Claims
- 1. A compound of the formula ##STR17## wherein one of R.sub.1 and R.sub.2 is hydrogen and the other is methyl, methoxy, methylthio, dimethylsulfamoyl, chloro, fluoro or trifluoromethyl; one of R.sub.3 and R.sub.4 is hydrogen and the other is methyl, methoxy, methylthio, dimethylsulfamoyl, chloro, fluoro or trifluoromethyl; n is 2; m is 0; X is oxygen, and R.sub.5 and R.sub.6 are hydrogen or taken together are the group ##STR18## or a salt thereof with a pharmaceutically acceptable acid.
- 2. A compound in accordance with claim 1, wherein R.sub.2 and R.sub.3 are hydrogen; R.sub.1 is methyl and R.sub.4 is chloro.
- 3. A compound in accordance with claim 1, wherein R.sub.2 and R.sub.4 are hydrogen; R.sub.1 is chloro and R.sub.3 is fluoro.
- 4. A compound in accordance with claim 1, wherein R.sub.1 and R.sub.3 are hydrogen; R.sub.2 is methoxy and R.sub.4 is methylthio.
- 5. A compound in accordance with claim 2, wherein R.sub.5 and R.sub.6 ar hydrogen, i.e., 3-{2-[4-(8-chloro-2-methyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone.
- 6. A compound in accordance with claim 1, wherein one of R.sub.1 and R.sub.2 is hydrogen and the other is methyl; one of R.sub.3 and R.sub.4 is hydrogen and the other is chloro; and R.sub.5 and R.sub.6 are hydrogen.
Priority Claims (2)
| Number |
Date |
Country |
Kind |
| 4605/73 |
Mar 1973 |
CH |
|
| 448/74 |
Jan 1974 |
CH |
|
CROSS-REFERENCE TO RELATED APPLICATIONS
This is a division of application Ser. No. 471,094, filed May 17, 1974, now U.S. Pat. No. 3,954,764, granted May 4, 1976, which in turn is a continuation-in-part of U.S. patent application Ser. No. 378,732 filed July 12, 1973, now abandoned.
The invention relates to compounds of the formulas ##STR2## wherein one of R.sub.1 and R.sub.2 or, respectively, R.sub.3 and R.sub.4 is hydrogen and the other is methyl, methoxy, methylthio, dimethylsulfamoyl, chloro, fluoro or trifluoromethyl, n is 2 or 3; m is 0 or 1; X is sulfur, oxygen, imino, lower alkylimino or methylene, and R.sub.5 and R.sub.6 are hydrogen or together are the group ##STR3## and salts thereof with pharmaceutically acceptable acids.
The invention relates to compounds of the formulas ##STR4## wherein one of R.sub.1 and R.sub.2 is hydrogen and the other is methyl, methoxy, methylthio, dimethylsulfamoyl, chloro, fluoro or trifluoromethyl; one of R.sub.3 and R.sub.4 is hydrogen and the other is methyl, methoxy, methylthio, dimethylsulfamoyl, chloro, fluoro or trifluoromethyl; n is 2 or 3; m is 0 or 1; X is sulfur, oxygen, imino, lower alkylimino or methylene; and R.sub.5 and R.sub.6 are hydrogen or taken together are the group ##STR5## and salts thereof with pharmaceutically acceptable acids.
According to the above-specified definition, the benzyl[b,f] thiepin of formulas I and Ia bears a substituent in each of the aromatic rings. One substituent is carried in the 2- or 3- position, and the other in the 7- or 8-position of the dibenzo[b,f]thiepin molecule. It has been found that the compounds of formulas I and Ia of the invention and their pharmaceutically acceptable addition salts which are new compounds, demonstrate a strong central depressant effect and neuroleptic activity. They can, therefore, for example, be utilized in the treatment of acute or chronic schizophrenia as well as tranquilizers. Of particular advantage is the fact that the compounds of the invention demonstrate a lack of or only weak cataleptic side effects so that no or insignificant motor disturbances are observed.
Preferred compounds of the invention are those of formula I, as well as their salts with pharmaceutically acceptable acids. Preferred compounds of formulas I and Ia are those wherein R.sub.2 and R.sub.3 are hydrogen, R.sub.1 is methyl and R.sub.4 is chloro, fluoro or methylthio, as well as their pharmaceutically acceptable acid addition salts.
Another preferred group of compounds of formulas I and Ia comprises one wherein R.sub.2 and R.sub.3 are hydrogen, R.sub.1 is chloro and R.sub.4 is fluoro, as well as their salts with pharmaceutically acceptable acids.
Yet another preferred group of compounds of formulas I and Ia comprises one wherein R.sub.1 and R.sub.3 are hydrogen; R.sub.2 is methoxy and R.sub.4 is methylthio, as well as their salts with pharmaceutically acceptable acids.
Still another preferred group of compounds of formulas I and Ia comprises one wherein n is 2; m is 0; X is oxygen or methylene and R.sub.5 and R.sub.6 are hydrogen, as well as their salts with pharmaceutically acceptable acids.
Preferred compounds of the invention are 1-{2-[4-(8-chloro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-pyrrolidinone, 3-{3-[4-(8-fluoro-10,11-dihydro-2-methyldibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone, 3-{2-[4-(2-chloro-8-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone and 3-{2-[4-(10,11-dihydro-2-methyl-8-methylthio-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone, as well as their salts with pharmaceutically acceptable acids.
The 10,11 -saturated compounds of formula I and their salts with pharmaceutically acceptable acids cam be prepared according to the processes hereinafter described:
A. A compound of the formula ##STR6## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as hereinbefore described, and Y is a leaving group,
B. A compound of the formula ##STR8## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4, n, m, X, R.sub.5 and R.sub.6 are as hereinbefore described,
C. A compound of the formula ##STR9## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as hereinbefore described,
The 10,11-unsaturated compounds of formula Ia and their pharmaceutically acceptable acid addition salts can be prepared in accordance with the invention by a process which is hereinafter described, that is, a compound of the formula ##STR11## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as hereinbefore described,
The leaving group Y in the starting material of formula II is preferably halogen or alkyl-substituted or aryl-substituted sulfonyloxy. Preferably, the alkyl group of the sulfonyloxy substituent is lower alkyl, such as methyl and preferably the aryl group of the sulfonyloxy substituent is phenyl or p-tolyl. The halogen substituent is preferably chlorine or bromine.
The Y group of the starting material of formula II can, for example, be introduced in the following manner:
When Y is to be halogen, the corresponding 10-hydroxy compound is reacted with an appropriate halogenating agent, for example, thionyl chloride, thionly bromide, or with a hydrogen halide in the presence of a dehydrating agent, for example, hydrogen chloride and calcium chloride.
When Y is to be alkyl-substituted or aryl-substituted sulfonyloxy, the corresponding 10-hydroxy compound is reacted with an alkyl-substituted or aryl-substituted sulfonic acid halide, for example, the chloride.
The starting materials of formula III can, for example, be prepared by the following reaction:
A compound of the formula ##STR13## wherein R.sub.7 is a protecting group, for example, benzyl or a lower alkoxycarbonyl group, for example, methoxycarbonyl, ethoxycarbonyl or the like,
The reaction of the starting materials of formulas II and III in accordance with the process of the invention can be carried out without the addition of a solvent. However, if a solvent is utilized, preferably it is an organic solvent, for example, an aromatic hydrocarbon such as benzene or toluene, a lower alkanol such as methanol or ethanol, a chlorinated hydrocarbon such as methylene chloride, trichloroethylene, chloroform, carbon tetrachloride or chlorobenzene, an aliphatic or cyclic ether such as diethyl ether, tetrahydrofuran or dioxane, or dimethylformamide or dimethylsulfoxide. The temperature at which the reaction is carried out, preferably is in the range of from about 30.degree. to about 200.degree.; the most preferred temperature is in the range of about 60.degree. to about 150.degree.. Advantageously, the reaction is carried out in the presence of an acid-binding agent, for example, in the presence of an alkali carbonate such as potassium carbonate or it is carried out in the presence of an excess of the starting material of formula III.
The starting enamines of formula IV are likewise end products of formula Ia. The enamines of formula IV are prepared in accordance with the invention by reacting the corresponding 10-oxo compound of formula VII with a compound of formula III. For example, the reaction is carried out in the presence of a strong acid in an aromatic solvent at a temperature, for example, in the range of from about 80.degree. to about 150.degree.. As the acid there can be utilized, for example, mineral acids such as sulfuric acid or hydrochloric acid, or a strong organic acid such as methanesulfonic acid or toluenesulfonic acid. As the aromatic solvent, preferably there is utilized benzene, toluene or o-, m-, or p-xylene. By heating, there is formed an azeotrope between the solvent and the water which is formed in the reaction, which can be distilled. The water which is formed can also be removed by the addition of a dehydrating agent such as titanium tetrachloride or the like.
The reduction of the enamines of formula IV in accordance with the invention, preferably is carried out by treatment with an alkali metal borohydride in the presence of a strong acid. As the alkali metal borohydride, preferably there can be used sodium or potassium borohydride, especially sodium borohydride. It is also possible to utilize lithium borohydride. The strong acid can either be an organic or an inorganic acid. As an organic acid, there can be utilized straight or branched chain lower mono- or dicarboxylic acids with up to 4 carbon atoms, which can be substituted by halogen, for example, formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, isobutyric acid, oxalic acid and the like. Preferred is acetic acid; especially preferred is oxalic acid. As an inorganic acid, there can be utilized, for example, sulfuric acid, hydrochloric acid, especially hydrochloric acid, and the like. A preferred inorganic acid is concentrated sulfuric acid.
The enamine of formula IV is unstable in the presence of water. Therefore, the reduction suitably is carried out in the absence of water. The reaction is preferably carried out in an anhydrous acid or only in such acids where should they contain water, the water is not released, for example, concentrated sulfuric acid.
The reaction of the alkali metal borohydride and the strong acid can, advantageously, be carried out in the presence of an ether such as diethyl ether, tetrahydrofuran, dioxane, diethyleneglycol dimethyl ether (diglyme) or dimethoxyethane, at a temperature in the range of about room temperature and the reflux temperature of the solvent. Preferred is the reflux temperature.
The reduction of the enamine of formula IV can be carried out by other methods, for example, by the treatment with formic acid or with zinc and acetic acid. The foregoing reaction is preferably carried out at a temperature between about room temperature and the reflux temperature of the solvent; preferably at the reflux temperature.
The starting material of formula V can, for example, be prepared by reacting a compound of formula II with a mono-N-protected piperazine, for example, N-carbethoxy-piperazine. The condensation product is subsequently hydrolyzed, for example, with the aid of an aqueous alkali. Yet another method comprises the reaction of the above-mentioned mono-N-protected piperazine, for example, N-carbethoxy-piperazine, essentially in the same manner as that described for the reaction between the compounds of formulas VII and III. The so-obtained N-protected enamine can have its 10,11-double bond reduced in a similar manner to that described above for the reduction of the enamine of formula IV, and subsequently the protecting group can be hydrolyzed, for example, with the aid of an aqueous alkali.
The leaving group of the starting material of formula VI has the same meaning as in the case described for the starting material of formula II. The starting materials of formula VI can be prepared, for example, by treatment of a lactam alkali metal salt of the formula ##STR16## wherein R.sub.5, R.sub.6, m and X are as previously described, and M is an alkali metal, such as sodium or the like,
Starting materials of formula VI wherein Y is a chlorine atom can also be prepared by reacting 1-bromo-2-chloroethane or 1-bromo-3-chloropropane with an alkali metal salt lactam of formula X.
The reaction of the starting materials of formulas V and VI in accordance with the invention, conveniently can be carried out in an inert organic solvent, for example, in an aromatic hydrocarbon such as benzene or toluene, a chlorinated hydrocarbon such as chloroform, an ether such as dioxane or dimethoxyethane, a lower alkanol such as methanol or ethanol, a ketone such as acetone or methylethyl ketone, or dimethylformamide or dimethylsulfoxide. It is preferred to carry out the above reaction in the presence of an acid-binding agent, for example, in the presence of an alkali metal carbonate, such as sodium or potassium carbonate, or in the presence of an inorganic base such as triethylamine. As the acid-binding agent, there can be utilized an excess of the base of formula V. The temperature at which the reaction is carried out preferably is in the range of about room temperature and the boiling point of the reaction mixture.
The starting materials of formula VII, as well as the corresponding 10-hydroxy compound referred to herein, are known compounds or can be prepared according to known procedures. The reaction of a compound of formula VII with a compound of formula III leads to a 10,11-unsaturated enamine of formula I. This reaction is carried out, for example, in the presence of a strong acidic agent in an aromatic solvent with heating, for instance, at a temperature in the range of from about 80.degree. C. to about 150.degree. C. Exemplary of the acidic agents which can be used are a mineral acid such as sulfuric acid or hydrochloric acid, a strong organic acid such as methanesulfonic acid or p-toluenesulfonic acid, or the like. As the aromatic solvent, there can be preferably used benzene, toluene or o-, m- or p-xylene. During the heating, an azeotrope is formed between the solvent and the water formed in the reaction. The azeotrope can be removed by distillation. The water which forms in the reaction can also be removed by adding a dehydrating agent such as, for example, titanium tetrachloride.
The bases of formulas I and Ia form salts with inorganic, as well as with organic acids, for example, they form salts with hydrohalic acids such as hydrochloric acid, hydrobromic acid or hydroiodic acid, with other mineral acids such as sulfuric acid, phosphoric acid, or nitric acid, as well as with organic acids such as acetic acid, citric acid, camphorsulfonic acid, methanesulfonic acid, toluenesulfonic acid, salicyclic acid, ascorbic acid, maleic acid, mandelic acid, or the like. Preferred salts are those formed with hydrohalic acids, especially preferred are those formed with hydrochloric acid and maleic acid. The acid addition salts can be prepared, preferably, in a solvent such as ethanol, acetone or acetonitrile, by treatment of the free base with the corresponding anhydrous acid. Depending on the molar ratio of free base to acid, there is obtained, because of the two nitrogen atoms in the piperazine moiety, a mono- or a di-salt with one or two moles of acid per mole of base, respectively. In the working up of a salt, there is obtained, depending on the solubility of the mono- or di-salt in the solvent used, the corresponding mono- or di-salt.
The bases of formulas I and Ia are partly crystalline, solid substances, which are relatively soluble in dimethylsulfoxide, dimethylformamide or in chlorinated hydrocarbons such as chloroform, methylene chloride or in an alkanol such as methanol or ethanol and are relatively insoluble in water.
The pharmaceutically acceptable acid addition salts of the bases of formulas I and Ia are crystalline, solid substances, which are freely soluble in dimethylsulfoxide, dimethylformamide, or in an alkanol such as methanol or ethanol, and partially soluble in chloroform, methylene chloride or water. They are relatively insoluble in benzene, ether or petroleum ether.
The compounds of formulas I and Ia are useful as central depressants and neuroleptic agents, substantially devoid of cataleptic activity or effect.
A cataleptic effect ("wax-like rigidity", that is, maintaining for an abnormally long period a forced upon body position) is considered to be a disturbing side effect with central depressants and neuroleptically active compounds and indicates motor disturbances. The products according to the invention have the advantage that they do not have this disturbing side effect or have it only to a very slight extent. To prove the lack of cataleptic activity, representative samples of the end products of the invention were administered intraperitoneally to rats. The following compounds were tested:
Product A: 1-{2-[4-(8-chloro-10,11-dihydro-2-methyldibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-pyrrolidinone maleate;
Product B: 3-{2-[4-(2-chloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone maleate;
Product C: 3-{2-[4-(8fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl] -ethyl}-2-oxazolidinone;
Product D: 3-{2-[4-(2-chloro-8-fluoro-10,11-dihydrodibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone maleate;
Product E: 3-{2-[4-(10,11-dihydro-2-methyl-8-methylthiodibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone maleate.
The foregoing compounds were compared to chloropromazine, a well-known central depressant, especially well known as a neuroleptic agent.
The test animals are considered to be cataleptic when the homolateral extremities remain in the crossed position for at least 10 seconds. The number of cataleptic animals is recorded every 30 minutes over a 6-hour period. The ED.sub.50 is the dose at which 50 percent of the animals are cataleptic.
Furthermore, Products A to E are considerably less toxic than chlorpromazine as can be seen from the acute toxicity results, which are detailed hereinafter, obtained in the mouse. The toxicity results are based on the duration of action the compounds of formulas I and Ia over a period of 24 hours.______________________________________RESULTS______________________________________Product LD.sub.50 mg/kg p.o.______________________________________1-{2-[4-(8-chloro-10,11-dihydro-2-methyl- dibenzo[b,f]thiepin-10-yl)-1-pip- erazinyl]-ethyl}-2-pyrrolidinone maleate (Product A) 37503-{2-[4-(2-chloro-7-fluoro-10,11- dihydro-dibenzo[b,f]thiepin-10- yl)-1-piperazinyl]-ethyl}-2-oxa- zolidinone maleate (Product B) 9003-{2-[4-(8-fluoro-10,11-dihydro-2- methyl-dibenzo[b,f]thiepin-10-yl)- 1-piperazinyl]-ethyl}-2-oxazol- idinone (Product C) 18753-{2-[4-(2-chloro-8-fluoro-10,11- dihydro-dibenzo[b,f]thiepin-10- yl)-1-piperazinyl]-ethyl}-2-oxa- zolidinone maleate (Product D) 4503-{2-[4-(10,11-dihydro-2-methyl-8-methyl- thio-dibenzo[b,f]thiepin-10-yl)-1- piperazinyl]-ethyl}-2-oxazolidinone maleate (Product E) 3750Chloropromazine 200______________________________________
To demonstrate the central depressant effect, especially the neuroleptic effects of the products of the invention, representative compounds were utilized in the following tests.
In the Rotating Rod Test, the ability of mice to achieve a coordinated motor performance is investigated. After peroral administration of the test substance, the mice are placed upon a horizontal slowly rotating rod and the time they remain on the rod is recorded. The ED.sub.50 is that dose which reduces the holding on period of the mice by 50 percent as compared to the holding on period prior to the administration of the test substance.
Products A, C and D in the test demonstrate a strong activity (Product A: ED.sub.50 = 7.3 mg/kg; Product C: ED.sub.50 = 2.1 mg/kg; Product D: ED.sub.50 = 1.0 mg/kg), which for C and D is superior to that of chlorpromazine (ED.sub.50 = 5 mg/kg) and for A approximates that of chlorpromazine.
Two hours prior to being killed, rats are injected with the test substance.
Thereafter, the homovanillinic acid is extracted from the supernatant portion of a homogenized mixture of the brains of the treated rats into butyl acetate and later into an aqueous solution and is oxidized with potassium ferric cyanide to a fluorescent dimer. From an increased concentration of homovanillinic acid (HVA), it can be demonstrated that the test substance works the same as chlorpromazine, that is, it increases the turnover of dopamine in the basal ganglions. The homovanillinic acid titer in untreated rats is arbitrarily set at 100 percent.__________________________________________________________________________RESULTS__________________________________________________________________________ Dose Increase inProduct mg/kg p.o. HVA, percent__________________________________________________________________________1-{2-[4-(8-chloro-10,11-dihydro-2- methyl-dibenzo[b,f]thiepin-10- yl)-1-piperazinyl]-ethyl}-2- pyrrolidinone maleate (Product A) 50 2953-{2-[4-(2-chloro-7-fluoro-10,11- dihydro-dibenzo[b,f]thiepin-10- yl)-1-piperazinyl]-ethyl}-2- oxazolidinone maleate (Product B) 50 2703-{2-[4-(8-fluoro-10,11-dihydro-2- methyl-dibenzo[b,f]thiepin-10- yl)-1-piperazinyl]-ethyl}-2- oxazolidinone maleate (Product C) 50 2353-{2-[4-(2-chloro-8-fluoro-10,11- dihydro-dibenzo[b,f]thiepin-10- yl)-1-piperazinyl]-ethyl}-2- oxazolidinone maleate (Product D) 45 3003-{2-[4-(10,11-dihydro-2-methyl-8- methylthio-dibenzo[b,f]thiepin- 10-yl)-1-piperazinyl]-ethyl}-2- oxazolidinone maleate (Product E) 50 255Chlorpromazine 20 321__________________________________________________________________________
In this test, Products A, B and D demonstrate an activity which is nearly as potent as that of chlorpromazine.
This test provides information about behavorial reactions of rats. Rats are trained to avoid, by climbing up a vertical pole in the test chamber, an electrical impulse (unconditioned impulse) released via the wire-latticed floor some seconds after an acoustic signal (conditioned impulse).
The blocking of the conditioned reaction is determined by the parameter ED.sub.50 (mg/kg p.o.); the blocking of the unconditioned reaction is determined by a parameter ED.sub.10 (mg/kg. p.o.).
The parameter ED.sub.50 (blocking of the conditioned reaction) gives a measure of the neuroleptic strength of action of the test substance. The quotient ED.sub.10 (blocking of the unconditioned reaction)/ED.sub.50 (blocking of the conditioned reaction) gives a measure of the quality of action of the test substance since, with increasing quotient, a greater selectivity of the neuroleptic action (slighter neurotoxic side-effect) is present.__________________________________________________________________________RESULTS__________________________________________________________________________ Quotient ED.sub.10 (blocking of ED.sub.50 (blocking of the the unconditioned reaction)/ conditioned reaction) ED.sub.50 (blocking of theProduct mg/kg. p.o. conditioned reaction)__________________________________________________________________________3-{2-[4-(8-fluoro-10,11-dihydro-2-methyl- dibenzo[b,f]thiepin-10-yl)-1-piper- azinyl]-ethyl}-2-oxazolidinone maleate (Product C) 14 233-{2-[4-(2-chloro-8-fluoro-10,11-dihydro- dibenzo[b,f]thiepin-10-yl)-1-piper- azinyl]-ethyl}-2-oxazolidinone - maleate (Product D) 17 7.63-{2-[4-(10,11-dihydro-2-methyl-8-methyl- thio-dibenzo[b,f]thiepin-10-yl(-1- piperazinyl]-ethyl}-2-oxazolidinone maleate (Product E) 25 12Chlorpromazine 11.8 2.5__________________________________________________________________________
Although the neuroleptic action in C, D and E lies somewhat below tht of chlorpromazine, the quality (selectivity) of the neuroleptic action of C, D and E substantially exceeds that of chlorpromazine.
The compounds of the invention, i.e., the compounds of formulas I and Ia can be used in the form of pharmaceutical preparations, which contain them or their salts in admixture with organic or inorganic pharmaceutically inert carriers suitable for enteral and parenteral application such as, for example, water, gelatin, gum arabic, lactose, starches, vegetable oils, polyalkyleneglycols, and the like. The pharmaceutical preparations can be in solid form, for example, tablets, dragees, suppositories or capsules, or in liquid form, for example, as solutions, suspensions or emulsions. The preparations may be sterilized and/or contain additives such as preservatives, stabilizers, wetting or emulsifying agents or salts for varying the osmotic pressure. The pharmaceutical preparations can also contain additional therapeutically active substances.
Preferably, the pharmaceutical dosage forms contain from about 1 to about 200 mg. of a compound of formula I or Ia or an equivalent amount of their respective salts. Preferably, the oral dosage range is between about 0.1 mg/kg/day to about 7.5 mg/kg/day. A preferable dosage range for parenteral preparations is between about 0.01 mg/kg/day to about 0.75 mg/kg/day. It is understood, however, that the above-mentioned ranges can be varied according to the individual needs and the prescription of the practitioner.
As is evident, the compounds of formulas I and Ia and their pharmaceutically acceptable acid addition salts have effects qualitatively similar to those of chlorpromazine, known for its therapeutic uses and properties. Thus, the compounds of the invention demonstrate a pattern of activity associated with neuroleptic agents of known efficacy and safety.
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Divisions (1)
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Number |
Date |
Country |
| Parent |
471094 |
May 1974 |
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Continuation in Parts (1)
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Number |
Date |
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| Parent |
378732 |
Jul 1973 |
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Patent Grant
4044010
