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US3851062A - Method of suppressing weight gain - Google Patents

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US3851062A
US3851062A US00384713A US38471373A US3851062A US 3851062 A US3851062 A US 3851062A US 00384713 A US00384713 A US 00384713A US 38471373 A US38471373 A US 38471373A US 3851062 A US3851062 A US 3851062A
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cis
hydrochloride
phenylisochroman
aminomethyl
hydrogen
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US00384713A
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M Klohs
F Petracek
N Sugisaka
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3M Co
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Minnesota Mining and Manufacturing Co
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    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only 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

Definitions

  • the compounds of the present invention are part of a group of compounds broadly described in United States Patent No. 3,743,659. These compounds, broadly speaking, are pharmacologically active materials which show significant effects on the mammalian central nervous sys tem.
  • the compounds which are useful in the method of the present invention for producing anorectic effects are a specific subgroup of the aforementioned larger series of compounds active on the central nervous system.
  • This invention relates to a method for producing anorectic effects (i.e. suppressing body weight gain and/ or reducing body weight) in mammals, which comprises administering to said mammals an effective dose less than the toxic amount of a compound of the formula wherein R is hydrogen, fluorine, chlorine or trifluoromethyl, R is hydrogen, fluorine or chlorine in the 6 or 7 position, Q is (i.e. Z-imidazolinyl) or '(CH2)m N wherein R and R are independently hydrogen or alkyl of 1 to 4 carbon atoms, m is zero, one or two and the alkylene chain (CH may contain a substituent methyl group; and salts thereof.
  • R substituents of the compounds used in the method of the invention are those wherein R is hydrogen or 4'-fluoro and most preferred is that R is hydrogen.
  • the R substituent is presently preferred to be 7-fluor0.
  • the Q substituent be CH NHR and it is most preferred to be CH NH
  • Preferred compounds for use in the method of the invention include sis-3 -aminomethy1-7-fiuoro-1-(4-fluorophenyl) isochroman,
  • the amino-substituted l-phenyliso'chromans described in this invention contain a basic nitrogen atom and therefore can, if desired, be converted into their pharmaceutrcally acceptable acid addition salts.
  • Salts which can be formed include, for example, salts with inorganic acids, such as the hydrochloride (presently preferred), hydrobromide, hydroiodide, sulfate, phosphate and the like. They also include salts with organic acids, including monobasic acids such as the acetate or propionate, and especially those with hydroxy organic acids, and polybasic acids, such as the citrate, tartrate, malate and maleate.
  • Quaternary ammonium salts e.g. such as those produced using lower alkyl iodides or bromides, can also be prepared by the methOds known to the art.
  • salts will not be substantially more toxic than the compound itself, and can be incorporated into conventional liquid or solid pharmaceutical dosage media.
  • Such pharmaceutically useful acid addition salts are the full equivalents of the bases from which they are derived and are included within the scope of this invention. Because of their specific solubility properties of the individual salts they are in some cases advantageously selected for a particular pharmaceutical use.
  • the compounds described herein can be combined with conventional pharmaceutical diluents and carriers to provide such dosage forms as tablets, suspensions, solutions, suppositories and the like. They can also be encapsulated as in the conventional hard gelatin capsules. They are preferably used in the method of the invention in such dosage forms.
  • cis-d,l-3-aminomethyl-7-fiuoro-l-phenylisochroman hydrochloride are mixed well with 15 parts of starch (U.S.P.) and 0.1 part of colloidal silica to form a pre-blend mixture.
  • the preblend mixture is passed through a 40 mesh screen twice and remixed after each pass.
  • Base granules consisting of parts lactose and 5 parts starch (U.S.P.) are prepared by mixing these ingredients with 7 to 10 ml. of U.S.P. water, then allowing to dry completely.
  • Base granules, 23.5 parts, are then placed in a mixer and 25.1 parts of the pre-blend mixture are added through a 40 mesh screen and mixed until homogeneous. Thereafter 1.3 to 3.9 parts of magnesium stearate are added through a 40 mesh screen with mixing and the final mixture is machine compressed into tablets of weight 263:1.6 mg, diameter A inch and thickness 4.56:0.06
  • the above tablets can be coated by a succession of spray applications to the tablets in a rotating drum to a film-coat weight of 5 mg. per tablet. Warm air is applied for interspray coat drying as needed. The tablets are then dried overnight.
  • the film coat consists of 2.67 parts of hydroxypropyl methylcellulose, N.F., 0.67 part of ethylcellulose, N.F., 0.01 part of saccharin, U.S.P., 0.33 part of acetylated monoglycerides, 1.32 parts of colorant (e.g. K-1-3134 Pastel Green) 17.35 parts (by volume) of ethanol (U.S.P.) and 42 parts (by volume) of methylene chloride.
  • colorant e.g. K-1-3134 Pastel Green
  • the anorectically active compounds of the invention are capable of existing in both cis and trans isomeric form, each having a different melting point. It is recognized that such isomers may differ in degree of activity, the cis isomer ordinarily being more active. Mixtures of cis and trans isomers are often employed, however, and these are included within the scope of the present invention.
  • Each of the compounds of the invention can, furthermore, exist in four different stereoisomeric forms, that is one cis and one trans form, each of which cis or trans compound exists as a d,l pair. The individual d and 1 forms can be isolated by known resolution methods.
  • the method of the invention is illustrated by standard pharmacological tests which are used to detect anoretic activity, in which the compounds described have been shown to possess useful activity. These tests are set forth in detail below.
  • mice Female Acute Anorectic Activity Method Groups of ten male mice were deprived of food for 17 to 23 hours prior to test. They were housed on shavings with free access to water during the fasting period. Mice were identified, weighed and administered the dose of test compound intraperitoneally 30 minutes prior to being placed individually in a ten cell stick cage. Ten minutes were allowed for accommodation in the stick cage before placing a single ration pellet in each cell. Immediately thereafter, a ten-minute scan of the group was made. The occurrences of nibbling were counted in this test. The means score per mouse and the standard error of this mean were calculated. Comparison of these values with the data from two control groups, consisting of non-fasted and fasted untreated groups, was made for the assessment of anorectic activity.
  • the individual unit dosage and frequency of administration is determined not only the nature and severity of the condition for which suppression of appetite is indicated, but in addition depends upon age, weight and species of subject, its underlying physical condition and the route of administration. It will, accordingly, be within the judgment and skill of the practitioner administering the drug to determine the exact amount to be administered so as to be non-toxic, yet pharmaceutically effective in suppressing appetite. However, dosage will usually be about 0.1 to 10 mg./ kg.
  • Some of the compounds of the invention have shown anorectic activity comparable to that produced by the known appetite-suppressant, d-amphetamine, without exhibiting any of the central nervous system stimulation commonly observed with d-amphetamine.
  • isochroman hydrochloride M P 16 5- Ammonia"-.- cis-3-aminomethyi-7-fluoro-1- (4-fluor0pheny1) isochroman hydrochloride, M.P. 210211.
  • a method for producing anorectic efiects in mammals in need thereof which comprises administering to said mammals an effective dose between 0.1 and 10 milligrams per kilogram of body weight of a compound of the formula wherein R is hydrogen, fluorine, chlorine or trifluoromethyl, R is hydrogen, fluorine or chlorine in the 6 or 7 position, and Q is Z-imidazolinyl or R3 (cm)mN wherein R and R are independently hydrogen or lower alkyl, m is zero, one or two and the alkylene chain -(CH may contain a substitucnt methyl group or pharmaceutically acceptable salts thereof.
  • R is hydrogen or fluorine
  • R is hydrogen or fluorine
  • Q is CH NHR wherein R is hydrogen, methyl or ethyl.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

WHEREIN R3 AND R4 ARE INDEPENDENTLY HYDROGEN OR LOWER ALKYL, M IS ZERO, ONE OR TWO AND THE ALKYLENE CHAIN -(CH2)N- MAY CONTAIN A SUBSTITUTENT METHYL GROUP OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF.

-(CH2)M-N(-R3)-R4

WHEREIN R1 IS HYDROGEN, FLUORINE, CHLORINE OR TRIFLUOROMETHYL, R2 IS HYDROGEN, FLUORINE OR CHLORINE IN THE 6 OR 7 POSITION, AND Q IS 2-IMIDAZOLINYL OR

1-(R1-PHENYL-),3-Q,R2-ISOCHROMAN

1. A METHOD FOR PRODUCING ANORECTIC EFFECTS IN MAMMALS IN NEED THEREOF WHICH COMPRISES ADMINISTERING TO SAID MAMMALS AN EFFECTIVE DOES BETWEEN 0.1 AND 10 MILLIGRAMS PER KILOGRAM OF BODY WEIGHT OF A COMPOUND OF THE FORMULA

Description

United States Patent 3,851,062 METHOD OF SUPPRESSING WEIGHT GAIN Murle K. Klohs, 19901 Nordhotf St., Tarzana, Calif. 91324; and Francis J. Petracek, Bloomington; and Nobuyuki Sugisaka, New Brighton, Minn. (both 3M Center, St. Paul, Minn. 55101) No Drawing. Filed Aug. 1, 1973, Ser. No. 384,713 Int. Cl. A61k 27/00 US. Cl. 424-283 10 Claims ABSTRACT OF THE DISCLOSURE Administration of certain amino-substituted l-phenylisochromans is a method for producing anorectic effects, i.e. suppression of gain in body weight or loss of body weight.
BACKGROUND OF THE INVENTION It is known that administration of d-amphetamine, fenfiuramine or other drugs to mammals can cause anorexia, and that the dose regimen can be adjusted to bring about useful effects in control of body weight gain or reduction of body weight. However, known agents such as d-amphetamine have disadvantageous side effects such as stimulation of the central nervous system, hypertensive effects and changes in the electrocardiogram.
The compounds of the present invention are part of a group of compounds broadly described in United States Patent No. 3,743,659. These compounds, broadly speaking, are pharmacologically active materials which show significant effects on the mammalian central nervous sys tem. The compounds which are useful in the method of the present invention for producing anorectic effects are a specific subgroup of the aforementioned larger series of compounds active on the central nervous system.
DETAILED DESCRIPTION OF THE INVENTION This invention relates to a method for producing anorectic effects (i.e. suppressing body weight gain and/ or reducing body weight) in mammals, which comprises administering to said mammals an effective dose less than the toxic amount of a compound of the formula wherein R is hydrogen, fluorine, chlorine or trifluoromethyl, R is hydrogen, fluorine or chlorine in the 6 or 7 position, Q is (i.e. Z-imidazolinyl) or '(CH2)m N wherein R and R are independently hydrogen or alkyl of 1 to 4 carbon atoms, m is zero, one or two and the alkylene chain (CH may contain a substituent methyl group; and salts thereof.
Particularly preferred R substituents of the compounds used in the method of the invention are those wherein R is hydrogen or 4'-fluoro and most preferred is that R is hydrogen.
The R substituent is presently preferred to be 7-fluor0.
Similarly, it is presently preferred that the Q substituent be CH NHR and it is most preferred to be CH NH Preferred compounds for use in the method of the invention include sis-3 -aminomethy1-7-fiuoro-1-(4-fluorophenyl) isochroman,
3-aminomethyl-7-fluorol-phenylisochroman,
cis-3 -aminomethyl-7-fiuorol-phenyli so chroman,
cis- )-3-aminomethyl-7-fluoro-1 -phenylisochroman,
cis-3 -aminomethyl-1- (4-fluorophenyl) isochroman,
cis-3- (N-ethylaminomethyl) -7-fiuoro-l-phenylisochroman,
and
cis-7-fluoro-3- (N-methylaminomethyl) -1-phenylisochroman;
and pharmaceutically acceptable acid addition salts of these compounds.
The amino-substituted l-phenyliso'chromans described in this invention contain a basic nitrogen atom and therefore can, if desired, be converted into their pharmaceutrcally acceptable acid addition salts. Salts which can be formed include, for example, salts with inorganic acids, such as the hydrochloride (presently preferred), hydrobromide, hydroiodide, sulfate, phosphate and the like. They also include salts with organic acids, including monobasic acids such as the acetate or propionate, and especially those with hydroxy organic acids, and polybasic acids, such as the citrate, tartrate, malate and maleate. Quaternary ammonium salts, e.g. such as those produced using lower alkyl iodides or bromides, can also be prepared by the methOds known to the art.
Pharmaceutically these salts will not be substantially more toxic than the compound itself, and can be incorporated into conventional liquid or solid pharmaceutical dosage media. Such pharmaceutically useful acid addition salts are the full equivalents of the bases from which they are derived and are included within the scope of this invention. Because of their specific solubility properties of the individual salts they are in some cases advantageously selected for a particular pharmaceutical use.
The compounds described herein, either as free bases or in the form of non-toxic, pharmaceutically acceptable acid addition salts, can be combined with conventional pharmaceutical diluents and carriers to provide such dosage forms as tablets, suspensions, solutions, suppositories and the like. They can also be encapsulated as in the conventional hard gelatin capsules. They are preferably used in the method of the invention in such dosage forms.
It is presently preferred to use tablets for oral administration. Flm-coated tablets or uncoated tablets are used.
The following method is exemplary of the preparation of tablets, each containing 10 mg. of active ingredient. All parts are by weight unless otherwise specified.
In a suitable container 10 parts of cis-d,l-3-aminomethyl-7-fiuoro-l-phenylisochroman hydrochloride are mixed well with 15 parts of starch (U.S.P.) and 0.1 part of colloidal silica to form a pre-blend mixture. The preblend mixture is passed through a 40 mesh screen twice and remixed after each pass.
Base granules consisting of parts lactose and 5 parts starch (U.S.P.) are prepared by mixing these ingredients with 7 to 10 ml. of U.S.P. water, then allowing to dry completely. Base granules, 23.5 parts, are then placed in a mixer and 25.1 parts of the pre-blend mixture are added through a 40 mesh screen and mixed until homogeneous. Thereafter 1.3 to 3.9 parts of magnesium stearate are added through a 40 mesh screen with mixing and the final mixture is machine compressed into tablets of weight 263:1.6 mg, diameter A inch and thickness 4.56:0.06
For film-coated tablets the above tablets can be coated by a succession of spray applications to the tablets in a rotating drum to a film-coat weight of 5 mg. per tablet. Warm air is applied for interspray coat drying as needed. The tablets are then dried overnight. The film coat consists of 2.67 parts of hydroxypropyl methylcellulose, N.F., 0.67 part of ethylcellulose, N.F., 0.01 part of saccharin, U.S.P., 0.33 part of acetylated monoglycerides, 1.32 parts of colorant (e.g. K-1-3134 Pastel Green) 17.35 parts (by volume) of ethanol (U.S.P.) and 42 parts (by volume) of methylene chloride.
The anorectically active compounds of the invention are capable of existing in both cis and trans isomeric form, each having a different melting point. It is recognized that such isomers may differ in degree of activity, the cis isomer ordinarily being more active. Mixtures of cis and trans isomers are often employed, however, and these are included within the scope of the present invention. Each of the compounds of the invention can, furthermore, exist in four different stereoisomeric forms, that is one cis and one trans form, each of which cis or trans compound exists as a d,l pair. The individual d and 1 forms can be isolated by known resolution methods. All of these mixtures are generally physiologically active, but the physiological activity will vary among the isomers of any particular compound, as is well known to the art. From the practical standpoint the mixtures, whether geometric or optical or both are useful. Mixtures are ordinarily obtained from the process of preparation. It is difiicult to prepare specific isomers alone, but it is possible to obtain pure isomers from the mixtures by processes for separation thereof as are well known to the art. Pure isomers may be desired because one of the isomers may be highly active and therefore might have a better therapeutic ratio.
The method of the invention is illustrated by standard pharmacological tests which are used to detect anoretic activity, in which the compounds described have been shown to possess useful activity. These tests are set forth in detail below.
Mouse Acute Anorectic Activity Method Groups of ten male mice were deprived of food for 17 to 23 hours prior to test. They were housed on shavings with free access to water during the fasting period. Mice were identified, weighed and administered the dose of test compound intraperitoneally 30 minutes prior to being placed individually in a ten cell stick cage. Ten minutes were allowed for accommodation in the stick cage before placing a single ration pellet in each cell. Immediately thereafter, a ten-minute scan of the group was made. The occurrences of nibbling were counted in this test. The means score per mouse and the standard error of this mean were calculated. Comparison of these values with the data from two control groups, consisting of non-fasted and fasted untreated groups, was made for the assessment of anorectic activity.
All compounds were dissolved in distilled water and administered in a constant volume of m1./kg.
The following compounds are shown to have anorectic activity in this test at an oral dose of mg./ kg. or less:
cis-3-aminomethyl-7-fluoro-l-phenylisochroman hydrochloride,
cis-3-aminomethyl-l-phenylisochroman hydrochloride and trans-3-aminomethyl-7-fluoro-l-phenylisochroman hydrochloride.
RAT SHORT-TERM LIQUID FOOD (METRECAL 1 TEST METHOD Male rats housed in individual cages and weighing 250 to 350 g. were trained to drink a liquid food, a chocolate drink (Metrecal -Dutcl1 Chocolate) one day a week in place of their normal animal laboratory food. The animals were fasted 24 hours before the day of testing. Compounds were dissolved in distilled water and administered orally in a constant volume of 1 mL/kg. one-half hour before presentation of the liquid food in graduated centrifuge (50 ml.) tubes. The amount of liquid food consumed in 60 minutes was recorded and compared to an appropriate vehicle control. Results are expressed as percent change in Metrecal consumption from the control group.
The following compounds are shown to have anorectic activity in this test at an oral dose of 20 mg./kg. or less:
cis-3 -aminomethyl-7-fiuorol-phenylisochrom an hydrochloride,
cis-3-aminomethyll-phenylisochroman hydrochloride,
cis-3- [2- Z-imidazolinyl) -1-phenylisochroman hydro chloride,
cis-( -1-aminomethyl-l-phenylisochroman hydro chloride,
3-aminomethyl- 1- (4'-fluorophenyl isochrom an hydrochloride,
3 -aminomethyl-7 -chlorol-phenylisochrom an hydrochloride,
cis-3 (N-methylamino) methyll-phenylisochrornan hydrochloride,
cis- 3-N,N-dimethylamino methyll-phenylisochroman hydrochloride,
trans-1-(4-ch1orophenyl) -3-(N,N-dimethylarnino)methylisochroman hydrochloride,
trans-3 -aminomethyl-7 -fiuorol-phenylisochroman hydrochloride,
3 -aminomethyl- 1- (4-trifluoromethylphenyl) iso chroman hydro chloride,
sis-3 -aminomethyl- 1- (4'-fluorophenyl) isochroman hydrochloride,
3- (N-isopropylamino methyl- 1 -phenylisochroman hydrochloride,
3 -aminomethyl- 6-fiuorol-phenylisochroman hydrochloride,
trans-3 l-amino) ethyll-phenylisochroman hydrochloride,
cis-3 -aminomethyll-phenylisochroman,
lrans-3-aminomethyl-l- (4'-fluorophenyl) isochrom an hydrochloride,
trans-3-aminomethyll -phenylisochroman hydrochloride,
cis- -3-aminomethyll-phenylisochroman hydrochloride and trans-3 (N-methylamino) methyll-phenylisochroman hydrochloride,
RAT SHORT-TERM SOLID FOOD TEST METHOD Sixty male albino rats weighing 200 to 400 g. were divided into six groups of ten each. All animals were housed in individual cages where Water was available ad libitum. Five animals from each group (a total of 30) were tested on Monday and Thursday. The remaining rats were tested on Tuesday and Friday. During the testing days the animals were placed in a behavioral cage (8 X 8 /2 x 11 inches, manufactured by Lafayette Electronics) for one hour. In the cage was a 16 oz. wide-mouth jar containing a large quantity of 97 mg. animal laboratory food pellets (4.6 mm. diameter x 4.9 mm. thick) supplied by the P. J. Noyes Co., Lancaster, N. Hamp. During the one-hour period these pellets were available ad libz'tum, and the grams of food consumed were measured at the end of the hour. During the days the animals were not tested, they were given four larger. animal laboratory food pellets (total of 20 .g.) for each 24 hours except for the days preceding testing. Then, 24 hours before the animals were to be tested, they were given only two of such pellets of food (total of 10 g.). Thus, the animals were only partially deprived before testing.
1 Commercially available dietary supplement.
The following compounds are shown to have anorectic activity in this test at an oral dose of 40 mg./kg. or less:
cis-3-arninomethyl-7-fluoro-l-phenylisochroman hydrochloride,
cis-3 -aminomethyl-7-fluoro- 1- 4'-fluorophenyl) isochroman hydrochloride,
cis-3-aminomethyl-6-fluoro-l-phenylisochroman hydrochloride,
3-(N-ethylamino)methy1-l-phenylisochroman hydrochloride,
cis-3 -aminomethyl- 1- (4'-fluorophenyl) isochroman hydrochloride,
cis-7-fluoro-3-(N-isopropylamino)methyl-l-phenylisochroman hydrochloride,
cis-3-(N-ethylamino)methyl-7-fluoro-l-phenylisochroman hydrochloride,
cis-3 (N, N-dimethyl amino methyl-7-fiuorol-phenylisochroman hydrochloride,
cis-3-(N-methylamino)methyl-7-fluoro-l-phenylisochroman hydrochloride,
cis- )-3-arninomethyl-7-fluorol-phenylisochroman hydrochloride,
cis-7-fluoro-3 (N-n-propylamino methyl- 1 -phenylisochroman hydrochloride,
cis-3- [2- (2-imidazolinyl) -1-phenylisochroman hydrochloride and 3-aminomethyl- 1- (2-chlorophenyl) isochroman hydrochloride.
For the method of the invention, the individual unit dosage and frequency of administration is determined not only the nature and severity of the condition for which suppression of appetite is indicated, but in addition depends upon age, weight and species of subject, its underlying physical condition and the route of administration. It will, accordingly, be within the judgment and skill of the practitioner administering the drug to determine the exact amount to be administered so as to be non-toxic, yet pharmaceutically effective in suppressing appetite. However, dosage will usually be about 0.1 to 10 mg./ kg.
Some of the compounds of the invention have shown anorectic activity comparable to that produced by the known appetite-suppressant, d-amphetamine, without exhibiting any of the central nervous system stimulation commonly observed with d-amphetamine.
Certain novel compounds first described specifically herein are prepared according to the synthetic methods described in U.S. Pat. 3,743,659. These compounds are shown in Table I.
isochroman hydrochloride, M P 16 5- Ammonia"-.- cis-3-aminomethyi-7-fluoro-1- (4-fluor0pheny1) isochroman hydrochloride, M.P. 210211.
Prepared from 1-chl0ro-3-(4-fluorophenyl)-2-propanol [Ex. 26a] and dichlorornethyl-4-fluorobenzene by condensation in the presence of zinc chloride.
What is claimed is:
1. A method for producing anorectic efiects in mammals in need thereof which comprises administering to said mammals an effective dose between 0.1 and 10 milligrams per kilogram of body weight of a compound of the formula wherein R is hydrogen, fluorine, chlorine or trifluoromethyl, R is hydrogen, fluorine or chlorine in the 6 or 7 position, and Q is Z-imidazolinyl or R3 (cm)mN wherein R and R are independently hydrogen or lower alkyl, m is zero, one or two and the alkylene chain -(CH may contain a substitucnt methyl group or pharmaceutically acceptable salts thereof.
2. The method of claim 1 wherein R is hydrogen or fluorine, R is hydrogen or fluorine and Q is CH NHR wherein R is hydrogen, methyl or ethyl.
3. The method of claim 1 wherein R is 4-fluoro and R is 7-fluoro.
4. The method of claim 1 wherein the basic compound is 3-aminomethyl-7- fluoro-l-phenylisochroman.
5. The method of claim 1 wherein the basic compound is cis-3-aminomethyl-7-fluorol-phenylisochroman.
6. The method of claim 1 wherein the basic compound is cis -3-aminomethyl-7-fiuorol-phenylisochroman.
7. The method of claim 1 wherein the basic compound is cis-3-(N-ethylaminomethyl)-7-fluoro-1 phenylisochroman.
8. The method of claim 1 wherein the basic compound is cis 3-aminomethyl-7-fluoro-1-(4-fiuorophenyl)isochroman.
9. The method of claim 1 wherein the basic compound is cis-3-aminomethyl- 1- (4-flu0ropheuyl) isochroman.
10. The method of claim 1 wherein the basic compound is cis-3-(N-methylaminomethyl)-7 fiuoro l phenylisochroman.
References Cited UNITED STATES PATENTS 7/1973 Klohs et al 424-283 6/1969 Kramer et al 424-283 ALBERT T. MEYERS, Primary Examiner N. A. DREZIN, Aissitant Examiner U.S. Cl. X.R. 424-273

Claims (1)

1. A METHOD FOR PRODUCING ANORECTIC EFFECTS IN MAMMALS IN NEED THEREOF WHICH COMPRISES ADMINISTERING TO SAID MAMMALS AN EFFECTIVE DOES BETWEEN 0.1 AND 10 MILLIGRAMS PER KILOGRAM OF BODY WEIGHT OF A COMPOUND OF THE FORMULA
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0020018A1 (en) * 1979-05-19 1980-12-10 Beecham Group Plc Chroman derivatives, processes for their preparation and pharmaceutical compositions containing them
WO2009133110A1 (en) * 2008-04-29 2009-11-05 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Modulators of dopamine neurotransmission

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0020018A1 (en) * 1979-05-19 1980-12-10 Beecham Group Plc Chroman derivatives, processes for their preparation and pharmaceutical compositions containing them
WO2009133110A1 (en) * 2008-04-29 2009-11-05 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Modulators of dopamine neurotransmission
US20110112065A1 (en) * 2008-04-29 2011-05-12 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Modulators of dopamine neurotransmission
JP2011518859A (en) * 2008-04-29 2011-06-30 エヌエスエイビー、フィリアル アヴ ノイロサーチ スウェーデン エービー、スヴェーリエ Modulator of dopamine neurotransmission
US8492372B2 (en) 2008-04-29 2013-07-23 Integrated Research Laboratories Sweden Ab Modulators of dopamine neurotransmission

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