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WO1993012791A1 - Antagonistes de la cholecystokinine centrale possedant une efficacite pharmaceutique - Google Patents

Antagonistes de la cholecystokinine centrale possedant une efficacite pharmaceutique Download PDF

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Publication number
WO1993012791A1
WO1993012791A1 PCT/US1991/009555 US9109555W WO9312791A1 WO 1993012791 A1 WO1993012791 A1 WO 1993012791A1 US 9109555 W US9109555 W US 9109555W WO 9312791 A1 WO9312791 A1 WO 9312791A1
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Prior art keywords
mammal
pharmaceutically acceptable
treatment
need
comprises administering
Prior art date
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PCT/US1991/009555
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English (en)
Inventor
David Christopher Horwell
John Hughes
Geoff Neil Woodruff
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Merck Sharp & Dohme Limited
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Application filed by Merck Sharp & Dohme Limited filed Critical Merck Sharp & Dohme Limited
Priority to EP92903432A priority Critical patent/EP0617621A4/fr
Priority to JP4503379A priority patent/JPH07507993A/ja
Priority to PCT/US1991/009555 priority patent/WO1993012791A1/fr
Publication of WO1993012791A1 publication Critical patent/WO1993012791A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D231/08—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen or sulfur atoms directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence

Definitions

  • CCK central cholecystokinin
  • CCK-peptides have been found in the brains of schizophrenic patients compared with controls (Roberts, Ferrier, Lee, Crow, Johnstone,
  • CCK peptides modulate dopaminergic function in the basal ganglia and particularly the nucleus accumbens (Weiss, Tanzer, and Ettenberg, Pharmacology. Biochemistry and
  • agents modifying CCK receptor activity may have therapeutic value in conditions associated with disturbed function of central
  • dopaminergic function such as schizophrenia and
  • CCK and gastrin peptides share a common carboxy terminal pentapeptide sequence and CCK peptides can bind to the gastrin receptor of the stomach mucosa and elicit acid secretion in many species including human (Konturek, Gastrointestinal Hormones , Ch. 23 , pp . 529-564, 1980, G. G. J. Glass , ed. , Raven Press , NY) .
  • Antagonists of the CCK-8 receptor would also be expected to be antagonists at the stomach gastrin receptor and thus be of value for conditions
  • CCK and gastrin peptides have trophic effects on the pancreas and various tissues of the gastrointestinal tract (Johnson, ibid. , pp. 507-527 ) , actions which are associated with increased DNA and RNA synthesis .
  • gastrin secreting cells are associated with certain gastrointestinal tumors as in the Zollinger-Ellison syndrome (Stadil, ibid. .
  • colorectal tumors may also be gastrin-/CCK-dependent (Singh, Walker, Townsend, and Thompson, Cancer Research 46 : 1612, 1986, and
  • Antagonists of CCK/gastrin receptors could,
  • cholecystokinin peptides are widely used as cholecystokinin peptides.
  • CCK peptides The high concentrations of CCK peptides in many brain areas also indicate major brain functions for these peptides (G. J. Dockray, Br. Med. Bull.
  • CCK is known to be present in some cortical interneurones which also contain gamma-aminobutyric acid (GABA) (H. Demeulemeester, et al, J.
  • GABA gamma-aminobutyric acid
  • Agents that modify GABA action may have utility as anxiolytic or hypnotic agents (S. C. Harvey, The Pharmacological Basis of Therapeutics (7th ed.), MacMillan, 1985, pp. 339-371. Thus, agents which modify CCK action may have parallel anxiolytic or hypnotic activities.
  • CCK-B ligands are useful as antipsychotic and as antianxiety agents. This includes all CCK-B ligands. CCK-B antagonists have now been shown to be agents useful in the treatment of withdrawal from drugs and alcohol.
  • CCK-A Although some ligands are CCK-A selective they do have some CCK-B activity as well and therefore are included also. Mixed CCK-A/-B ligands are also included.
  • the present invention is related to
  • compositions and methods of treating psychoses and/or anxiety and the withdrawal response caused by chronic treatment or abuse followed by withdrawal of drugs or alcohol using CCK-ligands and pharmaceutically acceptable salts thereof are found in United States Patents 4,791,215 and 4,820,834 and European Application 167,919. These documents are incorporated herein by reference.
  • the uses disclosed are gastric acid secretion disorders, gastrointestinal motility, pancreatic secretions, dopaminergic functions, analgesics, psychic disturbances, anorexia, weight increases in farm animals, and pathological cellular growth such as tumors.
  • the present invention relates to a
  • the present invention further relates to a pharmaceutical composition useful for the treatment of withdrawal symptoms, withdrawal from drugs or alcohol.
  • the composition comprises a therapeutically effective amount of at least one of the following CCK-antagonists or a pharmaceutically acceptable salt thereof in
  • R 1 is a phenyl group mono-, di-, or
  • R 2 is selected from the group consisting of
  • R 1 is H, C 1 -C 6 linear or branched alkyl
  • R 2 is H, loweralkyl, substituted or
  • unsubstituted phenyl (wherein the substituents may be 1 or 2 of halo, loweralkyl, loweralkoxy, lowralkylthio, carboxyl, carboxyloweralkyl, nitro, -CF 3 , or hydroxy), 2-, 3-, 4-pyridyl, , -X 12 SCH 3 , -X 12 SOCH 3 , -X 12 SO 2 CH 3 or -X 12 COOR 6 ;
  • R 3 is -X 11 R 7 , -X 11 CHR 7 , -X 11 C -X 11 CR 7 ,
  • R 4 and R 5 are independently R 6 or in combination with the N of the NR 4 R 5 group form an unsubstituted or mono or disubstituted, saturated or unsaturated, 4- to 7-membered heterocyclic ring or benzofused 4- to
  • phenylloweralkyl wherein the phenyl or phenylloweralkyl substituents may be 1 or 2 of halo, loweralkyl, loweralkoxy, nitro, or CF 3 ;
  • R 7 and R a 7 are independently ⁇ - or ⁇ -naphthyl, substituted or unsubstituted phenyl
  • substituents may be 1 or 2 of halo, -NO 2 , -OH, -X 11 NR 4 R 5 , loweralkyl, CF 3 ,
  • R 8 is H, loweralkyl, cycloloweralkyl, -X 12 CONH 2 , -X 12 COOR 6 , -X 12 -cycloloweralkyl , -X 12 NR 4 R 5 ,
  • R 9 and R 10 are independently H, -OH, or -CH 3 , R 11 and R 12 are independently loweralkyl or
  • R 13 is H, loweralkyl, acyl, O, or
  • R 14 is loweralkyl or phenylloweralkyl
  • R 15 is H, loweralkyl
  • R 18 is H, loweralkyl, or acyl
  • r is 1 or 2;
  • X 1 is H, -NO 2 , CF 3 , CN, OH, loweralkyl, halo, loweralkylthio, loweralkoxy, -X 11 COOR 6 , or -X 11 NR 4 R 5 -;
  • X 2 and X 3 are independently H, -OH, -NO 2 , halo, loweralkylthio, loweralkyl, or loweralkoxy;
  • X 4 is S, O, CH 2 , or NR 18 or NR 8 ;
  • X 5 is H, CF 3 , CN, -COOR 6 , NO 2 , or halo;
  • X 6 is O or HH
  • X 7 is O, S, HH, or NR 15 ;
  • X 8 is H or loweralkyl
  • X 9 and X a 9 are independently NR 18 or O;
  • X 10 is F, Cl, or Br
  • X 11 is absent or C 1-4 linear or branched
  • X 12 is C 1-4 linear or branched alkylidene
  • -- is a saturated or unsaturated bond
  • R 3 is -X 1 1 NR 18 (CH 2 ) q R 16 , -X 1 1 NR 18 CX 11 R 7 ,
  • R 7 is ⁇ - or ⁇ -naphthyl, substituted or
  • substituents may be 1 to 2 of halo, -NO 2 , -OH, -X 11 NR 4 R 5 , loweralkyl, CF 3 , CN, SCF 3 ,
  • R 16 is ⁇ - or ⁇ -naphthyl or 2-indolyl
  • R 18 is H or loweralkyl
  • composition of the instant invention are: lorglumide which is DL-4-(3,4-dichlorobenzoyl- amino)-5-(dipentylamino)-5-oxopentanoic acid, loxiglumide which is ( ⁇ )-4-[(3,4-dichlorobenzoyl)- amino]-5-[(3-methoxyproxyl)pentylamino]-5-oxo- pentanoic acid, L-364718 which is
  • compositions and methods of treatment of the instant invention are:
  • Virginiamycins, anthramycin, LY-262,690 which is trans-5-(2-chlorophenyl)-3-oxo-4-phenyl-N-[4-
  • LY-262,691 which is trans-5-(2-chlorophenyl)-3- oxo-4-phenyl-N-[4-(bromo)phenyl]-1- pyrazolidinecarboxamide
  • L-365091 which is 1-((3-((((4-chlorophenyl)- amino)carbonyl)amino)-2,3-dihydro-2-oxo-5-phenyl-1H- 1, 4-benzodiazepin-1-yl)acetyl)pyrrolidine,
  • Still other compounds useful in the compositions and methods of treatment of the instant invention are other known CCK antagonists. They are CCK-B
  • R 1 and R 2 are the same or different and respectively represent a hydrogen, a halogen, a C 1-20 alkyl or an aralkyl selected from the group consisting of benzyl, 1-phenylethyl, 2-phenylethyl,
  • R 1 and R 2 together form a ring selected from the group consisting of a cyclopentene ring, a cyclopentadiene ring, a cyclohexene ring, a cyclohexadiene ring, a benzene ring, a cycloheptene ring, a cycloheptadiene ring, and a cycloheptatriene ring;
  • R 3 represents an oxygen
  • R 4 represent a hydrogen, a C 1-20 alkyl, a C 2-8 alkenyl, or a group of the formula -(CH 2 ) m COOR 6 (wherein R 6 represents a hydrogen atom, a C 1-20 alkyl, a C 2-8 alkenyl, or an aralkyl selected from the group consisting of benzyl, 1-phenylethyl,
  • R 5 represents a hydrogen, a C 1-20 alkyl, a
  • R 7 represents a hydrogen, a C 1-20 alkyl, a C 2-8 alkenyl, or an aralkyl selected from the group consisting of benzyl,
  • 2-naphthylmethyl unsubstituted or substituted on the aromatic ring by one to three substituent (s) selected from the group consisting of halogen, alkyl, alkoxy, trifluoromethyl, nitro, amino, cyano, and hydroxy, and n represents an integer of 1 to 6);
  • Ar and X are the same or different and respectively represent an aryl selected from the group consisting of a phenyl, a phenyl substituted by
  • substituents selected from the group consisting of halogen, alkyl, alkoxy, and nitro, and a 2-naphthyl or a heteroaryl selected from the group consisting of a pyridyl, an indolyl, a thienyl, a benzofuranyl, a 1H-benzimidazol-2-yl, and a 2-benzothiazolyl; and p represents an integer of 1 to 6, or its salt.
  • Preferred compounds of Formula IV above are 4-(2-chlorophenyl)-2-ethyl-6-(2-indole- carboxamido)-9-methyl-6H-thieno[3,2-f][1,2,4]- triazolo[4,3-a][1,4]diazepine,
  • Patent 4,992,437 which is hereby incorporated by reference.
  • Disclosed utilities are agents acting on the central and peripheral nervous systems for pancreatic disorders and gastrointestinal ulcers.
  • R 2 is methylene, hydroxymethylene, carbonyl
  • R 5 is hydrogen, a straight or branched alkyl of from one to six carbon atoms, or R 12 is hydrogen;
  • R 4 is oxygen, sulfur, carbonyl.
  • n is an integer of from zero to four;
  • R 5 is hydrogen, straight or branched alkyl of from one to ten carbon atoms optionally interrupted by one or more atoms of oxygen or sulfur, phenyl, benzoyl, aralkyl of from seven to ten carbon atoms which is
  • alkyl unsubstituted or substituted by halogen, alkyl, nitro, alkoxy, carboxylalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, a cyclic group, unsaturated from five to seven atoms containing at least one sulfur, oxygen, pyridinylcarbonyl,
  • R 6 is hydrogen or a straight or branched alkyl of from one to six carbon atoms
  • R 7 and R 8 are the same or different and are
  • heteroatoms selected from oxygen, sulfur, and substituted by an alkylcarbonyl or alkoxycarbonyl of from two to five carbon atoms;
  • R 9 , R 10 , and R 11 are the same or different and are hydrogen or an alkyl of from one to six carbon atoms;
  • R 13 is hydrogen, straight or branched alkylcarbonyl of from two to six carbon atoms, or benzoyl; with the provisos that when R 1 is Z 3 then R 2 is not methylene, when R 1 is Z 0 and R 12 is hydrogen then R 2 is not
  • R 1 is Z 0
  • R 12 is hydrogen and R 2 is Y 1
  • n 1 and R 4 is carbonyl then R 5 is not methyl, isopropyl, or phenyl
  • R 1 is Z 0 and R 12 is hydrogen, then R 2 is not carbonyl.
  • R 1 is H, 1-4Calkyl, phenyl-1-3C alkyl, -Z 1 -NR 4 R 5 ,
  • Z 1 is 2-4C alkylene
  • Z 2 and Z 3 are 1-4C alkylene
  • R 4 , R 5 , R 7 , R 8 are H or 1-4C alkyl, or
  • R 4 NR 5 or R 7 NR 8 are morpholino, pyrrolidinyl,
  • R 6 is H or 1-6C alkyl
  • R 2 is H or 1-4C alkyl
  • R 3 is 5-8C cycloalkyl optionally substituted by one or more 1-4C alkyl, aromatic group, e.g., phenyl (optionally substituted by one or more halo, 1-6C alkyl, 1-3C alkoxy, or thioalkoxy), NO 2 , CF 3 , or a heterocycle containing O, S, or N; or
  • R 3 is furyl, thienyl, pyrrolyl, pyrazolyl,
  • R 1 + R 3 is a group of formula (a) fixed with the carbon atom of the phenyl attached to position 4 of the thiazole;
  • q 1 to 4.
  • X p is halo, 1-3C alkyl or alkoxy, NO 2 , or CF 3 ; np is 0 to 3;
  • z is heterocycle containing ⁇ 1, O, S, or N
  • Ellison Syndrome hyperplasia of the gastric cells, certain cancers, and for regulating appetite.
  • R 1 is aryl of up to 14C atoms (optionally
  • halogens alkyl, or alkoxy groups of up to 8C, dialkylamino of up to 16C, CF 3 , CN, or NO 2 ) , indolyl, pyridyl, piperidinyl, quinolyl, thiazolyl, aralkyl of up to 18C (optionally
  • R 1 is aryl
  • R 2 is a group Ar-CH-Ar; or a group of
  • Ar, Ar' is aryl of up to 14C (optionally
  • R 3 is H
  • N-R 2 R 3 is a 5-, 6-, or 7-membered heterocycle which may contain an O atom and may contain a second N atom, and which may be
  • R 4 is H (optionally cyclic), alkyl of up to 8C, aralkyl of up to 18C (optionally
  • the compounds are described as having utility in treating behavioral disorders.
  • R 2 is hydrogen
  • R 3 is hydrogen -trans or -cis.
  • X 0 is hydrogen, fluorine, chlorine, methoxy, or trifluoromethyl
  • X n is hydrogen, fluorine, chlorine, bromine,
  • X p is hydrogen, methoxy, ethoxy, isopropoxy
  • Y is hydrogen, methyl, methoxy, fluorine
  • R is hydrogen or methyl
  • a preferred compound is 2-[2-(5-bromo-1H-indol- 3-yl)ethyl]-3-[3-(1-methylethoxy)phenyl]-4(3H)- quinazolinone.
  • the instant invention also covers at least
  • the instant invention also relates to a
  • composition which is in oral dosage form.
  • the instant invention also relates to a method for treating psychoses, especially schizophrenia, in a mammal in need of such treatment which comprises administering a pharmaceutical composition of the instant invention in unit dosage form to said mammal.
  • the instant invention also relates to a method for treating anxiety in a mammal in need of such treatment which comprises administering a
  • composition of the instant invention in unit dosage form to said mammal.
  • the instant invention also relates to a method for treating the withdrawal response produced by chronic treatment followed by withdrawal of diazepam, nicotine, alcohol, or cocaine.
  • the compounds used in the invention may contain asymmetric carbon atoms.
  • the invention includes the use of diastereomers, mixtures of diastereomers, or the use of mixed or the individual optical
  • the invention includes all such forms of the compounds.
  • the compounds used in the instant invention include solvates, hydrates, and pharmaceutically acceptable salts thereof.
  • the pharmaceutically acceptable salts of the compounds used in the present invention include conventional nontoxic salts or quaternary ammonium salts.
  • the compounds of the instant invention are useful as anxiolytic agents as described and
  • Figure I illustrates the effectiveness of orally administered compound L-365,260.
  • Figure II illustrates the effectiveness of orally administered compound L-365,260.
  • mice Generally the number of mice used was 5 and the pretreatment time was about 40 minutes.
  • the compound was given PO in 1- and 10-mg/kg doses.
  • the apparatus was an open-topped box, 45 cm long, 27 cm wide, and 27 cm high, divided into a small (2/5) area and a large (3/5) area by a
  • partition that extended 20 cm above the walls. There was a 7.5 x 7.5 cm opening in the partition at floor level.
  • the small compartment was painted black and the large compartment white.
  • the floor of each compartment was marked into 9 cm squares.
  • the white compartment was illuminated by a 100-watt tungsten bulb 17 cm above the box and the black compartment by a similarly placed 60-watt red bulb. The laboratory was illuminated with red light.
  • Drugs such as alcohol, cocaine, diazepam, and nicotine can also be used in the light/dark
  • alcohol can be given in the drinking water as an 8% w/v solution for 14 days. After a 24-hour withdrawal period, the withdrawal response may be blocked by a composition of the instant invention when
  • Figure 1 Control mice, not treated with L-365,260, but subjected to the aversive stimulus, showed a high level of rearing and line crossing activity in the black compartment compared to the white compartment. Treatment with 10 mg/kg L-365,260 orally reversed. this response and the mice now showed higher rearing and line crossing activity in the white compartment than in the black compartment. Figure 1 also shows that L-365,260 reduced the total time spent by the mice in the black compartment and increased the time latency of the mice moving from the white side to the black side. These results show that L-365,260 possesses anxiolytic activity in this test.
  • compositions of the instant invention are also useful as antipsychotic agents.
  • the compounds of the instant composition were tested for their ability to reduce the effects of intra-accumbens amphetamine in the rat as described hereinafter.
  • Rats were anesthetized with chloral hydrate (400 mg/kg -1 SC) and placed in a Kopf stereotaxic frame. Chronically indwelling guide cannulae
  • the guides were kept patent during a 14-day recovery period using stainless steel stylets, 0.3 mm diameter, which extended 0.5 mm beyond the guide tips.
  • Rats were manually restrained and the stylets removed. Intracerebral injection cannulae, 0.3 mm diameter, were inserted and drugs delivered in a volume of 0.5 ⁇ L over 5 seconds (a further 55 seconds was allowed for deposition) from Hamilton syringes attached via polythene tubing to the injection units. Animals were used on a single occasion only.
  • amphetamine ( Figures 3 and 4). This test is known to be predictive of antipsychotic activity (Costall, Domeney, Naylor, and Tyers, Brit. J. Pharmac.
  • Figure III shows the anxiolytic effects of compound in the Rat Elevated X-Maze Test on a dose range of 0.01 to 1.0 mg/kg SC.
  • the anxiolytic effect is indicated by the time spent in the open arm end section compared with control C.
  • Elevated X-Maze The original reference to the Elevated X-Maze is Handley and Mithani, Naunyn-Schmiedebergs Arch.
  • the compound was first dissolved in 100% ethanol and serially diluted in alcohol. The required concentration was achieved by addition of 1.0% w/v carboxymethylcellulose, so that all solutions
  • the compound was administered subcutaneously
  • %TEOA Percent time spent on end half sections of open arms
  • %TEOA percent entries made onto end half sections of open arms
  • TE total entries
  • the stars (*) show the groups which are
  • the compound increased both %TEOA and TEEAA, indicating an anxiolytic-like action. This appears to be a specific effect due to a lack of effect on total entries.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient-sized molds and allowed to cool and solidify.
  • the powders and tablets preferably contain 5% to
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa better, and the like.
  • preparation is intended to include the formulation of the active component with
  • encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it .
  • cachets are included.
  • Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral
  • Liquid form preparations include solutions, suspensions, and emulsions.
  • Sterile water or water- propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration.
  • Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • the pharmaceutical preparation is in unit dosage form.
  • the preparation is divided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, for example, packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
  • 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 that patient's symptoms.
  • an effective daily dosage will be in the range of from about 0.05 mg/kg to about 50 mg/kg of body weight, and preferably, of from 0.5 mg/kg to about 20 mg/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 compound is dissolved in water and to the resulting solution the syrup is added with mild stirring.
  • Lactose USP Anhydrous q.s. or 250 g
  • Phenylacetic acid 54.46 g, 0.4 M was dissolved in acetic anhydride (80 mL).
  • O-chlorobenzaldehyde 56.23 g, 0.4 M was added slowly, with stirring. This was followed by the slow addition of
  • the product oiled out.
  • the ethanol water was decanted from the oil.
  • the oil was taken up in ether.
  • the ether solution was washed with cold water, then dried over MgSO 4 .
  • the ether solution was concentrated in vacuo. A small amount of ether was added to the residue.
  • the white solid was filtered and dried in vacuo to yield 9.56 g of product, mp 123-124°C.
  • Step 4 one obtains 3.6 g of the product

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Abstract

L'invention décrit des compositions pharmaceutiques et des procédés d'utilisation de ligands de la cholecystokinine centrale (CCK) comme antipsychotiques, comme anxiolytiques, et comme agents efficaces dans le traitement ou dans la prévention des symptomes de sevrage provoqués par l'arrêt de l'utilisation chronique ou prolongée de diazépam, d'alcool, de cocaïne ou de nicotine, ainsi que des agents anxiolytiques.
PCT/US1991/009555 1991-12-20 1991-12-20 Antagonistes de la cholecystokinine centrale possedant une efficacite pharmaceutique WO1993012791A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP92903432A EP0617621A4 (fr) 1991-12-20 1991-12-20 Antagonistes de la cholecystokinine centrale possedant une efficacite pharmaceutique.
JP4503379A JPH07507993A (ja) 1991-12-20 1991-12-20 医薬活性を有する中枢神経系コレシストキニンアンタゴニスト
PCT/US1991/009555 WO1993012791A1 (fr) 1991-12-20 1991-12-20 Antagonistes de la cholecystokinine centrale possedant une efficacite pharmaceutique

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PCT/US1991/009555 WO1993012791A1 (fr) 1991-12-20 1991-12-20 Antagonistes de la cholecystokinine centrale possedant une efficacite pharmaceutique

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WO1993012791A1 true WO1993012791A1 (fr) 1993-07-08

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EP (1) EP0617621A4 (fr)
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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5618812A (en) * 1992-07-29 1997-04-08 Merck Sharp & Dohme, Ltd. Benzodiazepine derivatives
FR2744363A1 (fr) * 1996-02-07 1997-08-08 Rhone Poulenc Rorer Sa Application de derives de thiazolidine a la preparation de medicaments destines au traitement de l'abus de drogues ou de substances donnant lieu a des pharmacomanies ou a un usage excessif
FR2744362A1 (fr) * 1996-02-07 1997-08-08 Rhone Poulenc Rorer Sa Application de derives de pyrrolidine a la preparation de medicaments destines au traitement de l'abus de drogues ou de substances donnant lieu a des pharmacomanies ou a un usage excessif
FR2744361A1 (fr) * 1996-02-07 1997-08-08 Rhone Poulenc Rorer Sa Application de derives de pyrrolidine a la preparation de medicaments destines au traitement de l'abus de drogues ou de substances donnant lieu a des pharmacomanies ou a un usage excessif
US6235953B1 (en) 1996-07-04 2001-05-22 Vinnolit Monomer Gmbh & Co. Kg Process for preparing 1,2-dichloroethane by direct chlorination
US6462037B1 (en) 1999-05-26 2002-10-08 Bristol-Myers Squibb Pharma Company 1,4-benzodiazepin-2-ones useful as HIV reverse transcriptase inhibitors
WO2007009691A2 (fr) * 2005-07-15 2007-01-25 Laboratorios Del Dr. Esteve, S.A. Combinaison de substances active s
EP1749525A1 (fr) * 2005-07-15 2007-02-07 Laboratorios Del Dr. Esteve, S.A. Combination de pyrazoline substitués et de médicaments contre la dépendance
US8247438B2 (en) 2008-02-27 2012-08-21 Neuropill, Inc. Methods for treating schizophrenia
US8796261B2 (en) 2010-12-02 2014-08-05 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9249161B2 (en) 2010-12-02 2016-02-02 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9328117B2 (en) 2011-06-17 2016-05-03 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9422292B2 (en) 2011-05-04 2016-08-23 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9493483B2 (en) 2012-06-06 2016-11-15 Constellation Pharmaceuticals, Inc. Benzo [C] isoxazoloazepine bromodomain inhibitors and uses thereof
US9624244B2 (en) 2012-06-06 2017-04-18 Constellation Pharmaceuticals, Inc. Benzo [B] isoxazoloazepine bromodomain inhibitors and uses thereof
US9969747B2 (en) 2014-06-20 2018-05-15 Constellation Pharmaceuticals, Inc. Crystalline forms of 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[C]isoxazolo[4,5-e]azepin-4-yl)acetamide

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US4769389A (en) * 1985-12-17 1988-09-06 Rotta Research Laboratories, S.P.A. Oxygenated-alkyl derivatives of glutamic and aspartic acids with antagonistic activity to bio-active polypeptides and a method for their preparation
US4791215A (en) * 1984-06-25 1988-12-13 Rotta Research Laboratorium S.P.A. Derivatives of glutamic acid and aspartic acid
US4820834A (en) * 1984-06-26 1989-04-11 Merck & Co., Inc. Benzodiazepine analogs
EP0434369A1 (fr) * 1989-12-18 1991-06-26 Merck & Co. Inc. Nouveaux analogues de benzodiazépine
EP0434360A1 (fr) * 1989-12-18 1991-06-26 Merck & Co. Inc. Analogues de benzodiazépines

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JPH0374328A (ja) * 1989-08-04 1991-03-28 Warner Lambert Co 薬学的活性を有する中枢コレシストキニン拮抗剤

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US3663771A (en) * 1971-01-12 1972-05-16 Gulf & Western Industries Distributor rotor with improved contact securing means
US4791215A (en) * 1984-06-25 1988-12-13 Rotta Research Laboratorium S.P.A. Derivatives of glutamic acid and aspartic acid
US4820834A (en) * 1984-06-26 1989-04-11 Merck & Co., Inc. Benzodiazepine analogs
US4769389A (en) * 1985-12-17 1988-09-06 Rotta Research Laboratories, S.P.A. Oxygenated-alkyl derivatives of glutamic and aspartic acids with antagonistic activity to bio-active polypeptides and a method for their preparation
EP0434369A1 (fr) * 1989-12-18 1991-06-26 Merck & Co. Inc. Nouveaux analogues de benzodiazépine
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Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5618812A (en) * 1992-07-29 1997-04-08 Merck Sharp & Dohme, Ltd. Benzodiazepine derivatives
FR2744363A1 (fr) * 1996-02-07 1997-08-08 Rhone Poulenc Rorer Sa Application de derives de thiazolidine a la preparation de medicaments destines au traitement de l'abus de drogues ou de substances donnant lieu a des pharmacomanies ou a un usage excessif
FR2744362A1 (fr) * 1996-02-07 1997-08-08 Rhone Poulenc Rorer Sa Application de derives de pyrrolidine a la preparation de medicaments destines au traitement de l'abus de drogues ou de substances donnant lieu a des pharmacomanies ou a un usage excessif
FR2744361A1 (fr) * 1996-02-07 1997-08-08 Rhone Poulenc Rorer Sa Application de derives de pyrrolidine a la preparation de medicaments destines au traitement de l'abus de drogues ou de substances donnant lieu a des pharmacomanies ou a un usage excessif
WO1997028798A1 (fr) * 1996-02-07 1997-08-14 Rhone-Poulenc Rorer S.A. Application de derives de pyrrolidine a la preparation de medicaments destines au traitement de l'abus de drogues
WO1997028800A1 (fr) * 1996-02-07 1997-08-14 Rhone-Poulenc Rorer S.A. Application de derives de thiazolidine a la preparation de medicaments destines au traitement de l'abus de drogues
WO1997028799A1 (fr) * 1996-02-07 1997-08-14 Rhone Poulenc Rorer S.A. Application de derives de pyrrolidine a la preparation de medicaments destines au traitement de l'abus de drogues
US6150387A (en) * 1996-02-07 2000-11-21 Rhone-Poulenc Rorer S.A. Heterocyclic carboxamide compounds effective in the treatment of drug abuse
US6235953B1 (en) 1996-07-04 2001-05-22 Vinnolit Monomer Gmbh & Co. Kg Process for preparing 1,2-dichloroethane by direct chlorination
US6462037B1 (en) 1999-05-26 2002-10-08 Bristol-Myers Squibb Pharma Company 1,4-benzodiazepin-2-ones useful as HIV reverse transcriptase inhibitors
WO2007009691A3 (fr) * 2005-07-15 2007-03-08 Esteve Labor Dr Combinaison de substances active s
EP1749525A1 (fr) * 2005-07-15 2007-02-07 Laboratorios Del Dr. Esteve, S.A. Combination de pyrazoline substitués et de médicaments contre la dépendance
WO2007009691A2 (fr) * 2005-07-15 2007-01-25 Laboratorios Del Dr. Esteve, S.A. Combinaison de substances active s
US8247438B2 (en) 2008-02-27 2012-08-21 Neuropill, Inc. Methods for treating schizophrenia
US8592466B2 (en) 2008-02-27 2013-11-26 Neuropill, Inc. Methods for treating conditions caused by higher-than-normal dopaminergic activity in basal ganglia
US9522920B2 (en) 2010-12-02 2016-12-20 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9249161B2 (en) 2010-12-02 2016-02-02 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US8796261B2 (en) 2010-12-02 2014-08-05 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9422292B2 (en) 2011-05-04 2016-08-23 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9328117B2 (en) 2011-06-17 2016-05-03 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9493483B2 (en) 2012-06-06 2016-11-15 Constellation Pharmaceuticals, Inc. Benzo [C] isoxazoloazepine bromodomain inhibitors and uses thereof
US9624244B2 (en) 2012-06-06 2017-04-18 Constellation Pharmaceuticals, Inc. Benzo [B] isoxazoloazepine bromodomain inhibitors and uses thereof
US9925197B2 (en) 2012-06-06 2018-03-27 Constellation Pharmaceuticals, Inc. Benzo [C] isoxazoloazepine bromodomain inhibitors and uses thereof
US9969747B2 (en) 2014-06-20 2018-05-15 Constellation Pharmaceuticals, Inc. Crystalline forms of 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[C]isoxazolo[4,5-e]azepin-4-yl)acetamide

Also Published As

Publication number Publication date
JPH07507993A (ja) 1995-09-07
EP0617621A1 (fr) 1994-10-05
EP0617621A4 (fr) 1995-04-05

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