(b) the term "glaucoma" refers to a group of eye diseases characterized by an increase in intraocular pressure, which can cause pathological changes in the optic disk and typically defects in the field of vision.
(c) the term "intraocular pressure" refers to the pressure within the eyeball.
(d) the term "anxiety" refers to a condition where a patient is experiencing fear, apprehension, uncertainty, etc., and can be accompanied with physical manifestations such as, tachycardia, tremors, sweating, etc.
(e) the term "psychosis" refers to a condition where the patient, e.g., a human, experiences a major mental disorder of organic and/or emotional origin characterized by derangement of the personality and loss of contact with reality, often with delusions, hallucinations or illusions, such as, for example, schizophrenia or mania.
(f) the term "treatment" refers to the ability to either relieve or alleviate the patient's disease.
(g) the term "patient" as used herein is taken to mean warmblooded animals, such as mammals, for example, dogs, rats, mice, cats, guinea pigs, horses, cattle, sheep and primates, including humans.
The compounds of Formula I exhibit the pharmacological action of increasing the motility of the upper gastrointestinal tract. This means that the compounds increase the rate at which the stomach empties its contents into the duodenum.
Thus, the compounds are useful in the treatment of gastric stasis. Gastric stasis refers to a condition where the stomach's ability to empty its contents into the duodenum is impaired. This typically produces discomfort in the patient.
The compounds are also useful in the treatment of gastroesophageal reflux. Gastroesophageal reflux refers to a condition, where small quantities of gastric juice are refluxed into the lower part of the esophagus. The acidic gastric juice irritates the mucosa of the esophagus causing pain and discomfort in the patient.
The quantity of compound required to produce this gastric motility stimulating effect described above will vary with the particular compound utilized, the patient, the route of administration, the severity of the patient's condition, the presence of other underlying disease states in the patient, and other medications which are being administered concurrently to the patient. Generally though, a patient will respond to dosage range of from 0.01 to 10 mg/kg/day.
One method of demonstrating that the compounds of Formula I increase gastric motility is the following test protocol. Male mice should be fasted overnight prior to being utilized in the test. One group of mice should be administered saline intraperitoneally, and the other group should be administered a compound of Formula I such as, for example, endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one, at a dose of 5 mg/kg intraperitoneally in a saline carier.
One hour after administration of either the drug or a saline control, the mice should be given 0.3 ml intragastrically of a suspension containing 10% w/v charcoal, and 5% w/v tragacanth gum with the aid of a feeding needle. Fifteen minutes later the animals should be sacrificed.
The stomachs should be surgically removed and then weighed. The contents should be washed from the stomach, and then the stomachs should be reweighed. The groups should then be compared utilizing the change in weight of the stomach after washing, as an indicator of the rate of gastric emptying.
As noted above, the compounds are also useful as antipsychotics. The quantity of compound required to produce this antipsychotic therapeutic effect will vary with the particular compound utilized, the patient, the severity of the patients illness, the presence of other disease states within the patient, and the mode of administration. Generally though, a patient's psychosis will respond to the compound at a dosage range at from about 0.01 mg/kg to about 10 mg/kg of patient body weight per dosage.
The compounds of Formula I are not dopamine antagonists. Therefor, patients being administered one of these compounds will not experience the numerous side effects that are typically associated with the neuroleptic agents that are currently available, such as chlorpromazine, haloperidol, fluphenazine, etc.
One manner of demonstrating the antipsychotic utility of these compounds is by their ability to block the hyperactivity which usually accompanies the intra-accumbens administration of amphetamine in rats. The following test protocol can be utilized to demonstrate this activity.
This pharmocological effect is measured indirectly. This is accomplished by measuring what effect the compound has upon the ability of a rat to avoid an electrical shock, which it has previously learned to avoid. Initially, the rat should be placed in a test chamber capable of delivering an electrical shock to the rat at a specified rate, for example once every 20 seconds. The test chamber should also be capable of delaying the rate at which electrical shocks are administered if the rat performs the proper avoidance behavior, such as moving from one side of the chamber to the other. The rat should be repeatedly exposed to this test chamber on a regular basis until it has learned to consistently engage in the behavior which delays the response. After it has learned this behavior it is suitable for further testing.
A bilateral cannulae should be implanted in the nucleus accumbens according to the following procedure. The rat should be anesthetized and mounted in a stereotaxic device. A small hole is drilled thru the skull at coordinates A1.5, L1.4.sup.1 (relative to bregma), bilaterally and an additional hole is drilled near by for a small machine screw. A 20 gauge cannulae is placed stereotaxically, so as to terminate 1 mm above, the nucleus (V6.0, brain surface).sup.1. Dental acrylic can be utilized to secure the cannulae to the anchor screw and a 25 gauge stylus can be utilized as a plug for each cannulae.
At least seven days after surgery, the rat should be exposed to the electrical stimuli in the test chamber in order to ascertain that it can still engage in the behavior which delays the rate at which shocks are administered. Rats demonstrating this avoidance response are suitable for use in the comparative tests.
The rat should be administered intra-accumbens amphetamine (10 mcg/side), subjected to electrical shock in the test chamber and its rate of avoidance recorded.
Thereafter, the rat can be administered the test compound (0.25 ng/side) via the intra-accumbens cannulae. Thirty minutes after administration of the test compound, the rat should be administered intra-accumbens amphetamine (10 mcg/side), subjected to electrical shock in the test chamber and its rate of avoidance recorded.
Rats administered amphetamine alone will exhibit an increased rate of avoidance. Rats administered both amphetamine and a compound of Formula I, such as for example, endo-hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one will not exhibit this increased rate of avoidance.
The compounds of the present invention exhibit the pharmacological activity of lowering intraocular pressures. Thus, these compounds are useful in the treatment of glaucoma.
The compounds can be administered via ophthalmic dosage forms such as, for example, ophthalmic drops, ophthalmic ointments, and ophthalmic disks. The ophthalmic drops of the present invention should contain from 0.1-10% w/w of one of the compounds of Formula I. Typically, it will be dissolved in a buffered, isotonic solution containing antimicrobial preservative agents. The ophthalmic ointments will also generally contain from 0.1-10% w/w of one of the compounds of Formula I admixed with a suitable base, such as white petrolatum and mineral oil, along with antimicrobial preservatives. The ophthalmic disks will typically be constructed so as to contain a core of active ingredient surrounded by a polymer matrix such as, for example, a hydrophobic ethylene/vinyl acetate copolymer. Specific methods of compounding these dosage forms, as well as appropriate ophthalmic pharmaceutical carriers are known in the art. REMINGTON PHARMACEUTICAL SCIENCES, 16th Ed. Mack Publishing Co. (1980).
Typically, the ophthalmic drops or ophthalmic ointments will be administered from 1 to 4 times daily. The ophthalmic disks will be administerd weekly.
If desired, the compounds of Formula I can be administered systemically in order to lower intraocular pressures. The quantity of compound required to produce this ocular hypotensive effect as the result of systemic administration will vary with the particular compound utilized, the patient, the route of administration, the severity of the patient's glaucoma, the presence of other underlying disease states in the patient, and other medications which are being administered concurrently to the patient. Generally though, a patients glaucoma will respond to dosage range of from 0.01 to 10 mg/kg/day, if administered systemically.
The compounds of Formula I are useful in the treatment of anxiety; that is relieving or alleviating the apprehension, fear, or uncertainty, etc., that patients suffering from anxiety commonly experience, as well as relieving or alleviating the physiological changes associated with anxiety such as tachycardia, tremors, sweating, etc.
The compounds of Formula I possess a significant advantage over the anxiolytic agents which are currently available to clinicians, such as chlordiazepoxide, diazepam, and other benzodiazepines. The benzodiazepines commonly cause sedation and impairment of motor skills at the dosage levels commonly used in the treatment of anxiety.
The compounds of Formula I do not suffer from this disadvantage. They exhibit a wide dosage range at which they demonstrate anxiolytic activity, without causing either sedation or impairment of motor skills.
The quantity of compound required to produce the anxiolytic effect described above will vary with the particular compound utilized, the patient, the route of administration, the severity of the patient's anxiety, the presence of other underlying disease states in the patient, and other medications which are being administered concurrently to the patient. Generally though, a patient's anxiety will respond to dosage range of from 0.01 to 10 mg/kg/day.
The novel compounds of Formula II are further useful for the treatment of pain, especially migraine, vascular and cluster headaches and trigeminal neuralgia. They are also useful in the treatment of nausea and vomiting arising from treatment with cancer chemotherapeutic agents.
In the past, acute attacks of migraine have been treated with a peripheral vasoconstrictor, such as ergotamine, which may be co-administered with caffeine, and dihydroergotamine; an antipyretic analgesic, such as acetylsalicylic acid or p-acetylaminophenol; and/or an antiemetic such as cyclizine, metoclopramide and thiethylperazine. It has also been reported (J. B. Hughes, Med. J. Aust. 2, No. 17, 580 (1977)) that immediate relief of an acute migraine attack can be obtained by slow intravenous injection of metoclopramide (10 mg).
It is believed that 5-hydroxytryptamine (5-HT) is the naturally occurring substance most likely to play a role in the pathophysiology of migraine. Increased amounts of 5-HT and its metabolite 5-hydroxyindoleacetic acid are excreted in the urine during most attacks. Further, plasma and platelet 5-HT concentrations fall rapidly at the onset of an attack and remain low while the headache persists. Moreover, attacks of migraine have been clearly associated with periods of thrombocytopaenia in certain patients. It has been proposed that compounds which block the activity of 5-HT would be of use in the symptomatic treatment of migraine (J. R. Fozard, International Headache Congress 1980, reported in Advances in Neurology, Vol 33., Raven Press, New York, 1982).
The known migraine prophylactic drugs, methysergide, propranolol, amitriptyline, and chlorpromazine have widely different pharmacological activities but all are 5-HT D-receptor antagonists at the doses used clinically for the prophylaxis of migraine. Metoclopramide is a potent 5-HT M-receptor antagonist and it has been proposed (J. R. Fozard supra) that a blockade of the M-receptor present on afferent sensory neurones affords symptomatic relief in an acute migraine attack.
The potency as 5-HT receptor antagonists of (-) cocaine and some related compounds, including pseudotropyl benzoate (i.e., benzoylpseudotropine) and 3,5-dichlorobenzoyltropine has been reported (J. R. Fozard et al., Eur. J. Pharmacol., 59, (1979) 195-210; J. R. Fozard, Naunyn-Schmiedeberg's Arch Pharmacol., 326, (1984), 36-44). The pA.sub.2 values reported for metoclopramide, pseudotropyl benzoate, nor (-) cocaine and benzoyltropine are 7.2, 7.0, 7.7, and 7.2 respectively whilst the pA.sub.2 value determined for 3,5-dichlorobenzoyltropine by the same procedure is 9.3 (J. R. Fozard et al., Eur. J. Pharmacol., 49, (1978) 109-112; J. R. Fozard, Naunyn-Schmiedeberg's Arch Pharmacol., 326, (1984), 36-44). In a double-blind clinical trial, 3,5-dichlorobenzoyltropine proved an effective treatment for the acute migraine attack (C. Loisy et al., Cephalalgia, 5, (1985) 79-82). A further series of tropine esters, with pA.sub.2 values for blockade of the 5-HT M-receptors between 7.7 and 13.6 have been described by Richardson et al., Nature, 316, (1985) 26-131.
The compounds of Formula II of the present invention block the M-receptors for 5-hydroxytryptamine (5-HT) on afferent sensory neurones, certain of which subserve the transmission of pain. As explained above, the blocking of such M-receptors appears to be a mechanism whereby the symptoms of migraine can be relieved. Accordingly, the compounds are useful in the treatment of migraine when administered in amounts sufficient to effectively block the said M-receptors.
In addition, compounds blocking 5-HT M-receptors, including metoclopramide, 3,5-dichlorobenzoyltropine and (3.alpha.-tropanyl)-1H-indole-3-carboxylic acid ester, are highly effective in preventing the nausea and vomiting induced by cancer chemotherapeutic agents in an animal experimental model (W. D. Miner et al., Brit. J. Pharmacol., 88, (1986) 374P; W. D. Miner and G. J. Sanger, Brit J. Pharmacol., 88, (1986) 497-499; B. Costall et al., Neuropharmacology, 25, (1986) 959-961). It is believed that cytotoxic drug-induced vomiting involves a 5-HT M-receptor mechanism (W. D. Miner and G. J. Sanger, Brit J. Pharmacol., 88, (1986) 497-499). Accordingly, the compounds of Formula II are useful in the treatment of cytotoxic drug-induced vomiting when administered in amounts sufficient to effectively block the said M-receptors.
The dosage range at which the compounds of Formula II exhibit their anti-migraine and anti-emetic effects will vary depending upon the particular compound utilized, the patient, the route of administration, the severity of the patient's condition, the presence of other underlying disease states in the patient, and other medications which are being administered concurrently to the patient. Generally though, a patient's condition will respond to a dosage range of from 0.01 to 10 mg/kg/day.
The compounds of Formula I can be administered in various manners to achieve the desired effect. The compounds are typically administered either orally or parenterally (subcutaneously, intravenously, intramuscularly). They can also be administered by suppository. As noted above, opthalmic preparations may also be utilized when glaucoma is being treated.
For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, suspensions, or emulsions. Solid unit dosage forms can be capsules of the ordinary gelatin type containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, and cornstarch or they can be sustained release preparations. In another embodiment, the compounds of Formula I can be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders, such as acacia, cornstarch, or gelatin, disintegrating agents such as potato starch or algenic acid, and a lubricant such as stearic acid or magnesium stearate. Liquid preparations are prepared by dissolving the active ingredient in an aqueous or non-aqueous pharmaceutically acceptable solvent which may also contain suspending agents, sweetening agents, flavoring agents, and preservative agents as are known in the art.
For parenteral administration, the compounds may be dissolved in a physiologically acceptable pharmaceutical carrier and administered as either a solution or a suspension. Illustrative of suitable pharmaceutical carriers are water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative, or synthetic origin. The pharmaceutical carrier may also contain preservatives, buffers, etc. as are known in the art.
The following examples are presented in order to further illustrate the compounds used in the present invention. However, they should not be construed as limiting the scope of the invention in any manner. These compounds are disclosed and claimed in European Patent Application 87116119.6.
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| Hyperactivity Following Withdrawal of Mesolimbic Dopamine Infusion and Neuroleptic Treatment is Reversed by GR380231, British Journal of Pharmacology, vol. 91, p. 338 P, (1987). |
| More on Beecham's 5HT Compounds, Scrip, No. 1193, p. 28, (Apr. 3rd 1987). |
| Increased Gut Cholinergic Activity and Antagonism of 5-Hydroxytryptamine M-Receptors by BRL 24924; Potential Clinical Importance of BRL 24924: Potential clinical Importance of BRL 24924, Br. J. pharmac., vol. 91, p. 77 (1987). |
| Effects of the 5HT.sub.3 Receptor Antagonists, GR 3803F, on Raised Dopaminergic Activity in the Mesolimibic System of the Rat and Marmoset Brain, British Journal of Pharmacology, vol. 92, pp. 881-894, (1987). |
| Research, High Hopes for Glaxo Drug, but Early Days Yet, The Pharmaceutical Journal, p. 14, Jan. 3, 1987. |
| Anxiogenesis Follows Abstinence Withdrawal from Long-Term Treatment with Diazepam but not GR 38032F, British Journal of Pharmacology, vol. 90, p. 420 P, (Mar. 1987). |
| The Anxiolytic Activities of GR 38032F, A 5HT.sub.3 Receptor Antagonists, in the Rat and Cynomolgus Monkey, British Journal of Pharmacology, vol. 90, p. 88P, (Mar. 1987). |
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Continuations (1)
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313119 |
Feb 1989 |
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Patent Grant
5011846
