GB2259013A

GB2259013A - Neuroprotective use of CCK antagonists

Info

Publication number: GB2259013A
Application number: GB9217475A
Authority: GB
Inventors: R G Hill; M Rigby
Original assignee: Merck Sharp and Dohme Ltd
Current assignee: Organon Pharma UK Ltd
Priority date: 1991-08-19
Filing date: 1992-08-17
Publication date: 1993-03-03
Also published as: GB9117852D0; GB9217475D0

Abstract

Use of CCK antagonists, especially those of formulae I-IV, in the formulation of medicaments having neuroprotective activity: <IMAGE> wherein formulae I to IV are defined in (1) US 4791215; (2) EP 0167919 and EP 0284256; (3) EP 0405537 and (4) J. Med.Chem. 34, 1508-8 (1991) respectively. The compounds are particularly useful in the treatment of stroke, hypoglycaemia, cerebral palsy, cerebral ischaemia, perinatal asphyxia, epilepsy, Huntington's chorea, Alzheimer's disease, Parkinsonism, anoxia and neurotoxemia. <IMAGE>

Description

NEUROPROTECTIVE USE OF CCK ANTAGONISTS This invention relates to antagonists of cholecystokinin and gastrin receptors for use as neuroprotective agents, and formulations thereof.

Cholecystokinins (CCK) and gastrin are structurally related neuropeptides which exist in gastrointestinal tissue and in the central nervous system (see, V. Mutt, Gastrointestinal Hormones, G.B.J. Green, Ed., Raven Press, N.Y., p.169 and G. Nission, ibid.

p.127).

The influence of proglumide, a putative CCK antagonist, on cerebral ischemia in the gerbil is discussed in C. Xu et al., Peptides. 8, 1987, 769-772.

United States Patents No. 4,791,215 discloses CCK antagonists of formula I:

wherein Ra represents hydroxyl, morpholino, piperidino or NRdRe, where Rd and Re each independently represent hydrogen or Cl,galkyl; Rb represents phenyl substituted by one, two or three substituents selected from Cl,qalkyl, halo, cyano and triflurormethyl; Rc represents hydroxyl, morpholino, piperidino or NRdRe, where Rd and Re are as above defined, except that Rc cannot be hydroxyl when Ra is hydroxyl, and Rc is hydroxyl when Ra is other than hydroxyl; and n is 1 or 2.

European Patent Application Nos. 167,919 and 284,256 disclose CCK antagonists of formula II:

wherein R represents hydrogen, C1-6alkyl, C2-5alkenyl, C2-5alkynyl, X12COOR6, X11(C3-7cycloalkyl), X12NR4R5, X12CONR4R5, X12CN or X11CX103 ; R2 represents hydrogen, C1-7alkyl, phenyl(optionally substituted by one or two substituents selected from halo, C1-7alkyl, C1-7alkoxy, C1-7alkylthio, carboxyl, carboxyC1-7alkyl, nitro, trifluoromethyl or hydroxy), 2-,3- or 4-pyridyl, X12SCH3, X12SOCH3, X12S02CH3, X12COOR6 or

R3represents X11R7,

X11NR18(CH2)qR7,

X11NR18SO2(CH2)qR7,

or =CHR7;; R4 and R5 each independently represent R6 or in combination with the nitrogen atom to which they are attached form an unsubstituted or mono- or disubstituted, saturated or unsaturated, 4-7 membered heterocyclic ring or benzofused 4-7 membered heterocyclic ring, which heterocyclic or benzofused heterocyclic ring may optionally include a second heteroatom selected from 0 and NCH3, and where the substituents are independently selected from C1-4alkyl ; R6 represents hydrogen, C1~7alkyl, C37cycloalkyl, optionally substituted phenyl or optionally substituted phenylC1-7alkyl, wherein the phenyl or phenylC1-7alkyl substituents may be 1 or 2 of halo, C1,7alkyl, C1-7alkoxy, nitro or trifluoromethane;; R7 and R7a independently represent a- or ss- naphthyl, optionally substituted phenyl (wherein the substituents may be 1 or 2 of halo, NO2, OH, X1lNR4R5, C1,7alkyl, CF3, CN, SCF3, C-CH, CH2SCF3, OCOCH3, OCHF2, SH, SPh, P03H, C1-7alkoxy, C1,7thio, COOH), 2-, 3-, 4pyridyl,

R8 represents hydrogen, C1-7alkyl, C3-7cycloalkyl, X12CONH2, X12COOR6, X12C1-7cycloalkyl, X12NR4R5,

R9 and R10 are independently H, -OH, or -CH3; Rll and R12 are independently C1-7alkyl or C3-7cycloalkyl ; R13 is H, C1-7alkyl, acyl, 0, or C3-7cycloalkyl ; R14 is C1-7alkyl or phenylC1-7alkyl ; R15 is H, C1-7alkyl,

R18 is H, C1-7alkyl, or acyl; p is 0 when its adjacent --- is unsaturated and 1 when its adjacent --- is saturated except that when R13 is 0, p = 1 and --- is unsaturated; q is 0-4; r is 1 or 2; X1 is H, NO2, CF3, CN, OH, C1-7alkyl, halo, C1-7alkylthio, C1-7alkoxy, X11CORR6, or X11NR4R5 ; X2 and X3 are independently H, OH, NO2, halo, C1-7alkylthio, C1-7alkyl, C1-7alkoxy ; X4 is S, O, CH2, NR18 or NR8; X5 is H, CF3, CN, -COOR6, NO2, or halo; X6 is O or HH; X7 is 0, S, HH or NR15 with the proviso that X7 can be NR15 only when R1 is not H; X8 is H, C1-7alkyl ; X9 and Xa9 are independently NR18 or 0; X10 is F, C1, or Br; X11 is absent or C1-4 linear or branched alkylidene; X12 is C1-4 linear or branched alkylidene;; --- is a saturated or unsaturated bond; and the pharmaceutically acceptable salts thereof.

The uses disclosed in United States Patents Nos. 4,791,215 and 4,820,834, and European Patent Application Nos. 167,919 and 284,256, are treatment of gastric acid secretion disorders, gastrointestinal motility, pancreatic secretions, dopaminergic functions, pain, psychic disturbances, anorexia and pathological cellular growth, such as tumours, and use in increasing weight gain in farm animals.

European Patent Application No. 405,537 discloses CCK receptor antagonists of formula III:

and the pharmaceutically acceptable salts thereof, wherein : R1 is a cyclo- or polycycloalkyl C3-12 hydrocarbon with from zero to four substituents, each independently selected from C1-6alkyl, halo, CN, OR SR*, CO2R*, CF3, NR5'R6', or -(CH2)n'OR5', wherein R* is hydrogen, C1-6alkyl, R5' and R6' are each independently hydrogen or C1-6alkyl ; and n' is O to 6; A' is -(CH2)n'CO-, -SO2-, -SO-, -NHCO-,

-SCO, -o-(CH2)n'CO- or -HC=CHCO- wherein n' is O to 6; R2 is C16 alkyl, -HC=CH2, -C=-CH, CH2CH=CH2, -CH2C=CH -CH2Ar', -CH2OR , -CH2OAr1, -(CH2)nCO2R*, -(CH2)n'NR5'R6' wherein n', R*, R51 and R6' are as defined above and Ar' is as defined below; R3' and R4' are each independently selected from hydrogen, R21, and -(CH2)n''-B'-D' wherein n'' is O to 3;; B' is a bond, -OCO(CH2)n'-, -o(CH2)n'-, NHCO(CH2)n'-, -CONH(CH2)n'-, NHCOCH=CH-, COO(CH2)n'-, -CO(CH2)n'-, -SO(CH2)n'-, -SO2(CH2)n'-,

wherein R71 and R8' are independently selected from hydrogen and R2' or together form a ring (CH2)m' wherein m' is 1 to 5 and n' is as defined above; D' is -COOR*, -CONR5'R6', - CN, NR5'R6', -OH, -H, and acid replacements such as

(where R10, is OH, NH2, CH3 or Cl), H03S- , HO2P- 1,2,40xadiazole,

(where R11' is CN, CO2H, CF3),

PhSO2NHCO- , CF3CONHCO- , CF3SO2NHCO H2NSO-, -CH2OR*, -CHR2 'OR*, CH2SR*, CHR2,SR*, wherein R*m R', R5' and R6' are as defined above; ; R9 is H, C1-6alkyl, -(Ch2)n'CO2R*, (CH2)nwOAr , (CH2)n'Ar , (CH2)nZNR5 R6 , wherein n', R*, R5 and R6' are as defined above or taken from R31 and Ar is taken from Ar' as defined below; R12' and R13' can each be independently hydrogen (in which case the carbon atom to which it is attached is a chiral center) or can each be taken with R ' and R4' respectively to form a moiety doubly bonded to the carbon atom (in which case the carbon atom is not chiral); and Ar' is a mono- or polycyclic unsubstituted or substituted carbo- or heterocyclic aromatic or hydroaromatic moiety.

J. Med. Chem., 1991, 34, 1505-1508 discloses CCK antagonists for formula IV

wherein RL is hydrogen or methyl; X0 is hydrogen, halo, methoxy or trifluoromethyl; Xm is hydrogen, halo, C1,3alkyl, Cl,galkoxy, cyclopropyloxy, trifluoromethyl, SCH3, N(CH3)2 or -OCH2O-; Xp is hydrogen, C1,3alkyl, C1-3alkoxy, SCH3 or N(CH3)2; and yLis hydrogen, halo, methyl or methoxy.

We have now found that certain CCK receptor antagonists are useful as neuroprotective agents, for example, in the treatment and/or prevention of neurodegenerative disorders arising as a consequence of such pathological conditions as stroke, hypoglycaemia, cerebral palsy, transient cerebral ischaemic attack, cerebral ischaemia during cardiac pulmonary surgery or cardiac arrest, perinatal asphyxia, epilepsy, Huntington's chorea, Alzheimer's disease, Amyotrophic Lateral Sclerosis, Parkinson's disease, Olivo-pontocerebellar atrophy, anoxia such as from drowning, spinal cord and head injury, and poisoning by neurotoxins, including environmental neurotoxins.

The present invention thus provides the use of a COK receptor antagonist for the preparation of a medicament for neuroprotection.

Specific compounds of use in the present invention include: 3-(2-indolylcarboxamido)-1-methyl-5-phenyl-1,4- benzodiazepin-2(3H)-one (MK329); and pharmaceutically acceptable salts thereof.

Compounds of formulae I and II may be prepared by the methods described un United States Patents Nos.

4,791,215 and 4,820,834, and in European Patent Application No. 167,919.

Processes for the preparation of compounds of formula III are described in European Patent Application No. 405,537.

Compounds of formula IV may be prepared as described in J. Med. Chem., 1991,34, 1505-1508.

As used herein, alkyl means linear or branched chain alkyl. Examples of suitable alkyl groups include methyl, ethyl, isopropyl and isobutyl groups.

Halo includes fluoro, chloro and bromo.

The pharmaceutically acceptable salts of the compounds of formulae I to IV include the conventional non-toxic salts or quaternary ammonium-salts formed, e.g., from non-toxic inorganic or organic salts.

For use in accordance with the invention, CCK antagonists and their salts and prodrugs, may be administered to animals, preferably to mammals, and most especially to a human subject either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical compostion, according to standard pharmaceutical practice. The compounds can be administered orally or, preferably, parenterally, including by intravenous, intramuscular, intraperitoneal or subcutaneous administration, or by topical administration.

For oral use of an antagonist of CCK, according to this invention, the selected compounds may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch.

When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavouring agents may be added.

For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered.

For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic.

For topical administration, a compound of formula (I) may be formulated as, for example, a suspension, lotion, cream or ointment.

For topical administration, pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or arylalkanols, vegetable oils, polyalkylene glycols, petroleum based jelly, ethyl cellulose, ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally-employed non-toxic, pharmaceutically acceptable organic and inorganic carriers.The pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting agents, bodying agents and the like, as for example, polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500, 4,000, 6,000 and 10,000, antibacterial components such as quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non-injurious in use, thimerosal, methyl and propyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredients such as sodium chloride, sodium borate, sodium acetates, gluconate buffers, and other conventional ingredients such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol, ethylenediamine tetraacetic acid, and the like.

When an antagonist of CCK is used according to the invention in a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms. However, in most instances, an effective daily dosage will be in the range from about 0.005mg/kg to about 50mg/kg of body weight, and preferably, of from 0.05mg/kg to about 30mg/kg, such as from about 0.5mg/kg to about 20mg/kg of body weight, administered in single or divided doses. In some cases, however, it may be necessary to use dosages outside these limits.

The neuroprotective effective of the compounds according to the invention may be demonstrated in the gerbil model of ischaemia. Gerbils are rendered ischaemic by five minute bilateral carotoid occlusion.

One hour later, the CCK antagonists are administered at 0.1 or lmg/kg (i.p.), dissolved in' methyl cellulose. The results obtained for MK 329 are tabulated below: Dose Mean area of damage Sem n P (mm2) Control occlusion 6.65 0.59 10 O.lmg/kg 4.80 0.58 9 < 0.05 lmg/kg 4.07 0.89 10 < 0.001

Claims

1. The use of a CCK receptor antagonist for the preparation of a medicament for neuroprotection.

2. The use of a CCK receptor antagonist for the preparation of a medicament for the treatment or prevention of neurodegenerative disorders.

3. The use as claimed in claim 1 or claim 2 wherein the CCK receptor antagonist is a compound of formula I

4. The use as claimed in claim 1 or claim 2 wherein the CCK receptor antagonist is a compound of formula II

wherein R represents hydrogen, C1-6alkyl, C2-5alkenyl, C2-5alkynyl, X12COOR6, X11(C3-7cycloalkyl), X12NR4R5, X12CONR4R5, X12CN or X11CX103 ; R2 represents hydrogen, C1-7alkyl, phenyl(optionally substituted by one or two substituents selected from halo, C1-7alkyl, C1-7aloxy, C1-7alkylthio, carboxyl, carboxyC1-7alkyl, nitro, trifluoromethyl or hydroxy), 2-,3- or 4-pyridyl, X12SCH3, X12SOCH3, X12SO2CH3, X12COOR6 or

R3represents X1lR7,

X11NR18(CH2)qR7,

X11NR18S02 (OH2) qR7,

or R4 and R5 each independently represent R6 or in combination with the nitrogen atom to which they are attached form an unsubstituted or mono- or disubstituted, saturated or unsaturated, 4-7 membered heterocyclic ring or benzofused 4-7 membered heterocyclic ring, which heterocyclic or benzofused heterocyclic ring may optionally include a second heteroatom selected from 0 and NCH3, and where the substituents are independently selected from C1-4alkyl ; R6 represents hydrogen, C1,7alkyl, C3-7cycloalkyl, optionally substituted phenyl or optionally substituted phenylC1-7alkyl, wherein the phenyl or phenylC17alkyl substituents may be 1 or 2 of halo, C1-7alkyl, C1-7alkoxy, nitro or trifluoromethane ;; R7 and R7a independently represent a- or ss- naphthyl, optionally substituted phenyl (wherein the substituents may be 1 or 2 of halo, NO2, OH, X1lNR4R5, C1-7alkyl, CF3, CN, SCF3, C-CH, CH2SCF3, OCOCH3, OCHF2, SH, SPh, PO3H, C1-7alkoxy, C1,7thio, COOH), 2-, 3-, 4pyridyl,

R9 and R10 are independently H, -OH, or -CH3; R11 and R12 are independently C1-7alkyl or C3-7cycloalkyl ; R13 is H, C1-7alkyl, acyl, 0, or C3-7cycloalkyl ; R14 is C1-7alkyl or phenylC1-7alkyl ; R15 is H, C1-7alkyl,

R18 is H, C1-7alkyl, or acyl; p is O when its adjacent --- is unsaturated and 1 when its adjacent --- is saturated except that when R13 is O, p = 1 and --- is unsaturated; q is 0-4; r is 1 or 2; X1 is H, NO2, CF3, CN, OH, C1-7alkyl, halo, C1-7alkylthio, C1-7alkoxy, X11COOR6, or X11NR4R5 ; X and X3 are independently H, OH, NO2, halo, C1-7alkylthio, C1-7alkyl, C1-7alkoxy ; X4 is S, 0, CH2, NR18 or NR8; X5 is H, CF3, CN, -COOR6, NO2, or halo; X6 is O or HH; X7 is O, S, HH or NR15 with the proviso that X7 can be NR15 only when R1 is not H; X8 is H, C1-7alkyl ; X9 and Xa9 are independently NR18 or O; X10 is F, Cl, or Br;; X11 is absent or C1-4 linear or branched alkylidene; X12 is C1-4 linear or branched alkylidene; --- is a saturated or unsaturated bond; and the pharmaceutically acceptable salts thereof.

5. The use as claimed in claim 1 or claim 2 wherein the CCK receptor antagonist is a compound of formula III

-SCO, -O-(CH2)n'CO- or -HC=CHCO- wherein n' is 0 to 6; R' is C1-6 alkyl, -HC=CH2, -C=CH, CH2CH=CH2, -CH2C=CH -CH2Ar', -CH2OR*, -CH2OAr', -(CH2)nCO2R*, -(CH2)n'NR5'R6' wherein n', R*, R5' and R6' are as defined above and Ar' is as defined below; R3, and R4 are each independently selected from hydrogen, R2', and -(CH2)n''-B'-D' wherein n'' is 0 to 3; B' is a bond, -OCO(CH2)n'-, -O(CH2)n'-, NHCO(CH2)n'-, -CONH(CH2)n'-, NHCOCH=CH-, COO(CH2)n'-, -CO(CH2)n'-, -SO(CH2)n'-, -SO2(CH2)n'-,

wherein R7' and R8' are independently selected from hydrogen and R' or together form a ring (CH2)mg wherein m' is 1 to 5 and n' is as defined above;; D' is -COOR*, -OONR51R6,, -CN, NR5,R61, -OH, -H, and acid replacements such as

(where R10' is OH, NH2, CH3 or Cl), HO3S- , HO2P1,2,4oxadiazole,

(where R11' is CN, CO2H, CF3),

PhSO2NHCO- , CF3CONHCO- , CF3SO2NHCO H2NSO- , -OH2OR*, -CHR2,OR*, OH2SR*, OHR21SR*, wherein R*, R2,, R5, and R6' are as defined above; R9 is H, C1-6alkyl, -(CH2)n'CO2R*, (CH2)n'OAr'', (CH2)n'Ar'', (Ch2)n',NR5'R6', wherein n', R*, R5' and R6' are as defined above or taken from R ' and Ar'' is taken from Ar' as defined below ; ; R12' and R13' can each be independently hydrogen (in which case the carbon atom to which it is attached is a chiral center) or can each be taken with R ' and R4 respectively to form a moiety doubly bonded to the carbon atom (in which case the carbon atom is not chiral); and Ar' is a mono- or polycyclic unsubstituted or substituted carbo- or heterocyclic aromatic or hydroaromatic moiety.

6. The use as claimed in claim 1 or claim 2 wherein the CCK receptor antagonist is a compound of formula IV

wherein RL is hydrogen or methyl; Xo is hydrogen, halo, methoxy or trifluoromethyl; Xm is hydrogen, halo, C1-3alkyl, C1-3alkoxy, cyclopropyloxy, trifluoromethyl, SCH3, N(CH3)2 or -OOH2O-; Xp is hydrogen, C1-3alkyl, C1-3alkoxy, SCH3 or N(CH3)2; and yL is hydrogen, halo, methyl or methoxy.

7. The use as claimed in claim 4 wherein the CCK receptor antagonist is 3-(2-indolylcarboxamido)-1-methyl-5-phenyl-1,4benzodiazepin-2(3H)-one (MK329).