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WO1997045415A1 - Derives polyamides d'ornithine, de lysine et de substances analogues ayant une activite antagoniste contre la gastrine et la cck-b - Google Patents

Derives polyamides d'ornithine, de lysine et de substances analogues ayant une activite antagoniste contre la gastrine et la cck-b Download PDF

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Publication number
WO1997045415A1
WO1997045415A1 PCT/EP1996/002288 EP9602288W WO9745415A1 WO 1997045415 A1 WO1997045415 A1 WO 1997045415A1 EP 9602288 W EP9602288 W EP 9602288W WO 9745415 A1 WO9745415 A1 WO 9745415A1
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WO
WIPO (PCT)
Prior art keywords
group
zero
compounds
general formula
indicated
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Application number
PCT/EP1996/002288
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English (en)
Inventor
Francesco Makovec
Walter Peris
Lucio Claudio Rovati
Luigi Angelo Rovati
Original Assignee
Rotta Research Laboratorium 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 Rotta Research Laboratorium S.P.A. filed Critical Rotta Research Laboratorium S.P.A.
Priority to PCT/EP1996/002288 priority Critical patent/WO1997045415A1/fr
Publication of WO1997045415A1 publication Critical patent/WO1997045415A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems

Definitions

  • the subj ect of the present invent ion is new polyamide derivatives which may be represented by the general formula ( I ) shown below
  • Ri is a simple phenyl group or a phenyl group mono- or di- substituted with chlorine ;
  • R 2 is H or CH 3 ;
  • R 3 is a heterocyclic spiro ring group represented by:
  • n oxygen
  • s is a whole number from 1 to 4
  • m, r and t are whole numbers selected independently and ranging from 0 (zero) to 2
  • z is 0 (zero) or 1;
  • R 4 is chosen independently from a simple phenyl group and a phenyl group mono- or di- substituted with methyl or chlorine, a l-(or 2-)naphthyl group, a 2- (or 3-) ⁇ ndolyl group, a 2- (or 3-) qumolinyl group.
  • the configuration of the chiral centre indicated * in the general formula (I) may be, independently, D (dextro) or racemic (DL) while the configuration of the chiral centre indicated ** m the general formula (I) may be, independently, D (dextro), racemic (DL) or L (laevo) .
  • R ⁇ is a phenyl group substituted with chlorine in the 3 and 5 positions
  • R > is the group 8- azaspiro [4.5]decan-8-yl
  • s is 2
  • R 4 is the group 1- naphthyl and, if z is 0 (zero), then m and r are both 1 while t is 0 (zero) or 1 while, when z is 1, m and t are both 0 (zero) and r is 2.
  • the compounds of the present invention have been shown to be powerful antagonists to the gastrin receptors at the peripheral level, that is, in the gastrointestinal tract, and powerful antagonists to the cholecystokinm (CCK) receptors at the level of the central nervous system (CCK-B-antagomsts) . It may thus be thought that they may be used to advantage in the treatment of various human illnesses related to imbalances in the physiological levels of gastrin and CCK or other bioactive polypeptides correlated therewith, whether in the gastrointestinal tract or m the central nervous system (CNS) or in other organs or systems m which these bioactive polypeptides play a physiological or pathological role.
  • CCK central nervous system
  • these compounds for the treatment, at the gastrointestinal level, of illnesses connected with disorders of motility and mucous trophism such as, for example, gastritis, peptic ulcers, colitis and certain gastrointestinal tumours sustained by gastrin or polypeptide hormones correlated therewith, and at the level of the CNS, for the treatment of mental disturbances such as, for example, anxiety, panic attacks, psychosis such as, for example, schizophrenia, anorexia, etc. They may also be used in the treatment and prevention of several pathological conditions of the eye such as, for example, myosis induced during surgical treatment for cataracts or chronic eye inflammation or other afflictions of the sensory organs.
  • compositions m question may be prepared by conventional techniques in the form of, for example, tablets, capsules, suspensions, solutions and suppositories, and may be administered orally, oarenterally, rectal, ocularly or transdermally, or m other ways suitable for achieving the therapeutic effect.
  • the active ingredient is typically administered to the patient in a reference dose variable from 0.01 to lOmg/kg bodyweight per dose.
  • a water- soluble salt of the compounds in question such as the sodium salt or another non-toxic and pharmaceutically acceptable salt.
  • Inactive ingredients may be substances which are commonly used in pharmaceutical methods such as eccipients, binders, aromatisers, dispersants, colorants, numectants etc.
  • the method for the preparation of the polyamide derivatives of the invention consists of the amidation of basic derivatives represented by the formula (II) :
  • the starting case derivatives of formula (II) m which the chiral centre indicated (*) is in the racemic configuration (DL) were prepared by conventional metho ⁇ s starting respectively from diaminopropionic acic, diaminobutyric aci ⁇ , ornithine and lysine, all m the DL- configuration, to give the respective oases of formula (II) in wnicr. "s" assumes the value 1, 2, 3 and 4 (Compounds II-l - II-4 of Table 2) respectively.
  • the -starting base derivatives cf formula (II, having t.-.e chiral centre indicated ('; ir. the D-configuraticn may conveniently be prepared from the corresponding acids, such as. for cxamole.
  • the precipitate (t ⁇ ethylammonium chloride) was filtered off and the THF evaporated; the oily residue was dissolved in ethyl acetate and washed first with 2N HCI and then with 2N NaOH; after washing until neutral, the solvent was dried and evaporated, 7g oil (0.0144 moles) being recovered which were dissolved in 150 mL of methyl alcohol and hydrogenated at ambient temperature and pressure in the presence of 0.2g palladium on carbon at 10% concentration. After 5 hours, the catalyst was filtered off and the solvent evaporated; 4.1g oil (0.0116 moles) were obtained which were dissolved in 100 mL of THF.
  • the yield was 56% (CziHsgCl ⁇ NaO-HCl) .
  • Table 1 shows several derivatives cf formula (I) obtained in this way together with some identifying physico-chemical characteristics.
  • Table 2 shows some physico-chemical data relating to the basic intermediates of formula (II) used in the preparation of the derivatives given in Table 1, while Table 3 shows data from the literature relating to the anhydrides of formula (III) previously described together witn several physico- chemical characteristics of the anhydrides (III) not previously known.
  • the parietal cells of the gastric mucosa are responsible for the secretion of HCI. They have specific membrane receptors which may be activated by gastrin and which have been defined as gastrin or type-B cholecystokinin receptors (CCK-B) .
  • CCK-B cholecystokinin receptors
  • Suspensions (0.8 x 10 6 /ml) of rabbit gastric mucosa cells were prepared by conventional techniques with the use of collagenase and pronase as digestive enzymes; estimation of the levels of [Ca 2+ ] x , basal or obtained after stimulation of the cellular system, were conducted in accordance with Grynkiewicz et al [J.Biol.Chem. 260 (1985) , 3440] . In the control samples the cells were stimulated with 5 x IO "8 gastrin while, in the samples in which the effect of the subject compounds was evaluated, the cells were incubated therewith before being stimulated with gastrin. The results were expressed as percentage [Ca 2+ h increases with respect to the control value.
  • the anti-gastrin activity of the compounds was expressed as IC 50 , that is, the concentration (in mmoles/litre) at which the response to the stimulus caused by gastrin is reduced by 50%.
  • IC 50 concentration (in mmoles/litre) at which the response to the stimulus caused by gastrin is reduced by 50%.
  • Table 5 The results obtained in this way for several of the compounds in question are reported in Table 5, which also gives an index obtained from the ratio between the peripheral anti-gastrin activity just described and the displacement activity derived from the study of binding to the cortical receptors in guinea pigs as previously described.
  • peripheral anti-gastrin activity essentially accords well with the anti-gastrin activity obtained centrally in the binding studies illustrated previously in Table 4.
  • the compounds 2 and 10 are again the most powerful of the compounds described, exhibiting an IC 5 o of nanomolar order of magnitude (5 and 3 nM respectively) .
  • the compounds in question have an anti-gastrin activity on this model at concentrations 2-8 times less than those obtained centrally.
  • the compound 10 increases the percentage time spent in the open arms at all doses; this increase is significant for doses of 0.1 and lmg/kg IP compared with the group of control animals treated with physiological saline only.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On décrit des composés pouvant être représentés par la formule (I) dans laquelle R1 représente un groupe phényle simple ou un groupe phényle monosubstitué ou bisubstitué par du chlore; R2 représente H ou CH3; R3 représente un groupe à anneau spiro hétérocyclique représenté par la formule (a) dans laquelle Y est sélectionné indépendamment entre CH2 et O (oxygène) et n vaut 0 (zéro) ou 1; s représente une nombre entier compris entre 1 et 4; m, r et t représentent des nombres entiers sélectionnés indépendamment et compris entre 0 (zéro) et 2; z vaut 0 (zéro) ou 1; R4 est sélectionné indépendamment entre un groupe phényle simple et un groupe phényle monosubstitué ou bisubstitué par du méthyle ou du chlore, un groupe 1- (ou 2-) naphthyle, un groupe 2- (ou 3-) indolyle, un groupe 2- (ou 3-) quinolinyle. La configuration du centre chiral indiqué par '*' dans la formule (I) peut être indépendamment D ou racémique alors que celle du centre chiral indiqué par '**' peut être indépendamment D, racémique ou L.
PCT/EP1996/002288 1996-05-28 1996-05-28 Derives polyamides d'ornithine, de lysine et de substances analogues ayant une activite antagoniste contre la gastrine et la cck-b WO1997045415A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/EP1996/002288 WO1997045415A1 (fr) 1996-05-28 1996-05-28 Derives polyamides d'ornithine, de lysine et de substances analogues ayant une activite antagoniste contre la gastrine et la cck-b

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP1996/002288 WO1997045415A1 (fr) 1996-05-28 1996-05-28 Derives polyamides d'ornithine, de lysine et de substances analogues ayant une activite antagoniste contre la gastrine et la cck-b

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004004714A1 (fr) * 2002-07-03 2004-01-15 H. Lundbeck A/S Piperidines spirocycliques utilisees comme antagonistes des mch1 et utilisations associees
EP2821069A4 (fr) * 2012-03-02 2015-06-03 Kyowa Hakko Bio Co Ltd Stimulateur de l'activité alimentaire et/ou de l'activité gastro-intestinale

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991006529A1 (fr) * 1989-11-02 1991-05-16 Rotta Research Laboratorium S.P.A. Derives d'acide glutamique et d'acide aspartique possedant une activite antigastrinique, et leur procede de preparation
WO1992010479A1 (fr) * 1990-12-11 1992-06-25 Rotta Research Laboratorium S.P.A. Derives amidiques presentant l'activite antigastrine des acides glumatique, aspartique et 2-amino adipeux
WO1993021172A1 (fr) * 1992-04-09 1993-10-28 Rotta Research Laboratorium S.P.A. Derives basiques d'acide glutamique et d'acide aspartique utiles comme antagonistes de gastrine ou de cholecystokinine
WO1995007261A1 (fr) * 1993-09-09 1995-03-16 Rotta Research Laboratorium S.P.A. Derives d'acide polyamidique a activite antigastrinemique, leur procede de preparation et leur utilisation pharmaceutique

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991006529A1 (fr) * 1989-11-02 1991-05-16 Rotta Research Laboratorium S.P.A. Derives d'acide glutamique et d'acide aspartique possedant une activite antigastrinique, et leur procede de preparation
WO1992010479A1 (fr) * 1990-12-11 1992-06-25 Rotta Research Laboratorium S.P.A. Derives amidiques presentant l'activite antigastrine des acides glumatique, aspartique et 2-amino adipeux
WO1993021172A1 (fr) * 1992-04-09 1993-10-28 Rotta Research Laboratorium S.P.A. Derives basiques d'acide glutamique et d'acide aspartique utiles comme antagonistes de gastrine ou de cholecystokinine
WO1995007261A1 (fr) * 1993-09-09 1995-03-16 Rotta Research Laboratorium S.P.A. Derives d'acide polyamidique a activite antigastrinemique, leur procede de preparation et leur utilisation pharmaceutique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MAKOVEC F ET AL: "STRUCTURE-ANTIGASTRIN ACTIVITY RELATIONSHIPS OF NEW (R)-4-BENZAMIDO-5-OXOPENTANOIC ACID DERIVATIVES", JOURNAL OF MEDICINAL CHEMISTRY, vol. 35, no. 1, 1 January 1992 (1992-01-01), pages 28 - 38, XP000561329 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004004714A1 (fr) * 2002-07-03 2004-01-15 H. Lundbeck A/S Piperidines spirocycliques utilisees comme antagonistes des mch1 et utilisations associees
EA007387B1 (ru) * 2002-07-03 2006-10-27 Х. Лундбекк А/С Спироциклические пиперидины, используемые в качестве антагонистов мкг1, и их применение
US7335665B2 (en) 2002-07-03 2008-02-26 H - Lundbeck A/S Spirocyclic piperidines as MCH1 antagonists and uses thereof
EP2821069A4 (fr) * 2012-03-02 2015-06-03 Kyowa Hakko Bio Co Ltd Stimulateur de l'activité alimentaire et/ou de l'activité gastro-intestinale

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