WO1983003410A1 - Isoindolin derivatives - Google Patents

Isoindolin derivatives Download PDF

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Publication number
WO1983003410A1
WO1983003410A1 PCT/JP1982/000096 JP8200096W WO8303410A1 WO 1983003410 A1 WO1983003410 A1 WO 1983003410A1 JP 8200096 W JP8200096 W JP 8200096W WO 8303410 A1 WO8303410 A1 WO 8303410A1
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WO
WIPO (PCT)
Prior art keywords
group
reaction
compound
substituted
acid
Prior art date
Application number
PCT/JP1982/000096
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English (en)
French (fr)
Japanese (ja)
Inventor
Ltd. Takeda Chemical Industries
Kentaro Hiraga
Yoshiaki Saji
Original Assignee
Takeda Chemical Industries Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Chemical Industries Ltd filed Critical Takeda Chemical Industries Ltd
Priority to PCT/JP1982/000096 priority Critical patent/WO1983003410A1/ja
Priority to US06/478,478 priority patent/US4590189A/en
Priority to DE8383301656T priority patent/DE3378763D1/de
Priority to AT83301656T priority patent/ATE39483T1/de
Priority to EP83301656A priority patent/EP0091241B1/en
Priority to DK136983A priority patent/DK161311C/da
Priority to CA000424994A priority patent/CA1196330A/en
Priority to JP58057228A priority patent/JPS58189163A/ja
Priority to KR1019830001350A priority patent/KR900007780B1/ko
Priority to HU831142A priority patent/HU189679B/hu
Publication of WO1983003410A1 publication Critical patent/WO1983003410A1/ja
Priority to SU843773895A priority patent/SU1376941A3/ru
Priority to US06/832,138 priority patent/US4788191A/en
Priority to US07/241,851 priority patent/US4879293A/en
Priority to SG993/90A priority patent/SG99390G/en
Priority to HK1041/90A priority patent/HK104190A/xx

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/5532—Seven-(or more) membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/59—Hydrogenated pyridine rings

Definitions

  • benzodiazebine compounds are commonly used as anxiolytics, have side effects such as drug dependence, drug dependence, hypnotic action and ⁇ relaxation action, and are not necessarily painful.
  • the present inventors have repeatedly studied to develop a non-benzodiazepine-based compound as an anti-anxiety agent, and as a result, succeeded in cracking a compound having an excellent action and completed the present invention.
  • the present invention uses the formula
  • ring A represents a benzene ring which may be substituted with halogen
  • X represents a cyclic group which may be simulated
  • Y represents a carboxyl group which may be esterified or amidated
  • ⁇ represents a 11S number
  • cyclic groups may have one to three substituents, such as halogen (eg, Cl, Bf, F, I), C 1-4 alkyl (methyl, Eteru, pro building, Isopuropiru, Butel, Lee Sobuteru), C 1 - 4 alkoxy (e.g., main bets carboxymethyl, ethoxy alkoxy, Purobokin, Lee Soburopokin), Mechirenjioki sheet, heat Dorokishi C 2 -.
  • substituents such as halogen (eg, Cl, Bf, F, I), C 1-4 alkyl (methyl, Eteru, pro building, Isopuropiru, Butel, Lee Sobuteru), C 1 - 4 alkoxy (e.g., main bets carboxymethyl, ethoxy alkoxy, Purobokin, Lee Soburopokin), Mechirenjioki sheet, heat Dorokishi C 2 -.
  • the carboxyl group represented by Y may be esterified or amidated, and the esterified carboxy group is represented by the formula
  • R 1 in the formula (a) is a C 1-4 alkyl (eg, methyl, ether,
  • f 2 and f 2 are the same or different and each represents hydrogen, C 1-4 alkynole (eg, methyl, ethyl, propyl, isopropyl), phenyl C 1-4 alkyl (! 1, benzyl. Phenethyl '). Monomethylbenzyl), phenyl'thiazolyl, benzothiazolyl, etc., such as halogen (eg, Cl, Br, F.I), hydroxy, C 1-4 alkoxy (eg, methoxydimethoxy).
  • halogen eg, Cl, Br, F.I
  • C 1-4 alkoxy eg, methoxydimethoxy
  • heterocyclic group examples include pyrrolidinyl, piperidino, piperazinyl, morpholino, thiazolidinyl, hexahydroazepinyl and the like.
  • These heterocyclic groups may have one to two substituents, such as ⁇ , for example, hydroxy, C14 alkoxy (, methoxy, ethoxy, proboquin, Sob ⁇ -poxy), C 1-4 alkyl (eg, meter, ethinole, propyl, isopropyl), C 2.—5 alkoxycarbonyl (eg, methoxycarb, ethoxycarbonyl), phenyl C1 Examples include 1-4 alkyl (!), Benzyl, phenethyl, monomethyl besosyl), phenyl, pyridino, pyridyl, and the like, and among these, ring-substituents (eg, phenyl, etc.) , A
  • the present compound (I) can be produced, for example, by the following method.
  • M s is a methanesulfo group
  • ⁇ symbols are of the same meaning as defined above compounds of general formula (VI is obtained by reducing i.e. (V) borohydride Ritekumu. This reaction Tetorahi The reaction is usually carried out at room temperature in drofuran, but if necessary, the reaction rate may be reduced by cooling or adding.
  • the methanesulfonyl chloride is reacted with ⁇ D with pyridine ⁇ to give mesylate ( W) is reacted with potassium cyanide to obtain a compound of the general formula (VI).
  • -BUREA C V.?I Can be This reaction is carried out by heating to reflux using water-containing methanol or ethanol as a solvent. The thus obtained is converted into a compound (1-1 :) in which n is 2 by a hydrolysis reaction.
  • the hydrolysis reaction can be carried out under general hydrolysis conditions for a ditolyl group, for example, heating under reflux in a concentrated salt g.
  • the compound of the second (1) was reacted with sodium iodide under heating in a solvent such as acetone, dimeterformamide, tetrahydrofuran, etc. under heating, and the iodide (E-panidi was derived.
  • Reaction with malon g diester eg, dimethyl methyl malonate, malon ⁇ jete
  • (I) is obtained by converting (I—1) from ⁇ [ ⁇ ').
  • R 1 has the same meaning as described above] to give an ester to form an ester.
  • the ester (1-2) can be obtained by heating the mixture in the presence of ⁇ ⁇ .
  • a dehydrating reagent such as zinclohexyl carposomemid or carbodidimidazole, which is Byone.
  • This reaction is usually performed in pyridine, but any other organic solvent may be used as long as the reaction is not inhibited.
  • the reaction temperature is in the range of about 20.about.15 O ⁇ C, and is usually conveniently carried out at room temperature.
  • examples of the reactive derivative of (1-1) include dehydration of one molecule of water from two molecules of acid, chloride (eg, acid chloride, dibromide), and ( ⁇ 1-1).
  • OVP1 ⁇ ⁇ zK product obtained by the above process wherein the hydrogen of the carboxyl group of (I-11) is replaced by, for example, an ethoxycarbonyl group, an isobuteroxycarbonyl group, a benzyloxycarbonyl group, etc. And so on.
  • the reaction between these and the alcohol (SI) can be usually performed in any solvent that does not hinder the reaction, such as, for example, ether, benzene, tetrahydrofuran, methylene chloride, chloroform-form, and dimethylformamide.
  • This reaction is carried out, if necessary, in the presence of a barrier such as pyridine, triethylamine, dimethylaminopyridine, di: probiethylamine, triethylenediamine, and the like. It is about 0 "to 100 ° C, preferably 0 ⁇ to 30 ° C.
  • ( ⁇ ⁇ 2) is also an alkali metal clay (sodium salt) or (-formula) of ( ⁇ -1).
  • R 1 has the same meaning as described above, and ⁇ represents a no or a logen].
  • the compound in which R 1 is a tertiary butter group can also be cleaved by adding (I-11) to isobutylene. This reaction is carried out in the presence of a medium such as sulfuric acid or boron trioxide.
  • Examples of the reactive derivative at the carboquinol group of the compound (I-I ;!) include those used in the above-mentioned method (2), such as N-hydroxydiacyl ⁇ (midesters ( ⁇ iL N-hydroxy And imidosteric acid, N-hydroxyphthalic acid imidester, N-hydroxy-15-norbornene-12,3-dicarboximide ester, etc.
  • the reaction is usually, for example, dichloromethane, Any solvent can be used as long as it does not hinder the reaction, as long as it does not hinder the reaction, such as bihydridine.
  • the reaction is carried out in the presence of a base such as amine, carbonated lime, sodium hydride, etc.
  • the reaction temperature is usually about 110 to 100, preferably 0 to 30 ⁇ .
  • a base such as amine, carbonated lime, sodium hydride, etc.
  • the reaction temperature is usually about 110 to 100, preferably 0 to 30 ⁇ .
  • -If 1) is used as a reactive derivative, if it is used as it is, the presence of water, such as dicyclohexylcarbodimid, dicarboxylic acid midole, methyl cyanophosphate, diphenyl phosphorylate, etc.
  • the reaction can also be carried out in the presence of a base such as pyridine, picolin, triesteramine, sodium hydroxide, potassium carbonate, etc.
  • the reaction temperature is usually about 1: 2.
  • O The reaction is performed in the range of ⁇ 150 ⁇ , and in most cases, the reaction is sufficiently performed even at room temperature.
  • (I-1) wherein Y is a canoleboxyl group can be isolated as a salt, for example, a metal salt such as sodium, potassium, calcium and the like.
  • the compound of the present invention when U is S-group, can be isolated in the form of a salt with an acid.
  • the strong salt include salts with inorganic acids (e.g., hydrochloride, nitrate, Sulfate.
  • the minimum effective dose is 2.5 or less in rats, the drug safety range is extremely wide, and the effects as side effects and muscles are lower than those of benzodiazepine drugs marketed as anxiolytic. It has a very weak relaxing effect and is safe and useful as an anxiolytic.
  • Target disease names include, for example, autonomic dyslexia, vomiting, ⁇ dermatitis, alopecia areata, and nerves.
  • Various psychosomatic disorders such as angina pectoris and dyspnea nervosa, and anxiety neurosis, can be used for the prevention or treatment of these diseases.
  • the compound also has anticonvulsant activity, and can be used, for example, in epilepsy and traumatic spasticity.
  • the compound is orally or parenterally administered to mammals including humans in various forms such as tablets, pills, capsules, injections, suppositories and the like.
  • the dosage varies depending on the disease species $ 1, the symptoms, etc., but for the control, it is usually about 0.001 to 50 ⁇ per body weight per person, and for humans is 0.1 to per day per adult: Preferably it is 0.5 to 20 ⁇ .
  • the compounds (1-1) and (1-2) of the present invention are useful as intermediates in the production of (1-3).
  • the pharmacological properties of the compound (I.) of the present invention were examined by measuring the ability of the radiolabeled diazepam to displace the benzodiazepine receptor.
  • reaction solution was concentrated under pressure, and the remaining water was added to the remaining water.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
PCT/JP1982/000096 1982-04-02 1982-04-02 Isoindolin derivatives WO1983003410A1 (en)

Priority Applications (15)

Application Number Priority Date Filing Date Title
PCT/JP1982/000096 WO1983003410A1 (en) 1982-04-02 1982-04-02 Isoindolin derivatives
US06/478,478 US4590189A (en) 1982-04-02 1983-03-24 Condensed pyrrolinone derivatives, their production and use
DE8383301656T DE3378763D1 (en) 1982-04-02 1983-03-24 Condensed pyrrolinone derivatives, and their production
AT83301656T ATE39483T1 (de) 1982-04-02 1983-03-24 Kondensierte pyrrolinon-derivate, und ihre herstellung.
EP83301656A EP0091241B1 (en) 1982-04-02 1983-03-24 Condensed pyrrolinone derivatives, and their production
DK136983A DK161311C (da) 1982-04-02 1983-03-25 Analogifremgangsmaade til fremstilling af 2-substituerede 3-karboxyalkyl-4,5-kondenserede pyrrolin-1-onderivater eller salte deraf
JP58057228A JPS58189163A (ja) 1982-04-02 1983-03-31 縮合ピロリノン誘導体
CA000424994A CA1196330A (en) 1982-04-02 1983-03-31 Condensed pyrrolinone derivatives, their production and use
KR1019830001350A KR900007780B1 (ko) 1982-04-02 1983-04-01 축합된 피롤리논 유도체의 제조방법
HU831142A HU189679B (en) 1982-04-02 1983-04-01 Process for producing condensed pyrrolinone derivatives
SU843773895A SU1376941A3 (ru) 1982-04-02 1984-07-10 Способ получени производных пирролинона или их кислотно-аддитивных солей
US06/832,138 US4788191A (en) 1982-04-02 1986-04-23 1,3-dithiolano-, 1,4-dithiino- and 1,4-dithiepino[2,3-C]pyrrole derivatives, their production and use
US07/241,851 US4879293A (en) 1982-04-02 1988-09-08 Pyrrols [3,4-8]pyrazine derivatives, their production and use as anti-anxiety agents
SG993/90A SG99390G (en) 1982-04-02 1990-12-13 Condensed pyrrolinone derivatives,and their production
HK1041/90A HK104190A (en) 1982-04-02 1990-12-13 Condensed pyrrolinone derivatives,and their production

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP1982/000096 WO1983003410A1 (en) 1982-04-02 1982-04-02 Isoindolin derivatives

Publications (1)

Publication Number Publication Date
WO1983003410A1 true WO1983003410A1 (en) 1983-10-13

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1982/000096 WO1983003410A1 (en) 1982-04-02 1982-04-02 Isoindolin derivatives

Country Status (4)

Country Link
DK (1) DK161311C (da)
SG (1) SG99390G (da)
SU (1) SU1376941A3 (da)
WO (1) WO1983003410A1 (da)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7064135B2 (en) 2001-10-12 2006-06-20 Novo Nordisk Inc. Substituted piperidines
US7767695B2 (en) 2001-09-14 2010-08-03 High Point Pharmaceuticals, Llc Substituted piperidines
EP2243776A1 (en) 2001-10-12 2010-10-27 High Point Pharmaceuticals, LLC Substituted piperidines and their use for the treatment of diseases related to the histamine H3 receptor

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2101081A1 (da) * 1970-08-19 1972-03-31 Rhone Poulenc Sa
US3987174A (en) * 1972-03-16 1976-10-19 Rhone-Poulenc S.A. Isoindolin-1-one derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2101081A1 (da) * 1970-08-19 1972-03-31 Rhone Poulenc Sa
US3987174A (en) * 1972-03-16 1976-10-19 Rhone-Poulenc S.A. Isoindolin-1-one derivatives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts, 85, 142944q, 8. November. 1976 (08.11.76) *
Chemical Abstracts, 86, 4433s, 3. January. 1977 (03.01.77) *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7767695B2 (en) 2001-09-14 2010-08-03 High Point Pharmaceuticals, Llc Substituted piperidines
US7064135B2 (en) 2001-10-12 2006-06-20 Novo Nordisk Inc. Substituted piperidines
EP2243776A1 (en) 2001-10-12 2010-10-27 High Point Pharmaceuticals, LLC Substituted piperidines and their use for the treatment of diseases related to the histamine H3 receptor

Also Published As

Publication number Publication date
DK136983A (da) 1983-10-03
DK161311B (da) 1991-06-24
SU1376941A3 (ru) 1988-02-23
DK161311C (da) 1991-12-30
SG99390G (en) 1991-02-14
DK136983D0 (da) 1983-03-25

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