WO1998045262A1 - Composes de pseudo-peptides en tant qu'antagonistes de neurokinines - Google Patents

Composes de pseudo-peptides en tant qu'antagonistes de neurokinines Download PDF

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Publication number
WO1998045262A1
WO1998045262A1 PCT/EP1998/002010 EP9802010W WO9845262A1 WO 1998045262 A1 WO1998045262 A1 WO 1998045262A1 EP 9802010 W EP9802010 W EP 9802010W WO 9845262 A1 WO9845262 A1 WO 9845262A1
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WO
WIPO (PCT)
Prior art keywords
methyl
alanyl
carbonyl
indol
phenylacetyl
Prior art date
Application number
PCT/EP1998/002010
Other languages
English (en)
Inventor
Alessandro Sisto
Christopher Fincham
Edoardo Potier
Rosa Terracciano
Original Assignee
Menarini Ricerche 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 Menarini Ricerche S.P.A. filed Critical Menarini Ricerche S.P.A.
Priority to AU75228/98A priority Critical patent/AU7522898A/en
Publication of WO1998045262A1 publication Critical patent/WO1998045262A1/fr

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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
    • C07D401/12—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
    • 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
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention refers to antagonists of the interaction between the P substance and the NK-1 receptor, the process for their preparation, and their use in pharmaceutical compositions which may be used in the treatment of pathological forms in which the P substance receptor is involved, and in particular in the treatment of the inflammation of airways, such as asthma and rhinitis, and in the treatment of emesis.
  • NK-1 receptor the process for their preparation
  • pharmaceutical compositions which may be used in the treatment of pathological forms in which the P substance receptor is involved, and in particular in the treatment of the inflammation of airways, such as asthma and rhinitis, and in the treatment of emesis.
  • R 5 is chosen from a group consisting of hydrogen or methyl, , is -CONH-
  • X 2 is -NR 12 CO-, wherein R 12 is hydrogen or methyl;
  • X 3 is chosen in the group consisting of -NR 12 CO-, NR 12 CONH-, where R 12 is as defined above;
  • B, C, D, and E independently from each other, may be CH or N;
  • R 6 , R 7 , R 8 and R 9 are independently hydrogen, OH or NR 13 R 14 , where R 13 and R 14 are chosen independently in the group consisting of hydrogen, methyl, cyclohexyl, or 4-piperidine; R 2 is chosen in the group consisting of
  • R 3 is chosen in the group consisting of aryl, aryl-alkyl radicals with a maximum of 15 carbon atoms, wherein the aryl group is chosen in the group consisting of benzene, naphtalene, benzofurane and indole and is possibly substituted on the ring with one or more substituents independently chosen in the group consisting of halogen, alkyl radical containing from 1 to 6 carbon atoms, possibly substituted with a number of fluorine atoms not higher than three (e.g., trifluoromethyl group), oxyalkyl radical containing from 1 to 6 carbon atoms, possibly substituted with a number of fluorine atoms not higher than three (e.g., trifluoromethoxyl group), tetrazole radical, -NH 2 , -NHR 10 , -N(R 10 ) 2 , -OR 10 , -CONHR 10 , COR 10 , COOR 10 , RuCOOR,
  • R 10 is chosen in the group consisting of hydrogen or alkyl radical with linear or branched chain containing from 1 to 6 carbon atoms
  • R113 is an alkyldene radical with linear or branched chain containing from 1 to 6 carbon atoms
  • the compounds of formula (I), which have a receptor tachykinin antagonist activity, prove useful in the treatment of illnesses where tachykinins play a pathogenetic role, in particular arthritis, emesis, Huntington's disease, neuritis, neuralgia, hemicrania, hypertension, urinary incontinence, urticaria, signs indicating carcinoid syndrome, influenza and common cold, illnesses of the immune system, diseases of the respiratory tract (e.g., asthma, rhinitis of various forms and obstructive chronic bronchitis), ophthalmic illnesses (e.g., conjunctivitis), cutaneous illnesses (e.g., allergic and contact dermatitis and psoriasis), intestinal illnesses (e.g., ulcerative colitis and Chron's
  • a preferred group of compounds of the present invention includes the compounds that may be described by the general formula (I), where where
  • R 3 a benzyl group possibly substituted with one or more substituents chosen, independently from each other, in the group consisting of: Cl, Br, F, I, CH 3 , CF 3 ,
  • R 2 , R 4 R 6 , R 7 , R 8 , R 9 , R 10 , R 11 t R 13 , R 14 , B, C, D, and E are as defined above.
  • alkyl radical as defined for R 3 and R 10 and the alkyl-moiety of the oxyalkyl radical defined for R 3 are chosen in the group consisting of methyl, ethyl, propyl, and butyl;
  • the aryl-alkyl radicals as defined for R 3 and the alkyliden-radicals as defined for R present an alkylidene radical chosen in the group consisting of: methylene, ethylidene and propylidene; and
  • the halogen radical is chosen in the group consisting of chlorine, fluorine, bromine, and iodine.
  • the invention refers to the various diastereoisomers included in the formula itself; in particular, the carbon atom bound to the substituent R 2 has R configuration.
  • the compounds of the present invention have shown an antagonist activity of the action of the P substance, neurokinin A, and neurokinin B. They can therefore be used as drugs in the treatment and prevention of illnesses where the tachykinins P substance, neurokinin A and neurokinin B are implicated as neuromodulators.
  • the following illnesses may be mentioned: arthritis, emesis, Huntington's disease, neuritis, neuralgia, hemicrania, hypertension, urinary incontinence, urticaria, signs indicating carcinoid syndrome, influenza and common cold, illnesses of the immune system, diseases of the respiratory tract (e.g., asthma, rhinitis of various forms and obstructive chronic bronchitis), ophthalmic illnesses (e.g., conjunctivitis), cutaneous illnesses (e.g., allergic and contact dermatitis and psoriasis), intestinal illnesses (e.g., ulcerative colitis and Chron's disease), tumors wherein the cells present a functionally espressed NK-1 receptor (in particular astrocytomas and gliomas).
  • diseases of the respiratory tract e.g., asthma, rhinitis of various forms and obstructive chronic bronchitis
  • ophthalmic illnesses e.g., conjunctivitis
  • the said intermediate of general formula lla being prepared, for example, according to scheme 1 , using a condensing agent that is well known to experts in the field or using, as species activated in the condensation reaction, an acyl halide.
  • the said intermediate of general formula Ilia is prepared, for example, according to scheme 2.
  • This acyl halide is prepared from the corresponding R 3 -COOH carboxylic acid, following conventional methods that are obvious for experts in the field.
  • the subsequent reaction is carried out in the presence of the alkyl halide of general formula R 12 -Hal, where Hal is chosen from among a group comprising chlorine, iodine or bromine, and R 12 is as previously described, in the presence of a base, chosen in the group comprising alkaline or alkaline-earth hydrides, in an aprotic polar inert solvent, for example tetrahydrofuran or dioxane.
  • a base chosen in the group comprising alkaline or alkaline-earth hydrides
  • an aprotic polar inert solvent for example tetrahydrofuran or dioxane.
  • the reaction is carried out at 0°C in tetrahydrofuran, using sodium hydride as a base and methyl iodide as alkylating agent.
  • An alternative procedure involves the use, as condensing agent, of 1-ethyl-3-(3'- dimehtylaminopropyl)carbodiimide (WSC.HCI).
  • condensation reaction which may be conveniently carried out at room temperature, conventional aprotic polar organic solvents are used, chosen in the group comprising dimethylformamide, dioxane, tetrahydrofuran, methylene chloride, dichloroethane, and chloroform.
  • a further characteristic of the present invention are therefore the processes of synthesis of the intermediates of general formulas (II) and (III), and the said intermediates that are obtained from the said processes.
  • the compounds of the present invention may exist in various isomeric forms.
  • the compounds of the present invention may be obtained as mixtures of diastereoisomers.
  • the said mixtures may be resolved by chromatography.
  • the compounds of formula (I) may in any case be used both in the optically active form and in the form of mixtures of isomers.
  • the compounds of the present invention may be administered through the parenteral intranasal, oral or sub-lingual routes.
  • the formulations containing the new compounds may be prepared, according to known techniques, combining the active principle with an inert vehicle, and possibly with suitably chosen conventional additives.
  • the compounds of the present invention may be administered in the form of tablets, capsules, drops, elixirs, etc., prepared using conventional vehicles/excipients, such as starch, sugars, water, alcohol, etc., and possibly containing flavouring agents, stabilizing agents, preserving agents, lubricants, etc.
  • vehicle of choice is sterile water for injections.
  • Additives may be added according to the known art.
  • the therapeutically effective daily dosage will vary according to the subject to be treated (weight, age, degree of seriousness of the illness) and administration route. In general, however, the compounds of the invention are active when they are administered in a daily dosage of between 0.005 and 10 mg/kg.
  • the pharmaceutical formulations of the present invention will thus contain the compounds of general formula (I) in quantities such as to guarantee an appropriate daily dosage within the range specified above, generally for administration from once to three times a day.
  • Example 1 (1 R,2S)-1 - ⁇ /-[(1 (H)indol-3-yl-carbonyl)-2- ⁇ /(N ⁇ methyl-N ⁇ (4-methyl-phenylacetyl)D- 3(2-naphthyl)alanyl)-diamino-cyclohexane and (1 S,2R)-1 - ⁇ /-[(1 (H)indol-3-yl- carbonyl)-2-N(N ⁇ methyl-N ⁇ (4-methyl-phenylacetyl)D-3(2-naphthyl) alanyl)- diaminocyclohexane
  • a solution of the acyl chloride (0.530 g) in tetrahydrofuran (THF) is added, in nitrogen atmosphere in a period of 2 hours, to a solution of cis 1 ,2 diaminocyclohexane (1.15 mi) and diisopropylethylamine (DIEA) (0.61 ml) in 50 ml of THF.
  • DIEA diisopropylethylamine
  • Oxalyl chloride (462 ⁇ l) is added to a solution of para-tolylacetic acid (0.530 g) in 10 ml of CH 2 CI 2 (DCM), and the solution is refluxed for 1 hour in nitrogen atmosphere. The solvent and the excess oxalyl chloride are eliminated to obtain the crude acyl chloride (0.595 g), which is passed on to the subsequent reaction without undergoing any further purification processes.
  • ⁇ /s(trimethylsilyl)acetamide (1.96 ml) is added to a suspension of D-3-(2-naphthyl)aianine (0.775 g) in 12 ml of THF. The suspension is kept stirred at room temperature until complete dissolution (approx.
  • the aqueous phase is acidified to pH 2 using HCI 1 N and extracted with EtOAc; the organic phase is washed with H 2 O, aqueous Na 2 S 2 0 3l and finally with an NaCI saturated aqueous solution.
  • the organic phase is filtered and dried.
  • the crude product is purified by flash chromatography, eluting with acetic acid/toluene (27/63 v/v) to yield 0.181 g of NT (4-methylphenyiacetyl)-N ⁇ methyl-D-3(2-naphthyl)alanine.
  • the residue is diluted in ethyl acetate and extracted with a 5% solution of NaHCO 3 , an aqueous solution of HCI 0.1 N, and an NaCI saturated aqueous solution.
  • the organic phase is dried.
  • the two diastereoisomers are isolated by means of reverse-phase chromatography using a Hibar Merck column with 7-m Lichrosorb RP-18 filling, eluting with a gradient of from 32% water in methanol to 12% water in methanol over a period of two hours, flow 8 ml/min.
  • HPLC analysis in the conditions of example 1a, revealed for each of the two products (defined as fast and slow according to whether they are eluted by the column before or after, respectively) a single peak: HPLC (fast) (Prog. 6)
  • NK-1 receptors were evaluated with binding and functional in vivo assays and in vivo inhibition of bronchospasm induced by the agonist via intravenous administration.
  • the IM9-cell [H]SP binding assay was carried out as described in patents WO 95/15311 and WO 95/19965, and affinity was measured as pKi.
  • [Sar 9 , Met(O 2 ) 11 ] P substance is administered by intravenous route in doses of 1 nmol./kg at 15, 30 and 45 minutes before, and at 5, 30, 60, 90, 120, 150, and 180 minutes after IV administration of the vehicle or of the compounds to be tested (dose 0.08-1 ⁇ mol./kg). Bronchoconstriction was evaluated in terms of increase in intra-pulmonary pressure.
  • the antagonist effect of the compound was determined as ED 50 , expressed in ⁇ mol./kg, defined as the dose of antagonist necessary to decrease by 50% the bronchoconstrictive effect of the agonist for the entire duration of period of observation.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Composés représentés par la formule générale (I) dans laquelle R1 représente (A) X1 représente -CONH-; X2 représente -NR12CO-, dans laquelle R12 représente hydrogène ou méthyle; X3 est sélectionné dans le groupe constitué par -NR12CO-, NR12CONH-, dans laquelle R12 est tel qu'il est défini ci-dessus; A représente (B) dans laquelle B, C, D, E, indépendamment les uns des autres, peuvent représenter CH ou N, R2 est sélectionné dans le groupe constitué par (C) étant donné que, quand une des variables B, C, D, E est N, les autres sont CH. Ces composés ont démontré qu'ils exercent une activité antagoniste contre l'action de la substance P, neurokinine A et neurokinine B.
PCT/EP1998/002010 1997-04-08 1998-04-07 Composes de pseudo-peptides en tant qu'antagonistes de neurokinines WO1998045262A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU75228/98A AU7522898A (en) 1997-04-08 1998-04-07 Pseudo-peptide compounds as antagonists of neurokinines

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITFI97A000072 1997-04-08
IT97FI000072A IT1291823B1 (it) 1997-04-08 1997-04-08 Composti pseudo-peptidici, loro preparazione ed uso in formulazioni farmaceutiche

Publications (1)

Publication Number Publication Date
WO1998045262A1 true WO1998045262A1 (fr) 1998-10-15

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AR (1) AR013342A1 (fr)
AU (1) AU7522898A (fr)
IT (1) IT1291823B1 (fr)
WO (1) WO1998045262A1 (fr)
ZA (1) ZA982952B (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003000680A1 (fr) * 2001-06-20 2003-01-03 Daiichi Pharmaceutical Co., Ltd. Derives de diamine
WO2003016302A1 (fr) * 2001-08-09 2003-02-27 Daiichi Pharmaceutical Co., Ltd. Derives de diamine
CN1293057C (zh) * 2000-04-05 2007-01-03 第一制药株式会社 乙二胺衍生物
US7273856B2 (en) 2001-10-29 2007-09-25 Menarini Ricerche S.P.A. Linear basic compounds having NK-2 antagonist activity and formulations thereof
US7342014B2 (en) 2001-06-20 2008-03-11 Daiichi Pharmaceutical Co., Ltd. Diamine derivatives
US7378409B2 (en) 2003-08-21 2008-05-27 Bristol-Myers Squibb Company Substituted cycloalkylamine derivatives as modulators of chemokine receptor activity
WO2008090117A1 (fr) 2007-01-24 2008-07-31 Glaxo Group Limited Nouvelles compositions pharmaceutiques

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994013694A1 (fr) * 1992-12-04 1994-06-23 A. Menarini Industrie Farmaceutiche Riunite S.R.L. Antagonistes de la tachyquinine, leur preparation et leur utilisation dans des formulations pharmaceutiques
WO1995012611A1 (fr) * 1993-11-01 1995-05-11 Japat Ltd. Antagonistes de recepteur d'endotheline
WO1995015311A1 (fr) * 1993-12-03 1995-06-08 A. Menarini Industrie Farmaceutiche Riunite S.R.L. Antagonistes de la tachykinine
WO1995019966A1 (fr) * 1994-01-19 1995-07-27 A. Menarini Industrie Farmaceutiche Riunite S.R.L. Antagonistes de tachykinines

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994013694A1 (fr) * 1992-12-04 1994-06-23 A. Menarini Industrie Farmaceutiche Riunite S.R.L. Antagonistes de la tachyquinine, leur preparation et leur utilisation dans des formulations pharmaceutiques
WO1995012611A1 (fr) * 1993-11-01 1995-05-11 Japat Ltd. Antagonistes de recepteur d'endotheline
WO1995015311A1 (fr) * 1993-12-03 1995-06-08 A. Menarini Industrie Farmaceutiche Riunite S.R.L. Antagonistes de la tachykinine
WO1995019966A1 (fr) * 1994-01-19 1995-07-27 A. Menarini Industrie Farmaceutiche Riunite S.R.L. Antagonistes de tachykinines

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
APRYLL M. STALCUP ET AL: "Effect of the configuration of the substituents of derivatized beta-cyclodextrin bonded phases on enantioselectivity in normal-phase liquid chromatography", JOURNAL OF CHROMATOGRAPHY, vol. 540, - 1991, pages 113 - 128, XP002076305 *
STEFAN TAUDIEN ET AL: "Unusual amino acids III. Asymmetric synthesis of 3-arylalanines", TETRAHEDRON: ASYMMETRY., vol. 4, no. 1, - 1993, OXFORD GB, pages 73 - 84, XP002076304 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1293057C (zh) * 2000-04-05 2007-01-03 第一制药株式会社 乙二胺衍生物
US7192968B2 (en) 2000-04-05 2007-03-20 Daiichi Pharmaceutical Co., Ltd. Ethylenediamine derivatives
JP4495896B2 (ja) * 2000-04-05 2010-07-07 第一三共株式会社 エチレンジアミン誘導体
US7935824B2 (en) 2000-04-05 2011-05-03 Daiichi Pharmaceutical Co., Ltd. Ethylenediamine derivatives
WO2003000680A1 (fr) * 2001-06-20 2003-01-03 Daiichi Pharmaceutical Co., Ltd. Derives de diamine
US7342014B2 (en) 2001-06-20 2008-03-11 Daiichi Pharmaceutical Co., Ltd. Diamine derivatives
US7365205B2 (en) 2001-06-20 2008-04-29 Daiichi Sankyo Company, Limited Diamine derivatives
WO2003016302A1 (fr) * 2001-08-09 2003-02-27 Daiichi Pharmaceutical Co., Ltd. Derives de diamine
US7273856B2 (en) 2001-10-29 2007-09-25 Menarini Ricerche S.P.A. Linear basic compounds having NK-2 antagonist activity and formulations thereof
US7378409B2 (en) 2003-08-21 2008-05-27 Bristol-Myers Squibb Company Substituted cycloalkylamine derivatives as modulators of chemokine receptor activity
WO2008090117A1 (fr) 2007-01-24 2008-07-31 Glaxo Group Limited Nouvelles compositions pharmaceutiques

Also Published As

Publication number Publication date
IT1291823B1 (it) 1999-01-21
ZA982952B (en) 1998-10-12
AU7522898A (en) 1998-10-30
ITFI970072A1 (it) 1998-10-08
ITFI970072A0 (it) 1997-04-08
AR013342A1 (es) 2000-12-27

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