WO2015191179A1 - Inhibiteurs de sécrétion de lipoprotéines basse densité de type tétrahydro-tétrazolo(1,5a)pyrimidine (ttp) dibsubstitués à petites molécules pour la prise en charge des maladies associées à des niveaux ldl sanguins élevés - Google Patents

Inhibiteurs de sécrétion de lipoprotéines basse densité de type tétrahydro-tétrazolo(1,5a)pyrimidine (ttp) dibsubstitués à petites molécules pour la prise en charge des maladies associées à des niveaux ldl sanguins élevés Download PDF

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Publication number
WO2015191179A1
WO2015191179A1 PCT/US2015/028730 US2015028730W WO2015191179A1 WO 2015191179 A1 WO2015191179 A1 WO 2015191179A1 US 2015028730 W US2015028730 W US 2015028730W WO 2015191179 A1 WO2015191179 A1 WO 2015191179A1
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WIPO (PCT)
Prior art keywords
ttp
compound
secretion
treatment
group
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PCT/US2015/028730
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English (en)
Inventor
Andrea Cuconati
Timothy M. Block
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Baruch S. Blumberg Institute
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Publication of WO2015191179A1 publication Critical patent/WO2015191179A1/fr

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • TTP tetrahydro-tetrazolo(l,5a)pyrimidine
  • Excess plasma lipid accumulation is one of the most common causes of disease in Western societies because they enhance risks for various cardiovascular and metabolic disorders such as hyperlipidemia, atherosclerosis, heart disease, and metabolic syndromes.
  • lipids are transported on lipoproteins that provide endogenously produced and dietary lipids to tissues.
  • Plasma lipid levels are controlled by lipoprotein assembly and their catabolism. Hence, reducing lipoprotein production is a useful approach to prevent or treat various cardiovascular and metabolic disorders.
  • Lipoproteins such as Low Density Lipoprotein (LDL) and Very Low Density
  • VLDL Lipoprotein
  • Apo B apolipoprotein B
  • MTP microsomal triglyceride transfer protein
  • compounds which inhibit MTP and/or otherwise inhibit ApoB secretion are useful in the treatment of hyperlipidemia, atherosclerosis, heart disease and other conditions related thereto. Such compounds are also useful in the treatment of other diseases or conditions in which, by inhibiting MTP and/or Apo B secretion, serum cholesterol and triglyceride levels may be reduced, such conditions may include hypercholesterolemia, hypertriglyceridemia, pancreatitis, and obesity (Wetterau et al., Science, 258, 999-1001, (1992), Wetterau et al., Biochem Biophys Acta, 875, 610-617 (1986), European patent application publication Nos. 0 584 446 A2, and 0 643 057 Al).
  • MTP inhibitors may be found in U.S. 5,712,279; 5,741,804; 5,968,950; and 6,121,283; PCT International Patent Application publications WO 96/40640, WO 97/43257, WO 98/27979, WO 99/33800 and WO 00/05201; and EP 584,446 B and EP 643,057 A.
  • LDL low density lipoprotein
  • the present invention provides a means to prevent LDL assembly and secretion by inhibiting the MTP protein using disubstituted tetrahydro-tetrazolo(l,5a)pyrimidine (TTP) compounds.
  • TTP disubstituted tetrahydro-tetrazolo(l,5a)pyrimidine
  • One embodiment of the present invention incorporates the use of TTP compounds identified by ELISA in a high-throughput screen from a library for compounds that inhibit surface antigen of the hepatitis B virus (HBsAg) secretion. While these compounds inhibit HBsAG secretion they also serve as a selective inhibitor of major LDL proteins such as
  • Apoliprotein B but not HDL Apolipoprotein Al.
  • TTP treatment results in the loss of recognition by conformation-specific HBsAg antibody, suggesting a change in conformation may be the same mechanism associated with inhibition of LDL. No compound-induced cytotoxicity was observed.
  • Another embodiment incorporates compounds associated with 7-(2-chloro-6-fluoro- phenyl)-5-(4-chloro-phenyl)-4,5,6,7-tetrahydro-tetrazolo(l,5a)pyrimidine compounds (see Formulas I through VI) (US2009/0088397 Ciconati et al.).
  • Another embodiment incorporates compounds associated with 7-(2-Chloro-6- fluorophenyl)-5-(4-chlorophenyl)-4,7-dihydro-[l,2,4]triazolo[l,5-a]pyrimidine compounds (see Formulas VII through XI) (US8,921,381 Xu et al.).
  • the present invention describes embodiments incorporating a pharmaceutical composition comprising an effective amount of a compound of formulas (I-XII) and a pharmaceutically acceptable carrier are disclosed for methods for reducing the level of Low Density Lipoprotein (LDL) and or Very Low Density Lipoprotein (VLDL) in individuals with hypercholesterolemia.
  • LDL Low Density Lipoprotein
  • VLDL Very Low Density Lipoprotein
  • Figure 1 Treatment of HepG2 and HepG.2.215 cells with 10.0 micromolar tetrazolo- and triazolo-pyrimidine inhibitors of HBsAg secretion causes reduction in secretion of
  • FIG. 1 Treatment with Triazolo-pyrimidine test compound (PBHVB-2-15) of UPA/SCID mice with humanized livers ("PXB mouse", produced by PhoenixBio Ltd, Japan) causes reduction in serum levels of Apolipoprotein B of Apolipoprotein Al in either cell line
  • FIG. 3 Treatment of HepG.2.215 cells with tetrazolo- and triazolo-pyrimidine inhibitors (10.0 micromolar PBHBV-001, 10.0 micromolar PBHBV-2-15, and 8, 4 and 2 micromolar HBF-0259) of HBsAg secretion did not induce endoplasmic reticulum stress and unfolded protein response (UPR) in HBsAg producing cells, as measured by induction of GRP78 expression.
  • UPR endoplasmic reticulum stress and unfolded protein response
  • Tunicamycin and Brefeldin A treatment for 24 hrs were positive controls for UPR induction.
  • Top figure GRP78 mRNA levels were measured over several days by quantitative reverse-transcription PCR; Bottom figure, GRP78 protein levels were determined by western blotting after 6 days of treatment as shown
  • Triazolo-pyrimidine test compound (PBHBV-2-15) does not cause body weight change during 14 days of twice-daily (BID) dosing, and is well-tolerated in UPA/SCID mice with humanized livers ("PXB mouse", produced by PhoenixBio Ltd, Japan).
  • the present invention relates to a method to prevent LDL assembly and secretion by inhibiting the MTP protein using TTP compounds.
  • One embodiment of the present invention incorporates an effective amount of a compound selected from Formulas I, II, III and mixtures thereof;
  • Ri-R6 are independently phenyl or Het, wherein each phenyl or Het is optionally substituted with at least one substituent independently selected from the group consisting of (C 1 _7)alkyl, (C 2 _
  • Xi-X 6 are independently a bond or a saturated or unsaturated alkylene group
  • R a and R b are each independently H, (C 1 _ 7 )alkyl, (C 3 _ 12 )cycloalkyl, (C 2 _ 7 )alkanoyl, (C 2 _ 7 )alkanoyloxy, or aryl, or R a and R b together with a nitrogen to which they are attached form a Het;
  • n 0, 1, or 2;
  • n 0, 1, 2, 3, or 4;
  • Another embodiment provides for an effective amount of a compound selected from Formulas IV, V, VI and mixtures thereof:
  • R 7 and Rg are independently phenyl or Het, wherein each phenyl or Het is optionally substituted with at least one substituent independently selected from the group consisting of (C 1 _ 7 )alkyl, (C 2-
  • X 7 and X 8 are independently a bond or a saturated or unsaturated alkylene group
  • R a and R b are each independently H, (C 1 _ 7 )alkyl, (C 3 _ 12 )cycloalkyl, (C 2 _ 7 )alkanoyl, (C 2 _ 7 )alkanoyloxy, or aryl, or R a and R b together with a nitrogen to which they are attached form a Het;
  • n 0, 1, or 2;
  • n 0, 1, 2, 3, or 4;
  • the compound is a compound of Formula VI when R y is methyl, p-MeOC 6 H 4 or p- BrOC 6 H 4 , Rg is unsubstituted phenyl, methyl, p-MeOC 6 H 4 , or p-BrOC 6 H 4 , and X 7 and Xg are each a single bond; and
  • the compound is a compound of Formula IV or VI when R y is H, Rg is an unsubstituted phenyl, p-MeOC 6 H 4 or p-BrOC 6 H 4 , and X 7 and X 8 are each a single bond.
  • One embodiment of the present invention is a pharmaceutical composition, wherein Ri and R 2 of Formula I are phenyl independently optionally substituted with at least one substitute independently selected from (C 1 _ 7 )alkyl, halo, and OR a .
  • a further embodiment (HBF-0259) of the invention is a compound wherein Xi and X 2 are each a bond and
  • Ri is and.
  • R-2 is
  • Another embodiment of the present invention incorporates an effective amount of compound selected from Formulas VII, VIII, IX, X, XI, XII and mixtures thereof;
  • Xi-X 12 are independently a bond or a saturated or unsaturated alkylene group
  • R a and R b are each independently H, (C 1 _ 7 )alkyl, (C 3 _ 12 )cycloalkyl, (C 2 _ 7 )alkanoyl, (C 2 _ 7 )alkanoyloxy, or aryl, or R a and R b together with a nitrogen to which they are attached form a Het;
  • n 0, 1, or 2;
  • n 0, 1, 2, 3, or 4;
  • R 13 is independently H, (C 1 - 7 )alkyl, (C 3 _ 12 )cycloalkyl, (C 2 _ 7 )alkanoyl, (C 2 _ 7 )alkanoyloxy, or aryl;
  • Methods for treating elevated VLDL/LDL levels in blood in a patient include the administration of an effective amount of a compound(s) from the present invention, together with a pharmaceutically acceptable carrier, that will reduce the serum level of VLDL/LDL in a patient.
  • a composition containing compounds from the present invention may be administered in any variety of suitable forms known in the art, for example, by inhalation, topically, parenterally, rectally, or orally.
  • a composition containing a compound of the present invention may be presented in forms permitting administration by the most suitable route.
  • the invention also relates to administering compositions containing a compound of the present invention which is suitable for use as a medicament in a patient.
  • These compositions may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients.
  • the adjuvants comprise, inter alia, diluents, serial aqueous media and the various non-toxic organic solvents.
  • the compositions may be presented in the form of oral dosage forms, or injectable solution, or suspensions.
  • aqueous suspensions When aqueous suspensions are used they may contain emulsifying agents or agents which facilitate suspension. Diluents such as sucrose, ethanol, polyols such as polyethylene glycol, propylene glycol and glycerol, and chloroform or mixtures thereof may also be used.
  • the compounds of the present invention may be incorporated into sustained-release preparations and formulations.
  • emulsions, suspensions or solutions of the compounds according to the invention in vegetable oil for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts
  • vegetable oil for example sesame oil, groundnut oil or olive oil
  • injectable organic esters such as ethyl oleate
  • sterile aqueous solutions of the pharmaceutically acceptable salts are used.
  • the injectable forms must be fluid to the extent that it can be easily syringed, and proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prolonged absorption of the injectable compositions can be brought about by use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersion can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils.
  • the aqueous solutions also comprising solutions of the salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilized by heating, irradiation, microfiltration, and/or by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • Sterile injectable solutions are prepared by incorporating the compounds in the required amount in the appropriate solvent with various amounts of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and the freeze drying technique, which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof.
  • Topical administration gels (water or alcohol based), creams or ointments containing the compounds be used.
  • the compounds may also be incorporated in a gel or matrix base for application in a patch, which would allow a controlled release of compound through transden-nal barrier.
  • the compounds may be dissolved or suspended in a suitable carrier for use in a nebulizer or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler.
  • the percentage of compound in the compositions used in the present invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time.
  • a dose employed may be determined by a physician or qualified medical professional, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient.
  • the doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation, from about 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from about 0.001 to about 10, preferably 0.01 to 10, mg/kg body weight per day by intravenous administration.
  • the doses are determined in accordance with the factors distinctive to the patient to be treated, such as age, weight, general state of health and other characteristics, which can influence the efficacy of the compound according to the invention.
  • the compounds used in the invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the compounds may be administered 1 to 4 times per day. Of course, for other patients, it will be necessary to prescribe not more than one or two doses per day. Examples of TTP treatment
  • Figure 1 demonstrates the ability of TTP compounds to inhibit secretion of both LDL and the surface antigen of the hepatitis B virus (HBsAg).
  • HBsAg hepatitis B virus
  • HbsAg particles exhibit a lipoprotein-like structure in which a compact phospholipid monolayer surrounds a more hydrophobic and fluid inner core, likely composed of triglycerides, fatty acids and sterol esters.
  • the HBsAg particle is similar to LDLs, differing only in the Apo B-100 location at the LDL surface with the S-proteins largely immersed in the lipid core.
  • HbsAg particles contain a larger quantity of protein (approximately 60% in mass) as compared to LDLs (20-25% in mass).
  • Figure 2 demonstrated a reduction in plasma levels of Apo B in a mouse model.
  • Panel A show Apo B plasma levels measure over 14 days in mice given 25 mg/kg or 75 mg/kg compared to control. Using both dosing regimens, Apo B levels were significantly reduced by day 7.
  • Figure 2, panel B confirms that Apo Al levels in mice does not change under the same conditions.
  • FIG. 3 panel A demonstrates results from the treatment of HepG.2.2.15 cells with the tetrazolo- and triazolo-pyrimidine (10.0 micromolar PBHBV-001, 10.0 micromolar PBHBV-2-15, and 8, 4 and 2 micromolar HBF-0259) which inhibits HBsAg Secretion but did not induce endoplasmic reticulum stress or an unfolded protein response (UPR) in HBSAg producing cells, measured through the induction of GRP78 expression.
  • Figure 3 panel B shows the induction of a UPR response with the treatment of Tunicamycin and Brefeldin A for 24 hours, demonstrating the ability of these same cells to elicit an unfolded protein response (UPR).
  • Figure 3 panel B on the top gel GRP78 mRNA levels were measure over several days by quantitative reverse transcription PCR).
  • Figure 3, panel B on the lower gel GRP78 protein levels were determined by western blotting after 6 days of treatment.
  • the Triazolo-pyrimidine compound (PBHBV-2-15) does not cause body weight change in mice during a 14 day dosing regimen of twice daily (BID) administration in UPA/SCID mice with humanized livers, see Figure 5.

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Abstract

Cette invention concerne un nouveau procédé d'inhibition de la sécrétion de la protéine microsomale de transfert des triglycérides (MTP) et/ou de l'apolipoprotéine B (ApoB) répondant aux Formules I à XI dans l'abaissement des lipides sériques et la prévention et le traitement des maladies associées. La régulation de la voie des VLDL/LDL à titre de moyen thérapeutique pour réduire l'hyperlipidémie est corroborée par des études portant sur des cellules hépatiques et sur un modèle animal. En conséquence, l'inhibition de la régulation ci-décrite est identifiée comme une nouvelle cible thérapeutique pour le traitement des maladies cardiovasculaires ou autres maladies associées aux maladies cardiovasculaires telles que l'hyperlipidémie. Le traitement des maladies cardiovasculaires et des états pathologiques ou maladies associés à l'aide de ces nouveaux inhibiteurs TTP selon l'invention permet de réduire la production des lipides associés à la protéine MTP sans les effets secondaires qui se produisent avec d'autres méthodes d'inhibition des lipides associés à la protéine MTP. De petites molécules (tétrahydro-tétrazolo(l,5a)pyrimidine (TTP) disubstituée) et leur procédé d'utilisation pour inhiber la sécrétion de l'ApoB et des LDL par cellules dérivées du foie en culture tissulaire et dans des modèles animaux sont en outre décrites. L'invention concerne également l'utilisation de ces petites molécules dans la prise en charge des maladies associées à des élévations de LDL circulants.
PCT/US2015/028730 2014-05-02 2015-05-01 Inhibiteurs de sécrétion de lipoprotéines basse densité de type tétrahydro-tétrazolo(1,5a)pyrimidine (ttp) dibsubstitués à petites molécules pour la prise en charge des maladies associées à des niveaux ldl sanguins élevés WO2015191179A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5883109A (en) * 1996-07-24 1999-03-16 Bristol-Myers Squibb Company Method for lowering serum lipid levels employing an MTP inhibitor in combination with another cholesterol lowering drug
US6066653A (en) * 1997-01-17 2000-05-23 Bristol-Myers Squibb Co. Method of treating acid lipase deficiency diseases with an MTP inhibitor and cholesterol lowering drugs
US20030203058A1 (en) * 1997-09-02 2003-10-30 The Ricex Company Method for treating hypercholesterolemia, hyperlipidemia, and atherosclerosis
US20090088397A1 (en) * 2006-05-04 2009-04-02 Andrea Cuconati Inhibitors of secretion of hepatitis b virus antigens for treatment of a chronic hepatitis virus
US20100297105A1 (en) * 2007-03-24 2010-11-25 Genzyme Corporation Administering antisense oligonucleotides complementary to human apolipoprotein b
US20130303552A1 (en) * 2010-10-04 2013-11-14 Institute For Hepalitis And Virus Research Novel inhibitors of secretion of hepatitis b virus antigens

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5883109A (en) * 1996-07-24 1999-03-16 Bristol-Myers Squibb Company Method for lowering serum lipid levels employing an MTP inhibitor in combination with another cholesterol lowering drug
US6066653A (en) * 1997-01-17 2000-05-23 Bristol-Myers Squibb Co. Method of treating acid lipase deficiency diseases with an MTP inhibitor and cholesterol lowering drugs
US20030203058A1 (en) * 1997-09-02 2003-10-30 The Ricex Company Method for treating hypercholesterolemia, hyperlipidemia, and atherosclerosis
US20090088397A1 (en) * 2006-05-04 2009-04-02 Andrea Cuconati Inhibitors of secretion of hepatitis b virus antigens for treatment of a chronic hepatitis virus
US20100297105A1 (en) * 2007-03-24 2010-11-25 Genzyme Corporation Administering antisense oligonucleotides complementary to human apolipoprotein b
US20130303552A1 (en) * 2010-10-04 2013-11-14 Institute For Hepalitis And Virus Research Novel inhibitors of secretion of hepatitis b virus antigens

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