WO1990007502A1 - Composes de decahydroisoquinoline - Google Patents

Composes de decahydroisoquinoline Download PDF

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Publication number
WO1990007502A1
WO1990007502A1 PCT/EP1989/001621 EP8901621W WO9007502A1 WO 1990007502 A1 WO1990007502 A1 WO 1990007502A1 EP 8901621 W EP8901621 W EP 8901621W WO 9007502 A1 WO9007502 A1 WO 9007502A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
group
methyl
alkyl
Prior art date
Application number
PCT/EP1989/001621
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English (en)
Inventor
Vittorio Vecchietti
Original Assignee
Dr. Lo. Zambeletti S.P.A.
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 Dr. Lo. Zambeletti S.P.A. filed Critical Dr. Lo. Zambeletti S.P.A.
Publication of WO1990007502A1 publication Critical patent/WO1990007502A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals

Definitions

  • This invention is concerned with novel decahydroisoquinoline derivatives, processes for their
  • kappa-receptor agonists act as analgesics through interaction with kappa opioid receptors.
  • morphine lies in their ability to cause analgesia while being devoid of morphine-like behavioural effects and addiction liability.
  • anti-hyponatraemic agents and/or as anti-cerebral ischaemia agents are examples of anti-hyponatraemic agents and/or as anti-cerebral ischaemia agents.
  • RCO is an acyl group in which the group R contains a substituted or unsubstituted carbocyolic aromatic or heterocyclic aromatic ring;
  • R 1 and R 2 are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl or C 4-12 cycloalkylalkyl groups, or together form a C 2-8 branched or linear polymethylene or C 2-6 alkenylene group, optionally substituted with a hetero-atom,
  • R 3 is hydrogen , C 1-6 alkyl, preferably methyl or ethyl, or phenyl, or R 3 together with R 1 form a
  • R 4 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy or halogen, preferably methyl, methoxy or chlorine.
  • the term 'carbocyclic aromatic group' includes single or fused rings, having 6 to 12 ring carbon atoms
  • the term 'heterocyclic aromatic group' includes single or fused rings having 5 to 12 ring atoms, comprising up to four hetero-atoms in the or each ring, selected from oxygen, nitrogen and sulphur .
  • one or both rings may be aromatic in character.
  • one of the rings is aromatic and the other is non-aromatic.
  • the C 1-6 alkyl groups may be either straight or
  • branched chain and examples are methyl, ethyl, propyl, n-butyl, n-pentyl or n-hexyl, preferaoiy methyl.
  • Examples of C 2-6 alkenyl groups are 1- and 2-propenyl; an example of a C 3-6 cycloalkyl group is cyclopropyl, and an example of a C 4-12 cycloalkylalkyl group is cyclopropyl methyl.
  • R 1 and R 2 together form a linear or branched polymethylene group
  • examples are propylene, butylene, pentylene or hexylene, preferably butylene or
  • hetero-atoms are oxygen and sulphur, particularly oxygen, and a suitable hetero-atom substituted polymethylene group is -CH 2 CH 2 OCH 2 CH 2 - .
  • R 1 and R 2 are both C 1-6 alkyl, they are
  • the group R preferably has the formula (II):
  • n 0, 1 or 2
  • m 0, 1 or 2
  • n' is 0, 1 or 2, provided m + m' ⁇ 2 ;
  • X is a direct bond, or 0, S or NR 7 in which R 7 is hydrogen or C 1-6 alkyl;
  • Ar is a substituted or unsubstituted carbocyclic or heterocyclic group
  • R 5 is hydrogen or C 1-6 alkyl, such as methyl or ethyl; each of R 6 and R 6 a is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, aryl, aralkyl, hy ⁇ roxy, C 1-6 alkoxy, thiol, C 1-6 alkylthio, C 1-6 haloalkoxy, C 1-6 haloalkylthio, halogen, NO 2 , CN, CF 3 , -OCF 3 , -OCHF 2 , -OCF 2 CF 2 H, -OCCl 2 CF 3 , -COOR 8 , -CONR 9 R 10 , -SO 3 R 11 , -SO 2 NR 12 R 13 and -COR 14 in which each of R 8 to R 14 is independently hydrogen, C
  • Preferred halogens are F, Cl and Br.
  • R 6 's When two R 6 's are linked they preferably form a fused cyclopentyl or cyclohexyl ring.
  • Ar is phenyl and Rg or R 6 a is preferably in the meta and/or para position.
  • R 6 or R 6 a is bromine, chlorine, NO 2 or CF 3 , particularly in the meta- or para- position.
  • R 6 or R 6 a is chlorine.
  • X is typically oxygen or a direct bond
  • n is typically 0 or 1.
  • the -CHR 3 NR 1 R 2 group is preferably located at the 1 or 3 position on the heterocyclic ring system, and R 4 is preferably located at the 5 position.
  • the compounds of formula I or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form.
  • pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • a substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of the compound of formula I or its salt or solvate.
  • One preferred pharmaceutically acceptable form is the crystalline form, including such form in a
  • Examples of a pharmaceutically acceptable salt of a compound of formula I include the acid addition salts with the conventional pharmaceutical acids, for
  • Examples of a pharmaceutically acceptable solvate of a compound of formula I include the hydrate.
  • the compounds of formula I have more than one
  • the present invention also provides a process for the preparation of a compound of formula I which comprises reacting a compound of formula (III):
  • R 1 ', R 2 ', R 3 ' and R 4 ' are R 1 , R 2 , R 3 and R 4 as defined for formula I, or are groups or atoms
  • R', R 1 ', R 2 ', R 3 ' or R 4 ' are other than R, R 1 , R 2 , R 3 or R 4 respectively, converting R', R 1 ', R 2 ', R 3 ' or R 4 ' to R, R 1 , R 2 , R 3 or R 4 respectively, to obtain a compound of formula (I), b) where R', R 1 ', R 2 ', R 3 ' or R 4 ' are R, R 1 , R 2 , R 3 or R 4 respectively, converting one R, R 1 , R 2 , R 3 or R 4 respectively to another R, R 1 , R 2 , R 3 or R 4
  • Suitable active derivatives of are acid
  • the compound of formula (III) may be coupled: a) with an acid chloride in the presence of an inorganic or organic base, b) with the acid in the presence of dicyclohexyl carbodiimide, N-dimethylaminopropyl-N'-ethyl
  • carbodiimide or carbonyl diimidazole c) with a mixed anhydride generated in situ from the acid and an alkyl (for example: ethyl)chloroformate.
  • a compound of formula (la) may be converted to a compound of formula (I), or one compound of formula (I) may be converted to another compound of formula (I), by interconversion of suitable substituents.
  • certain compounds of formula (I) and (la) are useful intermediates in forming other compounds of the present invention.
  • R 1 ' and R 2 ' may be alkyl groups and converted to
  • R 1 '/R 2 ' hydrogen atoms by conventional amine
  • R 1 ' or R 2 ' is benzyl or substituted benzyl it may be converted to an R 1 or R 2 hydrogen atom by catalytic hydrogenation or other conventional methods of reduction.
  • R 1 ' and R 2 ' as hydrogen atoms may be converted to R 1 and R 2 alkyl groups by
  • R 1 ' and R 2 ' are preferably R 1 and R 2 respectively.
  • the compound is typically of the formula (Ila) ⁇
  • R 6 ' is R 6 and (R 6 a )' is R 6 a are as. defined for formula (II), or a group or atom convertible to R 6 or R 6 a respectively, the other variables being as defined for formula (II).
  • a preferred compound is the equivalent acid halide of formula (IIb)
  • Hal is halogen, typically chlorine or bromine.
  • R 6 ' is preferably R 6 and (R 6 a )' is preferably R 6 a .
  • the compounds of formula (I) may be converted into their pharmaceutically acceptable acid addition salts by reaction with the appropriate organic or mineral acids.
  • Solvates of the compounds of formula I may be formed by crystallization or recrystallization from the
  • hydrates may be formed by crystallization or recrystallization from aqueous solutions, or solutions in organic solvents containing water.
  • salts or solvates of the compounds of formula I which are not pharmaceutically acceptable may be useful as intermediates in the production of pharmaceutically acceptable salts or solvates. Accordingly such salts or solvates also form part of this invention.
  • the compounds of formula I exist in more than one stereoisomeric form and the processes of the invention produce mixtures thereof.
  • the individual isomers may be separated one from another by standard
  • the single enantiomers may be separated by resolution using an optically active acid such as tartaric acid.
  • an asymmetric synthesis would offer a route to the
  • the compounds of formula (III) bearing the CHR 3 'NR 1 'R 2 ' substituent in position 1 may be obtained by catalytic hydrogenation of a compound of formula (IV), for example by hydrogenation in a mixture of acetic and trifluoroacetic acid in the presence of a platinum oxide catalyst.
  • the compounds of formula (III) bearing the CHR 3 'NR 1 'R 2 ' substituent in position 3 may be obtained from a compound of formula (VIII) by reduction with a mixed hydride, such as LiAlH 4 , in a solvent such as THF at room temperature, in accordance with the following reaction scheme:
  • a compound of formula (VII) reacting a compound of formula (VII) with an amine of formula HNR 1 'R 2 ' in a solvent, such as EtOH, at an elevated temperture, such as 90°C.
  • the compounds of formula (VII) may themselves be prepared from compounds of formula (VI) by catalytic hydrogenation in a solvent mixture such as ACOH/CF 3 COOH, with a catalyst such as platinum oxide.
  • the compounds formula (VI) may themselves be prepared from compounds of ferula (V) by known methods, such as for example by warming a compound of formula (V) in the presence of SOCI 2 in a solvent such as EtOH.
  • the compounds of formula (V) are known compounds or may be prepared from known compounds by known methods (see for example Hayashi et al (Chem. Pharm. Bull. 31, 312, 1983) and European Published Application No. 228246).
  • the activity of the compounds of formula (I) as kappa agonists indicates that they are of therapeutic utility in the treatment of pain and/or hyponatraemic disease states and/or of cerebral ischaemia.
  • the present invention also provides a compound of formula (I), or a pharmaceutically
  • the present invention further provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of a compound of formula (I), or a pharmaceutically
  • Such a medicament, ⁇ n ⁇ a composition of this invention may be prepared by admixture of a compound of the invention with an appropriate carrier. It may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner.
  • compositions of known analgesic agents and/or anti-hyponatraemic agents and/or anti-cerebral ischaemia agents may be employed for example as in the preparation of compositions of known analgesic agents and/or anti-hyponatraemic agents and/or anti-cerebral ischaemia agents.
  • Such preparations may be in a pack form accompanied by written or printed instructions for use as an agent in the treatment of pain and/or of
  • the suitable dosage range for the compounds of the invention depends on the compound to be employed and on the condition of the patient. It will also depend, inter alia, upon the relation of potency to
  • the compound or composition of the invention may be formulated for administration by any route, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage.
  • the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration. Preparations may be designed to give slow release of the active ingredient.
  • Compositions may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid
  • preparations for example solutions or suspensions, or suppositories.
  • compositions for example those suitable for oral administration, may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate;
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants for example magnesium stearate
  • disintegrants for example starch, polyvinylpyrrolidone, sodium starch glycollate or
  • microcrystalline cellulose or pharmaceutically
  • Solid compositions may be obtained by conventional methods of blending, filling, tableting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions
  • compositions When the composition is in the form of a tablet, powder, or lozenge, any carrier suitable for formulating solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in normal pharmaceutical
  • composition may also be in the form of an ingestible capsule, for example of gelatin containing the
  • compositions for oral administration as liquids may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose,
  • aluminium stearate gel hydrogenated edible fats
  • emulsifying agents for example lecithin, sorbitan mono-oleate, or acacia; aqueous or non-aqueous
  • oils for example almond oil, fractionated coconut oil, oily esters, for example esters of glycerine, or propylene glycol, or ethyl alcohol, glycerine, water or normal saline;
  • preservatives for example methyl or propyl
  • compositions may be formulated, for example for rectal administration as a suppository. They may also be formulated for
  • aqueous or non-aqueous solution e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids.
  • a pharmaceutically acceptable liquid e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids.
  • the liquid may contain
  • Such forms will be presented in unit dose form such as ampoules or disposable injection devices or in multi- dose forms such as a bottle from which the appropriate dose may be withdrawn or a solid form or concentrate which can be used to prepare an injectable formulation.
  • a unit dose will generally contain from 20 to 1000 mg and preferably will contain from 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.
  • the composition may be administered once or more times a day for example 2, 3 or 4 times daily, and the total daily dose for a 70 kg adult will normally be in the range 100 to 3000 mg.
  • the unit dose will contain from 2 to 20 mg of active ingredient and be administered in
  • the present invention also provides a method of
  • the reaction mixture was washed with 30 ml of 32% of NH 4 OH solution, and the organic layer separated, dried over Na 2 SO 4 and evaporated in vacuo to dryness.
  • the crude product obtained was chromatographed on silica gel eluting with CH 2 Cl 2 containing increasing amounts of MeOH (0.1-2.5%) to afford the least polar product which was crystallized as its maleate to yield 1.5 g of the title compound.
  • reaction mixture was taken up with a mixture of THF and 40 NaOH solution and filtered on randalite.
  • the mother liquors were evaporated in vacuo to dryness, taken up with a cone. NaOH solution and extracted with Et 2 O to afford 3.3 g of the title compound, as an oil, which was used for the subsequent reaction without further purification.
  • the reaction mixture was washed with 15 ml of 32% NH 4 OH solution and the organic layer separated, dried over Na 2 SO 4 and concentrated in vacuo to dryness.
  • the crude product obtained was chromatographed on silica gel eluting with CH 2 CI 2 containing increasing amounts of methanol (0.1-2.5%) to afford the least polar product which was crystallized as its hydrochloride to yield 2 g of the title compound.
  • the title compound was obtained as the free base as a oil.
  • the pharmacological activity of the compounds of this invention is illustrated by various in vitro and in vivo models, using the following test procedures, in which tne mouse tail flick test demonstrates analgesic activity.
  • mice Male Charles River mice (Swiss Strain), 22-34 g body weight are used. Animals are allowed food and water ad libitum and are randomized into groups of 10 prior to experimentation. Before administration of the test compound, the reaction time of each animal is determined by focusing a beam of light onto the tail, eliciting a reflex withdrawal after a certain latency; only mice exibiting a latency between 3-8 sec. are used subsequently in the evaluation of drug effects.
  • Test compounds are dissolved in either distilled water or distilled water plus 0.1 M AMS and administered by the subcutanous route in a final volume of 10 ml/Kg. Control animals receive 10 ml/kg of the appropriate vehicle alone. Following a pretreatment period of 30 min., the mice are again placed under the heat source and the reaction time redetermined.
  • Percentage guantal protection is determined as the number of mice in which the reaction time is doubled compared to pretreatment values, expressed as a percentage of the total number of mice in the group.
  • Radio receptor binding to ⁇ , k and ⁇ sites is performed on fresh guinea pig brain homogenate prepared according to
  • Tris-buffer pH 7.4 at 0oC
  • the pellet is then resuspended in the same buffer, incubated at 37°C for 45 min. and centrifuged again.
  • the binding to the k-sites is performed using 3 H- EthylKetocyclazocine, a non-selective benzomorphan compound which binds to ⁇ , ⁇ and k sites, in the presence of 100 nM of unlabelled DAGO and 100 nM of the enkephalin analogue
  • the radioactivity bound to the filters is counted by liquid scintillation spectrophotometry.
  • the non-specific binding is determined in the presence of

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composé, ou solvate ou sel de celui-ci, de formule (I) dans laquelle RCO représente un groupe acyle dans lequel le groupe R contient un anneau aromatique carbocyclique ou aromatique hétérocyclique à substitution; R1 et R2 représentent indépendamment des groupes hydrogène, alcoyle C1-6, alkényle C2-6, cycloalcoyle C3-6 ou cycloalcoylealcoyle C4-12, ou forment ensemble un groupe polyméthylène C2-8 ramifié ou linéaire ou alkénylène C2-6, facultativement remplacé par un hétéroatome, à condition que R1 et R2 ne représentent pas simultanément hydrogène; R3 représente hydrogène, alcoyle C1-6, ou phényle, ou R3 ainsi que R1 forment un groupe -(CH2)3- ou -(CH2)4-; et R4 représente hydrogène, alcoyle C1-6, alkoxy C1-6, hydroxy ou halogène.
PCT/EP1989/001621 1988-12-23 1989-12-21 Composes de decahydroisoquinoline WO1990007502A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB888830219A GB8830219D0 (en) 1988-12-23 1988-12-23 Novel compounds
GB8830219.5 1988-12-23

Publications (1)

Publication Number Publication Date
WO1990007502A1 true WO1990007502A1 (fr) 1990-07-12

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WO (1) WO1990007502A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992017467A1 (fr) * 1991-04-06 1992-10-15 Dr Lo. Zambeletti S.P.A. Composes azacycliques substitues, leur procede de preparation et leur utilisation a titre d'analgesiques
EP0527385A1 (fr) * 1991-08-10 1993-02-17 Bayer Ag Amines bicycliques saturés substitués en alpha pour un groupe trifluorométhyl, et procédé de préparation
US5760023A (en) * 1997-07-14 1998-06-02 Adolor Corporation Kappa agonist anti-pruritic pharmaceutical formulations and method of treating pruritus therewith
US6004964A (en) * 1997-07-14 1999-12-21 Adolor Corporation Kappa agonist anti-pruritic pharmaceutical formulaitons and method of treating pruritus therewith
US6476063B2 (en) 1996-03-08 2002-11-05 Adolor Corporation Kappa agonist compounds, pharmaceutical formulations and method of prevention and treatment of pruritus therewith
WO2004016587A1 (fr) * 2002-08-19 2004-02-26 Ono Pharmaceutical Co., Ltd. Composes contenant de l'azote
US6960612B2 (en) 1996-03-08 2005-11-01 Adolor Corporation Kappa agonist compounds, pharmaceutical formulations and method of prevention and treatment of pruritus therewith
WO2014113750A1 (fr) * 2013-01-18 2014-07-24 Dnj Pharma, Inc. Nouveaux inhibiteurs de ddp-iv

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0232989A2 (fr) * 1986-01-24 1987-08-19 Dr. Lo. Zambeletti S.p.A. Dérivés de l'isoquinoléine
EP0330469A2 (fr) * 1988-02-23 1989-08-30 Glaxo Group Limited Dérivés de la tétrahydroisoquinoléine
EP0330360A1 (fr) * 1988-02-19 1989-08-30 SmithKline Beecham Farmaceutici S.p.A. 1,2,3,4-Tetrahydroisoquinolines, procédé pour leur préparation et leur utilisation comme agoniste de Kappa-récepteur

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0232989A2 (fr) * 1986-01-24 1987-08-19 Dr. Lo. Zambeletti S.p.A. Dérivés de l'isoquinoléine
EP0330360A1 (fr) * 1988-02-19 1989-08-30 SmithKline Beecham Farmaceutici S.p.A. 1,2,3,4-Tetrahydroisoquinolines, procédé pour leur préparation et leur utilisation comme agoniste de Kappa-récepteur
EP0330469A2 (fr) * 1988-02-23 1989-08-30 Glaxo Group Limited Dérivés de la tétrahydroisoquinoléine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Derwent's abstract no. 08576X/05, SU-A-622-400, see the abstract. *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992017467A1 (fr) * 1991-04-06 1992-10-15 Dr Lo. Zambeletti S.P.A. Composes azacycliques substitues, leur procede de preparation et leur utilisation a titre d'analgesiques
EP0527385A1 (fr) * 1991-08-10 1993-02-17 Bayer Ag Amines bicycliques saturés substitués en alpha pour un groupe trifluorométhyl, et procédé de préparation
US5204471A (en) * 1991-08-10 1993-04-20 Bayer Aktiengesellschaft α-trifluoromethyl-substituted, saturated bicyclic amines
US6960612B2 (en) 1996-03-08 2005-11-01 Adolor Corporation Kappa agonist compounds, pharmaceutical formulations and method of prevention and treatment of pruritus therewith
US6476063B2 (en) 1996-03-08 2002-11-05 Adolor Corporation Kappa agonist compounds, pharmaceutical formulations and method of prevention and treatment of pruritus therewith
US6486165B2 (en) 1996-03-08 2002-11-26 Adolor Corporation Kappa agonist compounds, pharmaceutical formulations and method of prevention and treatment of pruritus therewith
US6492351B1 (en) 1996-03-08 2002-12-10 Adolor Corporation Kappa agonist compounds, pharmaceutical formulations and method of prevention and treatment of pruritus therewith
US7294647B2 (en) 1996-03-08 2007-11-13 Adolor Corporation Kappa agonist compounds and pharmaceutical formulations thereof
US5869521A (en) * 1997-07-14 1999-02-09 Adolor Corporation Kappa agonist anti-pruritic pharmaceutical formulations and method of treating pruritus therewith
US6004964A (en) * 1997-07-14 1999-12-21 Adolor Corporation Kappa agonist anti-pruritic pharmaceutical formulaitons and method of treating pruritus therewith
US6048860A (en) * 1997-07-14 2000-04-11 Adolor Corporation Kappa agonist anti-pruritic pharmaceutical formulations and method of treating pruritus therewith
US6156769A (en) * 1997-07-14 2000-12-05 Apolor Corp. Kappa agonist anti-pruritic pharmaceutical formulations and method of treating pruritus therewith
US5760023A (en) * 1997-07-14 1998-06-02 Adolor Corporation Kappa agonist anti-pruritic pharmaceutical formulations and method of treating pruritus therewith
WO2004016587A1 (fr) * 2002-08-19 2004-02-26 Ono Pharmaceutical Co., Ltd. Composes contenant de l'azote
WO2014113750A1 (fr) * 2013-01-18 2014-07-24 Dnj Pharma, Inc. Nouveaux inhibiteurs de ddp-iv
CN105102428A (zh) * 2013-01-18 2015-11-25 Dnj制药有限公司 新型dpp-iv抑制剂

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