WO2007075702A2 - Treatment of nonalcoholic fatty liver disease using cholesterol lowering agents and h3 receptor antagonist/inverse agonist - Google Patents

Treatment of nonalcoholic fatty liver disease using cholesterol lowering agents and h3 receptor antagonist/inverse agonist Download PDF

Info

Publication number
WO2007075702A2
WO2007075702A2 PCT/US2006/048455 US2006048455W WO2007075702A2 WO 2007075702 A2 WO2007075702 A2 WO 2007075702A2 US 2006048455 W US2006048455 W US 2006048455W WO 2007075702 A2 WO2007075702 A2 WO 2007075702A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
aryl
group
independently selected
substituted
Prior art date
Application number
PCT/US2006/048455
Other languages
French (fr)
Other versions
WO2007075702A3 (en
Inventor
Joyce J. Hwa
Margaret Van Heek
Harry Davis, Jr.
Original Assignee
Schering Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=37909708&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2007075702(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Schering Corporation filed Critical Schering Corporation
Priority to BRPI0620255-1A priority Critical patent/BRPI0620255A2/en
Priority to EP06845826A priority patent/EP1962835A2/en
Priority to CA002634940A priority patent/CA2634940A1/en
Priority to AU2006331770A priority patent/AU2006331770A1/en
Priority to JP2008547446A priority patent/JP2009521452A/en
Priority to MX2008008340A priority patent/MX2008008340A/en
Publication of WO2007075702A2 publication Critical patent/WO2007075702A2/en
Publication of WO2007075702A3 publication Critical patent/WO2007075702A3/en
Priority to NO20083235A priority patent/NO20083235L/en

Links

Classifications

    • 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Nonalcoholic fatty liver disease describes a spectrum of (iver diseases ranging from simple fatty liver (steatosis) to nonalcoholic steatohepatitis (NASH) with progressive fibrosis and liver failure.
  • NAFLD nonalcoholic steatohepatitis
  • hyperglycemia with or without evidence of hyperlipidemia is commonly associated with NAFLD.
  • the disease exhibits the histological features of alcohol-induced liver disease in patients who do not consume significant amounts of alcohol. All of the stages of NAFLD have in common the accumulation of fat in the liver cells. Farrell and Larter in Hepatology, 243:S99-S112 (2006) describe NASH as "the lynchpin" between hepatic steatosis and cirrhosis in the spectrum of NAFLD.
  • WO 2004/110368 describes combination therapies for the treatment of hypertension comprising the combination of an anti-obesity agent and an antihypertensive agent.
  • An alternative embodiment of this invention provide for the prevention or amelioration the symptoms or development of hepatic steatosis in a mammal in need thereof by administering at least one cholesterol lowering agent, e.g., a sterol abso ⁇ tion inhibitor, a 5- ⁇ -stanol abso ⁇ tion inhibitor or a HMG-CoA reductase inhibitor and/or at least one H 3 receptor antagonists/inverse agonist.
  • at least one cholesterol lowering agent e.g., a sterol abso ⁇ tion inhibitor, a 5- ⁇ -stanol abso ⁇ tion inhibitor or a HMG-CoA reductase inhibitor and/or at least one H 3 receptor antagonists/inverse agonist.
  • Fig. 3 depicts the effect of ezetimibe and the H 3 receptor antagonist/inverse agonist of Formula XIIIA on the levels of cholesterol ester in mice.
  • the wavy line ' ⁇ ⁇ as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (S)- stereochemistry.
  • the possible isomers e.g., containing (R)- and (S)- stereochemistry.
  • sterol abso ⁇ t ⁇ on inhibitor means a compound capable of inhibiting the absorption of one or more sterols, including but not limited to cholesterol, phytosterols (such as sitosterol, campesterol, stigmasterol and avenosterol), 5 ⁇ -stanols (such as cholestanol, 5 ⁇ -campestanol, 5 ⁇ -sitostanol), and/or mixtures thereof, when administered in a therapeutically effective (sterol and/or 5 ⁇ -stanol abso ⁇ tion inhibiting) amount to a mammal or human.
  • phytosterols such as sitosterol, campesterol, stigmasterol and avenosterol
  • 5 ⁇ -stanols such as cholestanol, 5 ⁇ -campestanol, 5 ⁇ -sitostanol
  • mixtures thereof when administered in a therapeutically effective (sterol and/or 5 ⁇ -stanol abso ⁇ tion inhibiting) amount to a mammal or human.
  • Ar 1 and Ar 2 are independently selected from the group consisting of aryl and
  • Ar is preferably R -substituted phenyl, more preferably (4-R )-substituted phenyl.
  • R 4 4 2 3 4 is (4-R )-substituted phenyl, R is preferably a halogen.
  • R is preferably halogen or -OR and R is preferably -OR , wherein R is lower alkyl or hydrogen. Especially preferred are
  • R and R are preferably -OR wherein R is hydrogen, or a group readily fi 9 6 7 metabolizable to a hydroxyl (such as -O(CO)R , -O(CO)OR and -O(CO)NR R , defined above).
  • m, n, p, q and r is preferably 2, 3 or 4, more preferably 3.
  • Preferred are compounds wherein m, n and r are each zero, q is 1 and p is 2.
  • Ar is phenyl or R -substituted phenyl and Ar is R - substituted phenyl. Also preferred are compounds in which Ar is phenyl or R -
  • Ar is phenyl or R -substituted phenyl, Ar is R -substituted phenyl, and the sum of m, n, p, q and r is 2, 3 or 4, more preferably 3. More preferred are
  • the compound of formula (II) can be in anhydrous or hydrated form.
  • a product containing ezetimibe compound is commercially available as ZETIA® ezetimibe formulation from MSP Pharmaceuticals.
  • Ar is R -substituted aryl
  • Ar is R -substituted aryl
  • Y and Z are independently selected from the group consisting of -CH 2 -, -CH(lower alkyl)- and -C(dilower alkyl)-;
  • R is 1 -3 substituents independently selected from the group consisting of -OR 6 , -O(CO)R 6 , -0(CO)OR 9 , -0(CH 2 ) ⁇ 5 OR 9 , -0(CO)NR 6 R 7 , -NR 6 R 7 , -NR 6 (CO)R 7 , - NR 6 (CO)OR 9 , -NR 6 (CO)NR 7 R 8 , -NR 6 SO 2 -lower alkyl, -NR 6 SO 2 -aryl, -CONR 6 R 7 , - COR 6 , -SO 2 NR 6 R 7 , S(0)o_ 2 -alkyl, SfO ⁇ -aryl, -0(CH 2 ) ⁇ 10 -COOR 6 , -0(CH 2 J 1 . ⁇ 7
  • Preferred compounds of formula III include those in which Ar is R 3 -substituted phenyl, especially (4-R )-substituted phenyl.
  • Ar is preferably R - substituted phenyl, especially (4-R )-substituted phenyl.
  • Ar is preferably R - 5 substituted phenyl, especially (4-R )-substituted phenyl.
  • Ar Ar , Ar and Ar is preferred.
  • R is hydrogen, or a group readily metabolizable to a hydroxyl (such as - fi Q R 7
  • R and R are preferably g independently hydrogen or lower alkyl, and R is preferably lower alkyl.
  • V is C 3 -C 6 cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6;
  • R is selected from: -CH-, -C(C 1 -C 6 alkyl)-, -CF-, -C(OH)-, -C(C 6 H 4 -R 9 )-, -N-, or- + NQ-
  • R and R are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C 1 -C ⁇ )alkyl,
  • R is hydrogen or (C 1 -C 6 )aIRyI
  • Q is a bond and R is lower alkylene, preferably propylene;
  • substituted azetidinones useful in the compositions, therapeutic combinations and methods of the present invention are represented by formula (V):
  • R 1 is -CH- or -C(OH)-
  • R 1 , R 2 , R 3 , R 1' , R 2 , and R 3' are independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, carboxy, NO2, NH2, OH, halogeno, lower alkylamino, dilower alkylamino, -NHC(O)OR 5 , R 6 ⁇ 2SNH- and -S(O)2NH2;
  • R 6 is OH, lower alkyl, phenyl, benzyl or substituted phenyl wherein the substituents are 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxy, carboxy, NO2, NH2, OH, halogeno, lower alkylamino and dilower alkylamino; or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • sterol absorption inhibitors useful in the compositions, therapeutic combinations and methods of the present invention are represented by formula (VIII):
  • R 26 is H or OG 1 ;
  • Ar 2 is aryl or R 1 1 -substituted aryl
  • M is -O-, -S-, -S(O)- or -S(O)2S
  • R 2 S is H, -OH or (Ci-C ⁇ )alkoxy.
  • T is independently selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;
  • R 3e is independently selected from the group consisting of H, unsubstituted alkyl, R ⁇ -substituted alkyl, unsubstituted cyctoalkyl and R ⁇ -substituted cycloalkyl;
  • R 37 and R 38 are each independently selected from the group consisting of (C 1 - C 6 )alkyl and aryl;
  • R26 is one to five substituents, each R 26 being independently selected from the group consisting of: a) H; b) -OH; c) -OCH 3 ; d) fluorine; e) chlorine; f) -O-G; g) -O-G 1 ; h) -O-G 2 ; i) -SO 3 H; and j) -PO 3 H; provided that when R 1 is H, R 26 is not H, -OH, -OCH 3 or -O-G;
  • M is -C-, -S-, -S(O)- or -S(O) 2 -;
  • R-IO and R ⁇ ⁇ are each independently selected from the group consisting of 1-3 substituents which are each independently selected from the group consisting of (Ci -
  • R 15 and R 17 are each independently selected from the group consisting of -OR 19 , -OC(O)R 19 , -OC(O)OR 21 , - OC(O)NR 19 R 20 ;
  • Ar 1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;
  • R 22 is H 1 (C 1 -C 6 )alkyl, aryl (C 1 -C 6 )alkyl, -C(O)R 19 or -COOR 19 ;
  • R 2 S is H, -OH or (C 1 -C 6 )alkoxy.
  • a more preferred compound is one represented by formula Xl:
  • azetidinone compounds include N-sulfonyl-2- azetidinones such as are disclosed in U.S. Patent No. 4,983,597, ethyl 4-(2- oxoazetidin-4-yl)phenoxy-alkanoates such as are disclosed in Ram et al., Indian J. Chem. Sect. B. 29B, 12 (1990), p. 1134-7, and diphenyl azetidtnones and derivatives disclosed in U.S. Patent Publication Nos. 2002/0039774, 2002/0128252, 2002/0128253 and 2002/0137689, and WO 2002/066464, each of which is incorporated by reference herein.
  • the compounds of formulae I-XII can be prepared by known methods, including the methods discussed above and, for example, WO 93/02048 describes the preparation of compounds wherein -R " ! -Q- is alkylene, alkenylene or alkylene interrupted by a hetero atom, phenylene or cycloalkylene; WO 94/17038 describes the preparation of compounds wherein Q is a spirocyclic group; WO 95/08532 describes the preparation of compounds wherein -R 1 -Q- is a hydroxy-substituted alkylene group; PCT/US95/03196 describes compounds wherein -R 1 -Q- is a hydroxy-substituted alkylene attached to the Ar 1 moiety through an -O- or S(O)0-2- group; and U.S.
  • Non-limiting examples of suitable cholesterol biosynthesis inhibitors include competitive inhibitors of HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis, squalene synthase inhibitors, squalene epoxidase inhibitors and mixtures thereof.
  • PPAR ⁇ regulates the metabolism of lipids.
  • PPAR ⁇ is activated by fibrates and a number of medium and long-chain fatty acids, and it is involved in stimulating ⁇ - oxidation of fatty acids.
  • the PPARy receptor subtypes are involved in activating the program of adipocyte differentiation and are not involved in stimulating peroxisome proliferation in the liver.
  • PPAR ⁇ has been identified as being useful in increasing high density lipoprotein (HDL) levels in humans. See, e.g., WO 97/28149.
  • fenofibrate such as TRICOR® micronized fenofibrate (2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoicacid, 1-methylethyl ester
  • TRICOR® micronized fenofibrate (2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoicacid, 1-methylethyl ester
  • LIPANTHYL® micronized fenofibrate which is commercially available from Labortoire Founier, France
  • These compounds can be used in a variety of forms, including but not limited to acid form, salt form, racemates, enanti ⁇ mers, zwitterions and tautomers.
  • Non-limiting examples of suitable PPARy activators include derivatives of glitazones or thiazolidinediones, such as, troglitazone; rosiglitazone (such as AVANDIA® rosiglitazone maleate (-5-[[4-[2-(methyl-2-pyridinylamino)ethoxy] phenyl] methyl]-2,4-thiazolidinedione-2-butenedioate) commercially available from SmithKline Beecham) and pioglitazone (such as ACTOSTM pioglitazone hydrochloride (5-[[4-[2-(5- ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-] thiazolidinedione monohydrochloride) commercially available from Takeda Pharmaceuticals).
  • troglitazone such as AVANDIA® rosiglitazone maleate (-5-[[4-[2-(methyl-2-pyridin
  • thiazolidinediones include ciglitazone, englitazone, darglitazone and BRL 49653 as disclosed in WO 98/05331 which is incorporated herein by reference; PPARy activator compounds disclosed in WO 00/76488 which is incorporated herein by reference; and PPARy activator compounds disclosed in U.S. Patent No. 5,994,554 which is incorporated herein by reference.
  • PPAR ⁇ compounds are useful for, among other things, lowering triglyceride levels or raising HDL levels.
  • PPAR ⁇ activators include suitable thiazole and oxazole derivatives, such as C.A.S. Registry No. 317318-32-4, as disclosed in WO 01/00603 which is incorporated herein by reference); certain fluoro, chtoro or thio phenoxy phenylacetic acids as disclosed in WO 97/28149 which is inco ⁇ orated herein by reference; suitable non- ⁇ -oxidizable fatty acid analogues as disclosed in U.S. Patent No. 5,093,365 which is inco ⁇ orated herein by reference; and PPAR ⁇ compounds as disclosed in WO 99/04815 which is incorporated herein by reference.
  • Non-limiting examples include certain substituted aryl compounds as disclosed in U.S. Patent No. 6,248,781; WO 00/23416; WO 00/23415; WO 00/23425; WO 00/23445; WO 00/23451; and WO 00/63153, all of which are inco ⁇ orated herein by reference, are described as being useful PPAR ⁇ and/or PPARy activator compounds.
  • PPAR ⁇ and/or PPARy activator compounds include activator compounds as disclosed in WO 97/25042 which is inco ⁇ orated herein by reference; activator compounds as disclosed m WO 00/63190 which is inco ⁇ orated herein by reference; activator compounds as disclosed in WO 01/21181 which is inco ⁇ orated herein by reference; biaryl-oxa(thia)zole compounds as disclosed in WO 01/16120 which is inco ⁇ orated herein by reference; compounds as disclosed in WO 00/63196 and WO 00/63209 which are incorporated herein by reference; substituted 5-aryl-2,4-thiazolidinediones compounds as disclosed in U.S. Patent No.
  • the methods of the present invention can further comprise nicotinic acid (niacin) and/or nicotinic acid receptor (“NAR”) agonists as lipid lowering agents.
  • nicotinic acid niacin
  • NAR nicotinic acid receptor
  • a total daily dosage of nicotinic acid can range from about 500 to about 10,000 mg/day, preferably about 1000 to about 8000 mg/day, and more preferably about 3000 to about 6000 mg/day in single or divided doses.
  • the total daily dosage of a NAR agonist can range from about 1 to about 100 mg/day/
  • compositions used in the methods of the present invention can further comprise one or more Cholesteryl Ester Transfer Protein ("CETP") Inhibitors coadministered with or in combination with the compound(s) of Formulae I-X discussed above.
  • CETP is responsible for the exchange or transfer of cholesteryl ester carrying HDL and triglycerides in VLDL.
  • the methods of the present invention can further comprise probucol or derivatives thereof (such as AGI-1067 and other derivatives disclosed in U.S. Patents Nos. 6,121 ,319 and 6,147,250), which can reduce LDL and HDL levels, as cholesterol lowering agents.
  • probucol or derivatives thereof such as AGI-1067 and other derivatives disclosed in U.S. Patents Nos. 6,121 ,319 and 6,147,250
  • a total daily dosage of LDL receptor activator(s) can range from about 1 to about 1000 mg/day in single or 2-4 divided doses.
  • the methods of the present invention can further comprise fish oil, which contains Omega 3 fatty acids (3-PUFA), which can reduce VLDL and triglyceride levels, as a lipid lowering agent.
  • a total daily dosage of fish oil or Omega 3 fatty acids can range from about 1 to about 30 grams per day in single or 2-4 divided doses.
  • the methods of the present invention can further comprise natural water soluble fibers, such as psyllium, guar, oat and pectin, which can reduce cholesterol levels.
  • natural water soluble fibers such as psyllium, guar, oat and pectin
  • a total daily dosage of natural water soluble fibers can range from about 0.1 to about 10 grams per day in single or 2-4 divided doses.
  • methods of the present invention can further comprise plant sterols, plant stanols and/or fatty acid esters of plant stanols, such as sitostanol ester used in BENECOL® margarine, which can reduce cholesterol levels.
  • a total daily dosage of plant sterols, plant stanols and/or fatty acid esters of plant stanols can range from about 0.5 to about 20 grams per day in single or 2-4 divided doses.
  • compositions, therapeutic combinations and methods of the present invention wherein at least one H 3 receptor antagonist/inverse agonist is a compound of the formula:
  • lower alkoxy e.g., Ci to C 6 alkoxy, preferably C 1 to C 4 alkoxy, most preferably Ci to C 2 alkoxy, more preferably methoxy
  • Z is a Ci - C 6 alkyl group
  • R 2 is a five or six-membered heteroaryl ring, said six-membered heteroaryl ring comprising 1 or 2 nitrogen atoms with the remaining ring atoms being carbon, and said five-membered heteroaryl ring containing 1 or 2 heteroatoms selected from: nitrogen, oxygen, or sulfur with the remaining ring atoms being carbon; said five or six membered heteroaryl rings being optionally substituted with 1 to 3 substituents independently selected from: halogen, hydroxyl, lower alkyl, lower alkoxy, -CF 3 , CF 3 O-, -NR 4 R 5 , phenyl, -NO 2 , -CO 2 R 4 , -CON(R 4 J 2 wherein each R 4 is the same or different, -0-!2NR 4 R 5 , -(N)C(NR 4 Rs) 2 , or -CN;
  • R 5 is selected from: hydrogen, Ci - C 6 alkyl, -C(O)R 4 , -C(O) 2 R 4 , or -C(O)N(R 4 J 2 wherein each R 4 is independently selected, and R 4 is as defined above;
  • Ri 3 is selected from: alkyl, hydroxyl, alkoxy, orfluoro;
  • n' is 1 , 2 or 3;
  • p' is 1 , 2 or 3, with the proviso that when M 3 and M 4 are both nitrogen, then p' is 2 or 3 (i.e., p' is not 1 when M 3 and M 2 are both nitrogen) is present in the therapeutic combinations.
  • Ri is preferably selected from:
  • substituted aryl e.g., substituted phenyl
  • substituents on said substituted aryl are most preferably selected from: (1) halo (e.g., monohalo or dihalo), more preferably chloro orfluoro, even more preferably monochloro, dichloro, monofluoro or difluoro; or (2) alkyl, more preferably u ⁇ branched (i.e., straight chain, e.g., methyl) alkyl, even more preferably substituted alkyl, still more preferably alkyl substituted with halo (e.g., 1 , 2 or 3 halo atoms, such as Cl or F), even still more preferably alkyl substituted with fluoro atoms, yet still more preferably trifluromethyl;
  • halo e.g., monohalo or dihalo
  • alkyl more preferably u ⁇ branched (i.e., straight chain, e.g., methyl) alkyl, even
  • heteroaryl most preferably a five or six membered heteroaryl ring, more preferably a six membered heteroaryl ring, and still more preferably pyridyl
  • heteroaryl rings include pyridyl, thienyl, pyrimidinyl, thiazolyl or pyridyl N- Oxide, most preferred heteroaryl rings are exemplified by
  • c' is most preferably 0 or 1 , and when c 1 is 1 then Re is most preferably halo, and when c' is 1 then R 6 is more preferably fluoro.
  • R 3 is preferably selected from H, alkyl or halo substituted alkyl (e.g., fluoro substituted alkyl, such as -CH 2 CF 3 ), most preferably alkyl, more preferably methyl or ethyl, and still more preferably methyl.
  • M 2 is nitrogen.
  • n' is preferably 2.
  • a' is preferably 0 or 1 , and most preferably 0.
  • b' is preferably 0 or 1, and most preferably 0.
  • c' is preferably 0 or 1, and most preferably 0, and when c is 1 then Re is preferably halo, and when c is 1 R 6 is most preferably fluoro.
  • e' is preferably 1-5.
  • M 3 and M 4 are preferably selected such that: (1) one is carbon and the other is nitrogen, or (2) both are nitrogen, with M 3 most preferably being carbon.
  • p' is preferably 2.
  • Z is preferably Ci to C 3 alkyl, and most preferably
  • R 3 is preferably H or alkyl, most preferably H or methyl.
  • R 4 is preferably H or lower alkyl, most preferably H or methyl, and more preferably H.
  • R 5 is preferably H, Ci to C 6 alkyl Or-C(O)R 4 , most preferably H or methyl, and more preferably H.
  • R 12 is preferably alkyl, hydroxyl or fluoro, and most preferably H.
  • R 13 is preferably alkyl, hydroxyl or fluoro, and most preferably H.
  • this invention provides for compositions, therapeutic combinations and methods of the present invention wherein at least one H 3 receptor antagonist/inverse agonist is a compound of the formula:
  • the dotted line represents an optional double bond
  • a' is 0 to 2
  • b' is 0 to 2
  • n' is 1 , 2 or 3
  • p 1 is 1, 2 or 3
  • r" is O, 1, 2, or 3; with the provisos that when M 2 is N, p 1 is not 1; and that when f is 0, M 2 is C(R3); and that the sum of p' and r" is 1 to 4;
  • M 1 is C(R 3 ) or N;
  • M 2 is C(R 3 ) or N;
  • X' is a bond or C 1 -C 6 alkylene
  • Z is a bond, C 1 -C 6 alkylene, C 1 -C 6 alkenylene, -C(O)-, -CH(CN)-, -SO 2 - or -CH 2 C(O)NR 4 -;
  • R 8 is H, C 1 -C 6 alkyl, halo(C 1 -C 6 )alkyl-, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl-, R 32 -aryl(C 1 - C 6 )alkyl-, R 32 -aryl, R 32 -heteroaryl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl-(C 1 -C 6 )alkyl l R 37 -heterocycloalkyl, N(R 30 )(R 3 i)-(C 1 -C 6 )alkyl- I R 29 -S(O) 2 -, halo(C 1 -C 6 )alkyl-S(O) 2 - > R 29 -S(0)o.i-(C 2 -C 6 )alkyl-, ha]o(C 1 -C 6 )alky
  • R 3 is H, halogen, C 1 -C 6 alkyl, -OH, (C 1 -C 6 )alkoxy or -NHSO 2 -(C 1 -C 6 )alkyl;
  • R 4 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, (C3-C 6 )cycloalkyl(C 1 -C 6 )alkyl, R 33 -aryl, R 33 -aryl(C 1 -C 6 )alkyl, and R 32 -heteroaryl;
  • R 5 is hydrogen, C 1 -C 6 alkyl, -C(O)R 20 , -C(O) 2 R 2 O, -C(O)N(R 20 ) 2 , (d-C 6 )alkyl- SO 2 -, or (C 1 -C 6 )aIkVl-SO 2 -NH-; or R 4 and R 5 , together with the nitrogen to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring; Re is 1 to 3 substituents independently selected from the group consisting of - OH, halogen, C 1 -C 6 alkyl-, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, -CF 3 , -NR 4 R 5 , -CH2-NR4R5. - NHSO2R22, -N(SO 2 R 2 2)2, phenyl, R 33 -
  • R 7 is -N(R 29 )-, -O- or-S(O)o- 2 -;
  • R 2 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, or aryl, wherein said aryl group is optionally substituted with from 1 to 3 groups independently selected from halogen, -CF 3 , -OCF 3 , hydroxyl, or methoxy; or when two R 20 groups are present, said two R 2 o groups taken together with the nitrogen to which they are bound can form a five or six membered heterocyclic ring;
  • R 22 is C 1 -C 6 alkyl, R 34 -aryl or heterocycloalkyl;
  • R 24 is H, C 1 -C 6 alkyl, -SO 2 R 2 or R 34 -aryl;
  • R 25 is independently selected from the group consisting of Ci-C 6 alkyl, halogen, -CN, -NO 2 , -CF 3 , -OH, C 1 -C 6 alkoxy, (C 1 -C 6 )alkyl-C(O)-, aryl-C(O)-, -C(O)OR 29 , - N(R 4 )(R 5 ), N(R 4 )(Rg)-C(O)-, N(R 4 )(R 5 )-S(O)i- 2 -, R 22 -S(O)o-2-, halo-(C 1 -C 6 )alkyl- or halo- (C 1 -C 6 )alkoxy- ⁇ C 1 -C 6 )alkyl-;
  • R29 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, R 3 5-aryl or R 35 -aryl(C 1 -C 6 )alkyl-;
  • R 30 is H, C 1 -C 6 alkyl-, R 35 -aryl or R 35 -aryl(C 1 -C 6 )alkyl-;
  • R 31 is H, C 1 -C 6 alkyl-, R 3 5-aryl, Rss-aryKC 1 -C 6 )alkyl-, R 35 -heteroaryl, (C 1 - C 6 )alkyl-C(O)-, R 35 -aryl-C(O)-, N(R 4 )(R 5 )-C(O)-, (C 1 -C 6 )alkyl-S(O) 2 - or R 3 5-aryl-S(O) 2 -; or R 30 and R 31 together are -(CH 2 J 4 - S -, -(CH 2 )2-O-(CH 2 ) 2 - or -(CH 2 ) 2 -N(R 38 )-(CH 2 ) 2 - and form a ring with the nitrogen to which they are attached; R 32 is 1 to 3 substituents independently selected from the group consisting of H 1 -OH, halogen, C 1 -C 6 alkyl, C 1
  • R 33 is 1 to 3 substituents independently selected from the group consisting of C 1 -C 6 alkyl, halogen, -CN, -NO 2 , -CF 3 , -OCF 3 , -OCHF 2 and -O-(d-C 6 )alkyl;
  • R 34 is 1 to 3 substituents independently selected from the group consisting of H, halogen, -CF 3 , -OCF 3 , -OH and -OCH 3 ;
  • R 36 is independently selected form the group consisting of H and C 1 -C 6 alkyl
  • R 38 is H, C 1 -C 6 alkyl, R 3 s-aryl, R 3 5-aryl(C 1 -C 6 )alkyl-, (C r C 6 )alkyl-SO 2 or halo(C 1 -C 6 )alkyl-SO 2 -;
  • R 39 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, (C 3 -C 6 )cycloalkyKC t -C 6 )alkyl, R 33 -aryl, R 33 -aryl(C 1 -C 6 )alkyl, and R 32 -heteroaryl; and
  • R 40 is hydrogen, C 1 -C 6 alkyl, -C(O)R 20 , -C(O) 2 R 2 O, -C(O)N(R 20 ) 2 , (C 1 -C 6 )alkyl- SO 2 -, or (C 1 -C 6 )alkyl-SO 2 -NH-; or R 39 and R AO , together with the nitrogen to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring.
  • this invention provides for compositions, therapeutic combinations and methods of the present inventions wherein the H 3 receptor antagonist /inverse agonist is a compound of the formula:
  • n' is 1 , 2 or 3;
  • p' is 1 , 2 or 3; rMs O, 1, 2, or3;
  • X' is a bond or C 1 -C 6 alkylene;
  • M 1 is CH or N;
  • M 2 is C(R 3 ) or N;
  • R 8 is H, C 1 -C 6 alkyl, haloid-C ⁇ alkyl-, (C 1 -QOalkoxy-fC ⁇ C 6 )alkyl-, R 32 -aryl(C 1 - C 6 )alkyl-, R 32 -aryl, R 32 -heteroaryl, R 32 -heteroaryl(C 1 -C 6 )alkyl-, (C 3 -C 6 )cycloalkyl, (C 3 - C 6 )cycloalkyl-(C 1 -C 6 )alkyl, R 37 -heterocycloalkyl, R 37 -heterocycloalkyl(C 1 -C 6 )alkyl, N(R 3 Q)(R 3 i)-(C 2 -C 6 )alkyl-, R 29 -S(O) 2 -, halo(C 1 -C 6 )alkyl-S(O) 2 -, R 29
  • VfV or heterocycloalkyl wherein said six-membered heteroaryl ring or said five- membered heteroaryl ring is optionally substituted by R 6 ;
  • R 3 is H, halogen, C 1 -C 6 alkyl, -OH or (C 1 -C 6 )alkoxy;
  • R 4 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, (Ca-C 6 )cycloalkyKC 1 -C 6 )alkyl, R 3 3-aryl, R 33 -aryl(C 1 -C 6 )alkyl, and R 33 -heteroaryl;
  • R 5 is hydrogen, C 1 -C 6 alkyl, -C(O)R 2 O, -C(O) 2 R 2 O, -C(O)N(R 20 ) 2 , R 33 ⁇ rVl(C 1 - C 6 )alkyl or (C-,-C 6 )alkyl-SO 2 -;
  • Re is 1 to 3 substituents independently selected from the group consisting of - OH, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -CF 3 , -NR 4 R 5 , -(C r C 6 )alkyl-NR 4 R 5 , phenyl, R 33 -phenyl, NO 2 , -CO 2 R 4 , -CON(R 4 ⁇ , -NHC(O)N(RO 2 , R 32 -heteroaryl-SO 2 -NH-, R 32 - aryHC-rC ⁇ alkyl-NH-, R 32 -heteroaryl-(C 1 -C 6 )alkyl-NH-, R 32 -heteroaryl-NH-C(O)-NH- and R 37 -heterocyclo-alkyl-N(R 29 )-C(O)-;
  • R 12 is independently selected from the group consisting of C 1 -C 6 alkyl, hydroxyl, C 1 -C 6 alkoxy, orfluoro, provided that when R 12 is hydroxy orfluoro, then R 12 is not bound to a carbon adjacent to a nitrogen; or R 12 forms a C 1 to C 2 alkyl bridge from one ring carbon to another ring carbon;
  • R 20 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, or aryl, wherein said aryl group is optionally substituted with from 1 to 3 groups independently selected from halogen, -CF 3 , -OCF 3 , hydroxyl, or methoxy; or when two R 2 o groups are present, said two R 20 groups taken together with the nitrogen to which they are bound can form a five or six membered heterocyclic ring;
  • F?22 is C 1 -C 6 alkyl, R34-aryl or heterocycloalkyl;
  • R24 is H, C1-C6 alkyl, -SO2R22 or R34-aryl;
  • R 25 is independently selected from the group consisting of C 1 -C 6 alkyl, halogen, -CF 3 , -OH, C 1 -C 6 alkoxy, (C 1 -C 6 )alkyl-C(O)-, aryl-C(O)-, N(R 4 )(Rs)-C(O)-, N(R 4 )(R 5 )- S(O)i- 2 -, halo-(C 1 -C ⁇ )alkyl- or halo-(C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl-;
  • R 30 is H, C 1 -C 6 alkyl-, R 35 -aryl or R 35 -aryl(C 1 -C 6 )alkyl-;
  • R 31 is H, C 1 -C 6 alkyl-, R 35 -aryl, R 35 -aryl(C 1 -C 6 )alk ' yl-, (C 1 -C 6 )alkyl-C(O)-, R 35 - aryl-C(O)-, N(R 4 )(Rg)-C(O)-, (C r C 6 )alkyl-S(O) 2 - or R 35 -aryl-S(O) 2 -; or R 30 and R 3 i together are -(CH2)4-5-. -(CH 2 ⁇ -O-(CH 2 V or — (CH2)2-N(R2g)-(CH2)2- and form a ring with the nitrogen to which they are attached;
  • R 32 is 1 to 3 substituents independently selected from the group consisting of H, -OH, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, R 35 -aryl-O-, -SR 22 , -CF 3 , -OCF 3 , -OCHF 2 , - NR 4 R 5 , phenyl, R 33 - ⁇ henyl, NO 2 , -CO 2 R 4 , -CON(R 4 J 2 , -S(O) 2 R 2 2, -S(O) 2 N(R 20 ⁇ , - N(R 24 )S(O) 2 R22, -CN, hydroxy-(C 1 -C 6 )alkyl-, -OCH 2 CH 2 OR 22 , and R 35 -aryl(C 1 -C 6 )alkyl- O-, wherein said aryl group is optionally substituted with 1 to 3 independently selected halogens;
  • R 33 is 1 to 3 substituents independently selected from the group consisting of C 1 -C 6 alkyl, halogen, -CN, -NO 2 , -OCHF 2 and -O-(C 1 -C ⁇ )alkyl;
  • Y 1 represents a direct bond from M 1 to M 2 ;
  • each R 11A is independently selected from: H, alkyl (e.g., i-propyl) or aryl (e.g., phenyl), preferably one R 11A is H and the other is phenyl or alkyl (e.g., i-propyl);
  • aryl or heteroaryl R 3 groups is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen (e.g., Br, F, or Cl, preferably F or Cl);
  • lower alkoxy e.g., Ci to C ⁇ alkoxy, preferably Ci to C 4 alkoxy, more preferably Ci to C 2 alkoxy, most preferably methoxy
  • cycloalkylalkyl e.g., cyclopropyl-CH 2 - or cyclohexyl-CH 2 -;
  • heterocycloalkylalky e.g., tetrahydrofuranyl-CH 2 -
  • aryl having a fused heterocycloalkyl ring bound to said aryl ring preferably the heteroatoms in said heterocycloalkyl ring are two oxygen atoms, e.g., phenyl having a heterocycloalkyl ring bound to said phenyl ring, such as
  • each R 12A is independently selected from phenyl or substituted phenyl, said substituted phenyl being substituted with 1 to 3 substituents independently selected from: halogen, -Oalkyl, -OCF 3 , -CF 3 , -CN, Or -NO 2 , e.g.,
  • each R 4B is independently selected from: H, heteroaryl (e.g., pyridyl), alkyl, alkenyl (e.g., allyl), a group of the formula
  • R 5 is selected from: hydrogen, C 1 -C 6 alkyl, -C(O) 2 O (e.g., -C(O)alkyl, such as -C(O)CH 3 ), -C(O) 2 R 20 , -C(O)N(R 20 ) 2 (wherein each R 2 o is the same or different);
  • R 13 forms an alkyl bridge from one ring carbon to another ring carbon
  • an example of such a bridged ring system is:
  • R 20 is selected from hydrogen, alkyl, or aryl, wherein said aryl group is optionally substituted with from 1 to 3 groups independently selected from: halogen, - CF 3 , -OCF 3 , hydroxyl, or methoxy; or when two R20 groups are present, said two R20 groups taken together with the nitrogen to which they are bound form a five or six membered heterocyclic ring;
  • R 22 is selected from: heterocycloalkyl (e.g., morpholinyl or pyrrolidinyl), alkyl or aryl, wherein said aryl group is optionally substituted with 1 to 3 groups independently selected from halogen, -CF 3 , -OCF 3 , hydroxyl, or methoxy;
  • heterocycloalkyl e.g., morpholinyl or pyrrolidinyl
  • alkyl or aryl wherein said aryl group is optionally substituted with 1 to 3 groups independently selected from halogen, -CF 3 , -OCF 3 , hydroxyl, or methoxy
  • (P) R24 is selected from: hydrogen, alkyl, -SO2R22. or aryl, wherein said aryl group is optionally substituted with 1 to 3 groups independently selected from halogen, -CF 3 , -OCF 3 , hydroxyl, or methoxy;
  • (Q) a' is 0 to 2;
  • (R) b" is 0 to 2;
  • (S) k' is 1 to 5;
  • n' is 1 , 2 or 3 with the proviso that when M 1 is N, then n' is not 1 ;
  • (V) p' is 1 , 2 or 3 with the proviso that when M 2 is N, then p' is not 1 ;
  • compositions, therapeutic combinations and methods of the present invention wherein at least one at least one H 3 receptor antagonist/inverse agonist is a compound of formula XVII:
  • the dotted line represents an optional double bond
  • a' is 0 to 3,- b' is 0 to 3
  • n' is 1 , 2 or 3
  • p' is 1 , 2 or 3
  • r 1 is O, 1, 2, or 3; with the provisos that when M 2 is N, p' is not 1 ; and that when r' is 0, M 2 is C; and that the sum of p' and r" is 1 to 4;
  • A' is a bond or C 1 -C 6 alkylene
  • M 1 is CH or N
  • R 2 is a six-membered heteroaryl ring having 1 or 2 heteroatoms independently selected from N or N-O, with the remaining ring atoms being carbon; a five-membered heteroaryl ring having 1 , 2 or 3 heteroatoms independently selected from N, O or S, with the remaining ring atoms being carbon; R 32 -quinolyl; R 32 -aryl; heterocycloalkyl; wherein said six-membered heteroaryl ring or said five-membered heteroaryl ring is optionally substituted by R 6 ;
  • X' is C or N
  • Q' is a bond or C 1 -C 6 alkylene
  • Q 1' is a bond, C 1 -C 6 alkylene or -N(R 4 )-;
  • R 3 is H, halogen, C 1 -C 6 alkyl, -OH or (C 1 -C 6 )alkoxy;
  • R 4 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, R 33 -aryl, R33-aryl(C 1 -C6)alkyl, and R 32 -heteroaryl;
  • R 5 is hydrogen, C 1 -C 6 alkyl, -C(O)R 20 , -C(O) 2 R20. -C(0)N(R 2 o)2 or (C 1 -C 6 )alkyl-SO 2 -;
  • R 6 is 1 to 3 substituents independently selected from the group consisting of - OH, halogen, C 1 -C 6 alkyl-, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, -CF 3 , -NR 4 R 5 , phenyl, R 33 - phenyl, NO 2 , -CO 2 R 4 , -CON(R 4 ) 2>
  • Ri 2 is independently selected from the group consisting of C 1 -C 6 alkyl, hydroxyl, C 1 -C 6 alkoxy, or fluoro, provided that when R 12 is hydroxy or fluoro, then Ri 2 is not bound to a carbon adjacent to a nitrogen; or R 12 forms a C 1 to C 2 alkyl bridge from one ring carbon to another ring carbon;
  • R 20 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, or aryl, wherein said aryl group is optionally substituted with from 1 to 3 groups independently selected from halogen, -CF 3 , -OCF 3 , hydroxyl, or methoxy; or when two R 20 groups are present, said two R 2 o groups taken together with the nitrogen to which they are bound form a five or six membered heterocyclic ring;
  • R2 2 is C 1 -C 6 alkyl, R 34 -aryl or heterocycloalkyl;
  • R 25 is independently selected from the group consisting of C 1 -C 6 alkyl, halogen, -CF 3 , -OH 1 C 1 -C 6 alkoxy, (C 1 -C 6 )alkyl-C(O)-, aryl-C(O)-, N(R 4 )(Rs)-C(O)-, N(R 4 )(R 5 )- S(O)i- 2 -, halo-(C 1 -C 6 )alkyl- or halo-(C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl-;
  • R 29 is H, C 1 -C 6 alkyl, R 35 -aryl or R 35 -aryl(Ct-C6)alkyl-;
  • R 30 is H, C 1 -C 6 alkyl-, R 35 -aryl or R 35 -BIyI(C 1 -C 6 )alkyl-;
  • R 31 is H, C 1 -C 6 alkyl-, R 35 -aryl, Rss-aryKC 1 -C 6 )alkyl-, (C 1 -C 6 )alkyl-C(O)-, R 35 - aryl-C(O)-, N(R 4 )(Rs)-C(O)-, (C 1 -C ⁇ )alkyl-S(O) 2 - or R 35 -aryl-S(O) 2 -; or R 30 and R 31 together are -(CH 2 ) ⁇ s-. -(CH 2 )2-O-(CH 2 ) 2 - or -(CH 2 )2-N(R29)-(CH 2 )2- and form a ring with the nitrogen to which they are attached;
  • R 32 is 1 to 3 substituents independently selected from the group consisting of H, -OH, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, R 35 -aryl-O-, -SR22, -CF 3 , -OCF 3 , -OCHF 2 , - NR 4 R 5 , phenyl, R 33 -phenyl, NO 2 , -CO 2 R 4 , -CON(R 4 J 2 , -S(O) 2 R 22 , -S(O) 2 N(R 2 O) 2 , - N(R 24 )S(O) 2 R 22 , -CN, hydroxy-(C 1 -C 6 )alkyl-, -OCH 2 CH 2 OR 22 , and R 35 -aryl(C-rC 6 )alkyl- O-, wherein said aryl group is optionally substituted with 1 to 3 independently selected halogens;
  • R 33 is 1 to 3 substituents independently selected from the group consisting of C 1 -C 6 alkyl, halogen, -CN, -NO 2 , -OCHF 2 and -O-(C 1 -C ⁇ )alkyl;
  • R 34 is 1 to 3 substituents independently selected from the group consisting of H, halogen, -CF 3 , -OCF 3 , -OH and -OCH 3 .
  • R 35 is 1 to 3 substituents independently selected from hydrogen, halo, C 1 -C 6 alkyl, hydroxy, C 1 -C 6 alkoxy, phenoxy, -CF 3 , -N(R 36 )2, -COOR2 0 and -NO 2 ;
  • R 36 is independently selected form the group consisting of H and C 1 -C 6 alkyl.
  • the more preferred compound of formula XVII include the following compounds:
  • R 1 is preferably R-substituted benzimidazolone, wherein R is preferably H, alkyl, alkoxyalkyl, R 32 -aryl, R 3 2-heteroaryl or heterocycloalkylalkyl. More preferably, R is -CH 3 , phenyl, 4-fluorophenyl, CH 3 -O-(CH 2 J 2 -,
  • F? 25 is preferably halogen or -CF 3 and k is 0 or 1.
  • Ri is an aza- or diaza derivative of benzimidazolone
  • R is preferably as defined for benzimidazolone, and ki and k 2 are preferably zero.
  • R 2 is preferably a six-rnembered heteroaryl ring, optionally substituted with one substituent. More preferably, R2 is pyridyl, pyrimidinyl or pyridazinyl, each optionally substituted with halogen or -NR 4 R 5 , wherein R 4 and R 5 are independently selected from the group consisting of H and or R 4 and R 5 together with the nitrogen to which they are attached form a pyrrolidinyl, piperidinyl or morpholinyl ring.
  • A' is preferably a bond.
  • Y 1 is preferably -C(O)-.
  • Z' is preferably straight or branched C 1 -C 3 alkyl.
  • M 1 is preferably N; a' is preferably 0; and n' is preferably 2; the optional double bond is preferably not present (i.e., a single bond is present).
  • M 2 is preferably C(Ra) wherein R 3 is hydrogen or halogen, especially fluorine; b" is preferably 0; r" is preferably 1 ; and p' is preferably 2.
  • H 3 receptor antagonists/inverse agonists are disclosed in U.S. Provisional Application Ser. Nos. 60/692,110 and 60/692,175, both filed on June 20, 2005, U.S. 2002/183309, 2002/177589, 2002/111340, 2004/0122033, 2003/0186963, 2003/0130253, 2004/0248938, 2002/0058659, 2003/0135056, 2003/134835, 2003/153548, 2004/0019099, 2004/0097483, 2004/0048843, 2004/087573, 2004/092521 , 2004/214856, 2004/248899, 2004/224953, 2004/224952, 2005/222151 , 2005/222129, 2005/182045, 2005/171181, 6,620,839, 6,515,013, 6,559,140, 6,316,475, 6,166,060, 6,448,282, 6,008,240, 5,652,258, 6,417,218, 6,673,829, 6,756,384, 6,437,147,
  • compositions, therapeutic combinations or methods of the present invention can further comprise one or more obesity control medications.
  • Useful obesity control medications include, but are not limited to, drugs that reduce energy intake or suppress appetite, drugs that increase energy expenditure and nutrient- partitioning agents.
  • Suitable obesity control medications include, but are not limited to, noradrenergic agents (such as diethylpropion, mazindol, phenylpropanolamine, phentermine, phendimetrazine, phendamine tartrate, methamphetamine, phendimetrazine and tartrate); CB1 receptor antagonists (such as rimonabant); topiramate; serotonergic agents (such as sibutramine, fenfluramine, dexfenfluramine, fluoxetine, fluvoxamine and paroxtine); thermogenic agents (such as ephedrine, caffeine, theophylline, and selective ⁇ 3-adrenergic agonists); an alpha-blocking agent; a ka
  • Preferred therapeutic combinations that may be used in the methods according to the present invention include combinations comprising at least one cholesterol lowering agent, such as a sternol or 5- ⁇ -stanol according to formulae I-IV and/or an HMG-CoA reductase inhibitor, and at least one H 3 receptor antagonist/inverse agonist, such as those according to formulae XIII to XVII.
  • Especially preferred combinations include ezetimibe and/or simvastatin as the cholesterol lowering agents, a compound of formula XUIA-XIIIC, and orlistat.
  • a total dosage of the above-described obesity control medications can range from 1 to 3,000 mg/day, desirably from about 1 to 1 ,000 mg/day and more desirably from about 1 to 200 mg/day in single or 2-4 divided doses.
  • Another embodiment of the present invention is therapeutic combinations comprising two cholesterol lowering agents and an hfe receptor antagonist/inverse agonist.
  • Preferred combinations include cholesterol absorption inhibitors, such as those described in formulae I to XII 1 and an HMG-CoA reductase inhibitor, PPAR activators, nicotinic acid (niacin) and/or nicotinic acid receptor agonists, or a bile acid sequestrant.
  • Preferred HMG-CoA reductase inhibitors include lovastatin, pravastatin, fluvastatin, simvastatin atorvastatin, cerivastatin, CI-981 , pravastatin and rosuvastatin.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Molecular Biology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

This invention provides for method for the treatment, prevention or ameliorating the symptoms of nonalcoholic fatty liver disease (NAFLD) in a mammal in need thereof comprising the step of administering an effective amount of a composition comprising a therapeutic combination of at least one cholesterol lowering agent and/or at least one H3 antagonist/inverse agonist.

Description

TREATMENT OF NONALCOHOLIC FATTY LIVER DISEASE
USING CHOLESTEROL LOWERING AGENTS AND/OR H3 RECEPTOR
ANTAGONIST/INVERSE AGONIST
FIELD OF THE INVENTION
The present invention relates to a method for treating nonalcoholic fatty liver disease in a mammal by administering an effective amount of therapeutic composition comprising at least one cholesterol lowering agent and/or at least one H3 receptor antagonist/inverse agonist.
RELATED APPLICATION
This application claims the benefit to provisional application USSN 60/855,178 filed October 30, 2006, provisional application USSN 60/752,710, filed December 21 , 2005, provisional application USSN 60/787,048, filed March 29, 2006, and provisional application USSN 60/836,642, filed August 9, 2006, all herein incorporated by reference.
BACKGROUND OF THE INVENTION
Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of (iver diseases ranging from simple fatty liver (steatosis) to nonalcoholic steatohepatitis (NASH) with progressive fibrosis and liver failure. Hyperglycemia with or without evidence of hyperlipidemia is commonly associated with NAFLD. The disease exhibits the histological features of alcohol-induced liver disease in patients who do not consume significant amounts of alcohol. All of the stages of NAFLD have in common the accumulation of fat in the liver cells. Farrell and Larter in Hepatology, 243:S99-S112 (2006) describe NASH as "the lynchpin" between hepatic steatosis and cirrhosis in the spectrum of NAFLD. See also, Palekar, et al., Liver int., 26(2): 151-6 (2006). In NASH, the fat accumulation of associated with varying degrees of inflammation and fibrosis. Conditions most commonly associated with NAFLD are obesity, type 2 diabetes and metabolic syndrome. US Publication No. 2004/29805 describes a method for preventing or treating NAFLD by administering an agent that antagonizes the receptor to glucose-dependent insulinotropic polypeptide. Yamagishi et al. advance a hypothesis that ezetimibe might be a new therapeutic approach for the treatment of NAFLD (Medical Hypotheses, 66, pp.844-846 (2006) ) (available on line in September 2005).
Treatments for NASH include diet and exercise and/or administering probucol, clofribrate, gemfibrozil, betaine, vitamins E and/or C, metformin, toglitaxone, rosiglitazone or plogitazone and vitamin E. M. Charlton, Clinical Gastroenterology and Hepatology, 2(12), 1048-56 (2004); P. Portincaso et al., Clinical Biochemistry, 38, 203-17 (2005). US Publication No. 2004/105870A1 describes a treatment for NASH which comprises administering a formulation comprising dietary lecithin supplement, vitamin B complex or an antioxidant. US Publication Nos. 2005/0032823A1 and 2004/0102466A1 describe pyrimidine derivatives, which are selective COX-2 inhibitors, as useful in treating NASH. Other compounds for the treatment of fatty liver disease are described in US Publication No. 2005/0004115A1. There is no mention of cholesterol absorption inhibitors or H3 receptor antagonists/inverse agonist as being useful in treating NAFLD or NASH.
Beltroy et al. (Abstract, American College of Gastroenterology Meeting, 2004) discuss the effect of ezetimibe treatment on Niemann-Pick type C mice. These mice have elevated liver enzymes (ACT and AST) and steatosis and, therefore, have steato hepatitis. Beltroy et al. indicate that ezetimibe treatment reduced hepatic cholesterol accumulation and improved histological abnormalities and liver enzymes.
Compounds that inhibit cholesterol absorption in the small intestine are well known in the art and are described, for example, in US RE 37,721; US 5,631,356; US 5,767,115; US 5,846,966; US 5,698,548; US 5,633,246; US 5,656,624; US 5,624,920; US 5,688,787; US 5,756,470; US Publication No. 2002/0137689; WO 02/066464; WO 95/08522 and WO96/19450. Each of the aforementioned publications is incorporated by reference. The art indicates that these compounds are useful in treating, for example, atherosclerotic coronary disease, either by administrating these compounds alone or with a second compound such as a cholesterol biosynthesis inhibitor. These documents do not indicate that these inhibitors are useful in treating NAFLD. U.S. Patents Nos. 5,846,966 and 5,661 ,145, respectively, disclose treatments for inhibiting atherosclerosis and reducing plasma cholesterol levels using such hydroxy-substituted azetidinone compounds or substituted β-lactam compounds in combination with HMG-CoA reductase inhibitor compounds, which act by blocking hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase (the rate-limiting enzyme in hepatic cholesterol synthesis). HMG-CoA reductase inhibitors, e.g., statins such as lovastatin, simvastatin, and pravastatin, slow the progression of atherosclerotic lesions in the coronary and carotid arteries. Simvastatin and pravastatin have also been shown to reduce the risk of coronary heart disease events in patients with hypercholesterolemia and/or atherosclerotic coronary heart disease (CHD).
Simvastatin is marketed worldwide, and sold in the U.S. under the tradename ZOCOR®. Methods for making it are described in U.S Patent Nos. 4,444,784; 4,916,239; 4,820,850; among other patent and literature publications.
H3 receptor antagonists/inverse agonists are well known in the art. H3 receptor sites are found on sympathetic nerves, where they modulate sympathetic neurotransmission and attenuate a variety of end organ responses under control of the sympathetic nervous system. Specifically, H3 receptor activation by histamine attenuates norepinephrine outflow to resistance and capacitance vessels, causing vasodilation. H3 receptor antagonists/inverse agonists are known to treat : allergy, allergy-induced airway (e.g., upper airway) responses, congestion (e.g., nasal congestion), hypotension, cardiovascular disease, diseases of the Gl tract, hyper and hypo motility and acidic secretion of the gastro-intestinal tract, obesity, sleeping disorders (e.g., hypersomnia, somnolence, and narcolepsy), disturbances of the central nervous system, attention deficit hyperactivity disorder (ADHD), hypo and hyperactivity of the central nervous system (for example, agitation and depression), and/or other CNS disorders (such as Alzheimer's, schizophrenia, and migraine) in a patient such as a mammal. These compounds are particularly useful for treating allergy, allergy-induced airway responses and/or congestion.
WO 95/14007 published May 26, 1995 and incorporated by reference discloses H3 receptor antagonists of the imidazole type.
WO99/24405 and incorporated by reference published May 20, 1999 discloses H3 receptor ligands of the imidazole type. U.S. Patent 6,720,328 B1, issued on April 13, 2004 and incorporated by reference, discloses non-imidazole H3 receptor antagonists. U.S. Publication US 2004/0019099, published on January 29, 2004 and incorporated by reference, discloses indole derivatives that are H3 receptor antagonists. U.S. Publication US 2004/0048843A1 , published on March 11 , 2004 and incorporated by reference, and U.S. Publication US 2004/0097483A1 , published on May 20, 2004 and incorporated by reference, disclose benzimidazole derivatives as H3 antagonists. Piperidine compounds that are H3 antagonists are disclosed in U.S. Patent 6,849,621 ; this document issued on February 1 , 2005 and is incorporated by reference.
WO 2004/110375 describes a combination therapy for the treatment of diabetes wherein the combination comprises an anti-obesity agent, such as an H3 receptor antagonist/inverse agonist and an anti-diabetic agent. The publication indicates that other pharmaceutical agents including anti-dislipidemic agents, such as bile acid sequestrants and cholesterol absorption inhibitors, such as azetidinones, may be included.
US 5,869,479 discloses compositions for the treatment of the symptoms of allergic rhinitis using a combination of at least one histamine H1 receptor antagonist and at least one histamine H3 receptor antagonist.
WO 2004/110368 describes combination therapies for the treatment of hypertension comprising the combination of an anti-obesity agent and an antihypertensive agent.
WO 2005/000217 describes combination therapies for the treatment of dyslipidemia comprising the administration of a combination of an anti-obesity agent and an anti-dysiipidemic agent.
WO 2004/110375 describes combination therapies for the treatment of diabetes comprising the administration of a combination of an anti-obesity agent and an anti-diabetic agent.
US 2004/0122033 describes combination therapies for the treatment of obesity comprising the administration of a combination of an appetite suppressant and/or metabolic rate enhancers and/or nutrient absorption inhibitors. US 2004/0229844 describes combination therapies for treating atherosclerosis comprising the administration of a combination of nicotinic acid or another nicotinic acid receptor agonist and a DP receptor antagonist. U.S. 6,437,147, 6,756,384, and 2003/0135056 describe combinations of imidazo heterocyclic compounds which bind to the H3 receptor with antiobesity agents or appetite regulating agents, including sibutramine, phentermine, topiramate, lovastatin, pravastatin, and simvastatin. SUMMARY OF THE INVENTION
The present invention provides for a method for the treatment, prevention or ameliorating the symptoms of nonalcoholic fatty liver disease (NAFLD) in a mammal in need thereof by administering an effective amount of a composition comprising at least one cholesterol lowering agent, e.g., a sterol absorption inhibitor, a 5-α-stanol absoφtion inhibitor or a HMG-CoA reductase inhibitor and/or at least one H3 antagonist/inverse agonist.
An alternative embodiment of this invention provide for the prevention or amelioration the symptoms or development of hepatic steatosis in a mammal in need thereof by administering at least one cholesterol lowering agent, e.g., a sterol absoφtion inhibitor, a 5-α-stanol absoφtion inhibitor or a HMG-CoA reductase inhibitor and/or at least one H3 receptor antagonists/inverse agonist.
Another embodiment of this invention also provides for the prevention or amelioration of the development of nonalcoholic steatohepatitis (NASH) in a mammal by administering an effective amount of a therapeutic combination comprising at ieast one cholesterol lowering agent, e.g., a sterol absoφtion inhibitor, a 5-α-stanol absoφtion inhibitor or an HMG-CoA reductase inhibitor and/or at least one H3 receptor antagonist/inverse agonist.
A further embodiment of this invention provides for the prevention or amelioration of the development of cirrhosis and heptacellular carcinoma in a mammal by administering an effective amount of a therapeutic combination comprising at least one cholesterol lowering agent, e.g., a sterol absoφtion inhibitor, a 5-α-stanol absoφtion inhibitor or an HMG-CoA reductase inhibitor and/or at least one H3 receptor antagonist/inverse agonist to said mammal. >
Another embodiment of this invention provides for a method for the treatment, prevention or ameliorating the symptoms of NAFLD or NASH in a mammal in need thereof by administering an effective amount of a composition comprising, in addition to at least cholesterol lowering agent, e.g., a sterol absorption inhibitor, a 5-α-stanol absoφtion inhibitor or an HMG-CoA reductase inhibitor, and/or at least one H3 antagonist/inverse agonist, an antiobesity agent.
The present invention also relates to a kit for the treatment, prevention or amelioration of the symptoms of NAFLD which comprises at least one cholesterol lowering agent and/or at least one H3 receptor/inverse agonist in separate form.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 depicts the effect of ezetimibe and the H3 receptor antagonist/inverse agonist of Formula XIiIA on liver to body weight ratio in mice.
Fig. 2 depicts the effect of ezetimibe and the H3 receptor antagonist/inverse agonist of Formula XIIIA on the levels of liver triglycerides in mice.
Fig. 3 depicts the effect of ezetimibe and the H3 receptor antagonist/inverse agonist of Formula XIIIA on the levels of cholesterol ester in mice.
Fig. 4 depicts the effect of ezetimibe and the H3 receptor antagonist/inverse agonist of Formula XlIIA on the levels of free cholesteryl in mice.
Fig. 5 depicts the effect of ezetimibe and the H3 receptor antagonist/inverse agonist of Formula XIIID on plasma alanine aminotransferase (ALT) enzyme activities in mice.
Fig. 6 depicts the effect of ezetimibe on liver to body weight ratio in mice.
Fig. 7 depicts the effect of ezetimibe on the levels of liver triglycerides in mice.
Fig. 8 depicts the effect of ezetimibe on the levels of cholesteryl ester in mice.
Fig. 9 depicts the effect of ezetimibe on the levels of free cholesterol in mice.
DETAILED DESCRIPTION
The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims: Chemical names, common names and chemical structures may be used interchangeably to describe that same structure. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of "alkyl" applies to "alkyl" as well as the "alkyl" protion of "hydroxyalkyl", "haloalkyl", "alkoxy" etc. As used above, and throughout the specification, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
"Patient" includes both human and animals.
"Mammal" means humans and other mammalian animals.
"Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain which may be optionally substituted with groups, such as, for example, hydroxy), cyano, halo, alkoxy, aryloxy, heteroaryl heteroxy, -C(O)OH, -C(O)Oalkyl, N3, amino, dialkylamino, . alkylamino, NO2 mercapto, alkylthio, cycloalkyl and the like. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl and decyl. Non-limiting examples of suitable substituted alkyl groups include fluoromethyl, trifluoromethyl and cyclopropylmethyl .
"Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon- carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyi chain. "Lower alkenyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut- 2-enyl, n-pentenyl, octenyl and decenyl.
"Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon- carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl, 3- methylbutynyl, n-pentynyl, and decynyl.
"Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more substituents , which may be the same or different, and are as defined herein or two substituents on adjacent
carbons can be linked together to form r ' S*"θ
Figure imgf000010_0001
Non-limiting examples of suitable aryl groups include phenyl and naphthyl.
"Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one to four of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more substituents, which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non- limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazoiyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1 ,2-aJpyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4- triazinyl, benzothiazolyl and the like.
"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more substituents which may be the same or different, and are as defined herein. Non-limiting examples of suitable monocyclic cycioalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non- limiting examples of suitable multicyclic cycioalkyls include 1-decalin, norbomyl, adamantyl and the like. Further non-limiting examples of cycloalkyl include the following:
Figure imgf000011_0001
"Cycloalkylether" means a non-aromatic ring of 3 to 7 members comprising an oxygen atom and 2 to 7 carbon atoms. Ring carbon atoms can be substituted, provided that substituents adjacent to the ring oxygen do not include halo or substituents joined to the ring through an oxygen, nitrogen or sulfur atom.
"Cycloalkenyl" means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. The cycloalkenyl ring can be optionally substituted with one or more substituents which may be the same or different, and are as defined herein. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.
"Heterocyclenyl" (or "heterocycloalkeneyl") means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon- nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more substituents. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N- oxide, S-oxide or S.S-dioxide. Non-limiting examples of suitable monocyclic azaheterocyclenyl groups include 1 ,2,3,4- tetrahydropyridyl, 1 ,2-dihydropyridyl, 1,4- dihydropyridyl, 1 ,2,3,6-tetrahydropyridyl, 1,4,5,6-tetrahydropyrimidyl, 2-pyrrolinyl, 3- pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Non-limiting examples of suitable oxaheterocyclenyl groups include S^-dihydro^H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and the like. Non-limiting example of a suitable multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl. Non-limiting examples of suitable monocyclic thiaheterocyclenyl rings include dihydrothiophenyl, dihydrothiopyranyl, and the like.
"Halo" means fluoro, chloro, bromo, or iodo groups. Preferred are fluoro, chloro or bromo, and more preferred are fluoro and chloro.
"Haloalkyl" means an alkyl as defined above wherein one or more hydrogen atoms on the alkyl is replaced by a halo group defined above.
"Heterocyclyl" (or heterocycloalkyl) means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which 1-3, preferably 1 or 2 of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heteracyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thϊa before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclyl can be optionally substituted by one or more which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non- limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,3-dioxolanyl, 1,4- dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
"Arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
"Arylcycloalkyl" means a group derived from a fused aryl and cycloalkyl as defined herein. Preferred arylcycloaikyls are those wherein aryl is phenyl and cycloalkyl consists of about 5 to about 6 ring atoms. The arylcycloalkyl can be optionally substituted by one or more substituents. Non-limiting examples of suitable arylcycloaikyls include indanyl and 1 ,2,3,4-tetrahydronaphthyl and the like. The bond to the parent moiety is through a non-aromatic carbon atom.
"Arylheterocycloalkyl" means a group derived from a fused aryl and heterocycloalkyl as defined herein. Preferred arylcycloaikyls are those wherein aryl is phenyl and heterocycloalkyl consists of about 5 to about 6 ring atoms. The arylheterocycloalkyl can be optionally substituted by one or more substituents. Non- limiting examples of suitable arylheterocycloalkyls include
Figure imgf000013_0001
The bond to the parent moiety is through a non-aromatic carbon atom.
"Acyl" means an organic group in which the -OH of the carboxyl group is replaced by some other substituent. Suitable non-limiting examples include H-C(O)-, alkyl-C(O)-, alkenyl-C(O)-, alkynyl-C(O)-, aryl-C(O)- or cycloalkyl-C(O)- group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and cyclohexanoyl.
"Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy. The bond to the parent moiety is through the ether oxygen.
"Alkyoxyalkyl" means a group derived from an alkoxy and alkyl as defined herein. The bond to the parent moiety is through the alkyl.
"Arylalkenyl" means a group derived from an aryl and alkenyl as defined herein. Preferred arylalkenyls are those wherein aryl is phenyl and the alkenyl consists of about 3 to about 6 atoms. The arylalkenyl can be optionally substituted by one or more substituents. The bond to the parent moiety is through a non-aromatic carbon atom.
"Arylalkynyl" means a group derived from a aryl and alkenyl as defined herein. Preferred arylalkynyls are those wherein aryi is phenyl and the alkynyl consists of about 3 to about 6 atoms. The arylalkynyl can be optionally substituted by one or more substituents. The bond to the parent moiety is through a non-aromatic carbon atom.
The suffix "ene" on alkyl, aryl, hetercycloalkyl, etc. indicates a divalent moiety, e.g., -CH2CH2- is ethylene, and *~\J~* is para-phenylene.
The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties, in available position or positions.
Substituents ("ring substituents") for the aryl, heteroayl, cycloalkyl, cycloalkylether, cycloalkenyl, heterocyclenyl, heterocyclyl, arylcycloalkyl, arylheterocycloalkyl, arylalkenyl and arylalkynyl groups described above, include, for example, alkyl, cycloalkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, cycloalkylether, cycloalkenyl, heterocyclenyl, heterocycly, arylcycloalkyl, arylheteroalkyl, arylalkenyl and arylalkynyl, said groups may in turn be substituted by ring substituents, as well as halo, haloalkyl, hydroxyl, alkoxy, halolkoxy, amino, alklamino, dialkylamino, NO2, mercapto, alkylthio, -N3, -COOH, and -C(O)O-alkyl.
Substitution on a cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl moiety includes substitution on the ring portion and/or on the alkyl portion of the group. When a variable appears more than once in a group, or a variable appears more than once in the structure of a formula, the variables can be the same or different.
With reference to the number of moieties (e.g., substituents, groups or rings) in a compound, unless otherwise defined, the phrases "one or more" and "at least one" mean that there can be as many moieties as chemically permitted, and the determination of the maximum number of such moieties is well within the knowledge of those skilled in the art. With respect to the compositions and methods comprising the use of the phrase "at least one" in a phrase such as "at least one cholesterol lowering agent" or "at least one H3 antagonist/inverse agonist" means one to three cholesterol lowering agents and independently one to three H3 receptor antagonists/inverse agonists can be administered at the same time, with preference to one of each.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The wavy line '^ΛΛΛ, as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (S)- stereochemistry. For example,
means containing both and
Figure imgf000015_0003
Figure imgf000015_0001
Figure imgf000015_0002
Lines drawn into the ring systems, such as, for example:
indicate that the indicated line (bond) may be- attached to any of the substitutable ring carbon atoms.
It is noted that the carbon atoms for formula I may be replaced with 1 to 3 silicon atoms so long as all valency requirements are satisfied.
(N) , for example in the structure
Figure imgf000016_0001
represents a nitrogen atom that is located at one of the 4 non-fused positions of the ring, i.e., positions 4, 5, 6 or 7 indicated below.
Figure imgf000016_0002
(2N /
Similarly, v — ' means that two nitrogens are located at any two of the 4 non- fused positions of the ring, e.g., the 4 and 6 positions, the 4 and 7 positions, or the 5 and 6 positions.
As well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom, unless stated otherwise. For example:
represents
Figure imgf000016_0004
Figure imgf000016_0003
It should also be noted that any heteroatom with unsatisfied valences in the text or structural formulae herein is assumed to have the hydrogen atom or atoms to satisfy the valences.
Those skilled in the art will recognize that certain compounds in the structural formulae disclosed herein are tautomeric and all such tautomeric forms are contemplated herein as part of the present invention.
As used herein, the term "cholesterol lowering agent" means any agent capable of lowering the cholesterol level in a mammal, such as a human. Non-limiting examples of compounds that act as lipid lowering agents include, for example, sterol absorption inhibitors, 5-α-stanol absorption inhibitors, HMG-CoA reductase inhibitors, bile acid sequestrants, nicotinic acid and/or nicotinic acid receptor agonists, agonists or activators of peroxisome proliferators-activated receptors (PPAR) etc. The term "H3 receptor antagonist inverse agonist" is any compound that acts as an antagonist or an inverse agonist to the H3 receptor.
The terms "combination therapy" or "therapeutic combination" means the administration of two or more therapeutic agents, such as a sterol absorption inhibitor and an H3 receptor antagonists/inverse agonist to prevent, treat or ameloriate NAFLD or NASH. The combinations and treatments of the present invention can be administered by any suitable means which produce contact of these compounds with the site of action in the body, for example in the plasma, liver or small intestine of a subject (mammal or human or other animal). Such administration includes coadministration of these therapeutic agents in a substantially simultaneous manner, such as in a single tablet or capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each therapeutic agent. Also, such administration includes use of each type of therapeutic agent in a sequential manner. In either case, the treatment using the combination therapy will provide beneficial effects in treating the condition. A potential advantage of the combination therapy disclosed herein may be a reduction in the required amount of an individual therapeutic compound or the overall total amount of therapeutic compounds that are effective in treating the condition. By using a combination of therapeutic agents, the side effects of the individual compounds can be reduced as compared to a monotherapy, which can improve patient compliance. Also, therapeutic agents can be selected to provide a broader range of complimentary effects or complimentary modes of action.
As discussed above, the therapeutic combinations and methods of the present invention may comprise one or more substituted azetidinone or substituted β-lactam sterol absorption inhibitors discussed in detail below. As used herein, "sterol absoφtϊon inhibitor" means a compound capable of inhibiting the absorption of one or more sterols, including but not limited to cholesterol, phytosterols (such as sitosterol, campesterol, stigmasterol and avenosterol), 5α-stanols (such as cholestanol, 5α-campestanol, 5α-sitostanol), and/or mixtures thereof, when administered in a therapeutically effective (sterol and/or 5α-stanol absoφtion inhibiting) amount to a mammal or human.
Non-limiting examples of suitable substituted azetidinones and methods of making the same include those disclosed in U.S. Patents Nos. RE 37,721, 5,306,817, 5,561,227, 5,618,707, 5,624,920, 5,631,365, 5,656,624, 5,627,176, 5,633,246, 5,661,145, 5,688,785, 5,688.787, 5,688,990, 5,698,548, 5,728,827, 5,739,321, 5,744,467, 5,756,470, 5,767,115, 5,846,966, 5,856,473, 5,886,171, 5,919,672, 6,093,812, 6,096,883, 6,133,001, 6,207,822, 6,627,757, 6,632,933, U.S. Patent Publication Nos. 2003/0105028, 2004/0180860, 2004/0180861, and 2004/0198700, N-sulfonyl-2-azettdiπones such as are disclosed in U.S. Patent No. 4,983,597, ethyl 4- (2-oxoazetidin-4-yl)phenoxy-alkanoates such as are disclosed in Ram et al., Indian J. Chem. Sect. B. 29B, 12 (1990), p. 1134-7, and diphenyl azetidinones and derivatives disclosed in U.S. Patent Publication Nos. 2002/0039774, 2002/0128252, 2002/0128253, 2002/0137689, 2004/0082561, and PCT Published Application Nos. WO 2002/066464, WO 04/000805, WO 04/005247, WO 04/000804, WO 04/000803, WO 04/014947, WO 04/087655, WO 05/009955, WO 05/023305, WO 05/021495, WO 05/021497, WO 05/044256, WO 05/042692, WO 05/033100, WO 05/030225, WO 05/047248, WO 05/046662, WO 05/061451, WO 05/061452, WO 05/062824, WO 05/02897, WO 05/000353, as well as the acetidiones disclosed in U.S. Patent Publication Nos. 2004/0077623, 2002/0137689, 2004/0067913, each of which is incorporated by reference herein.
In one embodiment, substituted azetidinones useful in the compositions, therapeutic combinations and methods of the present invention are represented by formula (I) below:
Figure imgf000018_0001
(0 or pharmaceutically acceptable salts or solvates of the compounds of formufa (I), wherein, in formula (I) above: Ar1 and Ar2 are independently selected from the group consisting of aryl and
4
R -substituted aryl;
Ar is aryl or R -substituted aryl;
X, Y and Z are independently selected from the group consisting of -CH2-, -CH(lower alkyl)- and -C(dilower alkyl)-;
R and R are independently selected from the group consisting of -OR , -C)(CO)R6, -0(CO)OR9 and -0(CO)NR6R7;
R and R are independently selected from the group consisting of hydrogen, lower alkyl and aryl; q is 0 or 1 ; r is 0 or 1 ; m, n and p are independently selected from 0, 1 , 2, 3 or 4; provided that at least one of q and r is 1 , and the sum of m, n, p, q and r is 1 , 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1 , the sum of m, q and n is 1 , 2, 3, 4 or 5;
4
R is 1 -5 substituents independently selected from the group consisting of lower alkyl, -OR6, -O(CO)R6, -O(CO)OR9, -0(CH2J1-5OR6, -0(CO)NR6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR?R8, -NR6Sθ2R9, -COOR6, -CONR6R7, -COR6, -SO2NR6R7, S(O)0.2R9, -0(CH2)^10-COOR6,
-0(CH2)L10CONR6R7, -(lower alkylene)COOR6, -CH=CH-COOR6, -CF3, -CN, -NO2 and halogen;
R is 1 -5 substituents independently selected from the group consisting of -OR6, -O(CO)Rβ, -O(CO)OR9, -0(CH2)^5OR6, -0(CO)NR6R7, -NR6R7, -NR6(CO)R7, - NR6(CO)OR9 S -NRβ(CO)NR7R8, -NR6SO2R9, -COOR6, -CONR6R7, -COR6, -SO2NR6R7, S(O)0-2R9, -0(CH2)^10-COOR6, -0(CH2)^10CONR6R7, -(lower alkylene)COOR6 and - CH=CH-COOR6;
R , R and R are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and R9 is lower alkyl, aryl or aryl-substituted lower alkyl. Preferably, R is 1-3 independently selected substituents, and R is preferably 1 -3 independently selected substituents.
Preferred compounds of formula (I) are those in which Ar is phenyl or R -substituted phenyl, more preferably (4-R )-substituted phenyl. Ar is preferably
4 4 3 phenyl or R -substituted phenyl, more preferably (4-R )-substituted phenyl. Ar is preferably R -substituted phenyl, more preferably (4-R )-substituted phenyl. When Ar
4 4 2 3 4 is (4-R )-substituted phenyl, R is preferably a halogen. When Ar and Ar are R - and R -substituted phenyl, respectively, R is preferably halogen or -OR and R is preferably -OR , wherein R is lower alkyl or hydrogen. Especially preferred are
1 2 3 compounds wherein each of Ar and Ar is 4-fluorophenyl and Ar is 4-hydroxyphenyl or 4-methoxyphenyl.
1 3
X1 Y and Z are each preferably -CH2-. R and R are each preferably
2 6 6 hydrogen. R and R are preferably -OR wherein R is hydrogen, or a group readily fi 9 6 7 metabolizable to a hydroxyl (such as -O(CO)R , -O(CO)OR and -O(CO)NR R , defined above).
The sum of m, n, p, q and r is preferably 2, 3 or 4, more preferably 3. Preferred are compounds wherein m, n and r are each zero, q is 1 and p is 2.
Also preferred are compounds of formula (I) in which p, q and n are each zero, r is 1 and m is 2 or 3. More preferred are compounds wherein m, n and r are each ft ft zero, q is 1 , p is 2, Z is -CH2- and R is -OR , especially when R is hydrogen.
Also more preferred are compounds of formula (I) wherein p, q and n are each
5 ft R zero, r is 1 , m is 2, X is -CH2- and R is -OR , especially when R is hydrogen.
Another group of preferred compounds of formula (I) is that in which Ar is
4 2 4 3 5 phenyl or R -substituted phenyl, Ar is phenyl or R -substituted phenyl and Ar is R - substituted phenyl. Also preferred are compounds in which Ar is phenyl or R -
2 4 3 5 substituted phenyl, Ar is phenyl or R -substituted phenyl, Ar is R -substituted phenyl, and the sum of m, n, p, q and r is 2, 3 or 4, more preferably 3. More preferred are
1 4 2 4 compounds wherein Ar is phenyl or R -substituted phenyl, Ar is phenyl or R - substituted phenyl, Ar is R -substituted phenyl, and wherein m, n and r are each zero, q is 1 and p is 2, or wherein p, q and n are each zero, r is 1 and m is 2 or 3.
In a preferred embodiment, a substituted azetidinoπe of formula (I) useful in the compositions, therapeutic combinations and methods of the present invention is represented by formula (II) (ezetimibe) below:
Figure imgf000021_0001
OD or pharmaceutically acceptable salts or solvates of the compound of formula (II). The compound of formula (II) can be in anhydrous or hydrated form. A product containing ezetimibe compound is commercially available as ZETIA® ezetimibe formulation from MSP Pharmaceuticals.
Compounds of formula I can be prepared by a variety of methods well know to those skilled in the art, for example such as are disclosed in U.S. Patents Nos. RE 37,721, 5,631,365, 5,767,115, 5,846,966, 6,207,822, PCT Patent Application No. 02/079174, and PCT Patent Application WO 93/02048, each of which is incorporated herein by reference.
Alternative substituted azetidinones useful in the compositions, therapeutic combinations and methods of the present invention are represented by formula (III) below:
Figure imgf000021_0002
(HI) or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein, in formula (III) above:
1 3
Ar Is R -substituted aryl;
2 4
Ar is R -substituted aryl;
Ar is R -substituted aryl;
Y and Z are independently selected from the group consisting of -CH2-, -CH(lower alkyl)- and -C(dilower alkyl)-;
A is selected from -O-, -S-, -S(O)- or -S(O)2-;
M R ft Q
R is selected from the group consisting of -OR , -O(CO)R , -0(CO)OR and - O(CO)NR R ; R is selected from the group consisting of hydrogen, lower alkyl and aryl; or R and R together are =O; q is 1 , 2 or 3; p is O1 1 , 2, 3 or 4;
R is 1 -3 substituents independently selected from the group consisting of -OR6, -O(CO)R6, -0(CO)OR9, -0(CH2)^5OR9, -0(CO)NR6R7, -NR6R7, -NR6(CO)R7, - NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2-lower alkyl, -NR6SO2-aryl, -CONR6R7, - COR6, -SO2NR6R7, S(0)o_2-alkyl, SfO^-aryl, -0(CH2)^10-COOR6, -0(CH2J1. ø 7
10CONR R , o-halogeno, m-halogeno, o-lower alkyl, m-lower afkyl, -(lower alkylene)- COOR6, and -CH=CH-COOR6;
3 4
R and R are independently 1-3 substituents independently selected from the
5 group consisting of R , hydrogen, p-lower alkyl, aryl, -NO2, -CF3 and p-halogeno; fi 7 ft
R , R and R are independently selected from the group consisting of
9 hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and R is lower alkyl, aryl or aryl-substituted lower alkyl.
Preferred compounds of formula III include those in which Ar is R3-substituted phenyl, especially (4-R )-substituted phenyl. Ar is preferably R - substituted phenyl, especially (4-R )-substituted phenyl. Ar is preferably R - 5 substituted phenyl, especially (4-R )-substituted phenyl. Mono-substitution of each of
1 2 3
Ar , Ar and Ar is preferred.
2 1
Y and Z are each preferably -CH2-. R is preferably hydrogen. R is preferably
R R
-OR wherein R is hydrogen, or a group readily metabolizable to a hydroxyl (such as - fi Q R 7
O(CO)R , -0(CO)OR and -0(CO)NR R , defined above). Also preferred are
1 2 compounds wherein R and R together are =O.
The sum of q and p is preferably 1 or 2, more preferably 1. Preferred are compounds wherein p is zero and q is 1. More preferred are compounds wherein p is
*l R fi zero, q is 1, Y is -CH2- and R is -OR , especially when R is hydrogen.
Another group of preferred compounds is that in which Ar is R -substituted phenyl, Ar is R -substituted phenyl and Ar is R -substituted phenyl.
1 3 2 4
Also preferred are compounds wherein Ar is R -substituted phenyl, Ar is R -
3 5 substituted phenyl, Ar is R -substituted phenyl, and the sum of p and q is 1 or 2,
1 3 2 especially 1. More preferred are compounds wherein Ar is R -substituted phenyl, Ar is R -substituted phenyl, Ar is R -substituted phenyl, p is zero and q is 1. A is preferably -O-. R3 is preferably -COOR6, -CONR6R7, -COR6, -SO2NR6R7, S(0)o_2-alkyl, S(O)0-2- aryl, NO2 or halogeno. A more preferred definition for R is halogeno, especially fluoro or chloro.
R is preferably hydrogen, lower alkyl, -OR6, -O(CO)R , -O(CO)OR9, fi 7 R 7 R R 7
-0(CO)NR R , -NR R , COR or halogeno, wherein R and R are preferably θ independently hydrogen or lower alkyl, and R is preferably lower alkyl. A more preferred definition for R is hydrogen or halogeno, especially fluoro or chloro. R5 is preferably -OR6, -O(CO)R6, -0(CO)OR9, -0(CO)NR6R7, -NR6R7, fi ft fi 7
-(lower alkylene)-COOR or -CH=CH-COOR , wherein R and R are preferably g independently hydrogen or lower alkyl, and R is preferably lower alkyl. A more preferred definition for R5 is -OR6, -(lower alkylene)-COOR6 or -CH=CH-COOR6, wherein R is preferably hydrogen or lower alkyl. Methods for making compounds of Formula III are well known to those skilled in the art. Non-limiting examples of suitable methods are disclosed in U.S. Patent No. 5,688,990, which is incorporated herein by reference.
In another embodiment, substituted azetidinones useful in the compositions, therapeutic combinations and methods of the present invention are represented by formula (IV):
Figure imgf000024_0001
(IV) or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein, in formula (IV) above:
2 2
A is selected from the group consisting of R -substituted heterocycloalkyl, R -
2 2 substituted heteroaryl, R -substituted benzofused heterocycloalkyl, and R -substituted benzofused heteroaryl;
1 3
Ar is aryl or R -substituted aryl;
2 4
Ar is aryl or R -substituted aryl;
Q is a bond or, with the 3-position ring carbon of the azetidinone, forms the
spiro group
Figure imgf000024_0002
; and
R is selected from the group consisting of:
-(CH2Jq-, wherein q is 2-6, provided that when Q forms a spiro ring, q can also be zero or 1 ;
-(CH2)e-G-(CH2)r-, wherein G is -O-, -C(O)-, phenyleπe, -NR - or -S(O)0-2-, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
-(C2-C6 alkenylene)-; and
-(CH2V V-(CH2Jg-, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6; R is selected from: -CH-, -C(C1-C6 alkyl)-, -CF-, -C(OH)-, -C(C6H4-R9)-, -N-, or-+NQ-
6 7
R and R are independently selected from the group consisting of -CH2-, -CH(C1-C6 alkyl)-, -C(di-(CrC6) alkyl), -CH=CH- and
-C(C1-C6 alkyl)=CH-; or R together with an adjacent R , or R together with an adjacent R , form a -CH=CH- or a -CH=C(C1-C6 alkyl)- group; a and b are independently 0, 1, 2 or 3, provided both are not zero; provided fi 7 that when R is -CH=CH- or -C(C1-C6 alkyl)=CH-, a is 1 ; provided that when R is - CH=CH- or -C(C1-C6 alkyl)=CH-, b is 1 ; provided that when a is 2 or 3, the R6's can be the same or different; and provided that when b is 2 or 3, the R "s can be the same or different; and when Q is a bond, R also can be selected from: R1°
-M -Yd- or
Figure imgf000025_0001
Figure imgf000025_0002
where M is -O-, -S-, -S(O)- or -S(O)2-;
X, Y and Z are independently selected from the group consisting of -CH2-, -CH(C1-C6 alkyl)- and -C^i-(C1-C6) alkyl);
R and R are independently selected from the group consisting of -OR14, -O(CO)R14, -O(CO)OR16 and -0(CO)NR14R15;
11 13
R and R are independently selected from the group consisting of hydrogen, (CrC6)alkyl and aryl; or R and R together are =O, or R and R together are =O; d is 1, 2 or 3; h is 0, 1 , 2, 3 or 4; s is 0 or 1 ; t is 0 or 1 ; m, n and p are independently 0-4; provided that at least one of s and t is 1 , and the sum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1, the sum of m, s and n is 1-5; and provided that when p is 0 and s is 1 , the sum of m, t and n is 1-5; v is 0 or 1 ; j and k are independently 1-5, provided that the sum of j, k and v is 1-5;
2
R is 1-3 substituents on the ring carbon atoms selected from the group consisting of hydrogen, (CrC10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl,
(C3-C6)cycloalkyl, (C3-C6)cycloalkenyl, R -substituted aryl, R -substituted benzyl, R -substituted benzyloxy, R -substituted aryloxy, halogeno, -NR R , NR R (C1- C6 alkylene)-, NR14R15C(O)(C1-C6 alkylene)-,-NHC(O)R16, OH1 C1-C6 alkoxy, - OC(O)R16, -COR14, hydroxy(CrC6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, NO2, -S(O)0-2R16, SO2NR R and -(C1-C6 alkylene)COOR ; when R is a substituent on a
heterocycloalkyl ring, R is as defined, or is =O or
Figure imgf000026_0001
; and, where R is a substituent on a substitutable ring nitrogen, it is hydrogen, (Cj-C8jalkyl, aryl, (C1-
*1 ft 1 ft
C6)alkoxy, aryloxy, (C^C^alkylcarbonyl, arylcarbonyl, hydroxy, -(CH2J1^CONR R ,
Figure imgf000026_0002
wherein J is -O-, -NH-, -NR18- or -CH2-;
3 4
R and R are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C1-Cβ)alkyl,
-OR14, -O(CO)R14, -O(CO)OR16, -0(CH2)^5OR14, -0(CO)NR14R15, -NR14R15, -NR14(CO)R15, -NR14(CO)OR16, -NR14(CO)NR15R19, -NR14Sθ2R16 -COOR14, -CONR14R15, -COR14, -SO2NR14R15, S(OV2R16, -0(CH2)L10-COOR14,
-0(CH2)^10CONR14R15, -(C1-C6 alkylene)-COOR14 -CH=CH-COOR14, -CF3, -CN, - NO2 and halogen;
R8 is hydrogen, (CrC6)alkyl, aryl (C1-C6)alkyl, -C(O)R14 or -COOR14;
9 17
R and R are independently 1-3 groups independently selected from the group consisting of hydrogen, (C,-C6)alkyl, (C1-C6)alkoxy, -COOH, NO2,
-NR R1 , OH and halogeno; R and R are independently selected from the group consisting of hydrogen, (C1-C6)aIRyI, aryl and aryl-substituted (C1-C6)aIRyI;
R is (C1-C6)aIRyI, aryl or R -substituted aryl;
1ft
R is hydrogen or (C1-C6)aIRyI; and
19
R is hydrogen, hydroxy or (C1-C6)aIRoXy.
Methods for making compounds of formula IV are well Rnown to those skilled in the art. Non-limiting examples of suitable methods are disclosed in U.S. Patent No. 5,656,624, which is incorporated herein by reference.
2
As used in formula (IV) above, "A" is preferably an R -substituted, 6-membered heterocycloalkyl ring containing 1 or 2 nitrogen atoms. Preferred heterocycloalRyl rings are piperidinyl, piperazinyl and morpholinyl groups. The ring "A" is preferably
2 joined to the phenyl ring through a ring nitrogen. Preferred R substituents are
19 hydrogen and lower alRyl. R is preferably hydrogen.
2 4 4
Ar is preferably phenyl or R -phenyl, especially (4-R )-substituted phenyl.
4
Preferred definitions of R are lower alkoxy, especially methoxy, and halogeno, especially fluoro.
1 3
Ar is preferably phenyl or R -substituted phenyl, especially
3
(4-R )-substituted phenyl.
There are several preferred definitions for the -R -Q- combination of variables: Q is a bond and R is lower alkylene, preferably propylene;
6 7
Q is a spiro group as defined above, wherein preferably R and R are each
_ i i ethylene and R is -CH- or -C(OH)- :
R10
Q is a bond and R1 is -M-Yd-C- Zn- wherein the variables
R11 are chosen such that R is -0-CH2-CH(OHJ-; Q is a bond and R1is the
Figure imgf000028_0001
variables are chosen such that R is -CH(OH)-(CH2)2-; and
»10
Q is a bond and R .1 - is -Xj-(C)V-Yk- S(O)0-2 _ wherein the
R11 variables are chosen such that R is -CH(OH)-CH2-S(O)0-2-.
In another embodiment, substituted azetidinones useful in the compositions, therapeutic combinations and methods of the present invention are represented by formula (V):
Figure imgf000028_0002
(V) or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein, in formula (V) above:
Ar is aryl, R -substituted aryl, heteroaryl or R10-substituted heteroaryl;
2 4
Ar is aryl or R -substituted aryl;
Ar is aryl or R -substituted aryl;
X and Y are independently selected from the group consisting Of -CH2-, -CH(lower alkyl)- and -C(dilower alkyl)-;
R is -OR6, -O(CO)R6, -O(CO)OR9 or -0(CO)NR6R7; R1 is hydrogen, lower alkyl or aryl; or R and R together are =O; q is O or 1 ; r is O, 1 or 2; m and n are independently O, 1 , 2, 3, 4 or 5; provided that the sum of m, n and q is 1, 2, 3, 4 or 5; 4
R is 1-5 substituents independently selected from the group consisting of lower alkyl, -OR6, -O(CO)R6, -O(CO)OR9, -0(CH2J1^OR6, -0(CO)NR6R7, -NR6R7, -NRβ(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2R9, -COOR6, -CONR6R7 -COR6, -SO2NR6R7, S(O)0-2R9. -0(CH2)L10-COOR6, -0(CH2)^10CONR6R7, -(lower alkylene)COOR6 and -CH=CH-COOR6;
R is 1-5 substituents independently selected from the group consisting of -OR6, -Q(CO)R8, -O(CO)OR9, -0(CH2)^5OR6, -0(CO)NR6R7, -NR6R7, -NR6(CO)R7, - NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2R9, -COOR6, -CONR6R7, -COR6, -SO2NR6R7, S(OV2R9, -0(CH2)^10-COOR6, -0(CH2)^10CONR6R7, -CF3, -CN, -NO2, halogen, - (lower alkylene)COOR6 and -CH=CH-COOR6;
R , R and R are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; g
R is lower alkyl, aryl or aryl-substituted lower alkyl; and R is 1-5 substituents independently selected from the group consisting of lower alkyl, -OR6, -O(CO)R6, -O(CO)OR9, -0(CH2)^5OR6, -0(CO)NR6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2R9, -COOR6, -CONR6R7, -COR6, -SO2NR6R7, -S(O)0.2R9, -0(CH2)^10-COOR6, -0(CH2J1.
10CONR6R7, -CF3, -CN, -NO2 and halogen.
Within the scope of Formula V, there are included two preferred structures. In formula VA, q is zero and the remaining variables are as defined above, and in formula VB, q is 1 and the remaining variables are as defined above:
Figure imgf000029_0001
4 5 10
R , R and R are each preferably 1-3 independently selected substituents as set forth above. Preferred are compounds of Formula (V) wherein Ar is phenyl, R -
10 2 substituted phenyl or thienyl, especially (4-R )-substituted phenyl or thienyl. Ar is preferably R4-substituted phenyl, especially (4-R4)-substituted phenyl. Ar3 is preferably phenyl or R -substituted phenyl, especially (4-R )-substituted phenyl.
1 10 10
When Ar is R -substituted phenyl, R is preferably halogeno, especially fluoro.
2 4 4 6 β
When Ar is R -substituted phenyl, R is preferably -OR , especially wherein R is hydrogen or lower alkyl. When Ar is R -substituted phenyl, R is preferably halogeno, especially fluoro. Especially preferred are compounds of formula (V) wherein Ar is
2 3 phenyl, 4-fluorophenyl or thienyl, Ar is 4-(alkoxy or hydroxy)phenyl, and Ar is phenyl or 4-fluorophenyl.
X and Y are each preferably -CH2-. The sum of m, n and q is preferably 2, 3 or 4, more preferably 2. When q is 1 , n is preferably 1 to 5.
Preferences for X, Y, Ar , Ar and Ar are the same in each of formulae (VA) and (VB).
In compounds of formula (VA), the sum of m and n is preferably 2, 3 or 4, more preferably 2. Also preferred are compounds wherein the sum of m and n is 2, and r is 0 or 1.
In compounds of formula (VB), the sum of m and n is preferably 1 , 2 or 3, more preferably 1. Especially preferred are compounds wherein m is zero and n is 1. R is
6 6 preferably hydrogen and R is preferably -OR wherein R is hydrogen, or a group readily metabolizable to a hydroxy! (such as -O(CO)R ,
-O(CO)OR9 and -0(CO)NR6R7, defined above), or R and R1 together form a =O group.
Methods for making compounds of formula V are well known to those skilled in the art. Non-limiting examples of suitable methods are disclosed in U.S. Patent No. 5,624,920, which is incorporated herein by reference.
In another embodiment, substituted azetidinones useful in the compositions, therapeutic combinations and methods of the present invention are represented by formula (Vl):
Figure imgf000030_0001
or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein: R1 Is
-CH-, -C(lower alkyl)-, -CF-. -C(OH)-, -C(C6H5)-, -C(C6H4-R15)-,
- N- or -+N O~ ;
R2 and R3 are independently selected from the group consisting of: -CH2-, -CH(lower alkyl)-, -C(di-lower alkyl)-, -CH=CH- and -C(lower alkyl)=CH-; or R1 together with an adjacent R2, or R1 together with an adjacent R3, form a -CH=CH- or a -CH=C(lower alkyl)- group; u and v are independently 0, 1 , 2 or 3, provided both are not zero; provided that when R2 is -CH=CH- or -C(lower alkyl)=CH-, v is 1; provided that when R3 is CH=CH- or -C(lower alkyl)=CH-, u is 1 ; provided that when v is 2 or 3, the R2ls can be the same or different; and provided that when u is 2 or 3, the R3ls can be the same or different;
R4 is selected from B-(CH2)mC(O)-, wherein m is 0, 1 , 2, 3, 4 or 5; B-(CH2)q-, wherein q is 0, 1, 2, 3, 4, 5 or 6; B-(CH2)e-Z-(CH2)r. wherein Z is -O-, - C(O)-, phenylene, -N(R8)- or -S(O)r>2-. e is 0, 1 , 2, 3, 4 or 5 and r is 0, 1 , 2, 3, 4 or 5, provided that the sum of e and r is 0, 1 , 2, 3, 4, 5 or 6; B-(C2-Cβ alkenylene)-; B-(C4- Cβ alkadienylene)-; B-(CH2)t-Z-(C2-C6 alkenyiene)-, wherein Z is as defined above, and wherein t is 0, 1 , 2 or 3, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6; B-(CH2)f-V-(CH2)g-, wherein V is C3- CQ cycloalkylene, f is 1, 2, 3, 4 or 5 and g is 0, 1, 2, 3, 4 or 5, provided that the sum of f and g is 1 , 2, 3, 4, 5 or 6; B-(CH2)fV-(C2-C6 alkenylene)- or B-(C2-C6 alkenylene)- V-(CH2)t-, wherein V and t are as defined above, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6; B-(CH2)a-Z-(CH2)b-V-(CH2)d-. wherein Z and V are as defined above and a, b and d are independently 0, 1 , 2, 3, 4, 5 or 6, provided that the sum of a, b and d is 0, 1, 2, 3, 4, 5 or 6; or T-(CH2)s-> wherein T is cycloalkyl of 3-6 carbon atoms and s is 0, 1, 2, 3, 4, 5 or 6; or
I
R1 and R4 together form the group B-CH=C- ; B is selected from indanyl, indenyl, naphthyl, tetrahydronaphthyl, heteroaryl or W-substituted heteroaryl, wherein heteroaryl is selected from the group consisting of pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl, oxazolyl and furanyl, and for nitrogen-containing heteroaryls, the N-oxides thereof, or
Figure imgf000032_0001
W is 1 to 3 substituents independently selected from the group consisting of lower alkyl, hydroxy lower aikyl, lower alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (lower alkoxyimino)-lower alkyl, lower alkanedioyl, lower alkyl lower alkanedioyl, allyloxy, -CF3, -OCF3, benzyl, R7-benzyl, benzyloxy, R7-benzyloxy, phenoxy, R7-phenoxy, dioxolanyl, NO2, -N(R8)(R9), N(R8)(R9)-lower alkylene-, N(R8)(R9)-lower alkylenyloxy-, OH1 halogeno, -CN, -N3, -NHC(O)OR10, -NHC(O)R10, R11O2SNH-, (R11O2S)2N-, -S(O)2NH2, -S(O)r>2R8, tert-butyldimethyl-silyloxymethyl, - C(O)R12, -COOR19, -CON(R8KR9), -CH=CHC(O)R12, -lower alkylene-C(O)R12,
R10C(O)(lower alkylenyioxyK N(R8)(R9)C(O)(lower alkylenyloxy)- and
Figure imgf000032_0002
for substitution on ring carbon atoms, and the substituents on the substituted heteroaryl ring nitrogen atoms, when present, are selected from the group consisting of lower alkyl, lower alkoxy, -C(O)OR10, - C(O)R10, OH, N(R8)(R9)-lower alkylene-, N(R8)(R9)-lower alkylenyloxy-, -S(O)2NH2 and 2-(trimethylsilyl)-ethoxymethyl;
R7 is 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxy, -COOH, NO2, -N(R8J(R9), OH, and halogeno;
R8 and R9 are independently selected from H or lower alkyl;
R10 is selected from lower alkyl, phenyl, R7-phenyl, benzyl or R7-benzyl;
R11 is selected from OH, lower alkyl, phenyl, benzyl, R7-phenyl or R7-benzyl; R12 is selected from H, OH, alkoxy, phenoxy, benzyloxy,
Figure imgf000033_0001
-N(R8XR9), lower alkyl, phenyl or R7-phenyl;
R13 is selected from -O-, -CH2-, -NH-, -N(lower alkyl)- or -NC(O)R19;
R15, R16 and R17 are independently selected from the group consisting of H and the groups defined for W; or R15 is hydrogen and R16 and R17, together with adjacent carbon atoms to which they are attached, form a dioxolanyl ring;
R19 is H, lower alkyl, phenyl or phenyl lower alkyl; and
R20 and R21 are independently selected from the group consisting of phenyl, W- substituted phenyl, naphthyl, W-substituted naphthyl, indanyl, indenyl, tetrahydronaphthyl, benzodioxolyl, heteroaryl, W-substituted heteroaryl, benzofused heteroaryl, W-substituted benzofused heteroaryl and cyclopropyl, wherein heteroaryl is as defined above.
One group of preferred compounds of formula Vl is that in which R21 is selected from phenyl, W-substituted phenyl, indanyl, benzofuranyl, benzodioxolyl, tetrahydronaphthyl, pyridyl, pyrazinyl, pyrimidinyl, quinolyl or cyclopropyl, wherein W is lower alkyl, lower alkoxy, OH, halogeno, -N(R8XR9), -NHC(O)OR10, -NHC(O)R10, NO2, -CN, -N3, -SH, -S(O)0-2-(lower alkyl), -COOR19, -CON(R8XR9), -COR12, phenoxy, benzyloxy, -OCF3, -CH=C(O)R12 or tert-butyldimethylsilyloxy, wherein R8, R9, R10, R12 and R19 are as defined for formula IV. When W is 2 or 3 substituents, the substituents can be the same or different.
Another group of preferred compounds of formula Vl is that in which R20 is phenyl or W-substituted phenyl, wherein preferred meanings of W are as defined above for preferred definitions of R21.
More preferred are compounds of formula Vl wherein R20 is phenyl or W- substituted phenyl and R21 is phenyl, W-substituted phenyl, indanyl, benzofuranyl, benzodioxolyl, tetrahydronaphthyl, pyridyl, pyrazinyl, pyrimidinyl, quinolyl or cyclopropyl; W is lower alkyl, lower alkoxy, OH, halogeno, -N(R8XR9), -NHC(O)OR10, -NHC(O)R10, NO2, -CN, -N3, -SH, -S(O)0-2-(lower alkyl), -COOR19, -CON(R8)(R9), -COR12, phenoxy, benzyloxy, - CH=CHC(O)R12, -OCF3 or tert-butyl-dimethyl-silyloxy, wherein when W is 2 or 3 substituents, the substituents can be the same or different, and wherein R8, R9, R10, R12 and R19 are as defined in formula Vl.
Also preferred are compounds of formula Vl wherein R1 is -CH- or -C(OH)- Another group of preferred compounds of formula Vl is in which R2 and R3 are each -CH2- and the sum of u and v is 2, 3 or 4, with u=v=2 being more preferred.
R4 is preferably B-(CH2)q- or B-(CH2)e-Z-(CH2)r, wherein B, Z, q, e and r are
as defined above. B is
Figure imgf000034_0001
wherein R16 and R17 are each hydrogen and wherein R15 is preferably H, OH, lower alkoxy, especially methoxy, or halogeno, especially chloro.
Preferably Z is -O-, e is 0, and r is 0.
Preferably q is 0-2.
R20 is preferably phenyl or W-substituted phenyl.
Preferred W substituents for R20 are lower alkoxy, especially methoxy and ethoxy, OH, and -C(O)R12, wherein R12 is preferably lower alkoxy.
Preferably R21 is selected from phenyl, lower alkoxy-substituted phenyl and F- phenyl.
Especially preferred are compounds of formula Vl wherein R1 is -CH- , or
-C(OH)- , R2 and R3 are each -CH2-, u=v=2, R4 is B-(CH2)q-, wherein B is phenyl or phenyl substituted by lower alkoxy or chloro, q is 0-2, R20 is phenyl, OH-phenyl, lower alkoxy-substituted phenyl or lower alkoxycarbonyl-substituted phenyl, and R21 is phenyl, lower alkoxy-substituted phenyl or F-phenyl.
An example of another useful compound of formula Vl is shown below in formula Via:
Figure imgf000035_0001
(Via)
Methods for making compounds of Formula Vl are well known to those skilled in the art. Non-limiting examples of suitable methods are disclosed in U.S. Patent No. 5,698,548, which is incorporated herein by reference.
In another embodiment, substituted azetidinones useful in the compositions, therapeutic combinations and methods of the present invention are represented by Formulas (VIIA) and (VIIB):
Figure imgf000035_0002
(VIIA) and
Figure imgf000035_0003
(VIIB) or a pharmaceutically acceptable salt or solvate thereof, wherein:
A is -CH=CH-, -C≡≡C- or -(CH2)p- wherein p is 0, 1 or 2; B is
B' is
Figure imgf000036_0001
D is -(CH2)mC(O)- or -(CH2)q- wherein m is 1 , 2, 3 or 4 and q is 2, 3 or 4;
E is C-10 to C20 a|ky' or -C(O)-(Cg to Cig)-alkyl, wherein the alkyl is straight or branched, saturated or containing one or more double bonds;
R is hydrogen, C1-C15 alkyl, straight or branched, saturated or containing one or more double bonds, or B-(CH2)r -, wherein r is 0, 1, 2, or 3;
R1, R2, R3, R1', R2, and R3' are independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, carboxy, NO2, NH2, OH, halogeno, lower alkylamino, dilower alkylamino, -NHC(O)OR5, R6θ2SNH- and -S(O)2NH2;
R4 is
Figure imgf000036_0002
wherein n is 0, 1 , 2 or 3;
R5 is lower alkyl; and
R6 is OH, lower alkyl, phenyl, benzyl or substituted phenyl wherein the substituents are 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxy, carboxy, NO2, NH2, OH, halogeno, lower alkylamino and dilower alkylamino; or a pharmaceutically acceptable salt thereof or a solvate thereof. In another embodiment, sterol absorption inhibitors useful in the compositions, therapeutic combinations and methods of the present invention are represented by formula (VIII):
Figure imgf000037_0001
or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein, in formula (VIII) above,
R26 is H or OG1 ;
G and G^ are independently selected from the group consisting of
Figure imgf000037_0002
provided that when R26 is H or
Figure imgf000037_0003
OH, G is not H;
R, Ra and RD are independently selected from the group consisting of H, -OH, halogeno, -NH2, azido, (C1-C6)alkoxy(C1-C6)-alkoxy or -W-R30;
W is independently selected from the group consisting of -NH-C(O)-, -O-C(Oh -O-C(O)-N(R31)-, -NH-C(O)-N(R31)- and -O-C(S)-N(R31)-;
R2 and R6 are independently selected from the group consisting of H, (C-J- C6)alkyl, aryl and aryl(C1-C6)alkyl;
R3, R4, R5f pj7f R3a ancj R4a are independently selected from the group consisting of H, (C1-C6)alkyl, aryl(C1-C6)alkyl, -C(O)(Ci -Ce )alkyl and -C(O)aryl; R30 js selected from the group consisting of R32-substituted T, R32-substituted-T-(C1-C6)alkyl, R32-substituted-(C2-C4)alkenyl, R32-substituted-(C1-C6)alkyl, R32-substituted-(C3-C7)cycloalkyl and R32-substituted-(C3-C7)cycloalky!(C1-C6)alkyl;
R31 is selected from the group consisting of H and (Ci-C4)alkyl;
T is selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;
R32 is independently selected from 1-3 substituents independently selected from the group consisting of halogeno, (Ci -C4)alkyl, -OH, phenoxy, -CF3, -Nθ2, (Ci-C4)alkoxy, methylenedioxy, oxo, (Ci -C4)alkylsulfanyl, (Ci-C4)alkylsulfinyl, (Ci-C4)alkylsulfonyl, -N(CH3)2, -C(O)-NH(Ci -C4)alkyl, -C(O)-N((Ci-C4)alkyl)2, -C(O)-(Ci -C4)alkyl, -C(O)-(Ci -C4)alkoxy and pyrrolidinylcarbonyl; or R32 is a covalent bond and R3^, the nitrogen to which it is attached and R32 form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (Ci-C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N- methylpiperazinyl, indolinyl or morpholinyl group; Art is aryl or R"O-substituted aryl;
Ar2 is aryl or R1 1 -substituted aryl;
Q is a bond or, with the 3-position ring carbon of the azetidinone,
forms the spiro group
Figure imgf000038_0001
and
R1 is selected from the group consisting of
-(CH2)q-, wherein q is 2-6, provided that when Q forms a spiro ring, q can also be zero or 1 ;
-(CH2)e-E-(CH2)r, wherein E is -O-, -C(O)-, phenylene, -NR22- or -S(O)0-2-, e »s 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
-(C2-C6)alkenylene-; and -(CH2)f-V-(CH2)g-, wherein V is C3-C6 cycloalkyleπe, f is 1-5 and g is 0- 5, provided that the sum of f and g is 1-6; R12 is
Figure imgf000039_0002
R13 and R14 are independently selected from the group consisting of -CH2-, -CH(C1-C6 alkyl)-, -C(di-(Ci-Ce) alkyl), -CH=CH- and
-C(Ci-Cβ alkyl)=CH-; or R12 together with an adjacent Rf 3, or R"12 together with an adjacent R14, form a -CH=CH- or a -CH=C(Ci -CQ alkyl)- group; a and b are independently 0, 1 , 2 or 3, provided both are not zero; provided that when R13 is -CH=CH- or -C(C1-C6 alkyl)=CH-, a is 1; provided that when R14 is -CH=CH- or -C(Ci-Ce alkyl)=CH-, b is 1 ; provided that when a is 2 or 3, the R13'S can be the same or different; and provided that when b is 2 or 3, the R14>s can be the same or different; and when Q is a bond, R1 also can be:
Figure imgf000039_0001
M is -O-, -S-, -S(O)- or -S(O)2S
X, Y and Z are independently selected from the group consisting of -CH2-, -CH(Ci -Ce)alkyl- and -C(di-(Ci -Cβ)alkyl);
R10 and R11 are independently selected from the group consisting of
1-3 substituents independently selected from the group consisting of (C1-C6)alkyl, -ORiQ1 -O(CO)R19, -O(CO)OR21 , -O(CH2)1-5OR19,
-O(CO)NR19R20, -NR19R20, -NR19(CO)R20, -NR19(CO)OR2I , -NR19(CO)NR20R25I -NR19SO2R21, -COOR19 -CONR19R20 F -COR^,
-SO2NR19R20 r S(O)rj-2R21. -0(CH2)1-10-COOR19
-O(CH2)1-10CONR19R20 ( -(Ci-Ce alkylene)-COOR19, -CH=CH-COOR^1 -CF3, -CN, -NO2 and halogen; R15 and R17 are independently selected from the group consisting of -OR19, -O(CO)R19, -G(CO)OR21 and -O(CO)NR19R20 ;
R16 and R18 are independently selected from the group consisting of H, (Ci -Cβ)alkyl and aryl; or R15 and R16 together are =O, or R17 and R18 together are =O; d is 1, 2 or 3; h is O, 1 , 2, 3 or 4; s is 0 or 1 ; t is 0 or 1 ; m, n and p are independently 0-4; provided that at least one of s and t is 1 , and the sum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1 , the sum of m, s and n is 1-5; and provided that when p is 0 and s is 1 , the sum of m, t and n is 1-5; v is 0 or 1 ; j and k are independently 1-5, provided that the sum of j, k and v is 1-5;
and when Q is a bond and R1 is
Figure imgf000040_0001
, Ar1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;
R19 and R20 are independently selected from the group consisting of H, (Ci- C6)alkyl, aryl and aryl-substituted (C-|-C6)alkyl;
R21 is (C1-C6)alkyl> aryl or R24-substituted aryl;
R22 is H, (C1-C6)alkyl, aryl (C1-C6)alkyl, -C(O)Ri 9 or -COOR19;
R23 and R24 are independently 1-3 groups independently selected from the group consisting of H, (C1-C6)alkyl, (Ci -Cβ)alkoxy, -COOH, NO2,
-NR19R20, -OH and halogeno; and
R2S is H, -OH or (Ci-Cβ)alkoxy.
Methods for making compounds of formula VIII are well known to those skilled in the art. Non-limiting examples of suitable methods are disclosed in U.S. Patent No. 5,756,470, which is incorporated herein by reference. In another embodiment, substituted azetidinones useful in the compositions, therapeutic combinations and methods of the present invention are represented by formula (IX) below:
Figure imgf000041_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein in Formula (IX): R1 is selected from the group consisting of H, G, G1, G2, -SO3H and -PO3H; G is selected from the group consisting of: H,
Figure imgf000041_0002
(sugar derivatives) wherein R, Ra and RD are each independently selected from the group consisting of H, -OH, halo, -NH2, azido, (C1-C6)alkoxy(C1-C6)alkoxy or -W-R30;
W is independently selected from the group consisting of -NH-C(O)-, -O-C(O)-, -0-C(O)-N(R31)-, -NH-C(O)-N(R3I)- and -O-C(S)-N(R31 )-;
R2 and R^ are each independently selected from the group consisting of H, (C1-C6)alkyl, acetyl, aryl and aryl(Ci -Cβ)alkyl; R3, R4, R5, R7, R3a and R^a are each independently selected from the group consisting of H, (C1-C6)alkyl, acetyl, aryl(C1-C6)alkyl, -C(O)(C1-C6)alkyl and - C(O)aryl;
R30 is independently selected from the group consisting of R32-substituted T, R32-substituted-T-(C1-C6)alkyl, R32-substituted-(C2-C4)alkenyl,
R32-substituted-(C1-C6)alkyl, R32-substituted-(C3-C7)cycloalkyl and R32-substituted- (C3-C7)cycloalkyl(C1-C6)alkyl;
R31 is independently selected from the group consisting of H and (Ci-C4)alkyl;
T is independently selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;
R32 is independently selected from 1-3 substituents which are each independently selected from the group consisting of H, halo, (Ci-C4)alkyl, -OH, phenoxy, -CF3, -NO2, (Ci-C4)alkoxy, methylenedioxy, oxo, (C-|-C4)alkylsulfanyl, (Ci- C4)alkylsulfinyl, (Ci-C4)alkylsulfpnyl, -N(CH3)2, -C(O)-NH(Ci -C4)alkyl, -C(O)-N((Ci-
C4)alkyl)2, -C(O)-(Ci -C4)alkyl, -C(O)-(Ci -C4)alkoxy and pyrrolidinylcarbonyl; or R32 is a covalent bond and R31, the nitrogen to which it is attached and R32 form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (Ci- C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;
G1 is represented by the structure: o
R33 wherein R33 is independently selected from the group consisting of unsubstituted alkyl, R^-substituted alkyl, (R35)(R36)alkyl-,
Figure imgf000042_0001
R34 is one to three substituents, each R34 being independently selected from the group consisting of HOOC-, HO-, HS-, (CH3)S-, H2N-, (NH2)(NH)C(NH)-, (NH2)C(O)- and HOOCCH(NH3 +)CH2SS-;
R35 is independently selected from the group consisting of H and NH2-;
R3e is independently selected from the group consisting of H, unsubstituted alkyl, R^-substituted alkyl, unsubstituted cyctoalkyl and R^-substituted cycloalkyl;
G2 is represented by the structure:
Figure imgf000043_0001
wherein R37 and R38 are each independently selected from the group consisting of (C1- C6)alkyl and aryl;
R26 is one to five substituents, each R26 being independently selected from the group consisting of: a) H; b) -OH; c) -OCH3; d) fluorine; e) chlorine; f) -O-G; g) -O-G1; h) -O-G2; i) -SO3H; and j) -PO3H; provided that when R1 is H, R26 is not H, -OH, -OCH3 or -O-G;
Ar1 is aryl, R10-substituted aryl, heteroaryl or R1 °-substituted heteroaryl;
Ar2 is aryl, R -substituted aryl, heteroaryf or R^ 1 -substituted heteroaryl; L is selected from the group consisting of: a) a covalent bond; b) -(CH2Jq-, wherein q is 1-6; c) -(CH2)e-E-(CH2)r> wherein E is -O-, -C(O)-, phenylene, -NR22- or -S(O)0-Z-, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6; d) -<C2-C6)alkenylene-; e) -(CH2)f-V-(CH2)g-, wherein V is C3-C6cycloalkylene, f is 1 -5 and g is 0-5, provided that the sum of f and g is 1-6; and
0
Figure imgf000044_0001
wherein M is -C-, -S-, -S(O)- or -S(O)2-;
X, Y and Z are each independently selected from the group consisting of -CH2-, -CH(C1-C6)alkyl- and -C(di-(C1-C6)alkyl)-;
R8 is selected from the group consisting of H and alkyl;
R-IO and R^ ^ are each independently selected from the group consisting of 1-3 substituents which are each independently selected from the group consisting of (Ci -
C6)alkyl, -OR19, -O(C0)R19, -O(CO)OR21 , -O(CH2)1-5OR19, -0(CO)NR19R20, - NR19R20, -NR19(CO)R20, -NR19(CO)OR21 ,
-NRi9(CO)NR2θR25f -NRi9sθ2R21, -COOR^1 -CONR19R20, _COR19, - SO2NR19R20 | S(O)0-2R21. -0(CH2)1-10-COOR19, -O(CH2)1-10CONR19R20 > _(C1- C6 alkyleneJ-COORiθ, -CH=CH-COOR^1 _CF3, -CN, -NO2 and halo;
R15 and R17 are each independently selected from the group consisting of -OR19, -OC(O)R19, -OC(O)OR21, - OC(O)NR19R20;
R16 and R18 are each independently selected from the group consisting of H, (d-C6)alkyl and aryl; or R15 and R16 together are =O, or R17 and R18 together are =O; d is 1 , 2 or 3; h is O, 1 , 2, 3 or 4; s is O or 1 ; t is O or 1 ; m, n and p are each independently selected from 0-4; provided that at least one of s and t is 1 , and the sum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1, the sum of m, n and p is 1-5; and provided that when p is 0 and s is 1 , the sum of m, t and n is 1 -5; v is O oM;
j and k are each independently 1-5, provided that the sum of j, k and v is 1-5; Q is a bond, -(CH2)q-, wherein q is 1-6, or, with the 3-position ring carbon of the azetidinone, forms the spiro group
Figure imgf000045_0001
wherein R12 js
-CH-, -C(C,-C6-alkyl), -CF-, -C(OH)-, - C(C6H4-R23)-, -N- , or -4NO"
R13 and R14 are each independently selected from the group consisting of -CH2-, -CH(Ci-Ce alkyl)-, -C(di-(C1-C6) alkyl), -CH=CH- and -C(Ci-Ce alkyl)=CH-; or
R12 together with an adjacent R13, or R12 together with an adjacent R14, form a - CH=CH- or a -CH=C(C1-C6 alkyl)- group; a and b are each independently 0, 1, 2 or 3, provided both are not zero; provided that when R13 is -CH=CH- or -C(Ci-Cg alkyl)=CH-, a is 1; provided that when R14 is -CH=CH- or -C(C1-C6 alkyl)=CH-, b is 1 ; provided that when a is 2 or 3, the R13's can be the same or different; and provided that when b is 2 or 3, the R14's can be the same or different;
and when Q is a bond and L is
Figure imgf000045_0002
then Ar1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;
R19 and R20 are each independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl-substituted (C1-C6)alkyl;
R21 is (C1-C6)alkyl. aryl or R24-su bstituted aryl;
R22 is H1 (C1-C6)alkyl, aryl (C1-C6)alkyl, -C(O)R19 or -COOR19;
R23 and R2^ are each independently selected from the group consisting of 1-3 substituents which are each independently selected from the group consisting of H, (Ci-Cβ)alkyl, (C1-C6)alkoxy, -COOH, NO2, -NR19R20, -OH and halo; and
R2S is H, -OH or (C1-C6)alkoxy.
Examples of compounds of formula (IX) which are useful in the compositions, therapeutic combinations and methods and combinations of the present invention and methods for making such compounds are disclosed in U.S. Patent Publication No. 2003/0105028 A1, filed June 11, 2002, incorporated herein by reference.
An example of a useful compound of this invention is one represented by the formula X:
Figure imgf000046_0001
X wherein R1 is defined as above.
A more preferred compound is one represented by formula Xl:
Figure imgf000047_0001
Another useful compound is represented by formula XII:
Figure imgf000047_0002
Other useful substituted azetidinone compounds include N-sulfonyl-2- azetidinones such as are disclosed in U.S. Patent No. 4,983,597, ethyl 4-(2- oxoazetidin-4-yl)phenoxy-alkanoates such as are disclosed in Ram et al., Indian J. Chem. Sect. B. 29B, 12 (1990), p. 1134-7, and diphenyl azetidtnones and derivatives disclosed in U.S. Patent Publication Nos. 2002/0039774, 2002/0128252, 2002/0128253 and 2002/0137689, and WO 2002/066464, each of which is incorporated by reference herein.
The compounds of formulae I-XII can be prepared by known methods, including the methods discussed above and, for example, WO 93/02048 describes the preparation of compounds wherein -R"! -Q- is alkylene, alkenylene or alkylene interrupted by a hetero atom, phenylene or cycloalkylene; WO 94/17038 describes the preparation of compounds wherein Q is a spirocyclic group; WO 95/08532 describes the preparation of compounds wherein -R1 -Q- is a hydroxy-substituted alkylene group; PCT/US95/03196 describes compounds wherein -R1 -Q- is a hydroxy-substituted alkylene attached to the Ar1 moiety through an -O- or S(O)0-2- group; and U.S. 5,633,246 describes the preparation of compounds wherein -R-I-Q- is a hydroxy-substituted alkylene group attached the azetidinone ring by a -S(O)0-2- group. Each of the aforementioned documents are incorporated by reference.
Other classes of cholesterol lowering agents include the following non-limiting classes of agents: HMG-CoA reductase inhibitors; bile acid sequestrants; PPAR agonists or activators; ileal bile acid transport ("IBAT) inhibitors (or apical sodium co- dependent bile acid transport ("ASBT) inhibitors; nicotinic acid (niacin) and/or nicotinic acid receptor agonists; acylCoA:cholesterol O-acyltransferase CACAT) inhibitors; cholesteryl ester transfer protein ("CETP") inhibitors; probucol or derivatives thereof; low-density lipoprotein ("LDL") receptor activators; omega 3 fatty acids ("3- PUFA"); natural water soluble fibers; plant sterols, plant stanols and/or fatty acid esters of plant stanols.
Non-limiting examples of suitable cholesterol biosynthesis inhibitors include competitive inhibitors of HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis, squalene synthase inhibitors, squalene epoxidase inhibitors and mixtures thereof. Non-limiting examples of suitable HMG-CoA reductase inhibitors include statins such as lovastatin (for example MEVACOR® which is available from Merck & Co.), pravastatin (for example PRAVACHOL® which is available from Bristol Meyers Squibb), fluvastatin, simvastatin (for example ZOCOR® which is available from Merck & Co.), atorvastatin, cerivastatin, CI-981, resuvastatin, rivastatin and pitavastatin (such as NK-104 of Negma Kowa of Japan), rosuvastatin; HMG-CoA reductase inhibitors, for example L-659,699 ({E,E)-1H3>R-(hydroxy-methyl)-4'-oxo- 2IR-oxetanyl]-3,5,7R-trimethyl-2,4-undecadienoic acid); squalene synthesis inhibitors, for example squalestatin 1; and squalene epoxidase inhibitors, for example, NB-598 ((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-K3,3'-bithiophen-5- yl)methoxy]benzene-methanamine hydrochloride) and other sterol biosynthesis inhibitors such as DMP-565. Preferred HMG-CoA reductase inhibitors include lovastatin, pravastatin and simvastatin. The most preferred HMG-CoA reductase inhibitor is simvastatin.
Generally, a total daily dosage of cholesterol biosynthesis inhibitors) can range from about 0.1 to about 160 mg per day, and preferably about 0.2 to about 80 mg/day in single or 2-3 divided doses. Other lipid lowering agents which are contemplated by the present invention include one bile acid sequestrants. Bile acid squestrants bind bile acids in the intestine, interrupting the enterohepatic circulation of bile acids and causing an increase in the faecal excretion of steroids.
Non-limiting examples of suitable bile acid sequestrants include cholestyramine (a styrene-divinylbenzene copolymer containing quaternary ammonium cationic groups capable of binding bile acids, such as QUESTRAN® or QUESTRAN LIGHT® cholestyramine which are available from Bristol-Myers Squibb), colestipol (a copolymer of diethyleπetriamine and 1-chloro-2,3~epoxypropane, such as COLESTID® tablets which are available from Pharmacia), colesevelam hydrochloride (such as WelChol® Tablets (poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)- trimethylammonium bromide) which are available from Sankyo), water soluble derivatives such as 3,3-ioene, N-(cycloalkyl) alkylamines and poligfusam, insoluble quaternized polystyrenes, saponins and mixtures thereof. Suitable inorganic cholesterol sequestrants include bismuth salicylate plus montmorillonite clay, aluminum hydroxide and calcium carbonate antacids.
Another embodiment of the present invention include activators or agonists of PPAR. The activators act as agonists for the peroxisome proliferator-activated receptors. Three subtypes of PPAR have been identified, and these are designated as peroxisome proliferator-activated receptor alpha (PPARα), peroxisome proliferator- activated receptor gamma (PPARv) and peroxisome proliferator-activated receptor delta (PPARδ). It should be noted that PPARδ is also referred to in the literature as PPARβ and as NUC1, and each of these names refers to the same receptor.
PPARα regulates the metabolism of lipids. PPARα is activated by fibrates and a number of medium and long-chain fatty acids, and it is involved in stimulating β- oxidation of fatty acids. The PPARy receptor subtypes are involved in activating the program of adipocyte differentiation and are not involved in stimulating peroxisome proliferation in the liver. PPARδ has been identified as being useful in increasing high density lipoprotein (HDL) levels in humans. See, e.g., WO 97/28149.
PPARα activator compounds are useful for, among other things, lowering triglycerides, moderately lowering LDL levels and increasing HDL levels. Useful examples of PPARα activators include fibrates. Non-limiting examples of suitable fibric acid derivatives ("fibrates") include clofibrate (such as ethyl 2-(p-chlorophenoxy)-2~methyl-propionate, for example ATROMID-S® Capsules which are commercially available from Wyeth-Ayerst); gemfibrozil (such as 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, for example LOPI D® tablets which are commercially available from Pfizer); ciprofibrate (C.A.S. Registry No. 52214-84-3, see U.S. Patent No. 3,948,973 which is incorporated herein by reference); bezafibrate (C.A.S. Registry No. 41859-67-0, see U.S. Patent No. 3,781,328 which is incorporated herein by reference); clinofibrate (C.A.S. Registry No. 30299-08-2, see U.S. Patent No. 3,716,583 which is incorporated herein by reference); binifibrate (C.A.S. Registry No. 69047-39-8, see BE 884722 which is incorporated herein by reference); lifibrol (C.A.S. Registry No. 96609-16-4); fenofibrate (such as TRICOR® micronized fenofibrate (2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoicacid, 1-methylethyl ester) which is commercially available from Abbott Laboratories or LIPANTHYL® micronized fenofibrate which is commercially available from Labortoire Founier, France) and mixtures thereof. These compounds can be used in a variety of forms, including but not limited to acid form, salt form, racemates, enantiαmers, zwitterions and tautomers.
Other examples of PPARσ activators useful in the practice of the present invention include suitable fluorophenyl compounds as disclosed in U.S. No. 6,028,109 which is incorporated herein by reference; certain substituted phenylpropionic compounds as disclosed in WO 00/75103 which is incorporated herein by reference; and PPARα activator compounds as disclosed in WO 98/43081 which is incorporated herein by reference.
Non-limiting examples of suitable PPARy activators include derivatives of glitazones or thiazolidinediones, such as, troglitazone; rosiglitazone (such as AVANDIA® rosiglitazone maleate (-5-[[4-[2-(methyl-2-pyridinylamino)ethoxy] phenyl] methyl]-2,4-thiazolidinedione-2-butenedioate) commercially available from SmithKline Beecham) and pioglitazone (such as ACTOS™ pioglitazone hydrochloride (5-[[4-[2-(5- ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-] thiazolidinedione monohydrochloride) commercially available from Takeda Pharmaceuticals). Other useful thiazolidinediones include ciglitazone, englitazone, darglitazone and BRL 49653 as disclosed in WO 98/05331 which is incorporated herein by reference; PPARy activator compounds disclosed in WO 00/76488 which is incorporated herein by reference; and PPARy activator compounds disclosed in U.S. Patent No. 5,994,554 which is incorporated herein by reference.
Other useful PPARy activator compounds include certain acetylphenols as disclosed in U.S. Patent No. 5,859,051 which is incorporated herein by reference; certain quinoline phenyl compounds as disclosed in WO 99/20275 which is incorporated herein by reference; aryl compounds as disclosed by WO 99/38845 which is incorporated herein by reference; certain 1 ,4-disubstituted phenyl compounds as disclosed in WO 00/63161; certain aryl compounds as disclosed in WO 01/00579 which is incorporated herein by reference; benzoic acid compounds as disclosed in WO 01/12612 & WO 01/12187 which are incorporated herein by reference; and substituted 4-hydroxy-phenylalconic acid compounds as disclosed in WO 97/31907 which is incoφorated herein by reference.
PPARδ compounds are useful for, among other things, lowering triglyceride levels or raising HDL levels. Non-limiting examples of PPARδ activators include suitable thiazole and oxazole derivatives, such as C.A.S. Registry No. 317318-32-4, as disclosed in WO 01/00603 which is incorporated herein by reference); certain fluoro, chtoro or thio phenoxy phenylacetic acids as disclosed in WO 97/28149 which is incoφorated herein by reference; suitable non-β-oxidizable fatty acid analogues as disclosed in U.S. Patent No. 5,093,365 which is incoφorated herein by reference; and PPARδ compounds as disclosed in WO 99/04815 which is incorporated herein by reference.
Moreover, compounds that have multiple functionality for activating various combinations of PPARα, PPARy and PPARδ are also useful with the practice of the present invention. Non-limiting examples include certain substituted aryl compounds as disclosed in U.S. Patent No. 6,248,781; WO 00/23416; WO 00/23415; WO 00/23425; WO 00/23445; WO 00/23451; and WO 00/63153, all of which are incoφorated herein by reference, are described as being useful PPARα and/or PPARy activator compounds. Other non-limiting examples of useful PPARα and/or PPARy activator compounds include activator compounds as disclosed in WO 97/25042 which is incoφorated herein by reference; activator compounds as disclosed m WO 00/63190 which is incoφorated herein by reference; activator compounds as disclosed in WO 01/21181 which is incoφorated herein by reference; biaryl-oxa(thia)zole compounds as disclosed in WO 01/16120 which is incoφorated herein by reference; compounds as disclosed in WO 00/63196 and WO 00/63209 which are incorporated herein by reference; substituted 5-aryl-2,4-thiazolidinediones compounds as disclosed in U.S. Patent No. 6,008,237 which is incorporated herein by reference; arylthiazolidinedione and aryloxazolidinedione compounds as disclosed in WO 00/78312 and WO 00/78313G which are incorporated herein by reference; GW2331 or (2-(4-[difluorophenylJ-1 heptylureido)ethyl]phenoxy)-2-methylbutyric compounds as disclosed in WO 98/05331 which is incorporated herein by reference; aryl compounds as disclosed in U.S. Patent No. 6,166,049 which is incorporated herein by reference; oxazole compounds as disclosed in WO 01/17994 which is incorporated herein by reference; and dithiolane compounds as disclosed in WO 01/25225 and WO 01/25226 which are incorporated herein by reference.
Other useful PPAR activator compounds include substituted benzylthiazolidine- 2,4-dione compounds as disclosed in WO 01/14349, WO 01/14350 and WO/01/04351 which are incorporated herein by reference; mercaptocarboxylic compounds as disclosed in WO 00/50392 which is incorporated herein by reference; ascofuranone compounds as disclosed in WO 00/53563 which is incorporated herein by reference; carboxylic compounds as disclosed in WO 99/46232 which is incorporated herein by reference; compounds as disclosed in WO 99/12534 which is incorporated herein by reference; benzene compounds as disclosed in WO 99/15520 which is incorporated herein by reference; o-anisamide compounds as disclosed in WO 01/21578 which is incorporated herein by reference; and PPAR activator compounds as disclosed in WO 01/40192 which is incorporated herein by reference.
The peroxisome proliferator-activated receptor(s) activators) are administered in a therapeutically effective amount to treat the specified condition, for example in a daily dose preferably ranging from about 50 to about 3000 mg per day, and more preferably about 50 to about 2000 mg per day, given in a single dose or 2-4 divided doses. The exact dose, however, is determined by the attending clinician and is dependent on such factors as the potency of the compound administered, the age, weight, condition and response of the patient.
In an alternative embodiment, the present invention includes the use of one or more IBAT inhibitors or ASBT inhibitors. The IBAT inhibitors can inhibit bile acid transport to reduce LDL cholesterol levels. Non-limiting examples of suitable IBAT inhibitors include benzothiepϊnes such as therapeutic compounds comprising a 2,3,4,5-tetrahydro-1-benzothiepine 1 ,1-dioxide structure such as are disclosed in PCT Patent Application WO 00/38727 which is incorporated herein by reference.
Generally, a total daily dosage of IBAT inhibitors) can range from about 0.01 to about 1000 mg/day, and preferably about 0.1 to about 50 mg/day in single or 2-4 divided doses.
In another alternative embodiment, the methods of the present invention can further comprise nicotinic acid (niacin) and/or nicotinic acid receptor ("NAR") agonists as lipid lowering agents.
As used herein, "nicotinic acid receptor agonist" means any compound comprising that will act as an agonist to the nicotinic acid receptor. Compounds include those that have a pyridine-3-carboxylate structure or a pyrazine-2-carboxylate structure, including acid forms, salts, esters, zwitterions and tautomers, where available. Examples of nicotinic acid receptor agonists include niceritrol, nicofuranose and acipimox (5-methyl pyrazine-2-carboxylic acid 4-oxide). Nicotinic acid and NAR agonists inhibit hepatic production of VLDL and its metabolite LDL and increases HDL and apo A-1 levels. An example of a suitable nicotinic acid product is NIASPAN® (niacin extended-release tablets) which are available from Kos.
Generally, a total daily dosage of nicotinic acid can range from about 500 to about 10,000 mg/day, preferably about 1000 to about 8000 mg/day, and more preferably about 3000 to about 6000 mg/day in single or divided doses. Generally, the total daily dosage of a NAR agonist can range from about 1 to about 100 mg/day/
In another alternative embodiment, the methods of the present invention can further comprise one or more ACAT inhibitors as lipid lowering agents. ACAT inhibitors reduce LDL and VLDL levels ACAT is an enzyme responsible for esterifying excess intracellular cholesterol and may reduce the synthesis of VLDL, which is a product of cholesterol esterification, and overproduction of apo B-100-containing lipoproteins.
Non-limiting examples of useful ACAT inhibitors include avasimibe ([[2,4,6- tris(1-methylethyl)phenyl]acetyl]sulfamic acid, 2,6-bis(1-methylethyl)phenyl ester, formerly known as CI-1011), HL-004, lecimibide (DuP-128) and CL-277082 (/V-(2,4- difluorophenyl)-/v"-[[4-(2,2-dimethylpropyl)phenyl]methyl]-/V-heptylurea). See P. Chang et a!., "Current, New and Future Treatments in Dyslipidaemia and Atherosclerosis", Drugs 2000 Jul;60(1 ); 55-93, which is incorporated by reference herein.
Generally, a total daily dosage of ACAT inhibitors) can range from about 0.1 to about 1000 mg/day in single or 2-4 divided doses.
In another alternative embodiment, the compositions used in the methods of the present invention can further comprise one or more Cholesteryl Ester Transfer Protein ("CETP") Inhibitors coadministered with or in combination with the compound(s) of Formulae I-X discussed above. CETP is responsible for the exchange or transfer of cholesteryl ester carrying HDL and triglycerides in VLDL.
Non-limiting examples of suitable CETP inhibitors are disclosed in PCT Patent Application No. WO 00/38721 and U.S. Patent No. 6,147,090, which are incorporated herein by reference. Pancreatic cholesteryl ester hydrolase (pCEH) inhibitors such as WAY-121898 also can be coadministered with or in combination with the fibric acid derivative(s) and sterol absorption inhibitors) discussed above.
Generally, a total daily dosage of CETP inhibitor(s) can range from about 0.01 to about 1000 mg/day, and preferably about 0.5 to about 20 mg/kg body weight/day in single or divided doses.
In another alternative embodiment, the methods of the present invention can further comprise probucol or derivatives thereof (such as AGI-1067 and other derivatives disclosed in U.S. Patents Nos. 6,121 ,319 and 6,147,250), which can reduce LDL and HDL levels, as cholesterol lowering agents.
Generally, a total daily dosage of probucol or derivatives thereof can range from about 10 to about 2000 mg/day, and preferably about 500 to about 1500 mg/day in single or 2-4 divided doses.
In another alternative embodiment, the methods of the present invention can further comprise one or more low-density lipoprotein (LDL) receptor activators, as lipid lowering agents. Non-limiting examples of suitable LDL-receptor activators include HOE-402, an imidazolidinyl-pyrimidine derivative that directly stimulates LDL receptor activity. See M. Huettinger et al., "Hypolipidemic activity of HOE-402 is Mediated by Stimulation of the LDL Receptor Pathway", Arterioscler. Thromb. 1993; 13:1005-12.
Generally, a total daily dosage of LDL receptor activator(s) can range from about 1 to about 1000 mg/day in single or 2-4 divided doses. In another alternative embodiment, the methods of the present invention can further comprise fish oil, which contains Omega 3 fatty acids (3-PUFA), which can reduce VLDL and triglyceride levels, as a lipid lowering agent. Generally, a total daily dosage of fish oil or Omega 3 fatty acids can range from about 1 to about 30 grams per day in single or 2-4 divided doses.
In another alternative embodiment, the methods of the present invention can further comprise natural water soluble fibers, such as psyllium, guar, oat and pectin, which can reduce cholesterol levels. Generally, a total daily dosage of natural water soluble fibers can range from about 0.1 to about 10 grams per day in single or 2-4 divided doses.
In another alternative embodiment, methods of the present invention can further comprise plant sterols, plant stanols and/or fatty acid esters of plant stanols, such as sitostanol ester used in BENECOL® margarine, which can reduce cholesterol levels. Generally, a total daily dosage of plant sterols, plant stanols and/or fatty acid esters of plant stanols can range from about 0.5 to about 20 grams per day in single or 2-4 divided doses.
As discussed above, the compositions, therapeutic combinations and methods of the present invention may comprise at least one H3 receptor antagonist/inverse agonist. In one embodiment, the H3 receptor antagonist inverse agonist can be one of the imidazole type, such as those described in WO 95/14007 and WO 99/21405, each herein incorporated by reference.
In yet another embodiment of present invention provides for compositions, therapeutic combinations and methods of the present invention, wherein at least one H3 receptor antagonist/inverse agonist is a compound of the formula:
Figure imgf000055_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein: (1) R1 is selected from: (a) aryl; (b) heteroaryl;
(C) heterocycloalkyl
(d) alkyl;
(e) cycloalkyl; or
(f) alkylaryl; wherein said Ri groups are optionally substituted with 1 to 4 substituents independently selected from:
(1) halogen (e.g., Br, F, or Cl, preferably F or Cl);
(2) hydroxyl (i.e., -OH);
(3) lower alkoxy (e.g., Ci to C6 alkoxy, preferably C1 to C4 alkoxy, most preferably Ci to C2 alkoxy, more preferably methoxy);
(4) -CF3;
(5) CF3O-;
(6) -NR4R5;
(7) phenyl;
(8) -NO2,
(9) -CO2R4;
(10) -CON(R4)2 wherein each R4 is the same or different;
(11) -S(O)m'N(R2o)2 wherein each R20 is the same or different H or alkyl group, preferably Ci to C4 alkyl, most preferably C1-C2 alkyl, and more preferably methyl;
(12) -CN; or
(13) alkyl; or
(2) R1 and X' taken together form a group selected from:
Figure imgf000056_0001
(3) X' is selected from: =C(O), =C(NOR3), =C(NNR4R5),
Figure imgf000056_0002
(4) M1 is carbon;
(5) M2 is selected from C or N; (6) M3 and M4 are independently selected from C or N;
(7) Y1 is selected from: is -CH2-, =C(O), =C(NOR20) (wherein R20 is as defined above), or =C(S);
(8) Z is a Ci - C6 alkyl group;
(9) R2 is a five or six-membered heteroaryl ring, said six-membered heteroaryl ring comprising 1 or 2 nitrogen atoms with the remaining ring atoms being carbon, and said five-membered heteroaryl ring containing 1 or 2 heteroatoms selected from: nitrogen, oxygen, or sulfur with the remaining ring atoms being carbon; said five or six membered heteroaryl rings being optionally substituted with 1 to 3 substituents independently selected from: halogen, hydroxyl, lower alkyl, lower alkoxy, -CF3, CF3O-, -NR4R5, phenyl, -NO2, -CO2R4, -CON(R4J2 wherein each R4 is the same or different, -0-!2NR4R5, -(N)C(NR4Rs)2, or -CN;
(10) R3 is selected from:
(a) hydrogen;
(b) C1 - C6 alkyl;
(c) aryl;
(d) heteroaryl;
(e) heterocycloalkyl;
(f) arylalkyl (e.g., aryl(Ci to C4)alkyl, e.g., -(CH2)w-aryl wherein w' is 1 to 4, preferably 1 or 2, and most preferably 1 , such as, for example -CH2phenyl or -CH2substituted phenyl);
(g) -(CH2)β-C(O)N(R4)2 wherein each R4 is the same or different, (h) -(CH2)S-C(O)OR4;
(i) -(CH2)e-C(O)R30 wherein R3o is a heterocycloalkyl group, such as, for example, morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl, including
Figure imgf000057_0001
G) -CF3; or
(k) -CH2CF3; wherein said aryl, heteroaryl, heterocycloalkyl, and the aryl portion of said arylalkyl are optionally substituted with 1 to 3 (preferably 1) substituents selected from: halogen (e.g., F or Cl), -OH, -OCF3, -CF3, -CN, -N(R4S)2, -CO2R45, Or-C(O)N(R4S)2, wherein each R45 is independently selected from: H, alkyl, alkylaryl, or alkylaryl wherein said aryl moiety is substituted with 1 to 3 substituents independently selected from -CF3, - OH, halogen, alkyl, -NO2, or -CN;
(11) R4 is selected from: hydrogen, Ci - C6 alkyl, aryl, alkylaryl, said aryl and alkylaryl groups being optionally substituted with 1 to 3 substituents selected from: halogen, -CF3, -OCF3, -OH, -N(R45J2, -CO2R45, -C(O)N(R45J2, or -CN; wherein R45 is as defined above;
(12) R5 is selected from: hydrogen, Ci - C6 alkyl, -C(O)R4, -C(O)2R4, or -C(O)N(R4J2 wherein each R4 is independently selected, and R4 is as defined above;
(13) or R4 and R5 taken together with the nitrogen atom to which they are bound forms a five or six membered heterocycloalkyl ring (e.g., morpholine);
(14) R6 is selected from: alkyl, aryl, alkylaryl, halogen, hydroxyl, lower alkoxy, -CF3, CF3O-, -NR4R5, phenyl, -NO2, -CO2R5, -CON(R4)Z wherein each R4 is the same o r d iff e rent, o r -CN ;
(15) Ri2 is selected from: alkyl, hydroxyl, alkoxy, orfluoro;
(16) Ri3 is selected from: alkyl, hydroxyl, alkoxy, orfluoro;
(17) a' (subscript for Ri2) is O to 2;
(18) b' (subscript for Ri2) is O to 2;
(19) c' (subscript for R6) is O to 2;
(20) e1 is O to 5;
(21) m' is 1 or2;
(22) n' is 1 , 2 or 3; and
(23) p' is 1 , 2 or 3, with the proviso that when M3 and M4 are both nitrogen, then p' is 2 or 3 (i.e., p' is not 1 when M3 and M2 are both nitrogen) is present in the therapeutic combinations.
More preferred definitions for the compounds of formula XIII are as follows: Ri is preferably selected from:
(A) aryl (most preferably phenyl);
(B) substituted aryl (e.g., substituted phenyl), wherein the substituents on said substituted aryl are most preferably selected from: (1) halo (e.g., monohalo or dihalo), more preferably chloro orfluoro, even more preferably monochloro, dichloro, monofluoro or difluoro; or (2) alkyl, more preferably uπbranched (i.e., straight chain, e.g., methyl) alkyl, even more preferably substituted alkyl, still more preferably alkyl substituted with halo (e.g., 1 , 2 or 3 halo atoms, such as Cl or F), even still more preferably alkyl substituted with fluoro atoms, yet still more preferably trifluromethyl;
(C) heteroaryl, most preferably a five or six membered heteroaryl ring, more preferably a six membered heteroaryl ring, and still more preferably pyridyl, examples of heteroaryl rings include pyridyl, thienyl, pyrimidinyl, thiazolyl or pyridyl N- Oxide, most preferred heteroaryl rings are exemplified by
Figure imgf000059_0001
wherein
Figure imgf000059_0002
is preferred more;
(D) substituted heteroaryl, most preferably halo or alkyl substituted heteroaryl (e.g., halopyridyl (e.g., fluoropyridyl) and alkylthiazolyl), more preferably substituted heteroaryl wherein the substituents are independently selected from the same or different alkyl groups (even more preferably one straight chain alkyl group, e.g., methyl), still more preferably alkyl substituted thiazolyl, and even more preferably
Figure imgf000059_0003
yet even more preferably
Figure imgf000059_0004
(E) when Ri is taken together with X', then the moiety is
Figure imgf000059_0005
wherein c' is most preferably 0 or 1 , and when c1 is 1 then Re is most preferably halo, and when c' is 1 then R6 is more preferably fluoro.
X' is preferably =C(NOR3) wherein R3 is preferably selected from H, alkyl or halo substituted alkyl (e.g., fluoro substituted alkyl, such as -CH2CF3), most preferably alkyl, more preferably methyl or ethyl, and still more preferably methyl.
Preferably M2 is nitrogen. n' is preferably 2. a' is preferably 0 or 1 , and most preferably 0. b' is preferably 0 or 1, and most preferably 0. c' is preferably 0 or 1, and most preferably 0, and when c is 1 then Re is preferably halo, and when c is 1 R6 is most preferably fluoro. e' is preferably 1-5.
Y' is preferably =C(O) (i.e., =C=O).
M3 and M4 are preferably selected such that: (1) one is carbon and the other is nitrogen, or (2) both are nitrogen, with M3 most preferably being carbon. p' is preferably 2.
Z is preferably Ci to C3 alkyl, and most preferably
CH3
R2 is preferably a six membered heteroaryl ring, most preferably pyridyl, substituted pyridyl, pyrimidinyl or substituted pyrimidinyl, more preferably pyridyl, pyridyl substituted with -NR4R5, pyrimidinyl or pyrimidinyi substituted with -NR4R5, still more preferably pyridyl, pyridyl substituted with -NH2 (i.e., R4 and R5 are H), pyrimidinyl or pyrimidinyl substituted with -NH2 (i.e., R4 and R5 are H), and even more preferably
Figure imgf000060_0001
and still even more preferably
Figure imgf000061_0001
R3 is preferably H or alkyl, most preferably H or methyl. R4 is preferably H or lower alkyl, most preferably H or methyl, and more preferably H.
R5 is preferably H, Ci to C6alkyl Or-C(O)R4, most preferably H or methyl, and more preferably H.
R12 is preferably alkyl, hydroxyl or fluoro, and most preferably H.
R13 is preferably alkyl, hydroxyl or fluoro, and most preferably H.
Methods for making compounds of formula XIII are well known to those skilled in the art. Non-limiting examples of suitable methods are disclosed in U.S. Patent No. 6,720,328 B1, herein incorporated by reference.
Examples of compounds of formula XIII that are useful in this invention are represented by the following formulae:
Figure imgf000061_0002
(XlIlB), and
Figure imgf000062_0001
In yet another embodiment, this invention provides for compositions, therapeutic combinations and methods of the present invention wherein at least one H3 receptor antagonist/inverse agonist is a compound of the formula:
Figure imgf000062_0002
or a pharmaceutically acceptable salt or solvate thereof, wherein: the dotted line represents an optional double bond; a' is 0 to 2; b' is 0 to 2; n' is 1 , 2 or 3; p1 is 1, 2 or 3; r" is O, 1, 2, or 3; with the provisos that when M2 is N, p1 is not 1; and that when f is 0, M2 is C(R3); and that the sum of p' and r" is 1 to 4;
M1 is C(R3) or N;
M2 is C(R3) or N;
X' is a bond or C1-C6 alkylene;
Y1 is -C(O)-, -C(S)-, -(CH2)q- -, -NR4 C(O)-, -C(O)NR4-, -C(O)CH2-, -SO2-, -N(R4)-, -NH-C(=N-CN)- or -C(=N-CN)-NH-; with the provisos that when M1 is N, Y' is not -NR4C(O)- or -NH-C(=N-CN)-; when M2 is N, Y' is not -C(O)NR4- or ~C(=N-CN)-NH-; and when Y' is -N(R4)-, M1 is CH and M2 is C(R3); q' is 1 to 5, provided that when both M1 and M2 are N, q' is 2 to 5;
Z is a bond, C1-C6 alkylene, C1-C6 alkenylene, -C(O)-, -CH(CN)-, -SO2- or -CH2C(O)NR4-;
Figure imgf000063_0001
Q1 Js -N(R8K -S- Or-O-; k' is O, 1, 2, 3 or 4; k1 is O, 1 , 2 or 3; k2 is O, 1 or 2; R is H, C1-C6 alkyl, halo(C1-C6)alkyl-, C1-C6 alkoxy, (C1-C6)alkoxy- (CrC6)alkyl-,
Figure imgf000064_0001
R32-aryl(C1-C6)alkoxy-, R32-aryl(C1-C6)alkyl-, R32-aryl, R32-aryloxy, R32-heteroaryl, (C3-Ce)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, (C3-C6)cycloalkyl-(C1-C6)alkoxy, (C3-C6)cycloalkyl-oxy-, R37-heterocycloalkyl, Raγ-heterocycloalkyl-oxy-, R3r-heterocycloalkyl-(C1-C6)alkoxy, N(R30)(R3I )-(C1-C6)alkyl-, -N(R30)(R3I ),
Figure imgf000064_0002
-NHC(O)NH(R29); R29-S(O)0-2-, halo(C1-C6)alkyl-S(O)0-2-. N(R3o)(R3i)-(C1-C6)alkyl-S(O)0-2- or benzoyl;
R8 is H, C1-C6 alkyl, halo(C1-C6)alkyl-, (C1-C6)alkoxy-(C1-C6)alkyl-, R32-aryl(C1- C6)alkyl-, R32-aryl, R32-heteroaryl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyll R37-heterocycloalkyl, N(R30)(R3i)-(C1-C6)alkyl-I R29-S(O)2-, halo(C1-C6)alkyl-S(O)2-> R29-S(0)o.i-(C2-C6)alkyl-, ha]o(C1-C6)alkyl-S(0)o-i-(C2-C6)alkyl-;
R3 is a six-membered heteroaryl ring having 1 or 2 heteroatoms independently selected from N or N-O, with the remaining ring atoms being carbon; a five-membered heteroaryl ring having 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S, with the remaining ring atoms being carbon; R32-quinolyl; R32-aryl; heterocycloalkyl; (C3-C6)cycloalkyl; C1-C6 alkyl; hydrogen; thianaphthenyl;
Figure imgf000064_0003
wherein said six-membered heteroaryl ring or said five-membered heteroaryl ring is optionally substituted by R6;
R3 is H, halogen, C1-C6 alkyl, -OH, (C1-C6)alkoxy or -NHSO2-(C1-C6)alkyl;
R4 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, R33-aryl, R33-aryl(C1-C6)alkyl, and R32-heteroaryl;
R5 is hydrogen, C1-C6 alkyl, -C(O)R20, -C(O)2R2O, -C(O)N(R20)2, (d-C6)alkyl- SO2-, or (C1-C6)aIkVl-SO2-NH-; or R4 and R5, together with the nitrogen to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring; Re is 1 to 3 substituents independently selected from the group consisting of - OH, halogen, C1-C6 alkyl-, C1-C6 alkoxy, C1-C6 alkylthio, -CF3, -NR4 R5, -CH2-NR4R5. - NHSO2R22, -N(SO2R22)2, phenyl, R33-phenyl, NO2, -CO2R4, -CON(R4)2,
Figure imgf000065_0001
R7 is -N(R29)-, -O- or-S(O)o-2-;
R12 is independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, or fluoro, provided that when R12 is hydroxy orfluoro, then Ri2 is not bound to a carbon adjacent to a nitrogen; or two R12 substituents form a Ci to C2 alkyl bridge from one ring carbon to another non-adjacent ring carbon; or Ri2 is =O;
R13 is independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, orfluoro, provided that when R13 is hydroxy orfluoro then R13 is not bound to a carbon adjacent to a nitrogen; or two R13 substituents form a Ci to C2 alkyl bridge from one ring carbon to another non-adjacent ring carbon; or R13 is =O;
R2 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, or aryl, wherein said aryl group is optionally substituted with from 1 to 3 groups independently selected from halogen, -CF3, -OCF3, hydroxyl, or methoxy; or when two R20 groups are present, said two R2o groups taken together with the nitrogen to which they are bound can form a five or six membered heterocyclic ring;
R22 is C1-C6 alkyl, R34-aryl or heterocycloalkyl;
R24 is H, C1-C6 alkyl, -SO2R2 or R34-aryl;
R25 is independently selected from the group consisting of Ci-C6 alkyl, halogen, -CN, -NO2, -CF3, -OH, C1-C6 alkoxy, (C1-C6)alkyl-C(O)-, aryl-C(O)-, -C(O)OR29, - N(R4)(R5), N(R4)(Rg)-C(O)-, N(R4)(R5)-S(O)i-2-, R22-S(O)o-2-, halo-(C1-C6)alkyl- or halo- (C1-C6)alkoxy-ζC1-C6)alkyl-;
R29 is H, C1-C6 alkyl, C3-C6 cycloalkyl, R35-aryl or R35-aryl(C1-C6)alkyl-;
R30 is H, C1-C6 alkyl-, R35-aryl or R35-aryl(C1-C6)alkyl-;
R31 is H, C1-C6 alkyl-, R35-aryl, Rss-aryKC1-C6)alkyl-, R35-heteroaryl, (C1- C6)alkyl-C(O)-, R35-aryl-C(O)-, N(R4 )(R5)-C(O)-, (C1-C6)alkyl-S(O)2- or R35-aryl-S(O)2-; or R30 and R31 together are -(CH2J4-S-, -(CH2)2-O-(CH2)2- or -(CH2)2-N(R38)-(CH2)2- and form a ring with the nitrogen to which they are attached; R32 is 1 to 3 substituents independently selected from the group consisting of H1 -OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, R35-aryl-O-, -SR22, -CF3, -OCF3, -OCHF2, - NR39R40, phenyl, R33-phenyl, NO2, -CO2R39, -CON(R39)2, -S(O)2R22, -S(O)2N(R2o)2, - N(R24)S(O)2R22, -CN, hydroxy-(C1-C6)alkyl-, -OCH2CH2OR22, and R35-aryl(C1-C6)alkyl-O-, or two R32 groups on adjacent carbon atoms together form a - OCH2O- or -O(CH2)2O- group;
R33 is 1 to 3 substituents independently selected from the group consisting of C1-C6 alkyl, halogen, -CN, -NO2, -CF3, -OCF3, -OCHF2 and -O-(d-C6)alkyl;
R34 is 1 to 3 substituents independently selected from the group consisting of H, halogen, -CF3, -OCF3, -OH and -OCH3;
R35 is 1 to 3 substituents independently selected from hydrogen, halo, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, phenoxy, -CF3, -N(R36J2, -COOR20 and -NO2;
R36 is independently selected form the group consisting of H and C1-C6 alkyl;
R37 is 1 to 3 substituents independently selected from hydrogen, halo, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, phenoxy, -CF3, -N(R36^, -COOR20, -C(O)N(R2^ and - NO2, or R37 is one or two =O groups;
R38 is H, C1-C6 alkyl, R3s-aryl, R35-aryl(C1-C6)alkyl-, (CrC6)alkyl-SO2 or halo(C1-C6)alkyl-SO2-;
R39 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6)cycloalkyKCt-C6)alkyl, R33-aryl, R33-aryl(C1-C6)alkyl, and R32-heteroaryl; and
R40 is hydrogen, C1-C6 alkyl, -C(O)R20, -C(O)2R2O, -C(O)N(R20)2, (C1-C6)alkyl- SO2-, or (C1-C6)alkyl-SO2-NH-; or R39 and RAO, together with the nitrogen to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring.
Methods for making compounds of formula XlV are well known to those skilled in the art. Non-limiting examples of suitable methods are disclosed in US Publication No US 2004/0097483A1 , herein incorporated by reference.
Another embodiment, this invention provides for compositions, therapeutic combinations and methods of the present inventions wherein the H3 receptor antagonist /inverse agonist is a compound of the formula:
Figure imgf000067_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein: a' is 0 to 3; b1 is 0 to 3; . n' is 1 , 2 or 3; p' is 1 , 2 or 3; rMs O, 1, 2, or3; X' is a bond or C1-C6 alkylene; M1 is CH or N; M2 is C(R3) or N;
with the provisos that when M2 is N, p' is not 1 ; and that when r" is 0, M2 is C(R3); and that the sum of p' and r* is 1 to 4;
Y' is -C(=O)-, -C(=S)-( -(CH2V -• -NR-A=O)-, -Cf=O)NR4-, -C(=O)CH2-, -SOL 2-, -C(=N-CN)-NH- or-NH-C(=N-CN)-; with the provisos that when M1 is N, Y' is not - NR4Cf=O)- or-NH-C(=N-CN)-; and when M2 is N, Y" is not -Ct=O)NR4- or-C(=N- CN)-NH-; q' is 1 to 5, provided that when M1 and M2 are both N, q' is not 1 ;
Z is a bond, C1-C6 alkylene, C2-C6 alkenylene, -C(=O)-, -CH(CN)- or -CH2C(=O)NR4-;
Figure imgf000068_0001
Q' is -N(R8)- , -S- or -O-; k1 is 0, 1 , 2, 3 or 4; k1 is O, 1, 2 or 3; k2 is O1 1 or 2; the dotted line represents an optional double bond;
R and R7 are independently selected from the group consisting of H, C1-C6 alkyl, halo(C1-C6)alkyl-, C1-C6 alkoxy, (Ci -C6)alkoxy-(C1 -C6)alkyl-, (d-CeO-alkoxy- (C1-C6)alkoxy, (d-C6)alkoxy-(C1-C6)alkyl-SOo^, R∞-aryKd-CfOalkoxy-, R32-aryl- (d-C6)alkyl-, R32-aryl, R32-aryloxy, R32-heteroaryl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl- (C1-C6)alkyl, (QrC6)cycloalkyKC1-C6)alkoxy, (C3-C6)CyClOa Ikyl-oxy-, R37-heterocyclo- alkyl, N(R30)(R3I )-(C1-C6)alkyl-, -N(R30)(R31), -NH-(C1-Cβ)alkyl-O-(C1-Cβ)alkyl, - NHC(O)NH(R29); R29-S(O)0-2-, halo(C1-C6)alkyl-S(O)0.2-, N(R30)(R31 )-(CrC6)alkyl- S(O)0-2-, benzoyl, (C1-C6)alkoxy-carbonyl, R37-heterocycloalkyl-N(R29)-C(0)-, (C1- C6)alkyl-N(R29)-C(O)-, (C1-C6)a^yI-N(C1-C6 alkoxy)-C(O)- and -C^NOR36)R36; and when the optional double bond is not present, R7 can be OH;
R8 is H, C1-C6 alkyl, haloid-C^alkyl-, (C1-QOalkoxy-fC^C6)alkyl-, R32-aryl(C1- C6)alkyl-, R32-aryl, R32-heteroaryl, R32-heteroaryl(C1-C6)alkyl-, (C3-C6)cycloalkyl, (C3- C6)cycloalkyl-(C1-C6)alkyl, R37-heterocycloalkyl, R37-heterocycloalkyl(C1-C6)alkyl, N(R3Q)(R3i)-(C2-C6)alkyl-, R29-S(O)2-, halo(C1-C6)alkyl-S(O)2-, R29-S(O)0-i-(C2-C6)alkyl- , halo(C1-C6)alkyl-S(0)o.1-(C2-C6)alkyl-, (d-C6)alkyl-NCRagJ-SO^, or R32-heteroaryl- SO2; R2 is a six-membered heteroaryl ring having 1 or 2 heteroatoms independently selected from N or N-O1 with the remaining ring atoms being carbon; a five-membered heteroaryl ring having 1 , 2 or 3 heteroatoms independently selected from N, O or S, with the remaining ring atoms being carbon; R32-quinolyl; R32-aryl;
"VfV or heterocycloalkyl; wherein said six-membered heteroaryl ring or said five- membered heteroaryl ring is optionally substituted by R6;
R3 is H, halogen, C1-C6 alkyl, -OH or (C1-C6)alkoxy;
R4 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, (Ca-C6)cycloalkyKC1-C6)alkyl, R33-aryl, R33-aryl(C1-C6)alkyl, and R33-heteroaryl;
R5 is hydrogen, C1-C6 alkyl, -C(O)R2O, -C(O)2R2O, -C(O)N(R20)2, R33^rVl(C1- C6)alkyl or (C-,-C6)alkyl-SO2-;
Re is 1 to 3 substituents independently selected from the group consisting of - OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, -CF3, -NR4R5, -(CrC6)alkyl-NR4R5, phenyl, R33-phenyl, NO2, -CO2R4, -CON(R4^, -NHC(O)N(RO2, R32-heteroaryl-SO2-NH-, R32- aryHC-rC^alkyl-NH-, R32-heteroaryl-(C1-C6)alkyl-NH-, R32-heteroaryl-NH-C(O)-NH- and R37-heterocyclo-alkyl-N(R29)-C(O)-;
R12 is independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, orfluoro, provided that when R12 is hydroxy orfluoro, then R12 is not bound to a carbon adjacent to a nitrogen; or R12 forms a C1 to C2 alkyl bridge from one ring carbon to another ring carbon;
R13 is independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, orfluoro, provided that when R13 is hydroxy orfluoro then Ri3 is not bound to a carbon adjacent to a nitrogen; or forms a C1 to C2 alkyl bridge from one ring carbon to another ring carbon; or R13 is =0;
R20 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, or aryl, wherein said aryl group is optionally substituted with from 1 to 3 groups independently selected from halogen, -CF3, -OCF3, hydroxyl, or methoxy; or when two R2o groups are present, said two R20 groups taken together with the nitrogen to which they are bound can form a five or six membered heterocyclic ring; F?22 is C1-C6 alkyl, R34-aryl or heterocycloalkyl;
R24 is H, C1-C6 alkyl, -SO2R22 or R34-aryl;
R25 is independently selected from the group consisting of C1-C6 alkyl, halogen, -CF3, -OH, C1-C6 alkoxy, (C1-C6)alkyl-C(O)-, aryl-C(O)-, N(R4)(Rs)-C(O)-, N(R4)(R5)- S(O)i-2-, halo-(C1-Cβ)alkyl- or halo-(C1-C6)alkoxy-(C1-C6)alkyl-;
R29 is H, C1-C6 alkyl, R35-aryl or R35-aryl(C1-C6)alkyl-;
R30 is H, C1-C6 alkyl-, R35-aryl or R35-aryl(C1-C6)alkyl-;
R31 is H, C1-C6 alkyl-, R35-aryl, R35-aryl(C1-C6)alk'yl-, (C1-C6)alkyl-C(O)-, R35- aryl-C(O)-, N(R4)(Rg)-C(O)-, (CrC6)alkyl-S(O)2- or R35-aryl-S(O)2-; or R30 and R3i together are -(CH2)4-5-. -(CH2^-O-(CH2V or — (CH2)2-N(R2g)-(CH2)2- and form a ring with the nitrogen to which they are attached;
R32 is 1 to 3 substituents independently selected from the group consisting of H, -OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, R35-aryl-O-, -SR22, -CF3, -OCF3, -OCHF2, - NR4R5, phenyl, R33-ρhenyl, NO2, -CO2R4, -CON(R4J2, -S(O)2R22, -S(O)2N(R20^, - N(R24)S(O)2R22, -CN, hydroxy-(C1-C6)alkyl-, -OCH2CH2OR22, and R35-aryl(C1-C6)alkyl- O-, wherein said aryl group is optionally substituted with 1 to 3 independently selected halogens;
R33 is 1 to 3 substituents independently selected from the group consisting of C1-C6 alkyl, halogen, -CN, -NO2, -OCHF2 and -O-(C1-Cβ)alkyl;
R34 is 1 to 3 substituents independently selected from the group consisting of H, halogen, -CF3, -OCF3, -OH and -OCH3.
R35 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, phenoxy, -CF3, -N(R36)2, -COOR20 and -NO2;
R36 is independently selected from the group consisting of H and C1-C6 alkyl; and
R37 is independently selected from the group consisting of H, C1-C6 alkyl and (d-C6)alkoxycarbonyl.
Preferred compounds of formula XV include the following wherein:
Ri is preferably 3-indolyl or 1-indolyl. The doubfe bond is preferably present in the Ri substituent R is preferably H, alkyl, R32-aryl, R32-heteroaryl, (C1-C6)alkoxy-carbonyl or (C1-C6)alkyl-N(R29)-C(O)-. When R is (C1-C6)alkyl-N(R29)-C(O)-, R29 is preferably H or C1-C6 alkyl. More preferably, R is R32-aryl or R32-heteroaryl. Especially preferred are R32-phenyl and R32-pyridyl. R7 is preferably H.
R8 is preferably H,
Figure imgf000071_0001
R32-aryl, R32-heteroaryl, (C1-C6)alkyl-N(R29)-SO2- or R37-heterocycloalkyl(C1-C6)alkyl-. Especially preferred are H, R32-benzyl, R32-pyridylmethyl, (C1-C6)alkyl-N(R29)-SO2- wherein R29 is H or Ct-C6 alkyl, and piperidinoethyl.
R25 is preferably H, halogen or -CF3 and k' is 0 or 1. When R1 is an aza- or diaza derivative of indole, R is preferably as defined above, and k1 and k2 are preferably zero.
X' is preferably a bond.
R2 is preferably a six-membered heteroaryl ring, optionally substituted with one substituent. More preferably, R2 is pyridyl, pyrimidyl or pyridazinyl, optionally substituted with -NH2.
Y" is preferably -C(O)-.
Z1 is preferably straight or branched C1-C3 alkyl. Methylene is an especially preferred Z group.
M1 is preferably N; a' is preferably 0; and n' is preferably 2; the optional double bond in the ring containing M1 is preferably not present (i.e., a single bond is present).
M2 is preferably C(R3) wherein R3 is hydrogen or fluoro; b' is preferably 0; r1 is preferably 1 ; and p' is preferably 2.
Methods for making compounds of formula XV are well known to those skilled in the art. Non-limiting examples of suitable methods are disclosed in US Publication No US 2004/0019099A1, herein incorporated by reference.
In yet another embodiment, this invention provides for compositions, therapeutic combinations and methods wherein at least one H3 receptor antagonist/inverse agonist is a compound of formula XVI:
Figure imgf000072_0001
armaceutically acceptable salt or solvate thereof, wherein:
(A) R1 i is selected from:
(1) aryl;
(2) heteroaryl;
(3) heterocycloalkyl
(4) alkyl;
(5) -C(O)N(R4B)2;
(6) cycloalkyl;
(7) arylalkyl;
(8) heteroarylheteroaryl (e.g. , isoxazoylthienyl or pyridylthienyl); or
(9) a group selected from:
Figure imgf000072_0002
Figure imgf000072_0003
said aryl (see (A)(1) above), heteroaryl (see (A)(2) above), aryl portion of arylalkyl (see (A)(7) above), phenyl ring of formula Il (see (A)(9) above), phenyl ring of formula III (see (A)(9) above), phenyl rings of formula IVB (see (A)(9) above), or phenyl rings of formula IVD (see (A)(9) above) are optionally substituted with 1 to 3 substituents independently selected from:
(1) halogen (e.g., Br, F, or Cl, preferably F or Cl);
(2) hydroxyl (i.e., -OH);
(3) lower alkoxy (e.g., Ci to C6 alkoxy, preferably Ci to C4 alkoxy, more preferably Ci to C2 alkoxy, most preferably methoxy);
(4) -Oaryl (i.e., aryloxy);
(5) -SR22;
(6) -CF3;
(7) -OCF3;
(8) -OCHF2;
(9) -NR4R5;
(10) phenyl;
(11) NO2,
(12) -CO2R4;
(13) -CON(R4^ wherein each R4 is the same or different;
(14) -S(O)2R22;
(15) -S(O)2N(R2O)2 wherein each R2o is the same or different;
(16) -N(R24)S(O)2R22;
(17) -CN;
(18) -CH2OH;
(19) -OCH2CH2OR22;
(20) alkyl (e.g., C1 to C4, such as methyl);
(21 ) substituted phenyl wherein said phenyl has 1 to 3 substituents independently selected from alkyl, halogen, -CN, -NO2, -OCHF2, - Oalkyl;
(22) -Oalkylaryl (preferably -Oalkylphenyl or -Oalkyl-substituted phenyl, e.g., -OCH2dichlorophenyl, such as -OCH2-2,6- dichlorophenyl or -OCH2-2-chloro-6-fIuorophenyl) wherein said aryl group is optionally substituted with 1 to 3 independently selected halogens; or (23) phenyl;
(B) X' Is selected from alky! (e.g., -(CH2)q- or branched alkyl) or -S(O)2-;
(C) Y' represents
(1) a single bond (i.e., Y1 represents a direct bond from M1 to M2); or
(2) Y' is selected from -C(O)-, -C(S)-, -(CH2)q- -, or -NR4C(O)-; with the provisos that:
(a) when M1 is N, then Y" is not -NR4C(O)-; and
(b) when Y' is a bond, then M1 and M2 are both carbon;
(D) M1 and M2 are independently selected from C or N;
(E) Z' is selected from: C1-C6 alkyl, -SO2-, -C(O)- or -C(O)NR4-;
(F) R2 is selected from:
(1) a six-membered heteroaryl ring having 1 or 2 heteroatoms independently selected from N or N-O (i.e., N-oxide), with the remaining ring atoms being carbon;
(2) a five-membered heteroaryl ring having 1 to 3 heteroatoms selected from nitrogen, oxygen, or sulfur with the remaining ring atoms being carbon; or
(3) an alkyl group, preferably a C1 to C4 alkyl group, more preferably methyl;
(4) an aryl group, e.g., phenyl or substituted phenyl (preferably phenyl), wherein said substituted phenyl is substituted with 1 to 3 substituents independently selected from: halogen, -Oalkyl, - OCF3, -CF3, -CN, -NO2, -NHC(O)CH3, or -O(CH2)q N(R10A)2;
(5) -N(R11A)2 wherein each R11A is independently selected from: H, alkyl (e.g., i-propyl) or aryl (e.g., phenyl), preferably one R11A is H and the other is phenyl or alkyl (e.g., i-propyl);
(6) a group of the formula:
Figure imgf000075_0001
(7) a heteroarylheteroaryl group, e.g.,
Figure imgf000075_0002
said five membered heteroaryl ring ((F)(2) above) or six-membered heteroaryl ring ((F)(I ) above) is optionally substituted with 1 to 3 substituents selected from:
(a) halogen;
(b) hydroxyl;
(c) lower alkyl;
(d) lower alkoxy;
(e) -CF3;
(f) -NR4R5;
(g) phenyl; (h) -NO2;
(i) -C(O)N(R4J2 (wherein each R4 is the same or different); (j) -C(O)2R4; or
(k) phenyl substituted with 1 to 3 substituents independently selected from: halogen, -Oalkyl, -OCF3, -CF3, -CN, -NO2 or -O(CH2)qN(R10A)2; (G) R3 is selected from:
(1) aryl;
(2) heteroaryl;
(3) heterocycloalkyl
(4) alkyl; or
(5) cycloalkyl; wherein said aryl or heteroaryl R3 groups is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen (e.g., Br, F, or Cl, preferably F or Cl);
(b) hydroxyl (i.e., -OH);
(c) lower alkoxy (e.g., Ci to Cβ alkoxy, preferably Ci to C4 alkoxy, more preferably Ci to C2 alkoxy, most preferably methoxy);
(d) -Oaryl (i.e., aryloxy);
(e) -SR22;
(f) -CF3;
(g) -OCF3; (h) -OCHF2; (i) -NR4R5; (j) phenyl; (k) -NO2,
(I) -CO2R4;
(m) -CON(R4J2 wherein each R4 is the same or different; (n) -S(O)2R22;
(o) -S(0)2N(R2o)2 wherein each R2o is the same or different; (P) -N(R24)S(O)2R22; (q) -CN; (r) -CH2OH; (s) -OCH2CH2OR22; or (t) alkyl; (H) R4 is selected from:
(1) hydrogen;
(2) C1-C6 alkyl;
(3) cycloalkyl;
(4) cycloalkylalkyl (e.g., cyclopropyl-CH2- or cyclohexyl-CH2-);
(5) heterocycloalkylalky (e.g., tetrahydrofuranyl-CH2-);
(6) bridged bicyclic cycloalkyl ring, such as, for example:
Figure imgf000076_0001
(7) aryl having a fused heterocycloalkyl ring bound to said aryl ring, preferably the heteroatoms in said heterocycloalkyl ring are two oxygen atoms, e.g., phenyl having a heterocycloalkyl ring bound to said phenyl ring, such as
Figure imgf000077_0001
(8) aryl;
(9) arylalkyl;
(10) alkylaryl;
(11 ) -(CH2)dCH(R12A)2 wherein d is 1 to 3 (preferably 1 ), and each R12A is independently selected from phenyl or substituted phenyl, said substituted phenyl being substituted with 1 to 3 substituents independently selected from: halogen, -Oalkyl, -OCF3, -CF3, -CN, Or -NO2, e.g.,
Figure imgf000077_0002
(12) heterocycloalkylheteroaryl, e.g.,
Figure imgf000077_0003
(13) -(Ci to C6)alkylene-O-R22 (e.g., -C3H6OCH3); wherein the aryl R4 group, the aryl portion of the arylalkyl R4 group, or the aryl portion of the alkylaryl R4 group is optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen;
(b) hydroxyl;
(c) lower alkyl;
(d) lower alkoxy; (e) -CF3;
(f) -N(R20)(R24),
(g) phenyl; (h) -NO2;
(i) -C(0)N(R2o)2 (wherein each R2o is the same or different), 0) -C(O)R22; (i) -(CH2)k-cycloalkyl;
Figure imgf000078_0001
(k) -(CH2V-OR22;
(I) each R4B is independently selected from: H, heteroaryl (e.g., pyridyl), alkyl, alkenyl (e.g., allyl), a group of the formula
Figure imgf000078_0002
arylalkyl (e.g., benzyl), or arylalkyl wherein the aryl moiety is substituted with 1-3 substituents independently selected from: halogen (e.g. -CH2-p-CI-phenyl); preferably one R4B is H;
(J) R5 is selected from: hydrogen, C1-C6 alkyl, -C(O)2O (e.g., -C(O)alkyl, such as -C(O)CH3), -C(O)2R20, -C(O)N(R20)2 (wherein each R2o is the same or different);
(K) each R10A is independently selected from H or Ci to Ce alkyl (e.g., methyl), or each R10A, taken together with the nitrogen atom to which they are bound, forms a 4 to 7 membered heterocycloalkyl ring;
(L) Ri2 is
(1 ) selected from alkyl, hydroxyl, alkoxy, or fluoro, provided that when Ri2 is hydroxy or fluoro then Ri2 is not bound to a carbon adjacent to a nitrogen; or
(2) Ri2 forms an alkyl bridge from one ring carbon to another ring carbon, an example of such a bridged ring system is:
Figure imgf000078_0003
(M) Ri 3 is (1 ) selected from alkyl, hydroxyl, alkoxy, or fluoro, provided that when Ri3 is hydroxy or fluoro then R13 is not bound to a carbon adjacent to a nitrogen; or
(2) R13 forms an alkyl bridge from one ring carbon to another ring carbon, an example of such a bridged ring system is:
Figure imgf000079_0001
(N) R20 is selected from hydrogen, alkyl, or aryl, wherein said aryl group is optionally substituted with from 1 to 3 groups independently selected from: halogen, - CF3, -OCF3, hydroxyl, or methoxy; or when two R20 groups are present, said two R20 groups taken together with the nitrogen to which they are bound form a five or six membered heterocyclic ring;
(O) R22 is selected from: heterocycloalkyl (e.g., morpholinyl or pyrrolidinyl), alkyl or aryl, wherein said aryl group is optionally substituted with 1 to 3 groups independently selected from halogen, -CF3, -OCF3, hydroxyl, or methoxy;
(P) R24 is selected from: hydrogen, alkyl, -SO2R22. or aryl, wherein said aryl group is optionally substituted with 1 to 3 groups independently selected from halogen, -CF3, -OCF3, hydroxyl, or methoxy;
(Q) a' is 0 to 2;
(R) b" is 0 to 2;
(S) k' is 1 to 5;
(T) m" is 2 to 5;
(U) n' is 1 , 2 or 3 with the proviso that when M1 is N, then n' is not 1 ;
(V) p' is 1 , 2 or 3 with the proviso that when M2 is N, then p' is not 1 ;
(W) q' is 1 to 5; and
(X) r' is 1 , 2, or 3 with the proviso that when r" is 2 or 3, then M2 is C and p' is 1.
Methods for making compounds of Formula XVI are well known to those skilled in the art. Non-limiting examples of suitable methods are disclosed in US Patent No. 6,849,621 B2, herein incorporated by reference. In yet another embodiment, this invention provides for compositions, therapeutic combinations and methods of the present invention wherein at least one at least one H3 receptor antagonist/inverse agonist is a compound of formula XVII:
Figure imgf000080_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein: the dotted line represents an optional double bond; a' is 0 to 3,- b' is 0 to 3; n' is 1 , 2 or 3; p' is 1 , 2 or 3; r1 is O, 1, 2, or 3; with the provisos that when M2 is N, p' is not 1 ; and that when r' is 0, M2 is C; and that the sum of p' and r" is 1 to 4;
A' is a bond or C1-C6 alkylene;
M1 is CH or N;
M2 is C(R3) or N;
Y' is-C(=O)-, -C(=S)-, -(CH2V -, -NR4C(=O)-, -Cf=O)NR4-, -C(=O)CH2-, -SOi-2-, -NH-C(=N-CN)- or-C(=N-CN)-NH-; with the provisos that when M1 is N, Y' is not -NR4Ct=O)- or-NH-C(=N-CN)-; and when M2 is N, Y1 is not -C(=O)NR4- or-C(=N- CN)-NH-; q' is 1 to 5, provided that when M1 and M2 are both N, q' is not 1 ;
2' is a bond, C1-C6 alkylene, C1-Cβ alkenylene, -C(=O)-, -CH(CN)-, or -CH2Cf=O)NR4-;
R1 is
Figure imgf000081_0001
k' is O, 1 , 2, 3 or 4; k1 is O, 1 , 2 or 3; k2 is 0, 1 or 2;
R is H, C1-C6 alkyl, hydroxy-(C2-C6)alkyl-, halo-(C1-C6)alkyl-, halo-(C1- C6)alkoxy-<CτC6)alkyl-, R29-O-C(OHC1-C6)alkyl-, (C1-C6)alkoxy-Cd-C6)alkyl-, N(R3o)(R3iHC1-C6)alkyl-I (C1-C6)alkoxy-(C1-C6)alkoxy-(C1-C6)alkyl-, R32-aryl, R32-aryKC1-C6)alkyl-, R32-aryloxy(C1-C6)alkyl-, R32-heteroaryl, R32-heteroaryl(C1- C6)alkyl-, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl-, N(R30)(R3I )-C(O)-(C1- Cβ)alkyl-, or heterocycloalkyl(C1-C6)alkyl-;
R2 is a six-membered heteroaryl ring having 1 or 2 heteroatoms independently selected from N or N-O, with the remaining ring atoms being carbon; a five-membered heteroaryl ring having 1 , 2 or 3 heteroatoms independently selected from N, O or S, with the remaining ring atoms being carbon; R32-quinolyl; R32-aryl; heterocycloalkyl;
Figure imgf000082_0001
wherein said six-membered heteroaryl ring or said five-membered heteroaryl ring is optionally substituted by R6;
X' is C or N;
Q' is a bond or C1-C6 alkylene;
Q1' is a bond, C1-C6 alkylene or -N(R4)-;
R3 is H, halogen, C1-C6 alkyl, -OH or (C1-C6)alkoxy;
R4 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, R33-aryl, R33-aryl(C1-C6)alkyl, and R32-heteroaryl;
R5 is hydrogen, C1-C6 alkyl, -C(O)R20, -C(O)2R20. -C(0)N(R2o)2 or (C1-C6)alkyl-SO2-;
R6 is 1 to 3 substituents independently selected from the group consisting of - OH, halogen, C1-C6 alkyl-, C1-C6 alkoxy, C1-C6 alkylthio, -CF3, -NR4R5, phenyl, R33- phenyl, NO2, -CO2R4, -CON(R4)2>
OCH3
Figure imgf000082_0002
Ri2 is independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, or fluoro, provided that when R12 is hydroxy or fluoro, then Ri2 is not bound to a carbon adjacent to a nitrogen; or R12 forms a C1 to C2 alkyl bridge from one ring carbon to another ring carbon;
Ri3 is independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, or fluoro, provided that when Ri3 is hydroxy or fluoro then R13 is not bound to a carbon adjacent to a nitrogen; or forms a Ci to C2 alkyl bridge from one ring carbon to another ring carbon; or R13 is =O;
R20 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, or aryl, wherein said aryl group is optionally substituted with from 1 to 3 groups independently selected from halogen, -CF3, -OCF3, hydroxyl, or methoxy; or when two R20 groups are present, said two R2o groups taken together with the nitrogen to which they are bound form a five or six membered heterocyclic ring;
R22 is C1-C6 alkyl, R34-aryl or heterocycloalkyl;
R24 is H, C1-C6 alkyl, -SO2R22 or R34-aryl;
R25 is independently selected from the group consisting of C1-C6 alkyl, halogen, -CF3, -OH1 C1-C6 alkoxy, (C1-C6)alkyl-C(O)-, aryl-C(O)-, N(R4)(Rs)-C(O)-, N(R4)(R5)- S(O)i-2-, halo-(C1-C6)alkyl- or halo-(C1-C6)alkoxy-(C1-C6)alkyl-;
R29 is H, C1-C6 alkyl, R35-aryl or R35-aryl(Ct-C6)alkyl-;
R30 is H, C1-C6 alkyl-, R35-aryl or R35-BIyI(C1 -C6)alkyl-;
R31 is H, C1-C6 alkyl-, R35-aryl, Rss-aryKC1-C6)alkyl-, (C1-C6)alkyl-C(O)-, R35- aryl-C(O)-, N(R4)(Rs)-C(O)-, (C1-Cβ)alkyl-S(O)2- or R35-aryl-S(O)2-; or R30 and R31 together are -(CH2)^s-. -(CH2)2-O-(CH2)2- or -(CH2)2-N(R29)-(CH2)2- and form a ring with the nitrogen to which they are attached;
R32 is 1 to 3 substituents independently selected from the group consisting of H, -OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, R35-aryl-O-, -SR22, -CF3, -OCF3, -OCHF2, - NR4R5, phenyl, R33-phenyl, NO2, -CO2R4, -CON(R4J2, -S(O)2R22, -S(O)2N(R2O)2, - N(R24)S(O)2R22, -CN, hydroxy-(C1-C6)alkyl-, -OCH2CH2OR22, and R35-aryl(C-rC6)alkyl- O-, wherein said aryl group is optionally substituted with 1 to 3 independently selected halogens;
R33 is 1 to 3 substituents independently selected from the group consisting of C1-C6 alkyl, halogen, -CN, -NO2, -OCHF2 and -O-(C1-Cβ)alkyl;
R34 is 1 to 3 substituents independently selected from the group consisting of H, halogen, -CF3, -OCF3, -OH and -OCH3.
R35 is 1 to 3 substituents independently selected from hydrogen, halo, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, phenoxy, -CF3, -N(R36)2, -COOR20 and -NO2; and
R36 is independently selected form the group consisting of H and C1-C6 alkyl.
The more preferred compound of formula XVII include the following compounds:
R1 is preferably R-substituted benzimidazolone, wherein R is preferably H, alkyl, alkoxyalkyl, R32-aryl, R32-heteroaryl or heterocycloalkylalkyl. More preferably, R is -CH3, phenyl, 4-fluorophenyl, CH3-O-(CH2J2-,
Figure imgf000083_0001
F?25 is preferably halogen or -CF3 and k is 0 or 1. When Ri is an aza- or diaza derivative of benzimidazolone, R is preferably as defined for benzimidazolone, and ki and k2 are preferably zero.
R2 is preferably a six-rnembered heteroaryl ring, optionally substituted with one substituent. More preferably, R2 is pyridyl, pyrimidinyl or pyridazinyl, each optionally substituted with halogen or -NR4 R5, wherein R4 and R5 are independently selected from the group consisting of H and
Figure imgf000084_0001
or R4 and R5 together with the nitrogen to which they are attached form a pyrrolidinyl, piperidinyl or morpholinyl ring.
A' is preferably a bond.
Y1 is preferably -C(O)-.
Z' is preferably straight or branched C1-C3 alkyl.
M1 is preferably N; a' is preferably 0; and n' is preferably 2; the optional double bond is preferably not present (i.e., a single bond is present).
M2 is preferably C(Ra) wherein R3 is hydrogen or halogen, especially fluorine; b" is preferably 0; r" is preferably 1 ; and p' is preferably 2.
Methods for making compounds of formula XVII are well known to those skilled in the art. Non-limiting examples of suitable methods are disclosed in US Publication No US 2004/0097483A1 , herein incorporated by reference.
Other non-limiting H3 receptor antagonists/inverse agonists are disclosed in U.S. Provisional Application Ser. Nos. 60/692,110 and 60/692,175, both filed on June 20, 2005, U.S. 2002/183309, 2002/177589, 2002/111340, 2004/0122033, 2003/0186963, 2003/0130253, 2004/0248938, 2002/0058659, 2003/0135056, 2003/134835, 2003/153548, 2004/0019099, 2004/0097483, 2004/0048843, 2004/087573, 2004/092521 , 2004/214856, 2004/248899, 2004/224953, 2004/224952, 2005/222151 , 2005/222129, 2005/182045, 2005/171181, 6,620,839, 6,515,013, 6,559,140, 6,316,475, 6,166,060, 6,448,282, 6,008,240, 5,652,258, 6,417,218, 6,673,829, 6,756,384, 6,437,147, 6,720,328, 5,869,479, 6,849,621, 6,908,929, 6,908,926, 6,906,060, 6,884,809, 6,884,803, 6,878,736, 6,638,967, 6,610,721 , 6,528,522, 6,518,287, 6,506,756, 6,489,337, 6,436,939, 6,448,282, 6,407,132, 6,355,665, 6,248,765, 6,133,291 , 6,103,735, 6,080,871 , 5,932,596, 5,929,089, 5,837,718, 5,821 ,259, 5,807,872, 5,639,775, 5,708,171 , 5,578,616, 5,990,147, 6,906,081 , WO 95/14007, WO 99/24405 (each of which is herein incorporated by reference). Other non-limiting examples of H3 receptor antagonists/inverse agonists are disclosed in U.S. Provisional Application Ser. No. 60/752,636 (Attorney Docket
No. CV06410L01US, entitled "Phenoxypiperidines and Analogues Thereof Useful as Histamine H3 Antagonists", and U.S. Provisional Ser. No. 60/752637 (Attorney Docket No. CV06411L01US), entitled "Substituted Aniline Derivatives Useful as Histamine H3 Antagonists", both filed on the same date as this application.
The compositions, therapeutic combinations or methods of the present invention can further comprise one or more obesity control medications. Useful obesity control medications include, but are not limited to, drugs that reduce energy intake or suppress appetite, drugs that increase energy expenditure and nutrient- partitioning agents. Suitable obesity control medications include, but are not limited to, noradrenergic agents (such as diethylpropion, mazindol, phenylpropanolamine, phentermine, phendimetrazine, phendamine tartrate, methamphetamine, phendimetrazine and tartrate); CB1 receptor antagonists (such as rimonabant); topiramate; serotonergic agents (such as sibutramine, fenfluramine, dexfenfluramine, fluoxetine, fluvoxamine and paroxtine); thermogenic agents (such as ephedrine, caffeine, theophylline, and selective β3-adrenergic agonists); an alpha-blocking agent; a kainite or AMPA receptor antagonist; a leptin-lipolysis stimulated receptor; a phosphodiesterase enzyme inhibitor; a compound having nucleotide sequences of the mahogany gene; a fibroblast growth factor-10 polypeptide; a monoamine oxidase inhibitor (such as befloxatone, moclobemide, brofaromine, phenoxathine, esuprone, befol, toloxatone, pirlindol, amiflamine, sercloremine, bazinaprine, lazabemide, milacemide and caroxazone); a compound for increasing lipid metabolism (such as evodiamine compounds); and a lipase inhibitor (such as orlistat). Preferred therapeutic combinations that may be used in the methods according to the present invention include combinations comprising at least one cholesterol lowering agent, such as a sternol or 5-α-stanol according to formulae I-IV and/or an HMG-CoA reductase inhibitor, and at least one H3 receptor antagonist/inverse agonist, such as those according to formulae XIII to XVII. Especially preferred combinations include ezetimibe and/or simvastatin as the cholesterol lowering agents, a compound of formula XUIA-XIIIC, and orlistat. Generally, a total dosage of the above-described obesity control medications can range from 1 to 3,000 mg/day, desirably from about 1 to 1 ,000 mg/day and more desirably from about 1 to 200 mg/day in single or 2-4 divided doses.
Another embodiment of the present invention is therapeutic combinations comprising two cholesterol lowering agents and an hfe receptor antagonist/inverse agonist. Preferred combinations include cholesterol absorption inhibitors, such as those described in formulae I to XII1 and an HMG-CoA reductase inhibitor, PPAR activators, nicotinic acid (niacin) and/or nicotinic acid receptor agonists, or a bile acid sequestrant. Preferred HMG-CoA reductase inhibitors include lovastatin, pravastatin, fluvastatin, simvastatin atorvastatin, cerivastatin, CI-981 , pravastatin and rosuvastatin. Other preferred cholesterol lowering agents to be used with a cholesterol absorption inhibitor, such as those described in formulae I-XII, include cholestryamine, cholestipol, clofibrate, gemfibrozil, and fenofibrate. Preferred H3 receptor antagonists/inverse agonists to be included in the therapeutic combinations include those described in formulae XIII-XVII, with the compounds of formulae XIIIA-XIHC being especially preferred.
Especially preferred therapeutic combination is VYTORIN, which is a combination of ezetimibe and simvastatin (see US 5,846,946, herein incorporated by reference), together with a compound of formulae XIIIA, XVIIIB or XIIIC.
Another embodiment of the present invention comtemplates kits and method of treatment as described above which comprise: (a) at least one cholesterol lowering agent, such as a sterol or 5-α-stanol absorption inhibitor; and (b) at least on H3 receptor antagonist/inverse agonists. Suitable cholesterol lowering agents include any of the compounds discussed above in formulae I-XII and suitable H3 receptor antagonists/inverse agonists include any of the compounds discussed above in formulae XIII-XVII. A kit is contemplated when two separate units ae combined: a pharmaceutical composition comprising at least one cholesterol absorption inhibitor and a separate pharmaceutical composition comprising at least one H3 receptor antagonist/inverse agonist. The kit will preferably include directions for the administration of the separate components. The kit form is particularly advantageous when the separate components must be administered in different dosage forms (e.g., oral and parenteral) or are administered at different dosage intervals.
Another embodiment of the present invention is the treatment, prevention or amelioration of the symptoms or the development of metabolic syndrome in a mammal in need thereof comprising the step of administering an effective amount of a therapeutic composition comprising of at least one cholesterol towering agent and optionally at least one H3 receptor antagonist/inverse agonist to said mammal. Metabolic syndrome is a clustering of atherosclerotic CHD risk factors including obesity, decreased HDL-C, and increased fasting plasma glucose levels, triglyceride levels and blood pressure. More preferably, the therapeutic combination comprises two or three different classes of cholesterol lowering agents, such as an azetinone (e.g. ezetimibe) an activator or agonists of PPAR (e.g., a fibrate, such as fenofibrate), or an HMG-CoA reductase inhibitor (e.g. simvastatin or atorvastatin).
Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term "prodrug", as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of formula I or a salt and/or solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto.
For example, if a compound of formulae l-XVll or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci-C8)alkyl, (C2- Ci2)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyI having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C1-C2)alkylamino(C2-C3)alkyl (such as β-dimethylamiπoethyl), carbamoyl-(C1-C2)alkyl, N,N-di
Figure imgf000088_0001
C2)alkyl and piperidino-, pyrrolidino- or moφholino(C2-C3)alkyl, and the like.
Similarly, if a compound of formulae I-XVII contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C1-C6)alkanoyloxymethyl, 1-((C1- C6)alkanoyloxy)ethyl, 1 -methyl-1 -((C1-C6)alkanoyloxy)ethyl, (d- C6)alkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1- C6)alkanoyl, α-amino(C1-C4)alkanyl, arylacyl and α-aminoacyl, or α-aminoacyl-α- aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(d-C6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxy! group of the hemiacetal form of a carbohydrate), and the like.
If a compound of formulae I-XVII Incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (C1-C10)alkyl, (C3-C7) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or natural α-aminoacyl, — C(OH)C(O)OY1 wherein Y1 is H, (d-C6)alkyl or benzyl, — C(OY2)Y3 wherein Y2 is (C1-C4) alkyl and Y3 is (C1-C6)alkyl, carboxy (d-C6)alkyl, amino(C1-C4)alkyl or mono-N — or di-N,N-(d-C6)alkylaminoalkyl, — C(Y4JY5 wherein Y4 is H or methyl and Y5 is mono-N— or di-N, N-(C1 -C6)alkylamino morpholino, piperidin-1 -yl or pyrrolidin-1-yl, and the like.
The compounds of formulae I-XVII may exists in unsolvated as well as solvated forms. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H2O. "Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective in treating the disease statebeing treated and thus producing the desired therapeutic effect in a suitable patient.
The compounds of formulae I-XVII form salts which are also within the scope of this invention. Reference to a compound of formulae I-XVII herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of formulae I-XVII contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the formulae l-XVII may be formed, for example, by reacting a compound of formulae I-XVII with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. Acids (and bases) which are generally considered suitable for the formation of pharmaceutically useful salts from basic (or acidic) pharmaceutical compounds are discussed, for example, by S. Berge ef a/, Journal of Pharmaceutical Sciences (1977) 66(1 ) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson ef a/, The Practice of Medicinal Chemistry (1996), Academic Press, New York; in The Orange Book (Food & Drug Administration, Washington, D.C. on their website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (2002) Int'l. Union of Pure and Applied Chemistry, pp. 330-331. These disclosures are incorporated herein by reference thereto.
Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, sulfonates (such as those mentioned herein), tartarates, thiocyanates, toluenesulfonates (also known as tosylates.) undecanoates, and the like.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, zinc salts, salts with organic bases (for example, organic amines) such as benzathines, diethylamine, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D- glucamines, N-methyl-D-glucamides, t-butyl amines, piperazine, phenylcyclohexylamine, choline, tromethamine, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. For example, if a compound formulae I-XVII incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chirai centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate" "prodrug" and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the inventive compounds.
Diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diasteromeric mixture by reaction with an appropriate optically active compound (e.g., chirai auxiliary such as a chirai alcohol or Mosher^s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of formulae I-XVII may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chirai HPLC column.
Polymorphic forms of the compounds of formulae 1-XVlI, and of the salts, solvates and prodrugs of the compounds of formulae -XVH, are intended to be included in the present invention
The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 17O, 31P1 32P, 35S, 18F, and 36CI, respectively.
Certain isotopically-labelled compounds of formulae I-XVII (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances, lsotopically labelled compounds ofdFormulae I-XVII can generally be prepared by following procedures analogous to those disclosed in the art, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
It should be noted that throughout the specification and Claims appended hereto any formula, compound, moiety or chemical illustration with unsatisfied valences is assumed to have the hydrogen atom to satisfy the valences unless the context indicates a bond.
The term "therapeutically effective amount" means that amount of therapeutic agents of the invention, such as the substituted azetidinone(s) and H3 receptor antagonist/inverse agonist and other pharmacological or therapeutic agents which may be present that will elicit a biological or medical response of a subject, tissue, system, animal or mammal that is being sought by the administrator (such as a researcher, doctor or veterinarian) which includes alleviation of the symptoms, prevention, slowing or halting of progression of one or more conditions associated with NAFLD.
The daily dose of the compound of formulae I-XVII administered to the mammal can range from about 1 to about 1000 mg per day, preferably about 1 to about mg/day, and more preferably about 100 mg per day, given in a single dose or 2-4 divided doses. The exact dose, however, is determined by the attending clinician and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient.
For administration of pharmaceutically acceptable salts of the above compounds, the weights indicated above refer to the weight of the acid equivalent or the base equivalent of the therapeutic compound derived from the salt.
For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 0.1 to about 7.5 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.
Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
Aerosol preparations suitable for inhalation may include solutions, suspensions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as a compressed gas, e.g. HFA.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
Preferably the compound is administered orally.
Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 to about 500 mg, preferably from about 1 mg to about 250 mg, more preferably from about 1 mg to about 100 mg, according to the particular application.
The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required. The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 100 mg/day, in two to four divided doses.
Some useful terms are described below:
Capsule - refers to a special container or enclosure made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredients. Hard shell capsules are typically made of blends of relatively high gel strength bone and pork skin gelatins. The capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and preservatives.
Tablet- refers to a compressed or molded solid dosage form containing the active ingredients with suitable diluents. The tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or dry blending.
Oral gels- refers to the active ingredients dispersed or solubilized in a hydrophillic semi-solid matrix.
Powders for constitution - refers to powder blends containing the active ingredients and suitable diluents which can be suspended or solubilized in water or juices.
Diluent - refers to substances that usually make up the major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn, rice and potato; and celluloses such as microcrystalline cellulose. The amount of diluent in the composition can range from about 10 to about 90% by weight of the total composition, preferably from about 25 to about 75%, more preferably from about 30 to about 60% by weight, even more preferably from about 12 to about 60%.
Disinteqrants - refers to materials added to the composition to help it break apart (disintegrate) and release the medicaments. Suitable disintegrants include starches; "cold water soluble" modified starches such as sodium carboxymethyl starch; natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose; microcrystalline celluloses and cross-linked microcrystalline celluloses such as sodium croscarmellose; alginates such as alginic acid and sodium alginate; clays such as bentonites; and effervescent mixtures. The amount of disintegrant in the composition can range from about 2 to about 15% by weight of the composition, more preferably from about 4 to about 10% by weight.
Binders - refers to substances that bind or "glue" powders together and make them cohesive by forming granules, thus serving as the "adhesive" in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose; starches derived from wheat, corn rice and potato; natural gums such as acacia, gelatin and tragacanth; derivatives of
seaweed such as alginic acid, sodium alginate and ammonium calcium alginate; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics such as magnesium aluminum silicate. The amount of binder in the composition can range from about 2 to about 20% by weight of the composition, more preferably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight.
Lubricant - refers to a substance added to the dosage form to enable the tablet, granules, etc. after it has been compressed, to release from the mold or die by reducing friction or wear. Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants such as sodium chloride, sodium beπzoate, sodium acetate, sodium oleate, polyethylene glycols and d'l-leucine. Lubricants are usually added at the very last step before compression, since they must be present on the surfaces of the granules and in between them and the parts of the tablet press. The amount of lubricant in the composition can range from about 0.2 to about 5% by weight of the composition, preferably from about 0.5 to about 2%, more preferably from about 0.3 to about 1.5% by weight.
Glidents - materials that prevent caking and improve the flow characteristics of granulations, so that flow is smooth and uniform. Suitable glidents include silicon dioxide and talc. The amount of glident in the composition can range from about 0.1% to about 5% by weight of the total composition, preferably from about 0.5 to about 2% by weight.
Coloring agents - excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes and food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide. The amount of the coloring agent can vary from about 0.1 to about 5% by weight of the composition, preferably from about 0.1 to about 1%.
Bioavailability - refers to the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed into the systemic circulation from an administered dosage form as compared to a standard or control. Examples
The following non-limiting example illustrates the invention.
Diet-induced obese (DΙO)mice, which had developed obesity, hepatic steatosis and dyslipidemia by feeding them a western diet contining 45% fat and 0.12% cholesterol for six months, were divided into four groups and treated with nothing (control), ezetimibe (formula II) (5 mg/kg/day), the compound of formula XIIIA (12 mg/kg/day), or a combination of ezetimibe (5 mgkg/day) and compound of formula XIIIA (12 mg/kg/day) for four weeks. The mice were sacrificed and the liver weight, liver triglyceride level and liver free cholesterol content were determined for each group were determined and summarized in Figs. 1 to 4.
Fig. 1 depicts the liver to body weight ratio of each of the four groups. Mice that received ezetimibe and/or a compound of formula XIIIA showed a decrease in liver weight, with the group receiving the combination showing the greatest decline in weight.
Fig. 2 depicts the triglyceride levels for each of the four groups. Mice that received ezetimibe and/or the compound of formula XIIIA all showed a decrease in liver triglyceride levels, with the group receiving the combination showing the greatest decrease.
Fig. 3 depicts the liver cholesterol ester content of each of the four groups. Again, all groups that received ezetimibe and/or the compound of XIIIA showed a decrease in liver cholesteryl ester content compared to the control with the group receiving the combinations showing the greatest decrease. Fig. 4 depicts the liver free cholesterol content for each of the four groups. All groups that received ezetimibe and/or the compound of fomula XIIIA show a decrease in liver cholesterol content compared to the control group, with the group receiving the combination showing the greatest decrease.
The data indicate that ezetimibe, the H3 antagonist/inverse agonist of formula XIIIA and the combination of both therapeutic agents are effective in treating NAFLD, with the combination showing a synergistic effect.
Example 2
Diet induced obese (DIO) mice, which had developed obesity, dyslipidemia, hepatic steatosis and fibrosis by feeding them a western diet containing 45% fat and 0.12% cholesterol for seven months, were divided into four groups and treated with nothing (control), ezetimibe (formula II) (2 mg/kg/day), the compound of formula XIIID (9mg/kg/day) or a combination of ezetimibe (2mg/kg/day) and compound of formula
XIIlD (9mg/kg/day) for four weeks. The mice were sacrificed and the plasma alanine aminotransferase (ALT) enzyme activities, a plasma biomarker of liver injury with steatohepatitis, were determined for each group, this is summarized in Fig. 5.
Fig. 5 depicts the plasma alanine aminotransferase (ALT) enzyme activities of each of the four groups. Mice that received a compound of formula XIIID showed a decrease in plasma ALT.
The data indicate that the H3 antagonist/inverse agonist of formula XIHD and the combination of both the compound of formula XIIID and ezetimibe can improve liver injury biomarker ALT and, therefore, are effective in treating NASH.
Example 3
C57BL/6J mice were fed a high fat/cholesterol diet (Research Diets, with 45% Kcal fat and 0.12% w/w cholesterol) for 7 months after weaning. After 4 weeks, the body weight of DIO mice treated with ezetimibe (0, 0.5, 1.6 and 5.3 mg/kb/day in the high fat/cholesterol diet) were not significantly different from control mice. However, liver wet weight and the liver to body weight ratio were significantly reduced in the ezetimibe-treated DIO mice as compared to the control. Livers from ezetimibe-treated mice had significantly lower cholesteryl esters free cholesterol and triglyceride These data are summarized in Fig. 6 to 9. Fig. 6 depicts the liver to body weight ratio of each of the four groups. Mice that received ezetimibe showed a dose-dependent decrease in liver to body weight ratio, with the group receiving the ezetimibe (53. mg/kg/day) showing the greatest decline in liver to body weight ratio.
Fig. 7 depicts the triglyceride levels for each of the four groups. All groups received ezetimibe showed a dose-dependent decrease in liver triglyceride levels.
Fig. 8 depicts the liver cholesteryl ester content for each of the four groups. Mice that received ezetimibe (1.6 and 5.3 mg/kg/day) showed a significant decrease in liver cholesteryl ester content compared to the control group.
Fig. 9 depicts the liver cholesterol content of each of the four groups. Mice that received ezetimibe (1.6 and 5.3 mg/kg/day) showed a significant decrease in liver cholesterol content compared to the control group.
After 4 weeks of ezetimibe treatment, total plasma cholesterol and triglyceride was significantly reduced by 30% and 15% respectively. There were significant decreases in VLDL-C and LDL-C, while HDL-C was not changed in the ezetimibe-
treated group. Although the VLDL-C was significantly reduced after ezetimibe treatment, the VLDL-TG production rates were comparable between ezetimibe-treated and control DlO mice. From this result one may conclude that ezetimibe may be used in the prevention of treatment of hepatic steatosis in a mammal.
It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefrom that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications that are within the spirit and scope of the invention, as defined by the appended claims.

Claims

What is claimed is:
1. A method for the treatment, prevention or ameliorating the symptoms of nonalcoholic fatty liver disease (NAFLD) in a mammal in need thereof comprising the step of administering an effective amount of a composition comprising a therapeutic combination of at least one cholesterol lowering agent and at least one H3 antagonist/inverse agonist.
2. The method according to claim 1 , wherein the cholesterol lowering agent is a sterol or 5-α-stanol absorption inhibitor.
3. The method according to claim 2, wherein the sterol or 5-α-stanol absorption inhibitor is a compound of formula (I):
Figure imgf000099_0001
0) or pharmaceutically acceptable salts or solvates thereof, wherein, in formula (I):
1 2
Ar and Ar are independently selected from the group consisting of aryl and
4
R -substituted aryl;
3 5
Ar is aryl or R -substituted aryl;
X, Y and Z are independently selected from the group consisting of -CH2-, -CH(lower alky!)- and -C(dilower alkyl)-;
R and R are independently selected from the group consisting of -OR , -O(CO)Rβ, -O(CO)OR9 and -0(CO)NR6R7;
1 3
R and R are independently selected from the group consisting of hydrogen, lower alkyl and aryl; q is O or 1 ; r is O or 1 ; m, n and p are independently selected from O, 1 , 2, 3 or 4; provided that at least one of q and r is 1 , and the sum of m, n, p, q and r is 1 , 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1 , the sum of m, q and n is 1 , 2, 3, 4 or 5; 4
R is 1 -5 substituents independently selected from the group consisting of lower alkyl, -OR6, O(CO)R6, -0(CO)OR9, -0(CH2)^5OR6, -0(CO)NR6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6Sθ2R9, -COOR6, -CONR6R7, -COR6, -SO2NR6R7, S(O)0.2R9, -0(CH2)^10-COOR6,
-0(CH2)^10CONR6R7, -(lower alkylene)COOR6, -CH=CH-COOR6, -CF3, -CN, -NO2 and halogen;
R is 1-5 substituents independently selected from the group consisting of -OR6, -O(CO)R6, -0(CO)OR9, -0(CH2V5OR6, -0(CO)NR6R7, -NR6R7, -NR6(CO)R?, - NR6(CO)OR9, -NR6(CO)NR7RB, -NR6SO2R9, -COOR6, -CONR6R7, -COR6, -SO2NR6R7, S(O)0.2R9, -0(CH2)^10-COOR6, -0(CH2)^10CONR6R7, -(lower alkylene)COOR6 and - CH=CH-COOR6;
6 7 8
R , R and R are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and
9
R is lower alkyl, aryl or aryl-substituted lower alkyl. 4. The method according to claim 3, wherein the sterol or 5-α-stanol absorption inhibitor is a compound of formula (II):
Figure imgf000100_0001
(II) or pharmaceutically acceptable salts or solvates thereof.
5. The method according to claim 2, wherein the sterol or 5-α-stanol absorption inhibitor is a compound of formula (III):
Figure imgf000101_0001
(III) or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein, in formula (III) above:
1 3
Ar is R -substituted aryl;
2 4
Ar is R -substituted aryl;
3 5
Ar is R -substituted aryl;
Y and Z are independently selected from the group consisting of -CH2-,
-CH(lower alkyl)- and -C(dilower alkyl)-; A is selected from -O-, -S-, -S(O)- or -S(O)2-;
R is selected from the group consisting of -OR , -O(CO)R , -0(CO)OR and - O(CO)NR R ; R is selected from the group consisting of hydrogen, lower alkyl and
1 2 aryl; or R and R together are =O; q is 1, 2 or 3; p is 0, 1 , 2, 3 or 4;
R is 1-3 substituents independently selected from the group consisting of -OR6, -O(CO)R6, -O(CO)OR9, -0(CH2)^5OR9, -0(CO)NR6R7, -NR6R7, -NR6(CO)R7, - NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2-lower alkyl, -NR6SO2-aryl, -CONR6R7, - COR6, -SO2NR6R7, S(O)0.2-alkyl, S(O)0.2-aryl, -0(CH2)^0-COOR6, -0(CH2),.
6 7
10CONR R , o-halogeno, m-halogeno, o-lower alkyl, m-lower alkyl, -(lower alkylene)- COOR6, and -CH=CH-COOR6;
3 4
R and R are independently 1-3 substituents independently selected from the group consisting of R , hydrogen, p-lower alkyl, aryl, -NO2, -CF3 and p-halogeno; fi 7 ft
R , R and R are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and R is lower alkyl, aryl or aryl-substituted lower alkyl.
6. The method according to claim 2, wherein the sterol or 5-α-stanol absorption inhibitor is a compound of formula (IV):
Figure imgf000102_0001
(IV) or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein, in Formula (IV):
2 2
A is selected from the group consisting of R -substituted heterocycloalkyl, R -
2 2 substituted heteroaryl, R -substituted benzofused heterocycloalkyl, and R -substituted benzofused heteroaryl;
1 3
Ar is aryl or R -substituted aryl;
2 4
Ar is aryl or R -substituted aryl;
Q is a bond or, with the 3-position ring carbon of the azetidinone, forms the
spiro group
Figure imgf000102_0002
; and
R is selected from the group consisting of:
-(CH2)q-, wherein q is 2-6, provided that when Q forms a spiro ring, q can also be zero or 1 ;
-(CH2X3-G-(CH2),.-, wherein G is -O-, -C(O)-, phenylene, -NR8- or -S(O)0-2-, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6; -(C2-C6 alkenylene)-; and
-(CH2)rV-(CH2)g-, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6; R is selected from: -CH-, -C(C1-C6 alkyl)-, -CF-, -C(OH)-, -C(C6H4-R9)-, -N-, or -+NO- ;
R 7
R and R are independently selected from the group consisting of -CH2-, -CH(C1-C6 alkyl)-, -C(di-(CrC6) alkyl), -CH=CH- and
-C(C1-C6 alkyl)=CH-; or R5 together with an adjacent R , or R together with an adjacent R , form a -CH=CH- or a -CH=C(C1-C6 alkyl)- group; a and b are independently 0, 1 , 2 or 3, provided both are not zero; provided fi 7 that when R is -CH=CH- or -C(C1-C6 alkyl)=CH-, a is 1 ; provided that when R is - CH=CH- or -C(C1-C6 alkyl )=CH-, b is 1 ; provided that when a is 2 or 3, the R% can be the same or different; and provided that when b is 2 or 3, the R 's can be the same or different; and when Q is a bond, R also can be selected from:
-M -Yd-
Figure imgf000103_0001
where M is -O-, -S-, -S(O)- or -S(O)2-;
X, Y and Z are independently selected from the group consisting of -CH2-, -CH(C1-C6 alkyl)- and -C^i-(C1-C6) alkyl);
R and R are independently selected from the group consisting of -OR14, -O(CO)R14, -0(CO)OR16 and -0(CO)NR14R15;
11 13
R and R are independently selected from the group consisting of hydrogen, (C.,-C6)alkyl and aryl; or R and R together are =O, or R and R together are =O; d is 1 , 2 or 3; h is 0, 1 , 2, 3 or 4; s is 0 or 1 ; t is 0 or 1 ; m, n and p are independently 0-4; provided that at least one of s and t is 1 , and the sum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1 , the sum of m, s and n is 1-5; and provided that when p is 0 and s is 1 , the sum of m, t and n is 1-5; v is 0 or 1 ; j and k are independently 1-5, provided that the sum of j, k and v is 1-5; 2
R is 1-3 substituents on the ring carbon atoms selected from the group consisting of hydrogen, (C1-C10JaIKyI, (C2-C10)alkenyl, (C2-C10)alkynyl,
(C3-C6)cycloalkyl, (C3-C6)cycloalKenyl, R -substituted aryl, R -substituted benzyl, R -substituted benzyloxy, R -substituted aryloxy, halogeno, -NR R , NR R (C1- C6 alkylene)-, NR14R15C(O)(C1-C6 alkylene)-,-NHC(O)R16, OH, C1-C6 alkoxy, - OC(O)R16, -COR14, hydroxy(CrC6)alkyl, (C1-C6)alkoxy(CrC6)alkyl, NO2, -S(O)0.2R16,
SO2NR R and -(C1-C6 alkylene)COOR ; when R is a substituent on a
heterocycloalkyl ring, R is as defined, or is =O or
Figure imgf000104_0001
; and, where R is a substituent on a substitutable ring nitrogen, it is hydrogen, (C1-C6)aIKyI, aryl, (C1-
C6)alkoxy, aryloxy, (C,-C6)alKylcarboπyl, arylcarboπyl, hydroxy, -(CH2J1-6CONR R ,
Figure imgf000104_0002
wherein J is -O-, -NH-, -NR18- or -CH2-;
R and R are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (C1-C6)aIKyI,
-OR14, -O(CO)R14, -0(CO)OR16, -0(CH2J1-5OR14, -0(CO)NR14R15, -NR1V5, -NR14(CO)R15, -NR14(CO)OR16, -NR14(CO)NR15R19, -NR14Sθ2R16, -COOR14,
-CONR
Figure imgf000104_0003
,
-0(CH2J1^0CONR14R15, -(C1-C6 alkyleneJ-COOR14, -CH=CH-COOR14, -CF3, -CN, - NO2 and halogen;
R8 is hydrogen, (C1-C6)aIKyI, aryl (C1-C6)aIKyI, -C(O)R14 or -COOR14;
9 17
R and R are independently 1-3 groups independently selected from the group consisting of hydrogen, (C1-C6)aIKyI, (C1-C6)aIKoXy, -COOH, NO2,
-NR R , OH and halogeno; 14 15
R and R are independently selected from the group consisting of hydrogen, (CrC6)alkyl, aryl and aryl-substituted (C.,-C6)alkyl;
16 17
R is (CpC^alkyl, aryl or R -substituted aryl; i R
R is hydrogen or (C1-C6)a!kyl; and
19
R is hydrogen, hydroxy or (C1-C6)alkoxy.
7. The method according to claim 2, wherein the sterol or 5-α-stanol absorption inhibitor is a compound of formula (V):
Figure imgf000105_0001
(V) or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein, in formula (V):
Ar is aryl, R -substituted aryl, heteroaryl or R10 substituted heteroaryl;
2 4
Ar is aryl or R -substituted aryl;
3 5
Ar is aryl or R -substituted aryl;
X and Y are independently selected from the group consisting of -CH2-, -CH(lower alkyl)- and -C(dilower alkyl)-;
R is -OR6, -O(CO)R6, -0(CO)OR9 or -0(CO)NR R7; R1 is hydrogen, lower alkyl or aryl; or R and R together are =O; q is 0 or 1 ; r is O, 1 or 2; m and n are independently 0, 1 , 2, 3, 4 or 5; provided that the sum of m, n and q is 1 , 2, 3, 4 or 5;
R is 1-5 substituents independently selected from the group consisting of lower alkyl, -OR6, -O(CO)R6, -O(C0)0R9, -0(CH2)^5OR6, -0(CO)NR6R7, -NR6R7, -NR6(CO)R?, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6Sθ2R9, -COOR6, -CONR6R7, -COR6, -SO2NR6R7, S(O)0.2R9, -0(CH2)^10-COOR6, -0(CH2)^10CONR6R7, -(lower alkylene)COOR6 and -CH=CH-COOR6;
R is 1-5 substituents independently selected from the group consisting of -OR6, -0(CO)R6, -0(CO)OR9, -0(CH2V5OR6, -0(CO)NR6R7, -NR6R7, -NR6(CO)R7 - NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2R9, -COOR6, -CONR6R7, -COR6, -SO2NR6R7, S(O)0.2R9, -0(CH2V10-COOR6, -0(CH2V10CONR6R7, -CF3, -CN, -NO2, halogen, - (lower alkylene)COOR and -CH=CH-COOR ;
R , R and R are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; g
R is lower alkyl, aryl or aryl-substituted lower alkyl; and R is 1-5 substituents independently selected from the group consisting of lower alkyl, -OR6, -O(CO)R6, -O(CO)OR9, -0(CH2V5OR6, -0(CO)NR6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2R9, -COOR6, -CONR6R7, -COR6, -SO2NR6R7, -S(O)0^R9, -0(CH2V10-COOR6, -0(CH2J1.
10CONR6R7 -CF3, -CN, -NO2 and halogen.
8. The method according to claim 2, wherein the sterol or 5-α-stanol absorption inhibitor is a compound of formula:
Figure imgf000106_0001
or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein, in formula (Vl): R1 is
-CH-, -C(lower alkyl)-, -CF-, -C(OH)-, -6(C6H5)-, -C(C6H4-R15)-,
- N- or -+N σ ; R2 and R3 are independently selected from the group consisting of: -CH2-, -CH(lower alkyl)-, -C(di-lower alkyl)-, -CH=CH- and -C(lower alkyl)=CH-; or R1 together with an adjacent R2, or R1 together with an adjacent Rβ, form a
-CH=CH- or a -CH=C(lower alkyl)- group; u and v are independently 0, 1 , 2 or 3, provided both are not zero; provided that when R2 is -CH=CH- or -C(lower alkyl)=CH-, v is 1 ; provided that when R3 is - CH=CH- or -C(lower alkyl)=CH-, u is 1 ; provided that when v is 2 or 3, the R2ls can be the same or different; and provided that when u is 2 or 3, the R3's can be the same or different;
R4 is selected from B-(CH2)mC(O)-, wherein m is 0, 1 , 2, 3, 4 or 5; B-(CH2)q-, wherein q is 0, 1 , 2, 3, 4, 5 or 6; B-(CH2)e-Z-(CH2)r, wherein Z is -O-, - C(O)-, phenylene, -N(Re)- or -S(O)0-2-» e is 0, 1 , 2, 3, 4 or 5 and r is 0, 1 , 2, 3, 4 or 5, provided that the sum of e and r is 0, 1 , 2, 3, 4, 5 or 6; B-(C2-Cβ alkenylene)-; B-(C4- C6 alkadienylene)-; B-(CH2)t-Z-(C2-C6 alkenylene)-, wherein Z is as defined above, and wherein t is 0, 1 , 2 or 3, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6; B-(CH2)f-V-(CH2)g-. wherein V is C3- Ce cycloalkylene, f is 1 , 2, 3, 4 or 5 and g is 0, 1 , 2, 3, 4 or 5, provided that the sum of f and g is 1 , 2, 3, 4, 5 or 6; B-(CH2)t-V-(C2-C6 alkenylene)- or B-(C2-C6 alkenylene)- V-(CH2)t-. wherein V and t are as defined above, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6; B-(CH2)a-Z-(CH2)b"v-(cH2)d-. wherein Z and V are as defined above and a, b and d are independently 0, 1 , 2, 3, 4, 5 or 6, provided that the sum of a, b and d is 0, 1 , 2, 3, 4, 5 or 6; or T-(CH2)s-. wherein T is cycloalkyl of 3-6 carbon atoms and s is 0, 1 , 2, 3, 4, 5 or 6; or
1 R1 and R4 together form the group B-CH=C- ;
B is selected from indanyl, indenyl, naphthyl, tetrahydronaphthyl, heteroaryl or W-substituted heteroaryl, wherein heteroaryl is selected from the group consisting of pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl, oxazolyl and furanyl, and for nitrogen-containing heteroaryls, the N-oxides thereof, or
Figure imgf000108_0001
W is 1 to 3 substituents independently selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (lower alkoxyimino)-lower alkyl, lower alkanedioyl, lower alkyl lower alkanedioyl, allyloxy, -CF3, -OCF3, benzyl, R7-benzyl, benzyloxy, R7-benzyloxy, phenoxy, R7-phenoxy, dioxolanyl, NO2, -N(R8)(R9), N(R8)(R9)-lower alkylene-, N(R8)(R9)-lower alkylenyloxy-, OH1 halogeno, -CN, -N3, -NHC(O)OR10, -NHC(O)R10, R11O2SNH-, (R11O2S)2N-, -S(O)2NH2, -S(O)r>2 R8, tert-butyldimethyl-silyloxymethyl, -C(O)R12, -COOR19, -CON(R8XR9), -CH=CHC(O)R12, -lower alkylene-C(O)R12,
R10C(O)(lower alkylenyloxy)-, N(R8)(R9)C(O)(lower alkylenyloxy)- and
Figure imgf000108_0002
for substitution on ring carbon atoms, and the substituents on the substituted heteroaryl ring nitrogen atoms, when present, are selected from the group consisting of lower alkyl, lower alkoxy, -C(O)OR10, - C(O)R10, OH, N(R8)(R9)-lower alkylene-, N(R8)(R9)-lower alkylenyloxy-, -S(O)2NH2 and 2-(trimethylsilyl)-ethoxymethyl;
R7 is 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxy, -COOH1 NO2, -N(R8)(R9), OH, and halogeno;
R8 and R9 are independently selected from H or lower alkyl;
R10 is selected from lower alkyl, phenyl, R7-phenyl, benzyl or R7-benzyl; R11 is selected from OH, lower alkyl, phenyl, benzyl, R7-phenyl or R7-benzyl;
R12 is selected from H1 OH, alkoxy, phenoxy, benzyloxy,
Figure imgf000109_0001
-N(R8)(R9), lower alkyl, phenyl or R7-phenyl;
R13 is selected from -O-, -CH2-, -NH-, -N(lower alkyl)- or -NC(O)R19;
R15, R16 and R17 are independently selected from the group consisting of H and the groups defined for W; or R15 is hydrogen and R16 and R17, together with adjacent carbon atoms to which they are attached, form a dioxolanyl ring;
R19 is H, lower alkyl, phenyl or phenyl lower alkyl; and
R20 and R21 are independently selected from the group consisting of phenyl, W- substituted phenyl, naphthyl, W-substituted naphthyl, indanyl, indenyl, tetrahydronaphthyl, benzodioxolyl, heteroaryl, W-substituted heteroaryl, benzofused heteroaryl, W-substituted benzofused heteroaryl and cyclopropyl, wherein heteroaryl is as defined above.
9. The method according to claim 2, wherein the sterol or 5-α-stanol absorption inhibitor is a compound of formula by formulae (VIIA) and (VIIB):
Figure imgf000109_0002
(VIIA) and
Figure imgf000110_0001
(VIIB) or a pharmaceutically acceptable salt or solvate thereof, wherein in formulae (VIIA) or (VIIB) :
A is -CH=CH-, -C≡C- or -(CH2)p- wherein p is 0, 1 or 2;
B is
B1 is
Figure imgf000110_0002
D is -(CH2)mC(O)- or -(CH2)q- wherein m is 1 , 2, 3 or 4 and q is 2, 3 or 4; E is C-JO to C20 alkyl or -C(O)-(Cg to Ci9)-alkyl, wherein the alkyl is straight or branched, saturated or containing one or more double bonds;
R is hydrogen, C1-C15 alkyl, straight or branched, saturated or containing one or more double bonds, or B-(CH2)r -. wherein r is 0, 1, 2, or 3;
R1, R2, R3, Rr, R2 , and R3' are independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, carboxy, NO2, NH2> OH, halogeno, lower alkylamino, dilower alkylamino, -NHC(O)OR5, R6O2SNH- and -S(O)2NH2; R4 is
Figure imgf000111_0001
wherein n is 0, 1 , 2 or 3;
R5 is lower alkyl; and
R6 is OH, lower alkyl, phenyl, benzyl or substituted phenyl wherein the substituents are 1 -3 groups independently selected from the group consisting of lower alkyl, lower alkoxy, carboxy, NO2, NH2, OH, halogeno, lower alkylamino and dilower alkylamino.
10. The method according to claim 2, wherein the sterol or 5-α-stanol absorption inhibitor is a compound of formula (VIII):
Figure imgf000111_0002
or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein, in formula (VIII) above, R26 is H or OGi; G and G1 are independently selected from the group consisting of
s H or
Figure imgf000111_0003
OH, G is not H;
R1 Ra and RD are independently selected from the group consisting of H, -OH, halogeno, -NH2, azido, (C1-C6)alkoxy(C-i-C-6)-alkoxy or -W-R30; W is independently selected from the group consisting of -NH-C(O)-, -O-C(O)-, -O-C(O)-N(R31 )-, -NH-C(O)-N(R3I)- and -O-C(S)-N(R31)-;
R2 and R6 are independently selected from the group consisting of H, (C-|- C6)alkyl, aryl and aryl(C1-C6)alkyl;
R3, R4, R5, R7, R3a and R4a are independently selected from the group consisting of H, (C<i-C6)alkyl, aryl(C-|-C6)alkyl, -C(O)(Ci -Cβ)alkyl and -C(O)aryl;
R3O is selected from the group consisting of R32-substituted T, R32-substituted-T-(C1-C6)alkyl, R32-substituted-(C2-C4)alkenyl, R32-substituted-(C1-C6)alkyl, R32-substituted-(C3-C7)cycloalkyl and R32-substituted-(C3-C7)cycloalkyl(C1-C6)alkyl;
R31 is selected from the group consisting of H and (Ci-C4)alkyl;
T is selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;
R32 is independently selected from 1-3 substituents independently selected from the group consisting of halogeno, (Ci-C-4)alkyl, -OH, phenoxy, -CF3, -NO2, (Ci-C4)alkoxy, methylenedioxy, oxo, (Ci-C4)alkylsulfanyl, (Ci-C4)alkylsulfinyl, (Ci-C4)alkylsulfonyl, -N(CH3)2, -C(O)-NH(Ci -C4)alkyl, -C(O)-N((Ci-C4)alkyl)2, -C(O)-(Ci -C4)alkyl, -C(O)-(Ci -C4)alkoxy and pyrrolidinylcarbonyl; or R32 is a covalent bond and R3^, the nitrogen to which it is attached and R32 form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or
morpholinyl group, or a (Ci -C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N- methylpiperazinyl, indolinyl or morpholinyl group;
Ar1 is aryl or R^ ^-substituted aryl;
Ar2 is aryl or R1 1 -substituted aryl;
Q is a bond or, with the 3-position ring carbon of the azetidinone,
forms the spiro group
Figure imgf000112_0001
; and R^ is selected from the group consisting of
-(CH2)q-, wherein q is 2-6, provided that when Q forms a spiro ring, q can also be zero or 1 ;
-(CH2)e-E-(CH2)r. wherein E is -O-, -C(O)-, phenylene, -NR22- Or -S(O)0-2-. e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6; -(C2-C-6)alkenylene-; and
-(CH2)f-V-(CH2)g-, wherein V is C3-C6 cycloalkylene, f is 1 -5 and g is 0-5, provided that the sum of f and g is 1-6; Ri2 js
-CH-, -C(C1-C6 alkyl)-, -CF-, -C(OH)-, -C(C6H4-R23)-, -N-, or -+NO" ;
R13 and R14 are independently selected from the group consisting of -CH2-, -CH(C1-C6 alkyl)-, -C(di-(C1-C6) alkyl), -CH=CH- and
-C(C1-C6 alkyl)=CH-; or R12 together with an adjacent R13, or R12 together with an adjacent R14, form a -CH=CH- or a -CH=C(Ci -CQ alkyl)- group; a and b are independently 0, 1 , 2 or 3, provided both are not zero; provided that when R13 is -CH=CH- or -C(C1-C6 alkyl)=CH-, a is 1 ; provided that when R14 is -CH=CH- or -C(Ci-Ce alkyl)=CH-, b is 1 ; provided that when a is 2 or 3, the R13's can be the same or different; and provided that when b is 2 or 3, the R14's can be the same or different; and when Q is a bond, R^ also can be:
-Yk-S(O)0_2-;
Figure imgf000113_0001
M is -O-, -S-, -S(O)- or -S(O)2-;
X, Y and Z are independently selected from the group consisting of -CH2-, -CH(C1-C6)alkyl- and -C(di-(C1-C6)alkyl);
R^O and R^ are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of (Ci-C-6)alkyl, - OR19, -O(CO)R19, -O(CO)OR21 , -O(CH2)1-5OR19, -O(CO)NR19R20, -NR19R20, -NR19(CO)R20, -NR19(CO)OR21 , -NR19(CO)NR20R25> -NR19Sθ2R21 , -COOR19, -CONR19R20, -COR19, -SO2NR19R20 > S(O)0-2R21. -O(CH2)1-10-COOR19 J -O(CH2)1-10CONR19R20 J -(Ci-Cβ alkylene)-COOR19, -CH=CH-COOR19, -CF3, -CN, -NO2 and halogen;
R15 and R17 are independently selected from the group consisting of -OR19, -O(CO)R19, -O(CO)OR21 and -0(CO)NR19R20;
R16 and R18 are independently selected from the group consisting of H, (C1-C6)alkyl and aryl; or R15 and R16 together are =O, or R17 and R18 together are =O; d is 1 , 2 or 3; h is O, 1 , 2, 3 or 4; s is 0 or 1 ; t is 0 or 1 ; m, n and p are independently 0-4; provided that at least one of s and t is 1 , and the sum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1 , the sum of m, s and n is 1-5; and provided that when p Is 0 and s is 1 , the sum of m, t and n is 1-5; v is 0 or 1 ; j and k are independently 1-5, provided that the sum of j, k and v is 1-5;
and when Q is a bond and R1 is
Figure imgf000114_0001
, Ar1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;
R19 and R20 are independently selected from the group consisting of H, (Ci- Cβ)alkyl, aryl and aryl-substituted (Ci-Cβ)alkyl;
R21 is (C1-C6)alkyl, aryl or R24-substituted aryl;
R22 is H, (C1-C6)alkyl, aryl (Ci-C6)alkyl, -C(O)R19 or -COOR19; R23 and R24 are independently 1-3 groups independently selected from the group consisting of H, (C1-C6)alkyl, (C-|-C6)alkoxy, -COOH, NO2,
-NR19R20, -OH and halogeno; and
R25 is H1 -OH or (C1-C6)alkoxy.
11. The method according to claim 2, wherein the sterol or 5-α-stanol absorption inhibitor is a compound of formula (IX):
Figure imgf000115_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein in formula (IX):
R1 is selected from the group consisting of H, G, G1, G2, -SO3H and -PO3H;
G is selected from the group consisting of: H,
Figure imgf000115_0002
(sugar derivatives) wherein R, Ra and RD are each independently selected from the group consisting of H, -OH, halo, -NH2, azido, (C1-C6)alkoxy(C1-C6)alkoxy or -W-R30;
W is independently selected from the group consisting of -NH-C(O)-, -O-C(O)-, -0-C(O)-N(R31)-, -NH-C(O)-N(R31)- and -O-C(S)-N(R31)-;
R2 and R6 are each independently selected from the group consisting of H, (C1-C6)alkyl, acetyl, aryl and aryl(C1-C6)alkyl;
R3, R4, R5, R7, R3a and R4a are each independently selected from the group consisting of H, (C1-C6)alkyl, acetyl, aryl(C1-C6)alkyl, -C(O)(Ci -Cβ)alkyl and - C(O)aryl;
R3O is independently selected from the group consisting of R32.substituted T, R32-substituted-T-(C«|-C6)alkyl, R32-substituted-(C2-C4)alkenyl,
R32_substituted-(C1-C6)alkyl, R32-substituted-(C3-C7)cycloalkyl and R32-substituted- (C3-CT)cycloalkyl(Ci -Cβ)alkyl;
R31 is independently selected from the group consisting of H and (Ci-C4)alkyl;
T is independently selected from the group consisting of phenyl, furyl, thϊenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;
R32 is independently selected from 1-3 substituents which are each independently selected from the group consisting of H, halo, (C-|-C4)alkyl, -OH, phenoxy, -CF3, -NO2, (C-|-C4)alkoxy, methylenedioxy, oxo, (Ci-C4)alkylsulfanyl, (Ci- C4)alkylsulfinyl, (Ci-C4)alkylsulfonyl, -N(CH3)2, -C(O)-NH(Ci -C4)alkyl, -C(O)-N((Ci- C4)alkyl)2, -C(O)-(Ci -C4)alkyl, -C(O)-(Ci -C4)alkoxy and pyrrolidinylcarbonyl; or R32 is a covalent bond and R31 , the nitrogen to which it is attached and R32 form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (Ci- C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group; G1 is represented by the structure:
O
R33 wherein R33 is independently selected from the group consisting of unsubstituted alkyl, R34-substituted alkyl, (R35)(R36)alkyl-,
Figure imgf000117_0001
R34 is one to three substituents, each R34 being independently selected from the group consisting of HOOC-, HO-, HS-, (CH3)S-, H2N-, (NH2)(NH)C(NH)-, (NH2)C(O)- and HOOCCH(NH3 +)CH2SS-;
R35 is independently selected from the group consisting of H and NH2-;
R36 is independently selected from the group consisting of H, unsubstituted alkyl, R34-substituted alkyl, unsubstituted cycloalkyl and R34-substituted cycloalkyl;
G2 is represented by the structure:
Figure imgf000117_0002
wherein R37 and R38 are each independently selected from the group consisting of (C1- C6)alkyl and aryl;
R26 is one to five substituents, each R2^ being independently selected from the group consisting of: a) H; d) -OH; e) -OCH3; d) fluorine; e) chlorine; f) -O-G; k) -O-G1; I) -O-G2; m) -SO3H; and n) -PO3H; provided that when R1 is H, R26 is not H, -OH, -OCH3 or -O-G;
Ar"! is aryl, R^ ^-substituted aryl, heteroaryl or R1 O-substituted heteroaryl; Ar2 is aryl, R1 1 -substituted aryl, heteroaryl or R1 1 -substituted heteroaryl; L is selected from the group consisting of: f) a covalent bond; g) -(CH2)q-, wherein q is 1-6; h) -(CH2)β-E-(CH2)r, wherein E is -O-, -C(O)-, phenylene, -NR22- or
-S(0)o-2-, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6; i) -(C2-C6)alkenylene-; j) -(CH2)rV-(CH2)g-, wherein V is C3-C6cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6; and f)
Figure imgf000118_0001
wherein M is -O-, -S-, -S(O)- or -S(O)2-;
X, Y and Z are each independently selected from the group consisting of -CH2-, -CH(CrC6)alkyl- and -C(di-(C1-C6)alkyl)-;
R8 is selected from the group consisting of H and aJkyl;
R10 and R^ 1 are each independently selected from the group consisting of 1 -3 substituents which are each independently selected from the group consisting of (Ci- C6)alkyl, -OR19, -O(CO)R19, -O(CO)OR21 , -O(CH2)1-5OR19, -O(CO)NR19R20, - NR19R20, -NR19(CO)R20, -NR19(CO)OR21 , -NR19(CO)NR20R25I -NR19SO2R21, -COOR19, -CONR19R20, -COR19, - SO2NR19R20 > S(O)0-2R21. -0(CH2)1-10-COOR19, -O(CH2)1-10CONR19R20, _(C1.
Ce alkylene)-COORi9, -CH=CH-COOR19, -CF3, -CN, -NO2 and halo;
R15 and R17 are each independently selected from the group consisting of -OR19, -OC(O)R19, -OC(O)OR21, - OC(O)NR19R20;
R16 and R18are each independently selected from the group consisting of H, (C1-C6)alkyl and aryl; or R15 and R16 together are =O, or R17and R18 together are =O; d is 1 , 2 or 3; h is O, 1 , 2, 3 or 4; s is O or 1 ; t is O or 1; m, n and p are each independently selected from 0-4; provided that at least one of s and t is 1 , and the sum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1 , the sum of m, n and p is 1-5; and provided that when p is 0 and s is 1 , the sum of m, t and n is 1 -5; v is 0 or 1 ; j and k are each independently 1-5, provided that the sum of j, k and v is 1-5;
Q is a bond, -(CH2)q-, wherein q is 1-6, or, with the 3-position ring carbon of the azetidinone, forms the spiro group
Figure imgf000119_0001
wherein R12 is
i I I l I ,, i J
-CH-, -C(CrC6-alkyl), -CF-, -C(OH)-, - C(C6H4-R23)-, -N- , or -+NO"
R13 and R14 are each independently selected from the group consisting of -CH2-, -CH(C1-C6 alkyl)-, -C(di-(C1-C6) alkyl), -CH=CH- and -C(C1-C6 alkyl)=CH-; or
R12 together with an adjacent R13, or R12 together with an adjacent R14, form a - CH=CH- or a -CH=C(Ci -Ce alkyl)- group; a and b are each independently 0, 1, 2 or 3, provided both are not zero; provided that when R13 is -CH=CH- or -C(Ci-Ce alkyl)=CH-, a is 1 ; provided that when R14 is -CH=CH- or -C(Ci-Cβ alkyl)=CH-, b is 1 ; provided that when a is 2 or 3, the R13'S can be the same or different; and provided that when b is 2 or 3, the R14's can be the same or different;
and when Q is a bond and L is
Figure imgf000120_0001
then Ar1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;
R19 and R20 are each independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl-substituted (C1-C6)alkyl;
R21 is (C1-C6)alkyl, aryl or R24-substituted aryl;
R22 is H1 (C1-C6)alkyl, aryl (C1-C6)alkyl, -C(O)Ri 9 or -COORi9;
R23 and R24 are each independently selected from the group consisting of 1-3 substituents which are each independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, -COOH, NO2, -NR1SR20, -OH and halo; and
R25 is H, -OH or (Ci-Cβ)alkoxy.
12. The method according to claim 2, wherein the H3 receptor antagonist/inverse agonist is of the imidazole type.
13. The method according to claim 2, wherein the H3 receptor antagonist/agonist is a compound of formula (XIII)
Figure imgf000121_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein in formula (XIII):
(1 ) Ri is is selected from:
(a) aryl;
(b) heteroaryl;
(c) heterocycloalkyl
(d) alkyl;
(e) cycloalkyl; or
(f) alkylaryl; wherein said Ri groups are optionally substituted with 1 to 4 substituents independently selected from:
(1) halogen;
(2) hydroxyl;
(3) lower alkoxy;
(4) -CF3;
(5) CF3O-;
(6) -NR4R5;
(7) phenyl;
(8) -NO2,
(9) -CO2R4;
(10) -CON(R4)2 wherein each R4 is the same or different;
(11) -S(0)m N(R2o)2 wherein each R20 is the same or different H or alkyl group;
(12) -CN; or
(13) alkyl; or
(2) R1 and X' taken together form a group selected from:
Figure imgf000122_0001
(3) X' is selected from: =C(O), =C(NOR3), ^(NNR4R5),
OR3 OR3
N R20 or R N
I l I I Il
— C CH — — CH-C — ;
(4) M1 is carbon;
(5) M2 is selected from C or N;
(6) M3 and M4 are independently selected from C or N;
(7) Y' is selected from: is -CH2-, =C(O), =C(NOR2o) (wherein R2o is as defined above), or =C(S);
(8) 2' is a C1 - C6 alkyl group;
(9) R2 is a five or six-membered heteroaryl ring, said six-memberad heteroaryl ring comprising 1 or 2 nitrogen atoms with the remaining ring atoms being carbon, and said flve-membered heteroaryl ring containing 1 or 2 heteroatoms selected from: nitrogen, oxygen, or sulfur with the remaining ring atoms being carbon; said five or six membered heteroaryl rings being optionally substituted with 1 to 3 substituents independently selected from: halogen, hydroxyl, lower alkyl, lower alkoxy, -CF3, CF3O-, -NR4R5, phenyl, -NO2, -CO2R4, -CON(R4)2 wherein each R4 is the same or different, -CH2NR4Rs, -(N)C(NR4Rs)2, or -CN;
(10) R3 is selected from:
(a) hydrogen;
(b) C1 - C6 alkyl;
(c) aryl;
(d) heteroaryl;
(e) heterocycloalkyl;
(f) arylalkyl;
(g) -(CH2)e-C(O)N(R4)2 wherein each R4 is the same or different, (h) -(CHa)8-C(O)OR4; (i) -(CH2)e-C(O)R3o wherein R3o is a heterocycloalkyl group;
(j) -CF3; or
(k) -CH2CF3; wherein said aryl, heteroaryl, heterocycloalkyl, and the aryl portion of said arylalkyl are optionally substituted with 1 to 3 substituents selected from: halogen, -OH, -OCF3, - CF3, -CN, -N(R45)2, -CO2R45. or-C(O)N(R45)2, wherein each R45 is independently selected from: H, alkyl, alkylaryl, or alkylaryl wherein said aryl moiety is substituted
with 1 to 3 substituents independently selected from -CF3, -OH, halogen, alkyl, -NO2, or -CN;
(11) R4 is selected from: hydrogen, Ci — C6 alkyl, aryl, alkylaryl, said aryl and alkylaryl groups being optionally substituted with 1 to 3 substituents selected from: halogen, -CF3, -OCF3, -OH, -N(R4S)2, -CO2R4Si -C(O)N(R4S)2, or -CN; wherein R45 is as defined above;
(12) R5 is selected from: hydrogen, Ci - C6 alkyl, -C(O)R4, -C(O)2R4, or -C(O)N(R4)S wherein each R4 is independently selected, and R4 is as defined above;
(13) or R4 and R5 taken together with the nitrogen atom to which they are bound forms a five or six membered heterocycloalkyl ring;
(14) Re is selected from: alkyl, aryl, alkylaryl, halogen, hydroxyl, lower alkoxy, -CF3, CF3O-, -NR4R5, phenyl, -NO2, -CO2R5, -CON(R4J2 wherein each R4 is the same or different, or -CN;
(15) R12 is selected from: alkyl, hydroxyl, alkoxy, or fluoro;
(16) Ri3 is selected from: alkyl, hydroxyl, alkoxy, or fluoro;
(17) a' (subscript for R12) is O to 2;
(18) b" (subscript for R12) is O to 2;
(19) c1 (subscript for R6) is O to 2;
(20) e' is O to 5;
(21 ) m' is 1 or 2;
(22) n1 is 1 , 2 or 3; and
(23) p' is 1 , 2 or 3, with the proviso that when M3 and M4 are both nitrogen, then p' is 2 or 3 (i.e., p is not 1 when M3 and M2 are both nitrogen).
14. The method according to claim 13, wherein the H3 receptor antagonist/agonist is a compound selected from the group consisting of:
IIIA),
Figure imgf000124_0001
(XIIIB), and
Figure imgf000124_0002
15. The method according to claim 13, wherein the sterol or 5-α-stanol absorption inhibitor is a compound of formula (I):
Figure imgf000124_0003
(I) or pharmaceutically acceptable salts or solvates thereof, wherein in formula (I): 1 2
Ar and Ar are independently selected from the group consisting of aryl and
4
R -substituted aryl;
3 5
Ar is aryl or R -substituted aryl;
X, Y and Z are independently selected from the group consisting of
-CH2-, -CH(lower alkyl)- and -C(dilower alkyl)-;
R and R are independently selected from the group consisting of -OR , -O(CO)R6, -O(CO)OR9 and -0(CO)NR6R7;
1 3
R and R are independently selected from the group consisting of hydrogen, lower alkyl and aryl; q is 0 or 1 ; r is 0 or 1 ; m, n and p are independently selected from 0, 1 , 2, 3 or 4; provided that at least one of q and r is 1 , and the sum of m, n, p, q and r is 1 , 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1 , the sum of m, q and n is 1 , 2, 3, 4 or 5;
4
R is 1-5 substituents independently selected from the group consisting of lower alkyl, -OR6, O(CO)R6, -O(CO)OR9, -0(CH2)^5OR6, -0(CO)NR6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2R9, -COOR6, -CONR6R7, -COR6, -SO2NR6R7, S(O)0-2R9, -0(CH2)^10-COOR6,
-0(CH2)^10CONR6R7, -(lower alkylene)COOR6, -CH=CH-COOR6, -CF3, -CN, -NO2 and halogen;
R is 1-5 substituents independently selected from the group consisting of -OR6, -O(CO)R6, -O(CO)OR9, -0(CH2)^5OR6, -0(CO)NR6R7, -NR6R7, -NR6(CO)R7, - NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2R9, -COOR6, -CONR6R7, -COR6, -SO2NR6R7, S(O)0.2R9, -0(CH2)^10-COOR6, -0(CH2)^10CONR6R7, -(lower alkylene)COOR6 and - CH=CH-COOR6;
R 7 R
R , R and R are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and
R is lower alkyl, aryl or aryl-substituted lower alkyl.
16. The method according to claim 14, wherein the sterol or 5-α-stanol absorption inhibitor is a compound of formula (VIA)
Figure imgf000126_0001
(Via) or pharmaceutically acceptable salts or solvates thereof.
17. The method according to claim 14, wherein the the sterol or 5-α-stanol absorption inhibitor is a compound of formula (II):
Figure imgf000126_0002
(II) or pharmaceutically acceptable salts or solvates thereof.
18. The method according to claim 15, which further comprises an effective amount of an HMG-CoA reductase inhibitor.
19. The method according to claim 18, wherein the HMG-CoA reductase inhibitor is selected from the group consisting of lovastatin, pravastatin fluvastatin, simvastatin, atorvastatin, cerivastatin, pravastatin, and rosuvastatin.
20. The method according to claim 17, which further comprises an effective amount of an HMG-CoA reductase inhibitor wherein said inhibitor is simvastatin.
21. The method according to claim 15, which further comprises as a third active component a PPAR activator, nicotinic acid and/or a nicotinic acid receptor agonist or a bile acid sequestrant.
22. The method according to claim 21 , wherein the third active component is cholestyramine, colestipol, clofibrate, gemfibrozil, fenofibrate, or niacin.
23. The method according to claim 2, wherein the H3 receptor antagonist/agonist is a compound of formula (XIV)
Figure imgf000127_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein, in formula (XIV): the dotted line represents an optional double bond; a' is 0 to 2; b' is 0 to 2; n' is 1 , 2 or 3; p' is 1 , 2 or 3; r" is 0, 1 , 2, or 3; with the provisos that when M2 is N, p' is not 1 ; and that when r1 is 0, M2 is C(R3); and that the sum of p' and r1 is 1 to 4;
M1 is C(R3) or N;
M2 is C(R3) or N;
X' is a bond or C1-C6 alkylene;
Y' is -C(O)-, -C(S)-, -(CH2)q- -, -NR4C(O)-, -C(O)NR4-, -C(O)CH2-, -SO2-, -N(R4)-, -NH-C(=N-CN)- or-C(=N-CN)-NH-; with the provisos that when M1 is N, Y1 is not -NR4C(O)- or -NH-C(=N-CN)-; when M2 is N, Y1 is not -C(O)NR4- or -C(=N-CN)-NH-; and when Y' is -N(R4)-, M1 is CH and M2 is C(R3); q' is 1 to 5, provided that when both M1 and M2 are N, q1 is 2 to 5; Z' is a bond, C1-C6 alkylene, C1-C6 alkenylene, -C(O)-, -CH(CN)-, -SO2- or -CH2C(O)NR4-;
Figure imgf000128_0001
Q' is -N(R8)-, -S- Or -O-; k' is 0, 1 , 2, 3 or 4; k1 is 0, 1 , 2 or 3; k2 is 0, 1 or 2;
R is H, C1-C6 alkyl, halo(C1-C6)alkyl-, C1-C6 alkoxy, (C1-C6)alkoxy- ( C1-C6)alkyl-, (C1-C6)-alkoxy-(C1-C6)alkoxy, (C1-C6)alkoxy-(C1-C6)alkyl-SO0-2, R32-aryl(C1-C6)alkoxy-, R32-aryl(C1-C6)alkyl-, R32-aryl, R32-aryloxy, R32-heteroaryl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, (C3-C6)cycloalkyl-(C1-C6)alkoxy, (C3-C6)cycloalkyl-oxy-, R37-heterocycloalkyl , R37-heterocycloalkyl-oxy-, R37-heterocycloalkyl-(C1-C6)alkoxy, N(R30)(R31)-(C1-C6)alkyl-, -N(R30)(R31), -NH-(C1-C6)alkyl-O-(C1-C6)alkyl, -NHC(O)NH(R29); R29-S(O)0-2-, halo(C1-C6)alkyl-S(O)0-2-, N(R30)(R31)-(C1-C6)alkyl-S(O)0-2- or benzoyl;
R8 is H, C1-C6 alkyl, haIo(C1 -C6)alkyl-, (C1-C6)alkoxy-(C1-C6)alkyl-, R32-aryl(C1- C6)alkyl-, R32-aryl, R32-heteroaryl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, R37-heterocycloalkyl, N(R30)(R31 )-(C1-C6)alkyl-, R29-S(O)2-, halo(C1-C6)alkyl-S(O)2-, R29-S(O)0-1-(C2-C6)alkyl-, halo(C1-C6)alkyl-S(O)0-1-(C2-C6)alkyl-; R3 is a six-membered heteroaryl ring having 1 or 2 heteroatoms independently selected from N or N-O, with the remaining ring atoms being carbon; a five-membered heteroaryl ring having 1 , 2, 3 or 4 heteroatoms independently selected from N, O or S,
with the remaining ring atoms being carbon; R32-quinolyl; R32-aryf; heterocycloalkyl; (C3-Cβ)cycloalkyl; C1-C6 alkyl; hydrogen; thianaphthenyl;
Figure imgf000129_0001
wherein said six-membered heteroaryl ring or said five-membered heteroaryl ring is optionally substituted by R6;
R3 is H, halogen, C1-C6 alkyl, -OH, (C1-C6)alkoxy or-NHSO2-(C1-C6)alkyl;
R4 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, R33-aryl, R33-aryi(C1-C6)a!kyl, and R32-heteroaryl;
R5 is hydrogen, C1-C6 alkyl, -C(O)R20, -C(O)2R20, -C(O)N(R20J2, (d-C6)alkyl- SO2-, or (C1-C6)alkyl-SO2-NH-; or R4 and R5, together with the nitrogen to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring;
R6 is 1 to 3 substituents independently selected from the group consisting of - OH, halogen, C1-C6 alkyl-, C1-C6 aikoxy, C1-C6 alkylthio, -CF3, -NR4 R5, -CH2-NR4 R5, - NHSO2R22, -N(SO2R22)2, phenyl, R33-phenyl, NO2, -CO2R4, -CON(R4)Z,
Figure imgf000129_0002
R7 is -N(R29)-, -O- or -S(O)0-2-;
Ri2 is independently selected from the group consisting of C1-C6 alkyl, hydroxy!, d-C6 aikoxy, orfluoro, provided that when R12 is hydroxy orfluoro, then R12 is not bound to a carbon adjacent to a nitrogen; or two R12 substituents form a Ci to C2 alkyl bridge from one ring carbon to another non-adjacent ring carbon; or Ri2 is =O;
Ri3 is independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 aikoxy, orfluoro, provided that when Ri3 is hydroxy orfluoro then R13 is not bound to a carbon adjacent to a nitrogen; or two R13 substituents form a Ci to C2 alkyl bridge from one ring carbon to another non-adjacent ring carbon; or R13 is =O;
R2 is independently selected from the group consisting of hydrogen, C1-Cβ alkyl, or aryl, wherein said aryl group is optionally substituted with from 1 to 3 groups independently selected from halogen, -CF3, -OCF3, hydroxy!, or methoxy; or when two
R20 groups are present, said two R20 groups taken together with the nitrogen to which they are bound can form a five or six membered heterocyclic ring;
R22 is C1-C6 alkyl, R34-aryl or heterocycloalkyl;
R24 is H, C1-C6 alkyl, -SO2R2 or R34-aryl;
R25 is independently selected from the group consisting of C1-C6 alkyl, halogen, -CN, -NO21 -CF3, -OH, C1-C6 alkoxy, (d-C6)alkyl-C(O)-, aryl-C(O)-, -C(O)OR29, - N(R4)(R5), N(R4)(Rs)-C(O)-, N(R4)(Rs)-S(O)1-2-, R22-S(O)0-2-, halo-(CrC6)alkyl- or halo- (C1-C6)alkoxy-(C1-C6)alkyl-;
R29 is H, C1-C6 alkyl, C3-C6 cycloalkyl, R35-aryl or R35-aryl(C1-C6)alkyl-;
R30 is H, C1-C6 alkyl-, R35-aryl or R35-aryl(C1-C6)alkyl-;
R3! is H, C1-C6 alkyl-, R35-aryl,
Figure imgf000130_0001
R35-heteroaryl, (C1- C6)alkyl-C(O)-, R35-aryl-C(O)-, N(R4)(Rs)-C(O)-, (C1-C6)alkyl-S(O)2- or R35-aryl-S(O)2-; or R30 and R31 together are -(CH2J4-B-, -(CH2)2-O-(CH2)2- or -(CH2J2-N(R38MC^)2- and form a ring with the nitrogen to which they are attached;
R32 is 1 to 3 substituents independently selected from the group consisting of H, -OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, R35-aryl-O-, -SR22, -CF3, -OCF3, -OCHF2, - NR39R40, phenyl, R33-phenyl, NO2, -CO2R39, -CON(R39)2, -S(O)2R22, -S(O)2N(R20)2, - N(R24)S(O)2R22, -CN, hydroxy-(C1-C6)alkyl-, -OCH2CH2OR22, and R35-aryl(C1-C6)alkyl-O-, or two R32 groups on adjacent carbon atoms together form a — OCH2O- or-O(CH2)2O- group;
R33 is 1 to 3 substituents independently selected from the group consisting of C1-C6 alkyl, halogen, -CN, -NO2, -CF3, -OCF3, -OCHF2 and -O-(C1-Cβ)alkyl;
R34 is 1 to 3 substituents independently selected from the group consisting of H, halogen, -CF3, -OCF3, -OH and -OCH3;
R35 is 1 to 3 substituents independently selected from hydrogen, halo, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, phenoxy, -CF3, -N(R36J2, -COOR2O and -NO2;
R36 is independently selected form the group consisting of H and C1-C6 alkyl; R37 is 1 to 3 substituents independently selected from hydrogen, halo, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, phenoxy, -CF3, -N(R36J2, -COOR20, -C(O)N(R29J2 and - NO2, or R37 is one or two =O groups;
R3S is H, C1-C6 alkyl, R35-aryl, R35-aryl(C1-C6)alkyl-, (C1-C6)alkyl-SO2 or halo(C1-C6)alkyl-SO2-;
R39 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6)cycloalkyKC1-C6)alkyl, R33-aryl, R33-aryl(C.|-C6)alkyl, and R32-heteroaryl; and
FUo is hydrogen, C1-C6 alkyl, -C(O)R20, -C(O)2R20, -C(O)N(R20)2, (C1-C6)alkyl- SO2-, or (d-C6)alkyl-SO^NH-; or R39 and Rω, together with the nitrogen to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring.
24. The method according to claim 2, wherein the H3 receptor antagonist/agonist is a compound of formula (XV)
Figure imgf000131_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein, in formula (XV): a' is 0 to 3; b" is 0 to 3; n' is 1 , 2 or 3; p' is 1 , 2 or 3; i* Is 0, 1, 2, or 3;
X' is a bond or C1-C6 alkylene;
M1 is CH or N;
M2 is C(R3) or N; with the provisos that when M2 is N, p1 is not 1 ; and that when r1 is 0, M2 is C(R3); and that the sum of p' and r1 is 1 to 4; Y' is -C(=O)-, -C(=S)-, -(CH2)q' -, -NR4CC=O)-, -C(^=O)NR4-, -C(=O)CH2-, -SO1. 2-, -C(=N-CN)-NH- or -NH-C(=N-CN)-; with the provisos that when M1 is N, Y is not - NR4CC=O)- or -NH-C(=N-CN)-; and when M2 is N1 Y' is not -C(O)NR4- or-C(=N- CN)-NH-; q' is 1 to 5, provided that when M1 and M2 are both N, q' is not 1;
11 is a bond, C1-C6 alkylene, C2-C6 alkenylene, -C(=O)-, -CH(CN)- or -CH2C(=O)NR4-;
R1 is
Figure imgf000132_0001
the dotted line represents an optional double bond;
R and R7 are independently selected from the group consisting of H1 C1-C6 alkyl, halo(C1-C6)alkyl-, C1-C6 alkoxy, (C1-C6)alkoxy-(C1-C6)alkyl-, (C1-C6)-alkoxy- (C1-C6)alkoxy, (C1-C6)alkoxy-(CTC6)alkyl-SOo-a. Raa-aryKC1-C6)alkoxy-, R32-aryl- (C1-C6)alkyl-, R32-aryl, R32-aryloxy, R32-heteroaryl, (C3-C6)cycloalkyl, (C3-C6)cycloa)kyl- (C1-C6)alkyl, (C3-C6)cycloalkyl-(C1-C6)alkoxy, (C3-C6)cycloalkyl-oxy-, R37-heterocyclo- alkyl, N(R3o)(R3iHC1-C6)alkyl-, -N(R30)(R3i), -NHKC.-C6ialkyl-O-(d-C6)alkyl, - NHC(O)NH(R29); R29-S(O)o-2-, halo(C1-C6)alkyl-S(O)0-2-, N(R30)(R3I )-(CrC6)alkyl- S(O)0-2-, benzoyl, (C1-C6)alkoxy-carbonyl, R37-heterocycloalkyl-N(R29)-C(O)-, (C1- C6)alkyl-N(R29)-C(O)-, (C1-C6)alkyl-N(C1-C6 alkoxy)-C(O)- and -C(=NOR36)R36; and when the optional double bond is not present, R7 can be OH; R8 is H, C1-C6 alkyl, halofC1-CeOalkyl-, (C1-C6)alkoxy-(C2-C6)alkyl-, R32-aryl(C1- C6)alkyl-, R32-aryl, R32-heteroaryl, R32-MeIeTOaFyI(C1 -C6)alkyl-, (C3-C6)cycloalkyl, (C3- C6)cycloalkyl-(C1-C6)alkyl, R37-heterocycloalkyl, R37-heterocycloalkyl(C1-C6)alkyl, N(R3o)(R3i)-(C2-C6)alkyl-, R2Q-S(O)2-, halo(C1-C6)alkyl-S(O)2-, R29-S(O)0-i-(C2-C6)alkyl- , halo(C1-C6)alkyl-S(0)o-i-(C2-C6)alkyi-1 (C1-C6)alkyl-N(R29)-SO2-, or R32-heteroaryl- SO2;
R2 is a six-membered heteroaryl ring having 1 or 2 heteroatoms independently selected from N or N-O, with the remaining ring atoms being carbon; a five-membered heteroaryl ring having 1 , 2 or 3 heteroatoms independently selected from N, O or S, with the remaining ring atoms being carbon; R32-quinolyl; R32-aryl;
Figure imgf000133_0001
or heterocycloalkyl; wherein said six-membered heteroaryl ring or said five- membered heteroaryl ring is optionally substituted by Re;
R3 is H, halogen, C1-C6 alkyl, -OH or (CrC6)alkoxy;
R4 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6)cycloalkyl(CrC6)alkyl, R33-aryl, R33-aryι(C1-C8)alkyl, and R33-heteroaryl;
R5 is hydrogen, CrC6 alkyl, -C(O)R2O, -C(O)2R2O, -C(O)N(R2O)2, R∞-aryKC-r C6)alkyt or (C1-C6)aIRyI-SO2-;
R6 is 1 to 3 substituents independently selected from the group consisting of - OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, -CF3, -NR4 R5,
Figure imgf000133_0002
phenyl, R33-phenyl, NO2, -CO2R4, -CON(R4J2, -NHC(O)N(R4J2, R32-heteroaryl-SO2-NH-, R32- aryl-(C1-C6)alkyl-NH-, Rs^heteroaryKd-C6)alkyl-NH-, R32-heteroaryl-NH-C(O)-NH- and R37-heterocyclo-alkyl-N(R2g)-C(O)-;
Ri2 is independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, orfluoro, provided that when Ri2 is hydroxy or fluoro, then R12 is not bound to a carbon adjacent to a nitrogen; or Ri2 forms a Ci to C2 alkyl bridge from one ring carbon to another ring carbon; Ri3 is independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, or fluoro, provided that when R13 is hydroxy orfiuoro then R13 is not bound to a carbon adjacent to a nitrogen; or forms a Ci to C2 alkyl bridge from one ring carbon to another ring carbon; or R13 is =O;
R20 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, or aryl, wherein said aryl group is optionally substituted with from 1 to 3 groups independently selected from halogen, -CF3, -OCF3, hydroxyl, or methoxy; or when two R20 groups are present, said two R2o groups taken together with the nitrogen to which they are bound can form a five or six membered heterocyclic ring;
R22 is C1-C6 alkyl, R34-aryl or heterocycloalkyl;
R24 is H, C1-C6 alkyl, -SO2R22 or R34-aryl;
R25 is independently selected from the group consisting of C1-C6 alkyl, halogen, -CF3, -OH, C1-C6 alkoxy, (C1-C6)alkyl-C(O)-, aryl-C(O)-, N(R4)(Rs)-C(O)-, N(R4)(R5)- S(O)i-2-, halo-(C1-C6)alkyl- or halo-(C1-C6)alkoxy-(C1-C6)alkyl-;
R29 is H, C1-C6 alkyl, R35-aryl or R35-aryl(CrC6)alkyl-;
R30 is H, C1-C6 alkyl-, R35-aryl or Rss-aryKCTC6)alkyl-;
R31 is H, C1-C6 alkyl-, R35-aryl, R35-aryl(C1-C6)alkyl-, (C1-C6)alkyl-C(O)-, R35- aryl-C(O)-, N(R4)(Rs)-C(O)-, (C1-C6)alkyl-S(O)2- or R35-aryl-S(O)2-; or R30 and R31 together are -(CH2)4-s-. -(CH2)2-O-(CH2)2- or -(CH2)2-N(R29)-(CH2)2- and form a ring with the nitrogen to which they are attached;
R32 is 1 to 3 substituents independently selected from the group consisting of H, -OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, R35-aryl-O-, -SR22, -CF3, -OCF3, -OCHF2, - NR4R5, phenyl, R33-phenyl, NO2, -CO2R4, -CON(R4J2, -S(O)2R22, -S(O)2N(R2o)2, - N(R24)S(O)2R22, -CN, hydroxy-(C1-C6)alkyl-I -OCH2CH2OR22, and R35-aryl(C1-C6)alkyl- O-, wherein said aryl group is optionally substituted with 1 to 3 independently selected halogens;
R33 is 1 to 3 substituents independently selected from the group consisting of C1-C6 alkyl, halogen, -CN, -NO2, -OCHF2 and -O-(C!-C6)alkyl;
R34 is 1 to 3 substituents independently selected from the group consisting of H, halogen, -CF3, -OCF3, -OH and -OCH3.
R35 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, phenoxy, -CF3, -N(R36^, -COOR20 and -NO2; R36 is independently selected from the group consisting of H and C1-Cβ alkyl; and
R37 is independently selected from the group consisting of H, C1-C6 alkyl and (C1-C6)alkoxycarbonyl.
25. The method according to claim 2, wherein the H3 receptor antagonist/agonist is a compound of formula (XVI)
Figure imgf000135_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein, in formula (XVI):
(A) Ri is selected from:
(1) aryt;
(2) heteroaryl;
(3) heterocycloalkyl
(4) alkyl;
(5) -C(O)N(R4B)2;
(6) cycloalkyl;
(7) arylalkyl;
(8) heteroarylheteroaryl; or
(9) a group selected from:
Figure imgf000135_0002
Figure imgf000136_0001
said aryl (see (A)(1 ) above), heteroaryl (see (A)(2) above), aryl portion of arylalkyl (see (A)(7) above), phenyl ring of formula Il (see (A)(9) above), phenyl ring of formula III (see (A)(9) above), phenyl rings of formula IVB (see (A)(9) above), or phenyl rings of formula IVD (see (A)(9) above) are optionally substituted with 1 to 3 substituents independently selected from:
(D halogen;
(2) hydroxy!;
(3) lower alkoxy;
(4) -Oaryl;
(5) -SR22;
(6) -CF3;
(7) -OCF3;
(8) -OCHF2;
(9) -NR4R5;
(10) phenyl;
(11) NO2,
(12) -CO2R*;
(13) -CON(R4)2 wherein each R4 is the same or different;
(14) -S(O)2R22;
(15) -S(O)2N(R2O)2 wherein each R2o is the same or different;
(16) -N(R24)S(O)2R22; (17) -CN;
(18) -CH2OH;
(19) -OCH2CH2OR22;
(20) alkyl;
(21) substituted phenyl wherein said phenyl has 1 to 3 substituents independently selected from alkyl, halogen, -CN, -NO2, -OCHF2, - Oalkyl;
(22) -Oalkylaryl (preferably -Oalkylphenyl or -Oalkyl-substituted phenyl, e.g., -OCH2dichlorophenyl, such as -OCH2-2,6- dichlorophenyl or-OCH2-2-chloro-6-fluorophenyl) wherein said aryl group is optionally substituted with 1 to 3 independently selected halogens; or
(23) phenyl;
(B) X' is selected from alkyl (e.g., -(CH2)q- or branched alkyl) or -S(O)2-;
(C) Y' represents
(1) a single bond (i.e., Y' represents a direct bond from M1 to M2); or
(2) Y' is selected from -C(O)-, -C(S)-, -(CH2)q- -, or -NR4C(O)-; with the provisos that:
(a) when M1 is N, then Y" is not -NR4C(O)-; and
(b) when Y is a bond, then M1 and M2 are both carbon;
(D) M1 and M2 are independently selected from C or N;
(E) Z' is selected from: C1-C6 alkyl, -SO2-, -C(O)- or -C(O)NR4-;
(F) R2 is selected from:
(1) a six-membered heteroaryl ring having 1 or 2 heteroatoms independently selected from N or N-O (i.e., N-oxide), with the remaining ring atoms being carbon;
(2) a five-membered heteroaryl ring having 1 to 3 heteroatoms selected from nitrogen, oxygen, or sulfur with the remaining ring atoms being carbon; or
(3) an alkyl group; (4) an aryl group or an aryl group that is substituted with 1 to 3 substituents independently selected from: halogen, -Oalkyl, - OCF3, -CF3, -CN1 -NO2, -NHC(O)CH3, or -O(CH2)q N(R10A)2;
(5) -N(R11A)2 wherein each R11A is independently selected from: H, alkyl or aryl;
(6) a group of the formula:
Figure imgf000138_0001
(7) a heteroarylheteroaryl group,?
said five membered heteroaryl ring ((F)(2) above) or six-membered heteroaryl ring ((F)(I) above) is optionally substituted with 1 to 3 substituents selected from:
(a) halogen;
(b) hydroxyl;
(c) lower alkyl;
(d) lower alkoxy;
(e) -CF3;
(f) -NR4R5;
(g) phenyl; (h) -NO2;
(i) -C(O)N(R4J2 (wherein each R4 is the same or different);
(j) -C(O)2R4; or
(k) phenyl substituted with 1 to 3 substituents independently selected from: halogen, -Oalkyl, -OCF3, -CF3, -CN, -NO2 or
-O(CH2)qN(R10A)2; (G) R3 is is selected from:
(1) aryl;
(2) heteroaryl;
(3) heterocycloalkyl
(4) alkyl; or (5) cycloalkyl; wherein said aryl or heteroaryl R3 groups is optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen;
(b) hydroxyl;
(C) lower alkoxy;
(d) -Oaryl;
(e) -SR22;
(0 -CF3;
(g) -OCF3;
(h) -OCHF2;
(0 -NR4R5;
G) phenyl;
(k) -NO2,
(0 -CO2R4;
(m) -CON(R4)2 wherein each R4 is the same or different; (π) -S(O)2R22;
(o) -S(O)2N(R20)2 wherein each R2Q is the same or different; (P) -N(R24)S(O)2R22; (q) -CN; (r) -CH2OH; (S) -OCH2CH2OR22; or (t) alkyl; (H) R4 is selected from:
(1) hydrogen;
(2) C1-C6 alkyl;
(3) cycloalkyl;
(4) cycloalkylalkyl ;
(5) heterocycloalkylalkyl;
(6) bridged bicyclic cycloalkyl ring;
(7) aryl having a fused heterocycloalkyl ring bound to said aryl ring;
(8) aryl; (9) arylalkyl;
(10) alkylaryl;
(11 ) -(CH2)dCH(R12A)2 wherein d is 1 to 3, and each R12A is independently selected from phenyl or substituted phenyl, said substituted phenyl being substituted with 1 to 3 substituents independently selected from: halogen, -Oalkyl, -OCF3, -CF3, -CN, or -NO2;
(12) heterocycloalkylheteroaryl; or
(13) -(C1 to C6)alkylene-O-R22; wherein the aryl R4 group, the aryl portion of the arylalkyl R4 group, or the aryl portion of the alkylaryl R4 group is optionally substituted with 1 to 3 substituents independently selected from:
(a) halogen;
(b) hydroxyl;
(c) lower alkyl;
(d) lower alkoxy;
(e) -CF3;
(f) -N(R20)(R24),
(g) phenyl;
(h) -NO2;
(i) -C(O)N(R20)2 (wherein each R2o is the same or different),
Q) -C(O)R22;
0) -(CH2)k.-cycloalkyl;
G) -(CH2)q-aryl; or
Figure imgf000140_0001
(I) each R4B is independently selected from: H, heteroaryl, alkyl, alkenyl, a group of the formula
Figure imgf000140_0002
arylalkyl, or arylalkyl wherein the aryl moiety is substitued with 1-3 substituents independently selected from: halogen; (J) R5 is selected from: hydrogen, C1-C6 alkyl, -C(O)R2 o, -C(O)2R2O, - C(O)N(R20)2 (wherein each R20 is the same or different);
(K) each R10A is independently selected from H or C1 to C6 alkyl or each R10A, taken together with the nitrogen atom to which they are bound, forms a 4 to 7 membered heterocycloalkyl ring;
(L) Ri2 is
(1 ) selected from alkyl, hydroxyl, alkoxy, or fluoro, provided that when Ri2 is hydroxy or fluoro then Ri2 is not bound to a carbon adjacent to a nitrogen; or
(2) Ri2 forms an alkyl bridge from one ring carbon to another ring carbon;
(M) Ri3 is
(1) selected from alkyl, hydroxyl, alkoxy, or fluoro, provided that when Ri3 is hydroxy or fluoro then R13 is not bound to a carbon adjacent to a nitrogen; or
(2) Ri3 forms an alkyl bridge from one ring carbon to another ring carbon;
(N) R20 is selected from hydrogen, alkyl, or aryl, wherein said aryl group is optionally substituted with from 1 to 3 groups independently selected from: halogen, -CF3, -OCF3, hydroxyl, or methoxy; or when two R2o groups are present, said two R20 groups taken together with the nitrogen to which they are bound form a five or six membered heterocyclic ring;
(O) R22 is selected from: heterocycloalkyl, alkyl or aryl, wherein said aryl group is optionally substituted with 1 to 3 groups independently selected from halogen, -CF3, -OCF3, hydroxyl, or methoxy;
(P) R24 is selected from: hydrogen, alkyl, -SO2R22, or aryl, wherein said aryl group is optionally substituted with 1 to 3 groups independently selected from halogen, -CF3, -OCF3, hydroxyl, or methoxy;
(Q) a' is 0 to 2;
(R) b' is 0 to 2;
(S) k1 is 1 to 5;
(T) m' is 2 to 5;
(U) n' is 1 , 2 or 3 with the proviso that when M1 is N, then n' is not 1 ; (V) p' is 1 , 2 or 3 with the proviso that when M2 is N, then p' is not 1 ;
(W) q1 is 1 to 5; and
(X) r" is 1 , 2, or 3 with the proviso that when r* is 2 or 3, then M2 is C and 'p is 1.
26. The method according to claim 2, wherein the H3 receptor antagonist/agonist is a compound of formula (XVII)
Figure imgf000142_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein, in formula XVII: the dotted line represents an optional double bond; a* is 0 to 3; b' is 0 to 3; n' is 1 , 2 or 3; p' is 1 , 2 or 3;
r" is 0, 1 , 2, or 3; with the provisos that when M2 is N, p' is not 1; and that when r' is 0, M2 is C; and that the sum of p' and r' is 1 to 4;
A' is a bond or C1-C6 alkylene;
M1 is CH or N;
M2 is C(R3) or N;
Y' is -C(=O)-, -C(=S)-, -(CH2^ -, -NR4Ct=Oh -Ci=O)NR4-, -C(=O)CH2-, -SO1-2-, -NH-C(=N-CN)- or-C(=N-CN)-NH-; with the provisos that when M1 is N, Y' is not -NR4C(=O)- or -NH-C(=N-CN)-; and when M2 is N, Y1 is not -CC=O)NR4- or-C(=N- CN)-NH-; q' is 1 to 5, provided that when M1 and M2 are both N, q' is not 1 ;
Z is a bond, C1-C6 alkylene, C1-C6 alkenylene, -C(=O)-, -CH(CN)-, or -CH2Ct=O)NR4-;
R1 Js
Figure imgf000143_0001
k' is O, 1 , 2, 3 or 4; k1 is O, 1 , 2 or 3; k2 is 0, 1 or 2;
R is H, C1-C6 alkyl, hydroxy-(C2-C6)alkyl-, halo-(C1-C6)alkyl-, halo-(C1- C6)alkoxy-(C1-C6)alkyl-( R29-O-C(O)-(C1-C6)alkyl-l (C1-C6)alkoxy-(C1-C6)alkyl-, N(R3o)(R3i)-(C1-C6)alkyl-I (C1-C6)alkoxy-(C1-Cβ)alkoxy-(C1-C6)alkyl-, R32-aryl, Rsa-aryKC1-C6)alkyl-, R32-aryloxy(C1-C6)alkyl-, R32-heteroaryl, R32-heteroaryl(C1- C6)alkyl-, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C-rC6)alkyl-, N(R30)(R3I)-C(O)-(C1- C6)alkyl-, or heterocycloalkyl(C1-C6)alkyl-;
R2 is a six-membered heteroaryl ring having 1 or 2 heteroatoms independently selected from N or N-O, with the remaining ring atoms being carbon; a five-membered heteroaryl ring having 1 , 2 or 3 heteroatoms independently selected from N, O or S, with the remaining ring atoms being carbon; R32-quinolyl; R32-aryl; heterocycloalkyl;
Figure imgf000144_0001
wherein said six-membered heteroaryl ring or said five-membered heteroaryl ring is optionally substituted by R6;
X' is C or N;
Q' is a bond or C1-C6 alkylene;
Q1 is a bond, C1-C6 alkylene or -N(R4)-;
R3 is H, halogen, C1-C6 alkyl, -OH or (C1-C6)alkoxy;
R4 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, R33-aryl, R33-aryl(C1-C6)alkyl, and R32-heteroaryl;
R5 is hydrogen, d-C6 alkyl, -C(O)R2O, -C(O)2R20, -C(O)N(R2O)2 or (C1-C6)aIlCyI-SOz-;
R6 is 1 to 3 substituents independently selected from the group consisting of - OH, halogen, C1-C6 alkyl-, C1-C6 alkoxy, C1-C6 alkylthio, -CF3, -NR4R5, phenyl, R33- phenyl, NO2, -CO2R4, -CON(R4J2,
Figure imgf000144_0002
R12 is independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, orfluoro, provided that when Ri2 is hydroxy orfluoro, then Ri2 is not bound to a carbon adjacent to a nitrogen; or Ri2 forms a Ci to C2 alkyl bridge from one ring carbon to another ring carbon;
Ri3 is independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, orfluoro, provided that when R13 is hydroxy orfluoro then R13 is not bound to a carbon adjacent to a nitrogen; or forms a Ci to C2 alkyl bridge from one ring carbon to another ring carbon; or R13 is =O;
R20 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, or aryl, wherein said aryl group is optionally substituted with from 1 to 3 groups independently selected from halogen, -CF3, -OCF3, hydroxyl, or methoxy; or when two R20 groups are present, said two R20 groups taken together with the nitrogen to which they are bound form a five or six membered heterocyclic ring;
R22 is C1-C6 alkyl, R34-aryl or heterocycloalkyl;
R24 is H, C1-C6 alkyl, -SO2R22 or R^-aryl;
R25 is independently selected from the group consisting of C1-C6 alkyl, halogen, -CF3, -OH, C1-C6 alkoxy, (C1-C6)alkyl-C(O)-, aryl-C(O)-, N(R4)(Rs)-C(O)-, N(R4)(R5)- S(O)I-2-, halo-(CrC6)alkyl- or halo-(CrC6)alkoxy-(C1-C6)alkyl-;
R29 is H, C1-C6 alkyl, R35~aryl or R35-aryl(C1-C6)alkyl-;
R30 is H, C1-C6 alkyl-, R35-aryl or R35-aryl(C1-C6)alkyl-;
R31 is H1 C1-C6 alkyl-, R35-aryl, R35-aryl(C1-C6)alkyl-, (C1-C6)alkyl-C(O)-, R35- aryl-C(O)-, N(R4)(Rs)-C(O)-, (CrC6)alkyl-S(O)2- or R35-aryI-S(O)2-; or R30 and R3i together are -(CH2)4-5-, -(CH2)2-O-(CH2)2- or -(CH2)2-N(R29)-(CH2)2- and form a ring with the nitrogen to which they are attached;
R32 is 1 to 3 substituents independently selected from the group consisting of H, -OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, R35-aryl-O-, -SR22, -CF3, -OCF3, -OCHF2, - NR4R5, phenyl, R33-phenyl, NO2, -CO2R4, -CON(R4J2, -S(O)2R22, -S(O)2N(R2o)2, - N(R24)S(O)2R22, -CN, hydroxyl-(C1-C6)alkyl-, -OCH2CH2OR22, and R35-aryl(C1- C6)alkyl-O-, wherein said aryl group is optionally substituted with 1 to 3 independently selected halogens;
R33 is 1 to 3 substituents independently selected from the group consisting of C1-C6 alkyl, halogen, -CN, -NO2, -OCHF2 and -O-(C1-C6)alkyl;
R34 is 1 to 3 substituents independently selected from the group consisting of H, halogen, -CF3, -OCF3, -OH and -OCH3.
R3S is 1 to 3 substituents independently selected from hydrogen, halo, C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, phenoxy, -CF3, -N(R36^, -COOR20 and -NO2; and
R36 is independently selected form the group consisting of H and C1-C6 alkyl.
27. The method according to claim 1 , wherein the cholesterol lowering agent inhibitor is a bile acid sequestrant.
28. The method according to claim 27, wherein the bile acid sequestrant is cholestyramine.
29. The method according to claim 1 , wherein the cholesterol lowering agent is an HMG-CoA reductase inhibitor.
30. The method according to claim 29, wherein the HMG-CoA reductase inhibitor is selected from the group consisting of lovastatin, pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, CI-981 , rivastatin, rosuvastatin and pravastatin.
31. The method according to claim 1 , wherein the cholesterol lowering agent is nicotinic acid (niacin) and/or a nicotinic acid agonist.
32. The method according to claim 1 , wherein the cholesterol lowering agent is an activator of peroxisome proliferator-activated receptor.
33. The method according to claim 1 wherein the activator is a fibrate.
34. The method according to claim 33, where in the fibrate is clofibrate, gemfibrozil, ciprofibrate, bezafibrate, clinofibrate, binifibrate, lifibrol, or fenofibrate.
35. The method according to claim 2, which further comprises an effective amount of an HMG-CoA reductase inhibitor.
36. The method according to claim 18, wherein the HMG-CoA reductase inhibitor is selected from the group consisting of lovastatin, pravastatin fluvastatin, simvastatin, atorvastatin, cerivastatin, pitavastatin, and rosuvastatin.
37. The method according to claim 2, which further comprises as a third active component a PPAR activator, nicotinic acid and/or a nicotinic acid receptor agonist or a bile acid sequestrant.
38. The method according to claim 1, which further comprises an obesity control agent.
39. The method according to claim 2, which further comprises an obesity control agent.
40. The method according to claim 38, wherein the obesity control agent is selected from the group consisting of diethylpropion, mazindol, phenylpropanolamine, phentermine, phendimetrazine, phendamine tartrate, methamphetamine, phendimetrazine tartrate, sibutramine, fenfluramine, dexfenfluramine, fluoxetine, fluvoxamine paroxtine befloxatone, moclobemide, brofaromine, phenoxathine, esuprone, befol, toloxatone, pirlindol, amiflamine, sercloremine, bazinaprine, lazabemide, milacemide, caroxazone, and orlistat.
41. The method according to claim 40, which further comprises an HMG- CoA reductase inhibitor.
42. A method for the treatment, prevention or ameliorating the symptoms of nonalcoholic fatty liver disease (NAFLD) in a mammal in need thereof comprising the step of administering an effective amount of at least one sternol or 5-α-stanol absorption inhibitor or a pharmaceutically acceptable salt thereof or a solvate thereof.
43. A method for the treatment, prevention or ameliorating the symptoms of nonalcoholic fatty liver disease (NAFLD) in a mammal in need thereof comprising the step of administering an effective amount of at least one H3 receptor antagonist/inverse agonist or a pharmaceutically acceptable salt thereof or a solvate thereof.
44. A method for the prevention or amelioration of the symptoms or the development of hepatic steatosis in a mammal in need there of comprising the step of administering an effective amount of antherapeutic composition comprising at least one cholesterol lowering agent and/or at least one H3 receptor antagonist/inverse agonist to said mammal.
45. The method according to Claim 44, which further comprises a HMG-CoA reductase inhibitor.
46. A method for the prevention or amelioration of the development of nonalcoholic steato hepatitis (NASH) in a mammal in need thereof by administering an effective amount of a therapeutic composition comprising at least one at least at least one H3 receptor antagonist/inverse agonist and, optionally at least one cholesterol lowering agent to said mammal.
47. The method according to claim 46, which further comprises a HMG-CoA reductase inhibitor.
48. A method for the prevention or amelioration of the the development of cirrhosis or heptacellular carcinoma in a mammal in need thereof comprising the step of administering an effective amount of a therapeutic composition comprising a at least one cholesterol lowering agent and/or at least one H3 receptor antagonist/inverse agonist to said mammal.
PCT/US2006/048455 2005-12-21 2006-12-19 Treatment of nonalcoholic fatty liver disease using cholesterol lowering agents and h3 receptor antagonist/inverse agonist WO2007075702A2 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
BRPI0620255-1A BRPI0620255A2 (en) 2005-12-21 2006-12-19 use of cholesterol lowering agents and / or h3 receptor antagonist / inverse agonist
EP06845826A EP1962835A2 (en) 2005-12-21 2006-12-19 Treatment of nonalcoholic fatty liver disease using cholesterol lowering agents and/or h3 receptor antagonist/inverse agonist
CA002634940A CA2634940A1 (en) 2005-12-21 2006-12-19 Treatment of nonalcoholic fatty liver disease using cholesterol lowering agents and h3 receptor antagonist/inverse agonist
AU2006331770A AU2006331770A1 (en) 2005-12-21 2006-12-19 Treatment of nonalcoholic fatty liver disease using cholesterol lowering agents and H3 receptor antagonist/inverse agonist
JP2008547446A JP2009521452A (en) 2005-12-21 2006-12-19 Treatment of nonalcoholic fatty liver disease using cholesterol-lowering agents and H3 receptor antagonists / inverse agonists
MX2008008340A MX2008008340A (en) 2005-12-21 2006-12-19 Treatment of nonalcoholic fatty liver disease using cholesterol lowering agents and h3 receptor antagonist/inverse agonist.
NO20083235A NO20083235L (en) 2005-12-21 2008-07-21 Use of cholesterol-lowering agents and H3 receptor antagonist / inverse agonist in the treatment of non-alcohol related fatty liver disease

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US75271005P 2005-12-21 2005-12-21
US60/752,710 2005-12-21
US78704806P 2006-03-29 2006-03-29
US60/787,048 2006-03-29
US83664206P 2006-08-09 2006-08-09
US60/836,642 2006-08-09
US85517806P 2006-10-30 2006-10-30
US60/855,178 2006-10-30

Publications (2)

Publication Number Publication Date
WO2007075702A2 true WO2007075702A2 (en) 2007-07-05
WO2007075702A3 WO2007075702A3 (en) 2007-08-16

Family

ID=37909708

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2006/048455 WO2007075702A2 (en) 2005-12-21 2006-12-19 Treatment of nonalcoholic fatty liver disease using cholesterol lowering agents and h3 receptor antagonist/inverse agonist

Country Status (10)

Country Link
US (1) US20070161578A1 (en)
EP (1) EP1962835A2 (en)
JP (1) JP2009521452A (en)
AU (1) AU2006331770A1 (en)
BR (1) BRPI0620255A2 (en)
CA (1) CA2634940A1 (en)
MX (1) MX2008008340A (en)
NO (1) NO20083235L (en)
TW (1) TWI329014B (en)
WO (1) WO2007075702A2 (en)

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008108957A2 (en) * 2007-03-02 2008-09-12 Schering Corporation Piperidinyl-piperidine and piperazinyl-piperidine for use in the treatment of diabetes or pain
WO2009154230A1 (en) * 2008-06-17 2009-12-23 持田製薬株式会社 Prophylactic/ameliorating or therapeutic agent for non-alcoholic steatohepatitis
US7863265B2 (en) 2005-06-20 2011-01-04 Astrazeneca Ab 2-azetidinone derivatives and their use as cholesterol absorption inhibitors for the treatment of hyperlipidaemia
US7906502B2 (en) 2005-06-22 2011-03-15 Astrazeneca Ab 2-azetidinone derivatives as cholesterol absorption inhibitors for the treatment of hyperlipidaemic conditions
WO2013081462A1 (en) * 2011-12-02 2013-06-06 Universiteit Maastricht Phytostanols for the prevention or treatment of hepatic inflammation
WO2013151982A1 (en) 2012-04-03 2013-10-10 Arena Pharmaceuticals, Inc. Methods and compounds useful in treating pruritus, and methods for identifying such compounds
RU2498795C2 (en) * 2007-11-30 2013-11-20 Те Риджентс Оф Те Юниверсити Оф Калифорния Method of treating non-alcoholic steatohepatitis (nash) with using cysteamine products
US8609680B2 (en) 2010-03-19 2013-12-17 Pfizer Inc. 2,3-dihydro-1H-inden-1-yl-2,7-diazaspiro[3.5] nonane derivatives
US9163075B2 (en) 2005-11-23 2015-10-20 Acceleron Pharma Inc. Isolated polynucleotide that encodes an ActRIIa-Fc fusion polypeptide
US9353356B2 (en) 2007-09-18 2016-05-31 Acceleron Pharma Inc. Activin-actriia antagonists for treating a follicle-stimulating horomone-secreting pituitary tumor
US9399669B2 (en) 2007-02-02 2016-07-26 Acceleron Pharma Inc. Variants derived from ActRIIB
US9480742B2 (en) 2005-11-23 2016-11-01 Acceleron Pharma Inc. Method of promoting bone growth by an anti-actriia antibody
US9493556B2 (en) 2010-11-08 2016-11-15 Acceleron Pharma Inc. Actriia binding agents and uses thereof
US9572865B2 (en) 2005-11-23 2017-02-21 Acceleron Pharma Inc. Activin-actriia antagonists and uses for treating multiple myeloma
US9617319B2 (en) 2009-11-17 2017-04-11 Acceleron Pharma Inc. ActRIIB proteins and variants and uses therefore relating to utrophin induction for muscular dystrophy therapy
US9745559B2 (en) 2009-06-12 2017-08-29 Acceleron Pharma Inc. Method for decreasing the body fat content in a subject by administering an ActRIIB protein
US9790284B2 (en) 2009-06-08 2017-10-17 Acceleron Pharma Inc. Methods for increasing thermogenic adipocytes
US9850298B2 (en) 2014-06-13 2017-12-26 Acceleron Pharma Inc. Methods for treating ulcers in thalassemia syndrome with an ActRIIB polypeptide
US9932379B2 (en) 2008-08-14 2018-04-03 Acceleron Pharma Inc. Isolated nucleotide sequences encoding GDF traps
US10093707B2 (en) 2006-12-18 2018-10-09 Acceleron Pharma Inc. Antagonists of activin-ActRIIa and uses for increasing red blood cell levels
US10112929B2 (en) 2015-03-09 2018-10-30 Bristol-Myers Squibb Company Lactams as inhibitors of rock
US10195249B2 (en) 2012-11-02 2019-02-05 Celgene Corporation Activin-ActRII antagonists and uses for treating bone and other disorders
US10377996B2 (en) 2008-08-14 2019-08-13 Acceleron Pharma Inc. Methods of identifying ActRIIB variants
US11471510B2 (en) 2014-12-03 2022-10-18 Celgene Corporation Activin-ActRII antagonists and uses for treating anemia
US11813308B2 (en) 2014-10-09 2023-11-14 Celgene Corporation Treatment of cardiovascular disease using ActRII ligand traps

Families Citing this family (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE485267T1 (en) 2003-12-23 2010-11-15 Astrazeneca Ab DIPHENYLAZETIDINONE DERIVATIVES WITH CHOLESTERINE ABSORPTION INHIBITING EFFECT
EP3489257A1 (en) 2004-07-23 2019-05-29 Acceleron Pharma Inc. Actrii receptor polypeptides, methods and compositions
SA06270191B1 (en) 2005-06-22 2010-03-29 استرازينيكا ايه بي Novel 2-Azetidinone Derivatives as Cholesterol Absorption Inhibitors for the Treatment of Hyperlipidaemic Conditions
AR060623A1 (en) 2006-04-27 2008-07-02 Astrazeneca Ab COMPOUNDS DERIVED FROM 2-AZETIDINONE AND A PREPARATION METHOD
PL2054049T3 (en) 2006-08-24 2016-11-30 Substituted acylanilides and methods of use thereof
TWI584815B (en) 2007-02-01 2017-06-01 艾瑟勒朗法瑪公司 Activin-actriia antagonists and uses for treating or preventing breast cancer
EP3818988A1 (en) * 2009-11-03 2021-05-12 Acceleron Pharma Inc. Methods for treating fatty liver disease
JP2011236160A (en) * 2010-05-11 2011-11-24 Shinshu Univ Medicine for treating nonalcoholic hepatic disease
ES2552657T3 (en) 2010-05-26 2015-12-01 Satiogen Pharmaceuticals, Inc. Inhibitors of the recycling of bile acids and satiogens for the treatment of diabetes, obesity, and inflammatory gastrointestinal conditions
US9045445B2 (en) 2010-06-04 2015-06-02 Albany Molecular Research, Inc. Glycine transporter-1 inhibitors, methods of making them, and uses thereof
WO2012071459A1 (en) * 2010-11-22 2012-05-31 The Regents Of The University Of California New indication for use of niacin (nicotinic acid) for treatment, prevention and reversal of fatty liver disease
EP2770990A4 (en) 2011-10-28 2015-03-11 Lumena Pharmaceuticals Inc Bile acid recycling inhibitors for treatment of hypercholemia and cholestatic liver disease
EP2771003B1 (en) 2011-10-28 2017-04-19 Lumena Pharmaceuticals LLC Bile acid recycling inhibitors for treatment of pediatric cholestatic liver diseases
EA037918B1 (en) 2011-12-21 2021-06-07 Новира Терапьютикс, Инк. Hepatitis b antiviral agents
JP5571650B2 (en) * 2011-12-27 2014-08-13 農業生産法人株式会社 熱帯資源植物研究所 Drugs for non-alcoholic fatty liver disease and / or non-alcoholic steatohepatitis
US10314807B2 (en) 2012-07-13 2019-06-11 Gtx, Inc. Method of treating HER2-positive breast cancers with selective androgen receptor modulators (SARMS)
US9622992B2 (en) 2012-07-13 2017-04-18 Gtx, Inc. Method of treating androgen receptor (AR)-positive breast cancers with selective androgen receptor modulator (SARMs)
US9969683B2 (en) 2012-07-13 2018-05-15 Gtx, Inc. Method of treating estrogen receptor (ER)-positive breast cancers with selective androgen receptor modulator (SARMS)
KR102122941B1 (en) 2012-07-13 2020-06-15 지티엑스, 인코포레이티드 A method of treating androgen receptor(ar)-positive breast cancers with selective androgen receptor modulator(sarms)
US10258596B2 (en) 2012-07-13 2019-04-16 Gtx, Inc. Method of treating HER2-positive breast cancers with selective androgen receptor modulators (SARMS)
US9744149B2 (en) 2012-07-13 2017-08-29 Gtx, Inc. Method of treating androgen receptor (AR)-positive breast cancers with selective androgen receptor modulator (SARMs)
US10987334B2 (en) 2012-07-13 2021-04-27 University Of Tennessee Research Foundation Method of treating ER mutant expressing breast cancers with selective androgen receptor modulators (SARMs)
CR20200276A (en) 2012-08-28 2021-01-27 Janssen Sciences Ireland Uc SULFAMOYLARYLAMIDES AND THEIR USE AS MEDICINES FOR THE TREATMENT OF HEPATITIS B (DIVISIONAL EXP. 2015-0059)
HUE034820T2 (en) 2013-02-28 2018-02-28 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis b
CA2907230A1 (en) 2013-03-15 2014-09-18 Lumena Pharmaceuticals, Inc. Bile acid recycling inhibitors for treatment of primary sclerosing cholangitis and inflammatory bowel disease
WO2014144485A1 (en) 2013-03-15 2014-09-18 Lumena Pharmaceuticals, Inc. Bile acid recycling inhibitors for treatment of barrett's esophagus and gastroesophageal reflux disease
HUE033542T2 (en) 2013-04-03 2017-12-28 Janssen Sciences Ireland Uc N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis b
JO3603B1 (en) 2013-05-17 2020-07-05 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b
CN105960400B (en) 2013-05-17 2019-05-31 爱尔兰詹森科学公司 Sulfamoylthiophene amide derivatives and its purposes for being used to treat hepatitis B as drug
WO2015011281A1 (en) 2013-07-25 2015-01-29 Janssen R&D Ireland Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b
UA117261C2 (en) 2013-10-23 2018-07-10 ЯНССЕН САЙЄНСЕЗ АЙРЛЕНД ЮСі Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis b
US10392349B2 (en) 2014-01-16 2019-08-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US9169212B2 (en) 2014-01-16 2015-10-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
AU2015214096B2 (en) 2014-02-05 2021-02-11 Novira Therapeutics, Inc. Combination therapy for treatment of HBV infections
AU2015214961B2 (en) 2014-02-06 2018-08-30 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
CN106659722A (en) * 2014-04-18 2017-05-10 株式会社Lg生命科学 Composition for preventing or treating fatty liver diseases
EP3271019A1 (en) 2015-03-19 2018-01-24 Novira Therapeutics Inc. Azocane and azonane derivatives and methods of treating hepatitis b infections
US10875876B2 (en) 2015-07-02 2020-12-29 Janssen Sciences Ireland Uc Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
JP6845231B2 (en) 2015-09-29 2021-03-17 ノヴィラ・セラピューティクス・インコーポレイテッド Crystalline form of hepatitis B antiviral drug
KR20180073597A (en) * 2015-11-06 2018-07-02 젬파이어 세러퓨틱스 인코포레이티드 Treatment of mixed dyslipidemia
SG11201808949SA (en) 2016-04-15 2018-11-29 Novira Therapeutics Inc Combinations and methods comprising a capsid assembly inhibitor
JP2020533013A (en) * 2017-09-13 2020-11-19 アレクセラ アーベー How to identify a therapeutic agent that interacts with STK24
US11340226B2 (en) * 2018-03-02 2022-05-24 The Chinese University Of Hong Kong Squalene epoxidase in the diagnosis and treatment of non-alcoholic fatty liver diseases
AU2019235522A1 (en) 2018-03-14 2020-09-03 Janssen Sciences Ireland Unlimited Company Capsid assembly modulator dosing regimen
WO2020154567A1 (en) * 2019-01-25 2020-07-30 Viscient Biosciences, Inc. Compositions and methods for the diagnosis and treatment of diseases of the liver
BR112021015815A2 (en) 2019-02-12 2022-01-18 Mirum Pharmaceuticals Inc Methods to treat cholestasis
US11096931B2 (en) 2019-02-22 2021-08-24 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
US11491148B2 (en) 2019-05-06 2022-11-08 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
US11285108B1 (en) * 2021-03-09 2022-03-29 Naturalis S.A. Phytosterols for the prevention or treatment of non-alcoholic steatohepatitis

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002032893A2 (en) * 2000-10-17 2002-04-25 Schering Corporation Piperidine compounds as anti-allergic
WO2003033488A1 (en) * 2001-10-15 2003-04-24 Schering Corporation Synthesis of 4-(piperidyl) (2-pyridyl)methanone-(e)-o-methyloxime and its salts

Family Cites Families (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4444784A (en) * 1980-08-05 1984-04-24 Merck & Co., Inc. Antihypercholesterolemic compounds
US4820850A (en) * 1987-07-10 1989-04-11 Merck & Co., Inc. Process for α-C-alkylation of the 8-acyl group on mevinolin and analogs thereof
US4916239A (en) * 1988-07-19 1990-04-10 Merck & Co., Inc. Process for the lactonization of mevinic acids and analogs thereof
US5688787A (en) * 1991-07-23 1997-11-18 Schering Corporation Substituted β-lactam compounds useful as hypochlesterolemic agents and processes for the preparation thereof
ATE147067T1 (en) * 1992-04-03 1997-01-15 Gist Brocades Nv SELECTIVE N-ACYLATION OF AMINO ALCOHOLS
LT3300B (en) * 1992-12-23 1995-06-26 Schering Corp Combination of a cholesterol biosynhtesis inhibitor and a beta- lactam cholesterol absorbtion inhibitor
LT3595B (en) * 1993-01-21 1995-12-27 Schering Corp Spirocycloalkyl-substituted azetidinones useful as hypocholesterolemic agents
US5631365A (en) * 1993-09-21 1997-05-20 Schering Corporation Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents
US5633246A (en) * 1994-11-18 1997-05-27 Schering Corporation Sulfur-substituted azetidinone compounds useful as hypocholesterolemic agents
US5624920A (en) * 1994-11-18 1997-04-29 Schering Corporation Sulfur-substituted azetidinone compounds useful as hypocholesterolemic agents
US5656624A (en) * 1994-12-21 1997-08-12 Schering Corporation 4-[(heterocycloalkyl or heteroaromatic)-substituted phenyl]-2-azetidinones useful as hypolipidemic agents
US5756470A (en) * 1996-10-29 1998-05-26 Schering Corporation Sugar-substituted 2-azetidinones useful as hypocholesterolemic agents
US5861145A (en) * 1997-06-09 1999-01-19 The Procter & Gamble Company Method of reducing body odor using perfumed, odor absorbing, two phase compositions
US5869479A (en) * 1997-08-14 1999-02-09 Schering Corporation Treatment of upper airway allergic responses
US6180139B1 (en) * 1998-12-04 2001-01-30 Viva America Marketing, Inc. Composition and method for treating nonalcoholic steatohepatitis
US6437147B1 (en) * 2000-03-17 2002-08-20 Novo Nordisk Imidazole compounds
GB0021494D0 (en) * 2000-09-01 2000-10-18 Glaxo Group Ltd Chemical comkpounds
HUP0401081A3 (en) * 2000-12-21 2010-06-28 Sanofi Aventis Deutschland Novel 1,2-diphenzylazetidinones, method for producing the same, medicaments containing said compounds, and their use
DE10103520A1 (en) * 2001-01-26 2002-08-01 Isad Electronic Sys Gmbh & Co Generator system, in particular for a motor vehicle, and method for controlling an inverter of an asynchronous generator
JP4522651B2 (en) * 2001-03-13 2010-08-11 シェーリング コーポレイション New non-imidazole compounds
GB0112810D0 (en) * 2001-05-25 2001-07-18 Glaxo Group Ltd Pyrimidine derivatives
IL159320A0 (en) * 2001-06-12 2004-06-01 Wellstat Therapeutics Corp Compounds for the treatment of metabolic disorders
NZ535764A (en) * 2002-04-18 2007-10-26 Schering Corp 1-(4-piperidinyl) benzimidazolones as histamine H3 antagonists
US7105505B2 (en) * 2002-04-18 2006-09-12 Schering Corporation Benzimidazole derivatives useful as histamine H3 antagonists
AR041089A1 (en) * 2003-05-15 2005-05-04 Merck & Co Inc PROCEDURE AND PHARMACEUTICAL COMPOSITIONS TO TREAT ATEROSCLEROSIS, DYSLIPIDEMIAS AND RELATED AFFECTIONS

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002032893A2 (en) * 2000-10-17 2002-04-25 Schering Corporation Piperidine compounds as anti-allergic
WO2003033488A1 (en) * 2001-10-15 2003-04-24 Schering Corporation Synthesis of 4-(piperidyl) (2-pyridyl)methanone-(e)-o-methyloxime and its salts

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
AHMED MOHAMED H ET AL: "Ezetimibe: effective and safe treatment for dyslipidaemia associated with nonalcoholic fatty liver disease. Response to: Toth PP, Davidson MH: simvastatin and ezetimibe: combination therapy for the management of dyslipidaemia. Expert Opin. Pharmacother. (2005) 6(1):131-139." EXPERT OPINION ON DRUG SAFETY JUL 2006, vol. 5, no. 4, July 2006 (2006-07), pages 487-488, XP002429940 ISSN: 1744-764X *
FARNIER MICHEL ET AL: "Efficacy and safety of the coadministration of ezetimibe with fenofibrate in patients with mixed hyperlipidaemia." EUROPEAN HEART JOURNAL MAY 2005, vol. 26, no. 9, May 2005 (2005-05), pages 897-905, XP002429941 ISSN: 0195-668X *
FEY THOMAS A ET AL: "Effects of A-423579, a Novel Histamine-3 Receptor Antagonist in Rodent Models of Diet-Induced Obesity" FASEB JOURNAL, vol. 18, no. 4-5, 2004, page ABST. 394.5, XP009082414 & FASEB MEETING ON EXPERIMENTAL BIOLOGY: TRANSLATING THE GENOME; WASHINGTON, DISTRICT OF COLUMBIA, USA; APRIL 17-21, 2004 ISSN: 0892-6638 *
HANCOCK A A ET AL: "Histamine H3 antagonists in models of obesity" INFLAMMATION RESEARCH, vol. 53, no. Suppl. 1, March 2004 (2004-03), pages S47-S48, XP002429942 ISSN: 1023-3830 *
KOTEISH AYMAN ET AL: "Animal models of steatohepatitis." BEST PRACTICE & RESEARCH. CLINICAL GASTROENTEROLOGY OCT 2002, vol. 16, no. 5, October 2002 (2002-10), pages 679-690, XP002429939 ISSN: 1521-6918 *
TOTH PETER P ET AL: "Simvastatin plus ezetimibe: combination therapy for the management of dyslipidaemia." EXPERT OPINION ON PHARMACOTHERAPY JAN 2005, vol. 6, no. 1, January 2005 (2005-01), pages 131-139, XP009082392 ISSN: 1744-7666 *

Cited By (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7863265B2 (en) 2005-06-20 2011-01-04 Astrazeneca Ab 2-azetidinone derivatives and their use as cholesterol absorption inhibitors for the treatment of hyperlipidaemia
US7906502B2 (en) 2005-06-22 2011-03-15 Astrazeneca Ab 2-azetidinone derivatives as cholesterol absorption inhibitors for the treatment of hyperlipidaemic conditions
US10071135B2 (en) 2005-11-23 2018-09-11 Acceleron Pharma Inc. Method of identifying an agent that promotes bone growth or increases bone density
US9572865B2 (en) 2005-11-23 2017-02-21 Acceleron Pharma Inc. Activin-actriia antagonists and uses for treating multiple myeloma
US11129873B2 (en) 2005-11-23 2021-09-28 Acceleron Pharma Inc. Method for promoting bone growth using activin-actriia antagonists
US10239940B2 (en) 2005-11-23 2019-03-26 Acceleron Pharma Inc. Method of promoting bone growth by an anti-actriia antibody
US9163075B2 (en) 2005-11-23 2015-10-20 Acceleron Pharma Inc. Isolated polynucleotide that encodes an ActRIIa-Fc fusion polypeptide
US9480742B2 (en) 2005-11-23 2016-11-01 Acceleron Pharma Inc. Method of promoting bone growth by an anti-actriia antibody
US10093707B2 (en) 2006-12-18 2018-10-09 Acceleron Pharma Inc. Antagonists of activin-ActRIIa and uses for increasing red blood cell levels
US10259861B2 (en) 2007-02-02 2019-04-16 Acceleron Pharma Inc. Variants derived from ActRIIB and uses therefor
US9399669B2 (en) 2007-02-02 2016-07-26 Acceleron Pharma Inc. Variants derived from ActRIIB
WO2008108957A3 (en) * 2007-03-02 2009-02-05 Schering Corp Piperidinyl-piperidine and piperazinyl-piperidine for use in the treatment of diabetes or pain
WO2008108957A2 (en) * 2007-03-02 2008-09-12 Schering Corporation Piperidinyl-piperidine and piperazinyl-piperidine for use in the treatment of diabetes or pain
US9353356B2 (en) 2007-09-18 2016-05-31 Acceleron Pharma Inc. Activin-actriia antagonists for treating a follicle-stimulating horomone-secreting pituitary tumor
RU2498795C2 (en) * 2007-11-30 2013-11-20 Те Риджентс Оф Те Юниверсити Оф Калифорния Method of treating non-alcoholic steatohepatitis (nash) with using cysteamine products
US20110105510A1 (en) * 2008-06-17 2011-05-05 Hiroshi Ishikawa Prophylactic/ameliorating or therapeutic agent for non-alcoholic steatohepatitis
WO2009154230A1 (en) * 2008-06-17 2009-12-23 持田製薬株式会社 Prophylactic/ameliorating or therapeutic agent for non-alcoholic steatohepatitis
JPWO2009154230A1 (en) * 2008-06-17 2011-12-01 持田製薬株式会社 Non-alcoholic steatohepatitis prevention / improvement / treatment drug
US10889626B2 (en) 2008-08-14 2021-01-12 Acceleron Pharma Inc. Combined use of GDF traps and erythropoietin receptor activators to increase red blood cell levels
US11162085B2 (en) 2008-08-14 2021-11-02 Acceleron Pharma Inc. Methods for treating anemia in a subject in need thereof
US9932379B2 (en) 2008-08-14 2018-04-03 Acceleron Pharma Inc. Isolated nucleotide sequences encoding GDF traps
US11155791B2 (en) 2008-08-14 2021-10-26 Acceleron Pharma Inc. Methods for treating anemia in a subject in need thereof
US11168311B2 (en) 2008-08-14 2021-11-09 Acceleron Pharma Inc. Methods for treating anemia in a subject in need thereof
US10377996B2 (en) 2008-08-14 2019-08-13 Acceleron Pharma Inc. Methods of identifying ActRIIB variants
US10829533B2 (en) 2008-08-14 2020-11-10 Acceleron Pharma Inc. Combined use of GDF traps and erythropoietin receptor activators to increase red blood cell levels
US10829532B2 (en) 2008-08-14 2020-11-10 Acceleron Pharma Inc. Combined use of gdf traps and erythropoietin receptor activators to increase red blood cell levels
US10689427B2 (en) 2008-08-14 2020-06-23 Acceleron Pharma Inc. Combined use of GDF traps and erythropoietin receptor activators to increase red blood cell levels
US9790284B2 (en) 2009-06-08 2017-10-17 Acceleron Pharma Inc. Methods for increasing thermogenic adipocytes
US10968282B2 (en) 2009-06-08 2021-04-06 Acceleron Pharma Inc. Methods for screening compounds for increasing thermogenic adipocytes
US11066654B2 (en) 2009-06-12 2021-07-20 Acceleron Pharma Inc. Methods and compositions for reducing serum lipids
US10358633B2 (en) 2009-06-12 2019-07-23 Acceleron Pharma Inc. Method for producing an ActRIIB-Fc fusion polypeptide
US9745559B2 (en) 2009-06-12 2017-08-29 Acceleron Pharma Inc. Method for decreasing the body fat content in a subject by administering an ActRIIB protein
US9617319B2 (en) 2009-11-17 2017-04-11 Acceleron Pharma Inc. ActRIIB proteins and variants and uses therefore relating to utrophin induction for muscular dystrophy therapy
US10968262B2 (en) 2009-11-17 2021-04-06 Acceleron Pharma Inc. Methods of increasing sarcolemmal utrophin
US8609680B2 (en) 2010-03-19 2013-12-17 Pfizer Inc. 2,3-dihydro-1H-inden-1-yl-2,7-diazaspiro[3.5] nonane derivatives
US9493556B2 (en) 2010-11-08 2016-11-15 Acceleron Pharma Inc. Actriia binding agents and uses thereof
WO2013081462A1 (en) * 2011-12-02 2013-06-06 Universiteit Maastricht Phytostanols for the prevention or treatment of hepatic inflammation
WO2013151982A1 (en) 2012-04-03 2013-10-10 Arena Pharmaceuticals, Inc. Methods and compounds useful in treating pruritus, and methods for identifying such compounds
US10195249B2 (en) 2012-11-02 2019-02-05 Celgene Corporation Activin-ActRII antagonists and uses for treating bone and other disorders
US10487144B2 (en) 2014-06-13 2019-11-26 Acceleron Pharma Inc. Methods for treating ulcers in a hemoglobinopathy anemia with a soluble actRIIB polypeptide
US9850298B2 (en) 2014-06-13 2017-12-26 Acceleron Pharma Inc. Methods for treating ulcers in thalassemia syndrome with an ActRIIB polypeptide
US11260107B2 (en) 2014-06-13 2022-03-01 Acceleron Pharma Inc. Methods and compositions for treating ulcers
US11813308B2 (en) 2014-10-09 2023-11-14 Celgene Corporation Treatment of cardiovascular disease using ActRII ligand traps
US11471510B2 (en) 2014-12-03 2022-10-18 Celgene Corporation Activin-ActRII antagonists and uses for treating anemia
US10112929B2 (en) 2015-03-09 2018-10-30 Bristol-Myers Squibb Company Lactams as inhibitors of rock

Also Published As

Publication number Publication date
AU2006331770A1 (en) 2007-07-05
EP1962835A2 (en) 2008-09-03
NO20083235L (en) 2008-09-19
TWI329014B (en) 2010-08-21
BRPI0620255A2 (en) 2011-11-08
MX2008008340A (en) 2008-09-03
TW200731968A (en) 2007-09-01
US20070161578A1 (en) 2007-07-12
CA2634940A1 (en) 2007-07-05
JP2009521452A (en) 2009-06-04
WO2007075702A3 (en) 2007-08-16

Similar Documents

Publication Publication Date Title
EP1962835A2 (en) Treatment of nonalcoholic fatty liver disease using cholesterol lowering agents and/or h3 receptor antagonist/inverse agonist
US20080103122A1 (en) Pharmaceutical combinations for lipid management and in the treatment of atherosclerosis and hepatic steatosis
JP4937836B2 (en) Combination of peroxisome proliferator activated receptor (PPAR) activator and sterol absorption inhibitor and treatment of vascular symptoms
AU2005234666B2 (en) Methods for treating or preventing vascular inflammation using sterol absorption inhibitor(s)
US6982251B2 (en) Substituted 2-azetidinones useful as hypocholesterolemic agents
JP2008514718A (en) Combinations of substituted azetidonones and CB1 antagonists
AU2002336609B2 (en) Treatment of xanthoma with azetidinone derivatives as sterol absorption inhibitors
PL205343B1 (en) The use of substituted azetidinone compounds for the treatment of sitosterolemia
JP2011153126A (en) Hdl-boosting combination therapy complex
JP2011516478A (en) Compositions and methods for immunotherapy
JP2004521894A (en) Combination of bile acid sequestrants and sterol absorption inhibitors and treatment of vascular indications
JP2004517920A (en) Combination of sterol absorption inhibitors and blood conditioning agents to treat vascular conditions
AU2002336609A1 (en) Treatment of xanthoma with azetidinone derivatives as sterol absorption inhibitors
JP2004517916A (en) Combination of nicotinic acid and its derivatives and sterol absorption inhibitors, and treatment of vascular indications
CN1820743A (en) Inhibitor or promoter of uridinediphosphate glucuronosyltransferase 2B (UGT2B)
CN101193656B (en) Novel triglyceride reducing agent
CN1256094C (en) Deoxyadenosine in aplication of preparing bypolipidemic
CN101426496A (en) Treatment of nonalcoholic fatty liver disease using cholesterol lowering agents and H3 receptor antagonist/inverse agonist
AU2007201970B2 (en) Combinations of peroxisome proliferator-activated receptor (PPAR) activator(s) and sterol absorption inhibitor(s) and treatments for vascular indications
AU2006202618B2 (en) Combinations of peroxisome proliferator-activated receptor (PPAR) activator(s) and sterol absorption inhibitor(s) and treatments for vascular indications
WO2007136696A2 (en) Use of substituted azetidinone compounds with cetp inhibitors for the treatment of sitosterolemia

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2006845826

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2008547446

Country of ref document: JP

Ref document number: 12008501497

Country of ref document: PH

Ref document number: 2006331770

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: MX/a/2008/008340

Country of ref document: MX

Ref document number: 2634940

Country of ref document: CA

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 569445

Country of ref document: NZ

ENP Entry into the national phase

Ref document number: 2006331770

Country of ref document: AU

Date of ref document: 20061219

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 200680051612.7

Country of ref document: CN

ENP Entry into the national phase

Ref document number: PI0620255

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20080623