WO1998057927A1 - Augmentation du taux du hdl cholesterol par 4-[(aminothioxomethyl)hydrazono]-4-arylbutyle carbamates - Google Patents

Augmentation du taux du hdl cholesterol par 4-[(aminothioxomethyl)hydrazono]-4-arylbutyle carbamates Download PDF

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Publication number
WO1998057927A1
WO1998057927A1 PCT/US1998/010460 US9810460W WO9857927A1 WO 1998057927 A1 WO1998057927 A1 WO 1998057927A1 US 9810460 W US9810460 W US 9810460W WO 9857927 A1 WO9857927 A1 WO 9857927A1
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WIPO (PCT)
Prior art keywords
phenyl
alkyl
hydrazono
oxy
carbonyl
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Application number
PCT/US1998/010460
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English (en)
Inventor
Thomas Joseph Commons
Susan Christman
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American Home Products Corporation
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Publication date
Application filed by American Home Products Corporation filed Critical American Home Products Corporation
Priority to AU75894/98A priority Critical patent/AU7589498A/en
Publication of WO1998057927A1 publication Critical patent/WO1998057927A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C337/00—Derivatives of thiocarbonic acids containing functional groups covered by groups C07C333/00 or C07C335/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C337/06—Compounds containing any of the groups, e.g. thiosemicarbazides
    • C07C337/08—Compounds containing any of the groups, e.g. thiosemicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. thiosemicarbazones
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine

Definitions

  • This invention relates to compounds useful in elevating high density lipoprotein, the "good" cholesterol.
  • Compounds of this invention increase plasma levels of HDL in a cholesterol fed rat model and as such these compounds may be useful for treating diseases such as atherosclerosis.
  • HDL is a "protective" lipoprotein [Gloria Lena Vega and Scott Grundy, Current Opinion in Lipidology, 7, 209-216 (1996)] and that increasing plasma levels of HDL may offer a direct protection against the development of atherosclerosis.
  • CHD coronary heart disease
  • HDL-C serum HDL cholesterol
  • Atherosclerosis is the process of accumulation of cholesterol within the arterial wall which results in the occlusion, or stenosis, of coronary and cerebral arterial vessels and subsequent myocardial infarction and stroke.
  • Angiographical studies have shown that elevated levels of some HDL particles in humans appears to be correlated to a decreased number of sites of stenosis in the coronary arteries of humans (Miller et al., Br. Med. J.. 282 (1981) 1741-1744).
  • HDL may protect against the progression of atherosclerosis.
  • Studies in vitro have shown that HDL is capable of removing cholesterol from cells (Picardo et al., Arteriosclerosis. £ (1986) 434-441).
  • Data of this nature suggest that one antiatherogenic property of HDL may lie in its ability to deplete tissues of excess free cholesterol and eventually lead to the delivery of this cholesterol to the liver (Glomset, J. Lipid Res.. 9 (1968) 155-167). This has been supported by experiments showing efficient transfer of cholesterol from HDL to the liver (Glass et al., Circulation. 66 (Suppl. I (1982) 102; MacKinnon et al., J. Biol. Chem..
  • HDL may serve as a reservoir in the circulation for apoproteins necessary for the rapid metabolism of triglyceride-rich lipoproteins (Grow and Fried, L. Biol. Chem.. 253 (1978) 1834-1841; Lagocki and Scanu, J. Biol. Chem.. 255 (1980) 3701-3706; Schaefer et al., J. Lipid Res.. 23 (1982) 1259-1273).
  • agents which increase HDL cholesterol concentrations are useful as anti-atherosclerotic agents, particularly in the treatment of dyslipoproteinemias and coronary heart disease.
  • the compounds of this invention which elevate plasma levels of HDL cholesterol are represented by the formula
  • R 1 , R 2 , and R 3 are independently hydrogen, - alkyl or -(CH 2 )o- 6 Ph where Ph is optionally substituted by halogen, cyano, nitro, C 1 -C 6 alkyl, Q. ⁇ -Q_ alkoxy, trifluoromethyl, Q ⁇ -C_ alkoxycarbonyl, -CO 2 H or OH; R 4 and R5 are independently hydrogen, Q.
  • Ar 1 is phenyl, naphthyl, furanyl, pyridinyl or thenyl and Ar 1 can be optionally substituted by halogen, cyano, nitro, Q ⁇ -Q_ alkyl, phenyl, C ⁇ -C $ alkoxy, phenoxy, trifluoromethyl, Ci- alkoxycarbonyl, -CO2H or OH; and Ar is phenyl, naphthyl, furanyl, pyridinyl or thienyl or Ar is optionally substituted by halogen, cyano, nitro, -C ⁇ alkyl, phenyl, Ci-C ⁇ alkoxy, phenoxy, trifluoromethyl, C1-C 6 alkoxycarbonyl, -CO 2 H or OH.
  • the compounds are tested in vivo in rats fed cholesterol-augmented
  • the compounds of this invention are conveniently prepared by the routes shown in Scheme I and Scheme II. Specific examples arc given in the Experimental Section. These examples are for illustrative purposes only and are not to be construed as limiting to this disclosure in any way. Those skilled in the art will be aware of other methods of preparing compounds of this invention.
  • the starting materials or intermediates are available commercially or can be prepared by standard literature procedures.
  • Examples 2 through 5 were prepared in the same manner as Example 1.
  • Example 2 4[(AminothioxomethyI)hydrazono]-4-phenylbuty-cydohexylcarbamate
  • step (c) cyclohexyl isocyanate is substituted for butyl isocyanate.
  • step (e) the solid formed in the reaction mixture is collected by filtration. Recrystalli--ation of this solid from isopropyl alcohol gave the title compound (3.1438g, 57%) as a white solid, mp 136-140°C.
  • step (c) phenyl isocyanate is substituted for butyl isocyanate.
  • Step (e) the solid formed in the reaction mixture is collected by filtration and dried to give the title compound (3.7924g, 86%) as a white solid, mp 140-142°C.
  • Example 4 Benzyl carbamic acid-4-[(aminothioxomethyI)hydrazono]-4-phenylbutyl ester
  • step (c) benzyl isocyanate is substituted for butyl isocyanate.
  • Example 5 4-[(AminothioxomethyI)hydrazono]-4-phenylbutyI(l-methylethyl)carbamate
  • step (c) isopropyl isocyanate is substituted for butyl isocyanate.
  • step (e) the solid formed in the reaction was collected by filtration and then dissolved in ethyl acetate and extracted five times with water. The organic phase was dried (MgSO 4 ) and the solvent removed under reduced pressure to give 2.73g of a yellow solid. RecrystaUization of this solid from isopropyl alcohol gave the title compound (2.19g, 46%) as a light yellow solid, mp 122-125°C.
  • naphthalen-1-yl carbamic acid 4-oxo-4-phenyl-butyl ester 5.08g, 86%) was isolated as a tan solid, mp 95-97°C.
  • biphenyl-2-yl-carbamic acid 4-hydroxy-4-phenyl- butyl ester (8.24g, 73%) was isolated as a clear oil, MS m/e [M+H] + 362.
  • biphenyl-2-yl-carbamic acid 4- oxo-4-phenyl-butyl ester (6.9 lg, 89%) was isolated as a white solid, mp 87-89°C.
  • Biphenyl-2-yl-carbamic acid 4-oxo-4-phenyl- butyl ester (6.48g, 18 mmol), prepared in the previous step, was suspended in 150 ml of methanol and the mixture warmed to dissolve the solid. While still warm 4.9 ml of 1 N HCl, 4.9 ml of water and thiosemicarbazide (1.65g, 18 mmol) were added and the reaction stirred under nitrogen for 23 hours. The reaction was concentrated under reduced pressure to remove the methanol. The residue was partitioned between methylene chloride and water. The organic layer was separated, extracted multiple times with water, dried (MgSO and the solvent removed under reduced pressure to give 7.55g of a white solid foam.
  • phenyl-carbamic acid 4-hydroxy-4-p-tolyl- butyl ester (14.6g, 81%) was isolated as a white solid, mp 69-72°C.
  • Phenyl-carbamic acid 4-oxo-4-p-tolyl-butyl ester (10.58g, 36 mmol), prepared in the previous step, was suspended in 220 ml of methanol and the mixture warmed to dissolve the solid. While still warm 9.6 ml of 1 N HCl, 9.6 ml of water amd thiosemicarbazide (3.24g, 36 mmol) were added and the reaction stirred under nitrogen for 22 hours. The solid formed was removed by filtration and recrys-allized from methanol to give the title compound (10.5g, 80%) as a white solid, mp 170-173°C.
  • test substances Male Sprague-Dawley rats weighing 200-225 g are housed two per cage and fed Purina Rodent Chow Special Mix 5001-S supplemented with 0.25% cholic acid and 1.0% cholesterol and water ad libitum for 8 days. Each test substance is administered to a group of six rats fed the same diet with the test diet mixed in as 0.005 - 0.1 % of the total diet Body weight and food consumption are recorded prior to diet administration and at termination. Typical doses of the test substances are 5 - 100 mg kg/day.
  • HDL cholesterol concentrations in serum are determined by separation of lipoprotein classes by fast protein liquid chromatography (FPLC) by a modification of the method of Kieft et al., J. Lipid Res., _Y2 (1991) 859-866. 25 ⁇ l of serum is injected onto Superose 12 and Superose 6 (Pharmacia), in series, with a column buffer of 0.05 M Tris (2-arnino-2-hydroxymethyl-l,3-propanediol) and 0.15 M sodium chloride at a flow rate of 0.5 ml/min. The eluted sample is mixed on line with Boehringer-Mannheim cholesterol reagent pumped at 0.2 ml/min.
  • FPLC fast protein liquid chromatography
  • the combined eluents are mixed and incubated on line through a knitted coil (Applied Biosciences) maintained at a temperature of 45° C.
  • the eluent is monitored by measuring absorbance at 490 nm and gives a continuous absorbance signal proportional to the cholesterol concentration.
  • the relative concentration of each lipoprotein class is calculated as the per cent of total absorbance.
  • HDL cholesterol concentration, in serum is calculated as the per cent of total cholesterol as determined by FPLC multiplied by the total serum cholesterol concentration.
  • Example 1 134.0 % ( 100 mg kg)
  • Example 2 129.9 % ( 100 mg/kg)
  • Example 3 150.0 % (100 mg/kg)
  • Example 4 56 % (100 mg/kg)
  • Example 6 31.0 % (100 mg/kg)
  • Example 7 33.4 % ( 100 mg/kg)
  • Example 9 26.7 % (100 mg/kg)
  • Example 10 55.0 % (100 mg/kg)
  • PHARMACEUTICAL COMPOSITION Compounds of this invention may be administered neat or with a pharmaceutical carrier to a patient in need thereof.
  • the pharmaceutical carrier may be solid or liquid.
  • Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary compression properties In suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
  • the active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat
  • a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat
  • the liquid carrier can contain other suitable pharmaceutical additives such a solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferable sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil).
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
  • the compounds of this invention may be administered rectally in the form of a conventional suppository.
  • the compounds of this invention may be formulated into an aqueous or partrially aqueous solution, which can then be utilized in the form of an aerosol.
  • the compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin.
  • the carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
  • the creams and ointments may be viscous liquid or semi-solid emulsions of either the oil in water or water in oil type.
  • Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable.
  • a variety of occlusive devices may be used to realease the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
  • the dosage to be used in the treatment of a specific patient suffering from high density lipoprotein insufficiency must be subjectively determined by the attending physician.
  • Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter the dosage is increased until the optimum effect under the circumstances is reached. Precise dosages for oral or parenteral administration will be determined by the administering physician based on experience with the individual subject treated and standard medical principles.
  • the pharmaceutical composition is in unit dosage form, e.g., as tablets or capsules.
  • the composition is sub-divided in unit doses containing appropriate quantities of the active ingredient;
  • the unit dosage form can be packaged compositions, for example packed powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Emergency Medicine (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne le traitement de l'athérosclérose par l'augmentation du taux du HDL cholestérol grâce à l'administration d'un composé représenté par la formule (I), dans laquelle R?1, R2 et R3¿ représentent individuellement un hydrogène, un alkyle C¿1?-C6 ou un -(CH2)0-6Ph, où Ph représente un phényle éventuellement substitué par un halogène, un cyano, un nitro, un alkyle C1-C6, un alcoxy C1-C6, un trifluorométhyle, un alcoxycarbonyle C1-C6, un -CO2H, ou un OH; R4 et R5 représentent individuellement un hydrogène, un alkyle C1-C6; un cycloalkyle C3-C8, ou un -(CH2)0-6Ar?1, où Ar1¿ représente un phényle, un naphtyle, un furanyle, un pyridinyle ou un thiényle, et où Ar1 peut être éventuellement substitué par un halogène, un cyano, un nitro, un alkyle C¿1?-C6, un phényle, un alcoxy C1-C6, un phénoxy, un trifluorométhyle, un alcoxycarbonyle C1-C6, un -CO2H ou un OH; et Ar représente un phényle, un naphtyle, un furanyle, un pyridinyle ou un thiényle, ou Ar est éventuellement substitué par un halogène, un cyano, un nitro, un alkyle C1-C6, un phényle, un alcoxy C1-C6, un phénoxy, un trifluorométhyle, un alcoxycarbonyle C1-C6, un CO2H ou un OH.
PCT/US1998/010460 1997-06-16 1998-05-19 Augmentation du taux du hdl cholesterol par 4-[(aminothioxomethyl)hydrazono]-4-arylbutyle carbamates WO1998057927A1 (fr)

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AU75894/98A AU7589498A (en) 1997-06-16 1998-05-19 Elevation of hdl cholesterol by 4-{(aminothioxomethyl)hydrazono}-4-arylbutyl carbamates

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US87621097A 1997-06-16 1997-06-16
US08/876,210 1997-06-16

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7196089B2 (en) 2003-01-29 2007-03-27 Asterand Uk Limited EP4 receptor antagonists
US7417068B2 (en) 2003-10-16 2008-08-26 Asterand Uk Limited EP4 receptor antagonists
US8604055B2 (en) 2004-12-31 2013-12-10 Dr. Reddy's Laboratories Ltd. Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors
US9000007B2 (en) 2011-09-27 2015-04-07 Dr. Reddy's Laboratories Ltd. 5-benzylaminomethyl-6-aminopyrazolo [3, 4 -B] pyridine derivatives as cholesteryl ester-transfer protein (CETP) inhibitors useful for the treatment of atherosclerosis
US9040558B2 (en) 2004-12-31 2015-05-26 Dr. Reddy's Laboratories Ltd. Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors
US9199967B2 (en) 2011-08-18 2015-12-01 Dr. Reddy's Laboratories Ltd. Substituted heterocyclic amine compounds as cholestryl ester-transfer protein (CETP) inhibitors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0431321A1 (fr) * 1989-11-06 1991-06-12 Warner-Lambert Company Inhibiteurs d'Acat

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0431321A1 (fr) * 1989-11-06 1991-06-12 Warner-Lambert Company Inhibiteurs d'Acat

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J.M. CHAPMAN JR, LIPIDS, vol. 25, no. 7, 1990, pages 391 - 397, XP002080248 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7196089B2 (en) 2003-01-29 2007-03-27 Asterand Uk Limited EP4 receptor antagonists
US7507754B2 (en) 2003-01-29 2009-03-24 Asterand Uk Limited EP4 receptor antagonists
US7528157B2 (en) 2003-01-29 2009-05-05 Asterand Uk Limited EP4 receptor antagonists
US7858644B2 (en) 2003-01-29 2010-12-28 Asterand Uk Limited EP4 receptor antagonists
US7417068B2 (en) 2003-10-16 2008-08-26 Asterand Uk Limited EP4 receptor antagonists
US7569602B2 (en) 2003-10-16 2009-08-04 Asterand Uk Limited Furan derivatives as EP4 receptor antagonists
US8604055B2 (en) 2004-12-31 2013-12-10 Dr. Reddy's Laboratories Ltd. Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors
US9040558B2 (en) 2004-12-31 2015-05-26 Dr. Reddy's Laboratories Ltd. Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors
US9782407B2 (en) 2004-12-31 2017-10-10 Dr. Reddy's Laboratories Ltd. Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors
US9199967B2 (en) 2011-08-18 2015-12-01 Dr. Reddy's Laboratories Ltd. Substituted heterocyclic amine compounds as cholestryl ester-transfer protein (CETP) inhibitors
US9000007B2 (en) 2011-09-27 2015-04-07 Dr. Reddy's Laboratories Ltd. 5-benzylaminomethyl-6-aminopyrazolo [3, 4 -B] pyridine derivatives as cholesteryl ester-transfer protein (CETP) inhibitors useful for the treatment of atherosclerosis

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ZA985153B (en) 1999-12-13

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