WO1992004017A1 - Cis-n-(2-aminocyclohexyl)benzamides et leurs enantiomeres en tant qu'agents anticonvulsivants - Google Patents

Cis-n-(2-aminocyclohexyl)benzamides et leurs enantiomeres en tant qu'agents anticonvulsivants Download PDF

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Publication number
WO1992004017A1
WO1992004017A1 PCT/US1991/005473 US9105473W WO9204017A1 WO 1992004017 A1 WO1992004017 A1 WO 1992004017A1 US 9105473 W US9105473 W US 9105473W WO 9204017 A1 WO9204017 A1 WO 9204017A1
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WIPO (PCT)
Prior art keywords
cis
aminocyclohexyl
enantiomers
benzamide
dichloro
Prior art date
Application number
PCT/US1991/005473
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English (en)
Inventor
John Raymond Palmer
Alexander R. Cazers
Philip F. Von Voigtlander
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The Upjohn Company
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Publication date
Application filed by The Upjohn Company filed Critical The Upjohn Company
Publication of WO1992004017A1 publication Critical patent/WO1992004017A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/79—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention provides a new use for some known benzamide compounds. More particularly, the present invention provides a method of treating or preventing Central Nervous System (CNS seizures), e.g., grand mal seizures, by the administration of certain cis-N-(2- aminocyclohexyl) benzamides.
  • CNS seizures Central Nervous System
  • the present invention also provides novel cis-N-(aminocyclohexyl) benzamide compounds that are useful as CNS anti-seizure drugs in valuable warm blooded animals, including humans.
  • U.S. Patent No. 4,098,904 discloses some N-(2- aminocycloaliphatic) benzamide compounds, e.g., N-methyl-N-[2-(l-pyrrolidinyl) cyclohexyl]-3,4- dichlorobenzamideand N-methyl-N-[2-(N' ,N'-dimethylamino) cyclohexyl]-4-bromobenzamide, and salts and hydrates thereof as analgesic drug compounds.
  • 4,145,435 discloses 2-aminocycloaliphatic alkanoyl amide compounds, e.g., N-methyl-N-[2-(N',N'-dimethylamino)cyclohexyl]-2-(4-bromophenyl) acetamide and their pharmaceutically acceptable salts as analgesic compounds.
  • U.S. Patent 4,215,114 discloses various methylamino-cyclohexyl-benzamide compounds useful as potent analgesics.
  • a non-salt form of N-methyl-N-(2-(N'- methylamino)cyclohexyl)-3.4-dichlorobenzamide is specified; however, this is one among a large list of compounds not indicated to be useful for controlling or treating seizures.
  • U.S. Patent No. 4,801,604 discloses certain cis-N-(2-amino-cycloaliphatic) benzamides, e.g., cis-3,4-dichloro-N-methyl-N-[2-(l-pyrrolidinyl)cyclohexyl]benzamides and salts thereof as anticonvulsants with little or no analgesic properties.
  • U.S. Patent 4,359,476 discloses N-[2-amino (oxy or thio group) substituted-cyclo- aliphatic]phenylacetamide and benzamide compounds which have analgesic activity. Wolf. T., et al, (1984), J. Or. Chem.
  • 49:3305-3310 discloses 2-(0-chlorophenyl)-2- benzoylmethylamino)cyclohexanone. Certain oxazolidine rings are disclosed in Bernardi, L., et al, (1968), Gazz. Chim. Ital. 98(7):836-84). Burak, K., et al, (1985), II Farmaco-Ed. Sc. 40(4):285-98 discloses aryl analogs of 2-0-chlorophenyl-2-methylaminocyclohexane-l-one hydrochloride which are useful as an anesthetic. None of the references cited above disclose that the compounds of the instant invention are useful as anticonvulsants.
  • the present invention provides novel monohydrochloride salt compounds: cis-N-(2-aminocyclohexyl)-3 ,4-dichlorobenzamide monohydrochloride and its enantiomers; cis-N-[2-(methylamino)cyclohexyl]-3,4-dichlorobenzamide monohydrochloride and its enantiomers; cis-N-(2-aminocyclohexyl)-3.4-dichloro-N-methyl-benzamide monohydrochlo ⁇ ride and its enantiomers; and cis-N-[2-(methylamino)cyclohexyl]-3,4-dichloro-N-methylbenzamide mono ⁇ hydrochloride and its enantiomers.
  • the present invention also provides novel methods of using the compounds of formula I:
  • salt we mean a compound that is prepared by reacting a formula I free base with a stoichiometric amount of an acid, e.g., hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, succinic acid, benzoic acid, salicylic acid, pamoic acid, cyclohexane-sulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, p-toluene-sulfonic acid, maleic, fumaric acid, oxalic acid.
  • an acid e.g., hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, succinic acid, benzoic acid, salicylic acid, pamoic acid, cyclohexane-sulfonic acid, methanesulfonic acid,
  • C j -C 3 alkyl we mean an alkyl of one to three carbon atoms, inclusive of methyl, ethyl, propyl and isomeric forms thereof.
  • treatment is meant the amelioration or total avoidance of the CNS disorder as described herein.
  • prevention is meant the avoidance of a currently recognized disease state, as described herein, in a patient evidencing a CNS disorder.
  • the present invention provides a method of treating or preventing certain CNS seizures in a patient susceptible to or experiencing said seizure comprising the systemic administration of certain cis-aminocyclohexyl-benzamide compounds or a pharmacologically acceptable salt thereof.
  • the present invention also provides novel benzamide compounds which are useful as anticonvulsants.
  • the compounds of the instant invention are metabolites of cis-3.4- dichloro-N-methyl-N-[2-(l-pyrrolidinyl) cyclohexyl]-benzamide in mice.
  • the compounds of the present invention are more effective as anticonvulsants than cis-3,4-dichloro-N-methyl-N-[2-(l -pyrrol idinyl)cyclohexyl]-benzamide.
  • the compounds of the instant invention are generated in only very small amounts from cis-3,4-dichloro-N-methyl-N-[2-l- (pyrrolidinyl)cyclohexyl]benzamide by humans.
  • cis-3,4-dichloro-N-methyl-N-[2-(l- pyrrolidinyl)cyclohexyl] benzamide is rapidly bioinactivated by primates, including man.
  • the compounds of the instant invention will be useful in the treatment of grand mal and other seizure disorders in man as well as in commercially important and pet animals.
  • the cis-N-(2-aminocyclohexyl)benzamides can be prepared in the following way.
  • the compounds of this invention while being anti-seizure drugs, e.g., anti-convulsant drugs at reasonable dosages, have little or no analgesic activity and will not show some of the side effects of other anticonvulsants, e.g., hyperplasia of the gums, cerebellar degeneration, gastric distress and serious skin rashes.
  • compositions containing one of the compounds of the instant invention as an active ingredient in a pharmaceutical carrier are useful in pharmaceutical dosage unit forms for systemic administration (oral, rectal, parenteral, including intravenous, intramuscular and intra-arterial administration form) for treating warm-blooded animal patients, cats, dogs, horses and other commercially valuable animals and human patients suspected of being susceptible to or to stop CNS seizures, such as convulsions, grand mal, petit mal and other seizure disorders.
  • dosage unit form refers to physically discrete units suitable as unitary dosages for mammalian subjects, each unit containing a predetermined quantity of the essential active ingredient compounds of this invention calculated to produce die desired effect in combination with the required pharmaceutical means which adapt the said ingredient for topical or systemic administration.
  • the specifications for the novel dosage unit forms of the invention are indicated by and directly dependent on the physical characteristics of the essential active material for beneficial effects in humans and animals.
  • suitable dosage unit forms in accordance with this invention are tablets, capsules, orally administered liquid preparations in suitable liquid vehicles for intramuscular and intravenous administration, suppositories and sterile clay preparations for the extemporaneous preparation of sterile injectable preparations in a suitable liquid vehicle.
  • Suitable solid diluents are known in the art, e.g., starch, sucrose, lactose, kaolin, dicalcium phosphate, gelatin, acacia, corn syrup, corn starch, and talc.
  • the pharmaceutical dosage unit forms are prepared in accordance with the preceding general description to provide from about 1.0 to about 100 mg of the essential active ingredient per dosage unit form.
  • the amount of me essential active ingredient provided in die pharmaceutical dosage unit forms is that amount sufficient to obtain a reduction in the CNS seizure effects and a return to more normal CNS stability or to prevent the occurrence of CNS seizures in a patient who is suspected to be subject to such seizure.
  • an amount of the essential active ingredient is provided to a recipient within a range of from about 0.1 mg per kg to about 100 mg per kg of body weight of d e recipient.
  • Preferred dosages for most applications are 1.0 to 10.0 mg, per kg of body weight.
  • the useful dosage unit forms of these compounds in pharmaceutical formulations is preferably adapted for oral administration to obtain anticonvulsant effects comprising an effective, nontoxic amount of the compound as described herein or as its pharmalogically acceptable salt.
  • the invention relates to methods of obtaining such CNS anti-seizure effects in mammals, e.g., humans and valuable warm-blooded animals such as dogs, cats, horses and other commercially valuable animals by administering systemically to the mammals pharmaceutical dosage unit forms, as described herein, supplying an effective, nontoxic amount for anticonvulsant effects.
  • the compounds are less active when given intracerebroventricularly.
  • Cis-N-(2- aminocyclohexyl)-3,4-dichlorobenzamide monohydrochloride is the preferred compound.
  • the most preferred compound is cis-N-[2-(methylamino)cyclohexyl]-3,4-dichlorobenzamide monohydro ⁇ chloride.
  • Example 1 Cis-N-(2-aminocyclohexyl)-3.4-dichlorobenzamide monohydrochloride
  • Example 2 3,4-dichloro-N-(2-oxocyclohexyl)benzamide Jones reagent (8N, 1.5 ml) is added in three equal portions to a solution of starting amido- alcohol (1.35 g) in acetone (150 ml) at room temperature. The oxidation is complete after the last addition (tic). Excess Jones reagent is quenched with isopropanol. The mixture is filtered with the aid of Celite and the filtrate is concentrated in vacuo. The solid is dissolved in dichloromethane and washed with water.
  • cis-N-(2-aminocyclohexyl)-3,4-dichloro benzamide can be prepared in the following way.
  • a solution of starting oxime (1.0 g) in methanolic ammonia (150 ml) is treated wid one- half tablespoon of washed (3X with Ethanol) Raney Nickel (Aldrich) in a Parr bottle.
  • the bottle is charged with H 2 gas (35psi). After 2 hours, the gas uptake will ceased.
  • the catalyst is removed by filtration with the aid of Celite. The filtrate is concentrated in vacuo to give .9 g of an oil.
  • Solid 1,1-carbonyldiimidazole (1.83 g) is added in one portion to a solution of BOC-L- Phenylalanine (3.00 g) in THF (30 ml) at 0° under an Argon atmosphere. After the addition, the coolant is removed and the reaction is allowed to warm to 20-25°C for 1.5 hours. Recooled d e reaction flask to 0°, a solution of cis-N-(2-aminocyclohexyl)-3,4-dichlorobenzamide (3.24) in THF (30 ml) is added dropwise within 10 min. The reaction flask is allowed to warm gradually to room temperature overnight.
  • the reaction is diluted with aqueous saturated potassium carbonate solution and ethyl acetate.
  • the phases are separated.
  • the EtOAc phase is washed widi water, dried (anhydrous sodium sulfate), and concentrated in vacuo to a mixture of diasteromeric amides.
  • the amide mixture is dissolved in hot EtOAc-EtOH solvent mixture and allowed to crystallize at room temperature to give 1.7 g of a pure diasteromeric amide; mp. 224-225°C. This isomer is labeled A.
  • the mixture is chromatographed (silica gel. 240-400 mesh, eluant: 2% methanol-chloroform). Like fractions are combined and concentrated in vacuo.
  • Cis-N-2-(aminocyclohexyl) benzamide In a manner similar to me preparation of cis-N-2-(aminocyclohexyl-3,4-dichlorobenzamide, cis-N-2-(aminocyclohexyI) benzamide is prepared from benzoyl chloride and cis-l,2-diamino- cyclohexane. The free base of the product is converted to d e hydrochloride salt with ethereal hydrochloric acid and recrystallizes from ethanol-emer.
  • cis-N-(2-aminocyclohexyI,)-4-chlorobenzamidemono-hydrochloride is prepared from 4-chlorobe ⁇ zoyl chloride.
  • cis-N-(2-aminocyclohexyl)-4-bromobenzamide mono ⁇ hydrochloride is prepared from 4-bromobenzoyl chloride.
  • Titanium tetrachloride (.94g) in dichloromediane (10ml) is added dropwise to a solution of 2-[N-(tert-butyloxy)carbonyI]-N-methylamino]cyclohexanone (B.R. deCosta, et al., J. Med Chem., 32, 1996 (1989)), (2.04g) and N-methylbenzylamine(6.55g) in THF (40ml) at 0°C under an argon atmosphere.
  • the mixture is stirred at room temperature for 20h.
  • the precipitate is filtered and washed widi dichloromethane (3 x 50ml).
  • Example 10 Anti-convulsants activity of cis-N-(2-aminocyclohexyl)-3,4-dichlorobenza- mide monohydrochloride and cis-N-[2-(methylamino)cyclohexyl]-3,4- dichlorobenzamide monohydrochloride.
  • the anticonvulsant activity of diese compounds were tested in Charles River CF-1 (18-22 gm) male mice.
  • mice are dosed either orally (PO), intravenously (TV) or intracerebroventricularly (ICV) with cis-N-(2-aminocyclohexyl)-3,4-dichlorobenzamide monohydrochloridepis-3,4-dichloro-N-[2-(methylamino)cyclohexyl]benzamidenonohydrochloride, and cis,-3,4-dichloro-N-methyl-N-[2-(l-pyrrolidinyl)cyclohexyl] benzamide.
  • PO intravenously
  • IMV intracerebroventricularly
  • the oral and intravenous doses of the compound ranged from 6.25 to 200 mg/kg, and the compound is dissolved in 0.9% saline and injected in a volume of 0.2 cc/20 gm.
  • the intracerebroventricular doses ranged from 6.25 to 200 ug/mouse and are administered in 10 ul of saline.
  • mice used for die oral study had free access to water, but food is withdrawn 12 hours prior to oral injection.
  • a curved gavage needle widi a bulbus tip is used to administer drugs orally.
  • Mice are intravenously injected via the tail vein using a 26 gauge needle.
  • Intracerebroventricular injection into the left lateral ventricle is effected widi a Hamilton 50 microliter syringe (model 705) widi a fixed needle and provided widi a stainless steel cuff to limit penetration.
  • Anticonvulsant activity is assessed by determination of electroshock induced seizure thresholds.
  • Generally 10 mice are utilized to establish the mA direshold for tonic seizures at each of the time intervals studied. The data is calculated as mA50 increase (threshold for treated mice- threshold of control mice) or as anticonvulsant ED 50 's based on die ability of die test compound to block seizures induced by a 100 mA 0.2 second stimulus.
  • Dose response data determined at 30, 60, 120, 240, and 480 minutes after oral administration shows mat cis-N-(2-aminocyclohexyl)-3-,4-dichlorobenzamide monohydrochloride and cis-N-[2-(meti ⁇ ylamino)cyclohexyl]-3,4-dichlorobenzamide monohydrochloride are more potent tha cis-4-dichloro-N-methyl-N-[2-(l-pyrrolidinyl)cyclohexyl]-benzamide.
  • die results are reversed.
  • Cis-N-(2-aminocyclohexyl)-3-4-dichloroben2 ⁇ midemonohydrochlorideand cis-3,4-dichloro-N-[2-(methylamino)cyclohexyl]benzamide monohydrochloride are comparatively ineffective when administered ICV.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Méthode servant à prévenir et à traiter des maladies du système nerveux central et consistant à administrer certains cis-N-(2-aminocyclohexyl)benzamides. On décrit aussi de nouveaux benzamides utiles en tant que médicaments servant à lutter contre des maladies du système nerveux central.
PCT/US1991/005473 1990-09-10 1991-08-06 Cis-n-(2-aminocyclohexyl)benzamides et leurs enantiomeres en tant qu'agents anticonvulsivants WO1992004017A1 (fr)

Applications Claiming Priority (4)

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US58037990A 1990-09-10 1990-09-10
US580,379 1990-09-10
US60599990A 1990-10-30 1990-10-30
US605,999 1990-10-30

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003000657A1 (fr) * 2001-06-20 2003-01-03 Daiichi Pharmaceutical Co., Ltd. Derives de diamine
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
WO2019005841A1 (fr) * 2017-06-26 2019-01-03 Rutgers, The State University Of New Jersey Composés thérapeutiques et méthodes pour traiter une infection
US11180459B2 (en) 2017-03-10 2021-11-23 Rutgers, The State University Of New Jersey Bacterial efflux pump inhibitors
US11826357B2 (en) 2017-05-26 2023-11-28 Rutgers, The State University Of New Jersey Bacterial efflux pump inhibitors
US11938114B2 (en) 2017-03-10 2024-03-26 Rutgers, The State University Of New Jersey Bacterial efflux pump inhibitors
US11993571B2 (en) 2017-03-10 2024-05-28 Rutgers, The State University Of New Jersey Indole derivatives as efflux pump inhibitors

Citations (2)

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Publication number Priority date Publication date Assignee Title
US4215114A (en) * 1976-11-12 1980-07-29 The Upjohn Company Analgesic N-[2-(furyl-methylamino and 2-thienylmethylamino)cycloaliphatic]be
US4801604A (en) * 1985-10-25 1989-01-31 The Upjohn Company Cis-N-(2-aminocycloaliphatic)benzamide anti-convulsants

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4215114A (en) * 1976-11-12 1980-07-29 The Upjohn Company Analgesic N-[2-(furyl-methylamino and 2-thienylmethylamino)cycloaliphatic]be
US4801604A (en) * 1985-10-25 1989-01-31 The Upjohn Company Cis-N-(2-aminocycloaliphatic)benzamide anti-convulsants

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Drug Development Research, volume 18, no. 3, 1989, Alan R. Liss Inc. (New York, US), P.F. VonVoigtlander et al.: "Relationship of anticonvulsant activity to brain concentrations of the chiral anticonvulsant U-54494a", pages 205-216, see abstract; introduction; pages 209,215, (cited in the application) *
Heterocycles, volume 31, no. 10, 1990, B.R. de Costa et al.: "A practical synthesis, optical resolution and determination of absolute configuration of enantiomerically pure 1S,2R-(+)- and 1R,2S-(-)-CIS-2-(1-pyrrolidinyl)cyclohexylamines: important precursors for a new class of sigma-receptor ligands and anticonvulsant drugs", pages 1837-1846, see page 1837 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003000657A1 (fr) * 2001-06-20 2003-01-03 Daiichi Pharmaceutical Co., Ltd. Derives de diamine
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
US11180459B2 (en) 2017-03-10 2021-11-23 Rutgers, The State University Of New Jersey Bacterial efflux pump inhibitors
US11938114B2 (en) 2017-03-10 2024-03-26 Rutgers, The State University Of New Jersey Bacterial efflux pump inhibitors
US11993571B2 (en) 2017-03-10 2024-05-28 Rutgers, The State University Of New Jersey Indole derivatives as efflux pump inhibitors
US11826357B2 (en) 2017-05-26 2023-11-28 Rutgers, The State University Of New Jersey Bacterial efflux pump inhibitors
WO2019005841A1 (fr) * 2017-06-26 2019-01-03 Rutgers, The State University Of New Jersey Composés thérapeutiques et méthodes pour traiter une infection
US11458121B2 (en) 2017-06-26 2022-10-04 Rutgers, The State University Of New Jersey Therapeutic compounds and methods to treat infection

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