US3833591A - 1,3,4,5-tetrahydropyrrolo(4,3,2-d,e)isoquinolines and related compounds - Google Patents

1,3,4,5-tetrahydropyrrolo(4,3,2-d,e)isoquinolines and related compounds Download PDF

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US3833591A
US3833591A US00228743A US22874372A US3833591A US 3833591 A US3833591 A US 3833591A US 00228743 A US00228743 A US 00228743A US 22874372 A US22874372 A US 22874372A US 3833591 A US3833591 A US 3833591A
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mole
tetrahydro
compounds
isopropyl
indole
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Manus J Mc
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Pfizer Corp Belgium
Pfizer Inc
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Pfizer Corp Belgium
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Priority to US00228743A priority patent/US3833591A/en
Priority to GB423373A priority patent/GB1418354A/en
Priority to DE2306605A priority patent/DE2306605A1/de
Priority to FR7305356A priority patent/FR2181738B1/fr
Priority to JP1846373A priority patent/JPS5516434B2/ja
Priority to US447074A priority patent/US3904645A/en
Priority to US447075A priority patent/US3898245A/en
Priority to US447073A priority patent/US3906000A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems

Definitions

  • Preferred member compounds include 1,3,45- tetrahydro 3 isopropylpyrrolo[4,3,2 d,e]isoquinoline, 3,4,5,6-tetrahydro-3-isopropyl 8,10 dimethoxy-lH-azacino[3,4,5-c,d]indole and 3,4,5,6-tetrahydro-3-isopropyl-8- methoxy-lH 1,4 oxazocino[6,7,8-c,d]indole, and their pharmaceutically acceptable acid addition salts.
  • This invention relates to new and useful tricyclicazaindole derivatives, which are effective in reducing blood sugar levels. More particularly, it is concerned with certain novel alkyl and aryl substituted tricyclicazaindoles and their pharmaceutically acceptable acid addition salts, which are useful as oral hypoglycemic agents for lowering the blood sugar levels of diabetic subjects.
  • novel tricyclicazaindole derivatives i.e., non-sulfonylureas
  • novel compounds of this invention are all selected from the group consisting of tricyclicazaindole bases of the formulae:
  • R and R are each a member selected from the group consisting of hydrogen and methoxy
  • n is an integer of from one to three, inclusive
  • R is a member selected from the group consisting of alkyl having from one to six carbon atoms, cycloalkyl having from three to six carbon atoms, phenylalkyl having up to three carbon atoms in the alkyl moiety, phenyl, chlorophenyl, tolyl, anisyl and thienyl.
  • R in the aforesaid structural formulae is alkyl having from one to six carbon atoms (and most preferably, isopropyl), or it is cyclohexyl or phenyl.
  • Typical member compounds of the preferred class include such tricyclicazaindole compounds as 1,3,4,5-tetrahydro-3-isopropyl-pyrrolo- [4,3,2,-d,e]isoquinoline, l,3,4,5-tetrahydro 3 isopropyl- 6,8-dimethoxypyrrolo[4,3,2 d,e]isoquinoline, 3,4,5,6-tetrahydro-3-isopropyl-lH-azepino[3,4,5,-c,d] indole, 3,4,5,6- tetrahydro-3-isopr0pyl-8,10- dimethoxylH-azacino [3 ,4,5- c,d]indole and 3,4,5,6-tetrahydro-3-isopropyl-8-methoxy- 1H-1,4-oxazocino [6,7, 8-c,d]indole, and their pharmaceutically acceptable acid addition salts such as the hydrochlorides and acetate
  • an appropriately substituted 4-aminoalkylindole or a corresponding 4-aminoethoxyindole is reacted with a suitable aldehyde reagent of the formula R CHO, where R is as previously defined, to form the desired tricyclicazaindole final product of respectively either formula I or II, as the case may be.
  • This particular reaction is normally conducted in a suitable reaction-inert aprotic organic solvent in the presence of an acid at a temperature that is generally in the range of from about 20 C. up to about C. for a period of about one-half to about 20 hours.
  • aprotic solvents for use in the reaction include cyclic ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbon solvents such as benzene, toluene and Xylene, as well as N,N-dialkyl lower alkanoamides like N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide and so on, while preferred organic acids include the lower alkanoic acids such as formic acid, acetic acid, propionic acid, and the like, with glacial acetic acid being most preferred.
  • the desired product is readily recovered from the spent reaction mixture by using such conventional means as concentration and crystallization, etc., or else by first diluting said mixture with water, followed by basification and subsequent extraction with an organic solvent to yield the corresponding free base compound per se.
  • the aforementioned 4-aminoalkylindole starting materials, used in the reaction process of this invention for preparing the compounds of formula I, are either known compounds or else they are easily prepared by those skilled in the art from readily available materials in accordance with the standard procedures of organic chemistry for preparing classical amines.
  • the 4-aminomethylindole compounds are either known or else readily prepared in two steps from the corresponding 4carboxaldehyde, via formation of the intermediate oxime and its subsequent reduction with nascent hydrogen.
  • the 4-aminoethylindoles are obtained by treating said aldehyde with nitromethane in a condensation reaction and reducing the resulting nitroolefin intermediate with lithium aluminum hydride.
  • the 4-aminopropylindoles are also obtained from said corresponding aldehyde in a series of synthetic organic steps involving (1) a condensation reaction with diethyl malonate (malonic ester) to yield an unsaturated diester; (2) reduction of said ester via catalytic hydrogenation to give a fully saturated compound that is subsequently hydrolyzed to the corresponding dibasic acid; (3) decarboxylation of said diacid to the corresponding monobasic acid and its subsequent conversion to an amide, and '(4) reduction of said amide with lithium aluminum hydride to give the desired amine.
  • These two last synthetic steps can be briefly illustrated by the following reaction scheme, where R represents the desired indole ring moiety, viz.,
  • the 4-aminoethoxyindole starting materials are all new per se, but are readily prepared by those skilled in the art starting from easily available reagents and employing the conventional methods of organic chemistry.
  • the appropriate 4-hydroxyindole compound can be simply converted to the corresponding cyanomethoxy derivative via the use of chloroacetonitrile and thereafter reduced as such to the desired amine by means of treatment with lithium aluminum hydride, as is hereinafter illustrated by the following reaction scheme where R has the same meaning as before, viz.,
  • the pharmaceutically acceptable acid addition salts of the tricyclicazaindole base compounds of this invention are prepared my simply treating the aforementioned organic bases with various mineral and organic acids which form non-toxic acid addition salts having pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, maleate, fumarate, citrate or acid citrate, tartrate or bitartrate, succinate, gluconate, saccharate, methanesulfonate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate salts.
  • pharmacologically acceptable anions such as the hydrochloride, hydrobromide, hydroiodide, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, maleate, fumarate, citrate or acid citrate, tart
  • the salt-formation step may be carried out using a substantially equimolar amount of the chosen acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the solid salt product is readily obtained.
  • the tricyclicazaindole compounds of this invention are all readily adapted to therapeutic use as oral hypoglycemic agents, in view of their ability to lower the blood sugar levels of diabetic and non-diabetic subjects to a statistically significant degree.
  • 1,3,4,5-tetrahydro-3-isopropylpyrrolo[4,3,2- d,e]isoquinoline a typical and preferred agent of the present invention, has been found to consistently lower blood sugar levels in the normal fasted rat to a statistically significant degree when given by the intraperitoneal route of administration at levels ranging from mg./ kg. to 32 mg./kg., respectively, without showing any substantial signs of toxic side effects.
  • the other compounds of this invention also cause similar results.
  • the tricyclicazaindole compounds of this invention may be administered either alone or in combination with pharameceutically acceptable carriers and that such administration can be carried out in both single and multiple dosages.
  • the novel compounds of the invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically-acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, aqueous suspensions, elixirs, syrups and the like.
  • Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
  • Such oral pharmaceutical compositions can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for just such a purpose.
  • the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 0.5% to about by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage.
  • tablets containing various excipients such as sodium citrate, calcium carbonate and dicalcium phosphate may be employed along with various disintegrants such as starch and preferably potato or tapioca starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules; preferred materials in this connection would also include the high molecular weight polyethylene glycols.
  • the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents as well,,together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • the activity of the compounds of the present invention is determined by their ability to lower blood sugar levels in the normal fasted rat when tested therein for such purposes according to the procedure described by W. S. Hoffman, as reported in the Journal of Biological Chemistry, Vol. 120, p. 51 (1937).
  • the latter method measures directly the amount of glucose in the blood at any given time and from this, the maximum percent decrease in blood sugar can be readily calculated and reported as hypoglycemic activity per se.
  • the present tricyclicazaindole compounds are shown to markedly reduce the blood sugar levels of anesthetized rats when administered to them at dose levels as low as 32 mg./kg. (a dose level at which chlorpropamide fails to elicit a strong response).
  • the free base compound was thereafter liberated from the latter acid addition salt, by adding same to a solution of 20% aqueous sodium hydroxide, followed by extraction with diethyl ether. Upon drying the ether layer in the usual manner (over anhydrous magnesium sulfate) and subsequently concentrating the resulting filtrate in vacuo, there was obtained pure 1,3,4,5-tetrahydro-3-iso-propyl-6,8- dimethoxypyrrolo[4,3,2-d,e]isoquinoline as the residual base. After recrystallization from benzene, the analytical sample melted at 191-194 C.
  • EXAMPLE V A mixture consisting of 4.9 g. (0.024 mole) of 5,7- dimethoxy-4-indolecarboxaldehyde and 1.8 g. (0.024 mole) of ammonium acetate in 20 ml. of nitromethane was heated on a steam bath for a period of 20 minutes. The reaction mixture was then cooled in an ice bath, and the precipitate which formed at this point was subsequently collected by means of suction filtration. The latter crude product was slurried in water, filtered again and then air dried to constant weight to aiford 3.26 g. of pure 4-(2-nitrovinyl)-5,7-dimethoxyindole, m.p. 159-162 C. After recrystallization from benzene, the analytical sample melted at 167-169" C.
  • the resulting mixture was stirred in the cold for a period of one hour and then allowed to attain room temperature prior to being concentrated in va'cuo.
  • the residual solids obtained in this manner were then subsequently triturated with 80 ml. of water, and the treated product 'was filtered and air dried to constant weight to give 4.6 g. of 8-(5,7-dimethoxy 4 indole)propionamide, m.p. 163-165 C. After recrystallization from toluene, the analytical sample melted at 165l66 C.
  • Example VII A mixture of 5.3 g. (0.02 mole) of 4-benzyloxy-5-methoxyindole [M. Julia et al., Bulletin de al socite' chimique de France, p. 1417 (1965)] and 2.0 g. of 5% palladiumon-carbon catalyst in 50 ml. of ethanol was shaken in a hydrogen atmosphere at room temperature (-25 C.) and 50 p.s.i.g. of hydrogen (initial pressure) for a period of ten minutes. Upon completion of this step, the catalyst was removed from the mixture by means of filtration and washed on the filter funnel with some ethanol.
  • a solution consisting of 5.0 g. (0.028 mole) of 4-cyanomethoxy 5 methoxyindole in 48 ml. of tetrahydrofuran was prepared and added dropwise during the course of a 30-minute period to a well-stirred slurry of 2.0 g. (0.056 mole) of lithium aluminum hydride in 40 ml. of the same said solvent, while under a dry nitrogen atmosphere at -10 C.
  • the excess hydride reagent was carefully decomposed by the dropwise addition of 2.0 ml. of water in 10 m1.
  • a dry solid pharmaceutical composition is prepared by blending the following materials together in the proportions by weight specified below:
  • a dry solid pharmaceutical composition is prepared by combining the following materials together in the proportions by weight indicated below:
  • EXAMPLE XV The tricyclicazaindole final products of Example I, III-IV and VI-VIII were tested for hypoglycemic activity in groups of 8-10 male albino rats (each weighing 200 g.) of the Sprague-Dawley strain, fasted for appr0ximately 18-24 hours prior to administration.
  • the rats were first lightly anesthetized with pentobarbital (at 15 mg./ kg., i.v.), a blood sample was then taken from the tail vein and the test compound was administered intraperitoneally at dose levels of 32, 18 and 10 mg./kg., respectively. Additional blood samples were then taken at 1, 2 and 4 hour intervals after administration of the drug. Blood glucose was determined by adapting the method of W.
  • hypoglycemic activity for the various compounds listed in the table below:
  • Hypoglycemlc activity (max. percent fal 1.
  • R and R are each a member selected from the group consisting of hydrogen and methoxy and R is a member selected from the group consisting of alkyl having from one to six carbon atoms, cycloalkyl having from three to six carbon atoms, phenylalkyl having up to three carbon atoms in the alkyl moiety, phenyl, chlorophenyl, tolyl, anisyl and thienyl.
  • R and R are each hydrogen and R is cycloalkyl having from three to six carbon atoms.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
US00228743A 1972-02-23 1972-02-23 1,3,4,5-tetrahydropyrrolo(4,3,2-d,e)isoquinolines and related compounds Expired - Lifetime US3833591A (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
BE795451D BE795451A (fr) 1972-02-23 Agents hypoglycemiants aza indoliques tricycliques
US00228743A US3833591A (en) 1972-02-23 1972-02-23 1,3,4,5-tetrahydropyrrolo(4,3,2-d,e)isoquinolines and related compounds
GB423373A GB1418354A (en) 1972-02-23 1973-01-26 Tricyclicicazaindole hypoglycemic agents
DE2306605A DE2306605A1 (de) 1972-02-23 1973-02-10 Substituierte tricycloazaindole
FR7305356A FR2181738B1 (en)) 1972-02-23 1973-02-15
JP1846373A JPS5516434B2 (en)) 1972-02-23 1973-02-16
US447074A US3904645A (en) 1972-02-23 1974-03-01 Tricyclicazaindole derivatives
US447075A US3898245A (en) 1972-02-23 1974-03-01 Tricyclicazaindole derivatives
US447073A US3906000A (en) 1972-02-23 1974-03-01 Tricyclicazaindole derivatives

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3900477A (en) * 1973-11-06 1975-08-19 Ayerst Mckenna & Harrison 5-amino-and 5-hydrazinodihydropyrroloisoquinoline derivatives
US3950343A (en) * 1973-11-06 1976-04-13 Ayerst, Mckenna And Harrison Ltd. Pyrroloisoquinoline derivatives
US3978066A (en) * 1973-11-06 1976-08-31 Ayerst, Mckenna And Harrison Ltd. Certain 4,6-dihydropyrrolotriazoline-quinoline derivatives
US4545935A (en) * 1983-09-12 1985-10-08 Iowa State University Research Foundation, Inc. Amidoalkylation reactions of anilines
US4959360A (en) * 1988-06-01 1990-09-25 Smithkline Beecham Corporation α-adrenergic receptor antagonists
US4963547A (en) * 1988-06-01 1990-10-16 Smithkline Beecham Corporation Alpha-andrenergic receptor antagonists and use thereas
US4978660A (en) * 1988-06-01 1990-12-18 Smithkline Beecham Corporation α-adrenergic receptor antagonists
US4981849A (en) * 1989-02-23 1991-01-01 Smithkline Beecham Corporation Alpha-adrenergic receptor antagonists
US4981848A (en) * 1989-02-23 1991-01-01 Smithkline Beecham Corporation Alpha-adrenergic receptor antagonists
US5006521A (en) * 1988-06-01 1991-04-09 Smithkline Beecham Corporation α-adrenergic receptor antagonists and methods of use thereas
WO2008110598A1 (en) * 2007-03-13 2008-09-18 Biovitrum Ab (Publ) Tricyclic isoquinoline derivatives for treatment of obesity

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4029672A (en) * 1976-02-26 1977-06-14 American Hoechst Corporation Aminoalkylpyrrolobenzoxazalkanes
JPS5729817U (en)) * 1980-07-26 1982-02-17
DE3525564A1 (de) * 1985-07-15 1987-02-05 Schering Ag Tricyclische verbindungen mit indolstruktur, verfahren zu ihrer herstellung und deren verwendung als arzneimittel
EP0344979B1 (en) * 1988-06-01 1994-11-09 Smithkline Beecham Corporation Alfa-adrenergic receptor antagonists
ATE114310T1 (de) * 1988-06-01 1994-12-15 Smithkline Beecham Corp Alpha-adrenergische rezeptorantagonisten.
EP0344980A3 (en) * 1988-06-01 1991-05-15 Smithkline Beecham Corporation Alpha-adrenergic receptor antagonists
ATE109483T1 (de) * 1988-06-01 1994-08-15 Smithkline Beecham Corp Alpha-adrenergische rezeptorantagonisten.
US6765004B1 (en) * 1999-06-17 2004-07-20 Ortho-Mcneil Pharmaceutical, Inc. Indoloazepines as vasopressin receptor antagonists

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3182071A (en) * 1961-06-27 1965-05-04 Warner Lambert Pharmaceutical Acylated indole derivatives

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3900477A (en) * 1973-11-06 1975-08-19 Ayerst Mckenna & Harrison 5-amino-and 5-hydrazinodihydropyrroloisoquinoline derivatives
US3950343A (en) * 1973-11-06 1976-04-13 Ayerst, Mckenna And Harrison Ltd. Pyrroloisoquinoline derivatives
US3978066A (en) * 1973-11-06 1976-08-31 Ayerst, Mckenna And Harrison Ltd. Certain 4,6-dihydropyrrolotriazoline-quinoline derivatives
US4545935A (en) * 1983-09-12 1985-10-08 Iowa State University Research Foundation, Inc. Amidoalkylation reactions of anilines
US4978660A (en) * 1988-06-01 1990-12-18 Smithkline Beecham Corporation α-adrenergic receptor antagonists
US4963547A (en) * 1988-06-01 1990-10-16 Smithkline Beecham Corporation Alpha-andrenergic receptor antagonists and use thereas
US4959360A (en) * 1988-06-01 1990-09-25 Smithkline Beecham Corporation α-adrenergic receptor antagonists
US5006521A (en) * 1988-06-01 1991-04-09 Smithkline Beecham Corporation α-adrenergic receptor antagonists and methods of use thereas
US4981849A (en) * 1989-02-23 1991-01-01 Smithkline Beecham Corporation Alpha-adrenergic receptor antagonists
US4981848A (en) * 1989-02-23 1991-01-01 Smithkline Beecham Corporation Alpha-adrenergic receptor antagonists
WO2008110598A1 (en) * 2007-03-13 2008-09-18 Biovitrum Ab (Publ) Tricyclic isoquinoline derivatives for treatment of obesity
US20080293694A1 (en) * 2007-03-13 2008-11-27 Biovitrum Ab (Publ.) New compounds
US8138333B2 (en) 2007-03-13 2012-03-20 Proximagen Limited Sulfonyl-indole derivatives
EA016592B1 (ru) * 2007-03-13 2012-06-29 Биовитрум Аб (Пабл) Трициклические производные изохинолина для лечения ожирения

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BE795451A (fr) 1973-08-16
FR2181738A1 (en)) 1973-12-07
JPS5516434B2 (en)) 1980-05-01
JPS4892400A (en)) 1973-11-30
FR2181738B1 (en)) 1976-03-05
GB1418354A (en) 1975-12-17
DE2306605A1 (de) 1973-09-06

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