WO2007120575A2 - Niacin receptor agonists, compositions containing such compounds and methods of treatment - Google Patents
Niacin receptor agonists, compositions containing such compounds and methods of treatment Download PDFInfo
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- WO2007120575A2 WO2007120575A2 PCT/US2007/008584 US2007008584W WO2007120575A2 WO 2007120575 A2 WO2007120575 A2 WO 2007120575A2 US 2007008584 W US2007008584 W US 2007008584W WO 2007120575 A2 WO2007120575 A2 WO 2007120575A2
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- 0 *c1c(NC(CCc2ccc(cccc3)c3c2)=O)[s]c(Cl)c1 Chemical compound *c1c(NC(CCc2ccc(cccc3)c3c2)=O)[s]c(Cl)c1 0.000 description 4
- IQDQFSAKNCVOKC-UHFFFAOYSA-N CC(Cc(cc1)cc(cc2)c1c(Cl)c2OC)C(Nc1c[s]cc1C(O)=O)=O Chemical compound CC(Cc(cc1)cc(cc2)c1c(Cl)c2OC)C(Nc1c[s]cc1C(O)=O)=O IQDQFSAKNCVOKC-UHFFFAOYSA-N 0.000 description 1
- SPBDGJDXLFDBHJ-UHFFFAOYSA-N CC1C=Cc2cc(CCC(Nc3c(C(O)=O)[s]cc3C#N)=O)ccc2C1 Chemical compound CC1C=Cc2cc(CCC(Nc3c(C(O)=O)[s]cc3C#N)=O)ccc2C1 SPBDGJDXLFDBHJ-UHFFFAOYSA-N 0.000 description 1
- IIRHSSAQVPNITE-UHFFFAOYSA-N CN/C(/c(cc1)ncc1O)=N\OCNc([s]cc1)c1C(O)=O Chemical compound CN/C(/c(cc1)ncc1O)=N\OCNc([s]cc1)c1C(O)=O IIRHSSAQVPNITE-UHFFFAOYSA-N 0.000 description 1
- DGGJQLCAYQCPDD-UHFFFAOYSA-N COC(c1c(N)[s]cc1)=O Chemical compound COC(c1c(N)[s]cc1)=O DGGJQLCAYQCPDD-UHFFFAOYSA-N 0.000 description 1
- SJQWMMSUYOXPFQ-UHFFFAOYSA-N COC(c1c(NC(CCc2cc(cccc3)c3cc2)=O)[s]c(Cl)c1)=O Chemical compound COC(c1c(NC(CCc2cc(cccc3)c3cc2)=O)[s]c(Cl)c1)=O SJQWMMSUYOXPFQ-UHFFFAOYSA-N 0.000 description 1
- TYXZZXSJYUBFHG-UHFFFAOYSA-N Cc1c[s]c(NC(CCc(cc2)ccc2-c2ccccc2)=O)c1C(O)=O Chemical compound Cc1c[s]c(NC(CCc(cc2)ccc2-c2ccccc2)=O)c1C(O)=O TYXZZXSJYUBFHG-UHFFFAOYSA-N 0.000 description 1
- QUNKEVRRAIMVIH-UHFFFAOYSA-N Cc1nc(C(O)=O)c(NC(CCc(cc2)ccc2-c(c(Cl)c2)ccc2O)=O)[s]1 Chemical compound Cc1nc(C(O)=O)c(NC(CCc(cc2)ccc2-c(c(Cl)c2)ccc2O)=O)[s]1 QUNKEVRRAIMVIH-UHFFFAOYSA-N 0.000 description 1
- NJCQBDKCJLCVAM-UHFFFAOYSA-N N#Cc1cc(C(O)=O)c(NC(CCc2cc(cccc3)c3cc2)=O)[s]1 Chemical compound N#Cc1cc(C(O)=O)c(NC(CCc2cc(cccc3)c3cc2)=O)[s]1 NJCQBDKCJLCVAM-UHFFFAOYSA-N 0.000 description 1
- LGEMVVPDTIDWMI-UHFFFAOYSA-N OC(c1c[s]cc1NC(CCc1ccc(cccc2)c2c1)=O)=O Chemical compound OC(c1c[s]cc1NC(CCc1ccc(cccc2)c2c1)=O)=O LGEMVVPDTIDWMI-UHFFFAOYSA-N 0.000 description 1
- CXEDDUGFFNGMDI-UHFFFAOYSA-N OC(c1c[s]cc1NC(CCc1nc(-c(cc2)ncc2O)n[o]1)=O)=O Chemical compound OC(c1c[s]cc1NC(CCc1nc(-c(cc2)ncc2O)n[o]1)=O)=O CXEDDUGFFNGMDI-UHFFFAOYSA-N 0.000 description 1
- GEZZGKVDLZPIOY-UHFFFAOYSA-N OC1C=CC(c2n[o]c(CCC(Nc([s]cc3)c3C(O)=O)=O)n2)=NC1 Chemical compound OC1C=CC(c2n[o]c(CCC(Nc([s]cc3)c3C(O)=O)=O)n2)=NC1 GEZZGKVDLZPIOY-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D333/40—Thiophene-2-carboxylic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- the present invention relates to heterocyclic acid compounds, their derivatives, compositions containing such compounds and methods of treatment or prevention in a mammal relating to dyslipidemias.
- Dyslipidemia is a condition wherein serum lipids are abnormal. Elevated cholesterol and low levels of high density lipoprotein (HDL) are independent risk factors for atherosclerosis
- Atherosclerosis and cardiovascular disease Factors known to affect serum cholesterol include genetic predisposition, diet, body weight, degree of physical activity, age and gender. While cholesterol in normal amounts is a vital building block for cell membranes and essential organic molecules such as steroids and bile acids, cholesterol in excess is known to contribute to cardiovascular disease. For example, cholesterol, through its relationship with foam cells, is a primary
- Atherosclerosis 5 component of plaque which collects in coronary arteries, resulting in the cardiovascular disease termed atherosclerosis.
- !0 compounds such as soluble fiber, vitamin E, soy, garlic, omega-3 fatty acids, and niacin have all received significant attention and research funding.
- Niacin or nicotinic acid is a drug that reduces coronary events in clinical trials. It is commonly known for its effect in elevating serum levels of high density lipoproteins (HDL). Importantly, niacin also has a beneficial effect on other lipid profiles. Specifically,
- LDL low density lipoproteins
- VLDL very low density lipoproteins
- TG triglycerides
- nicotinic acid is limited by a number of adverse side-effects including cutaneous vasodilation, sometimes called flushing.
- the present invention relates to compounds that have been discovered to have effects in modifying serum lipid levels. 5
- the invention thus provides compositions for effecting reduction in total cholesterol and triglyceride concentrations and raising HDL, in accordance with the methods described. Consequently one object of the present invention is to provide a nicotinic acid receptor agonist that can be used to treat dyslipidemias, atherosclerosis, diabetes, metabolic syndrome and related conditions while minimizing the adverse effects that are associated with niacin treatment.
- Yet another object is to provide a pharmaceutical composition for oral use. 5
- X 1 , X 2 and X 3 represents a sulfur atom, and the other two represent carbon or nitrogen atoms
- ring A represents a 6-10 membered aryl, or a 5-13 membered heteroaryl or partially aromatic heterocyclic group, said heteroaryl and partially aromatic heterocyclic group containing at least 5 one heteroatom selected from O, S, S(O), S(O) 2 and N, and optionally containing 1 other heteroatom selected from O and S, and optionally containing 1-3 additional N atoms, with up to 5 heteroatoms being present
- each R 2 and R 3 is independently H, Ci -3 alkyl, haloC] -3 alkyl, OCi -3 alkyl, haloC 1-3 alkoxy, OH or F
- [Q n represents an integer of from 2 to 4
- each R 4 is H or is independently selected from halo, SCi ⁇ alkyl, CN, C !-4 al
- halo OH 3 CO 2 H 5 CN, NH 2, S(O) 0-2 R", C(O)R", OC(O)R e and CO 2 R e , wherein R e is or phenyl, each being optionally substituted with 1-3 groups, 1-3 of which are halo or Ci- 3 alkyl, and 1-2 of which are selected from OCi -3 alkyl, haloCi. 3 alkyl, haloC 1-3 alkoxy, OH, NH 2 and NHCi -3 alkyl;
- Ci -6 alkyl and OCi- ⁇ alkyl said C ⁇ alkyl and alkyl portion of OCi ⁇ alkyl being optionally substituted with 1-3 groups, 1-3 of which are halo and 1-2 of which are selected from: OH, JO CO 2 H, CO 2 C M alkyl, CO 2 C M haloalkyl, OCO 2 C I-4 aIkyl, NH 2 , NHC ⁇ alkyl, N(C M alkyl) 2 , Hetcy and CN; c) NHCi ⁇ alkyl and N(C M aIkVl) 2 , the alkyl portions of which are optionally substituted as set forth in (b) above; d) C(O)NH 2 , C(O)NHC 1-4 alkyl, C(O)N(C 1 ..alkyl) 2 , C(O)Hetcy, C(O)NHOC 1-4 alkyl and the alkyl portions of which are optionally
- R" represents (a) Ci.galkyl optionally substituted with 1-4 groups, 0-4 of which are halo, and 0-1 of which are selected from the group consisting of: OCi- ⁇ alkyl, OH, CO 2 H, CO 2 C 1-4 alkyl, 0 CO 2 Ci. 4 haloalkyl, NH 2 , 2 , CN 5 Hetcy, Aryl and HAR, said Hetcy, Aryl and HAR being further optionally substituted with 1-3 halo, C 1- 4alkyl, C ]-4 alkoxy, haloC 1-4 alkyl or haloC 1-4 alkoxy groups;
- Alkyl as well as other groups having the prefix “alk”, such as alkoxy, alkanoyl and the J5 like, means carbon chains which may be linear, branched, or cyclic, or combinations thereof, containing the indicated number of carbon atoms. If no number is specified, 1-6 carbon atoms are intended for linear and 3-7 carbon atoms for branched alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and the like.
- Cycloalkyl is a subset of alkyl; if no number of atoms is specified, 3-7 carbon atoms are intended, forming 1-3 carbocyclic rings that are fused. "Cycloalkyl” also includes monocyclic rings fused to an aryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl and the like.
- alkenyl means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.
- Alkynyl means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-l-pentynyl, 2-heptynyl and the like.
- Aryl (Ar) means mono- and bicyclic aromatic rings containing 6-10 carbon atoms. Examples of aryl include phenyl, naphthyl, indenyl and the like.
- Heteroaryl (HAR) unless otherwise specified, means mono-, bicyclic and tricyclic aromatic ring systems containing at least one heteroatom selected from O, S, S(O), SO 2 and N, with each ring containing 5 to 6 atoms.
- HAR groups may contain from 5-14, preferably 5-13 atoms.
- Examples include, but are not limited to, pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzopyrazolyl, benzotriazolyl, furo(2,3-b)pyridyl, benzoxazinyl, tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl., quinolyl, isoquinolyl, indolyl, dihydroindolyl
- Heteroaryl also includes aromatic carbocyclic or heterocyclic groups fused to heterocycles that are non-aromatic or partially aromatic, and optionally containing a carbonyl.
- additional heteroaryl groups include indolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, and aromatic heterocyclic groups fused to cycloalkyl rings. Examples also include the following:
- Heteroaryl also includes such groups in charged form, e.g., pyridinium.
- Heterocyclyl (Hetcy) unless otherwise specified, means mono- and bicycHc saturated rings and ring systems containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen.
- heterocyclyl include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, tetrahydrofuranyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl and the like.
- Heterocycles can also exist in tautomeric forms, e.g., 2- and 4-pyridones. Heterocycles moreover includes such moieties in charged form, e.g., piperidinium.
- "Halogen" includes fluorine, chlorine, bromine and iodine.
- flushing refers to the side effect that is often seen when nicotinic acid is administered in therapeutic amounts.
- the flushing effect of nicotinic acid usually becomes less frequent and less severe as the patient develops tolerance to the drug at therapeutic doses, but the flushing effect still occurs to some extent and can be transient.
- "in the absence of substantial flushing” refers to the reduced severity of flushing when it occurs, or fewer flushing events than would otherwise occur.
- the incidence of flushing is reduced by at least about a third, more preferably the incidence is reduced by half, and most preferably, the flushing incidence is reduced by about two thirds or more.
- the severity is preferably reduced by at least about a third, more preferably by at least half, and most preferably by at least about two thirds. Clearly a one hundred percent reduction in flushing incidence and severity is most preferable, but is not required.
- One aspect of the invention relates to a compound represented by formula I:
- X 1 , X 2 and X 3 represents a sulfur atom, and the other two represent carbon or nitrogen atoms
- ring A represents a 6-10 membered aryl,- or a 5-13 membered heteroaryl or partially aromatic heterocyclic group, said heteroaryl and partially aromatic heterocyclic group containing at least one heteroatom selected from O, S, S(O), S(O) 2 and N, and optionally containing 1 other heteroatom selected from O and S, and optionally containing 1-3 additional N atoms, with up to 5 heteroatoms being present
- each R 2 and R 3 is independently H, Ci -3 alkyl, haloC 1 .
- n represents an integer of from 2 to 4; each R 4 is H or is independently selected from halo, C u 4 alkoxy, and each R 1 is H or is independently selected from the group consisting of: a) halo, OH, CO 2 H, CN, NH 2 , S(O) 0-2 R 6 , C(O)R e , OC(O)R e and CO 2 R e , wherein R e is or phenyl, each being optionally substituted with 1-3 groups, 1-3 of which are halo or Ci -3 alkyl, and 1-2 of which are selected from OCi.
- Ci- 6 alkyl and being optionally substituted with 1-3 groups, 1-3 of which are halo and 1-2 of which are selected from: OH, CO 2 H, CO 2 C 1-4 alkyl, COzd ⁇ haloalkyl, OCO 2 Ci-4alkyl, NH 2 , NHC M alkyl, N(C M alkyl) 2, Hetcy and CN; c) and N(C M alkyl) 2 , the alkyl portions of which are optionally substituted as set forth in (b) above; d) C(O)NH 2 , C(O)NHC w alkyl, C(O)N(C 1 ⁇ alkylK C(O)Hetcy, C(O)NHOC 1-4 alkyl and
- R' represents H, Ci -3 alkyl or haloC ]-3 alkyl
- R" represents (a) optionally substituted with 1-4 groups, 0-4 of which are halo, and 0-1 of which are selected from the group consisting of: OH, CO 2 H, CO 2 Ci- 4 alkyl, CO 2 C M haloalkyl, NH 2 , NHC 1-4 alkyl, N(C M alkyl) 2 , CN, Hetcy, Aryl and HAR, said Hetcy, Aryl and HAR being further optionally substituted with 1-3 halo, Ci- 5 4alkyl, groups;
- Hetcy, Aryl or HAR each being optionally substituted with 1-3 members selected from the group consisting of: halo, haloQ ⁇ alkyl and haloCu 4 alkoxy groups; and R'" representing H or R";
- a subset of compounds that is of interest relates to compounds of formula I wherein ring A is a phenyl or naphthyl group, a 5-6 membered monocyclic heteroaryl group, or a 9-13 membered !5 bicyclic or tricyclic heteroaryl group.
- ring A is a phenyl or naphthyl group, a 5-6 membered monocyclic heteroaryl group, or a 9-13 membered !5 bicyclic or tricyclic heteroaryl group.
- ring A is selected from the group consisting of: phenyl, naphthyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, triazolyl, thienyl, tO pyrimidyl, benzothiazolyl, or a member selected from the group consisting of:
- a subset of compounds that is of interest relates to compounds of formula I wherein ring A is selected from the group consisting of: phenyl, naphthyl, isoxazolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, and benzothiazolyl.
- ring A is selected from the group consisting of: phenyl, naphthyl, isoxazolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, and benzothiazolyl.
- a subset of compounds that is of interest relates to compounds of formula I wherein ring A is selected from the group consisting of: phenyl, naphthyl and oxadiazolyl.
- ring A is selected from the group consisting of: phenyl, naphthyl and oxadiazolyl.
- Another subset of compounds that is of interest relates to compounds of formula I wherein one of X 1 , X 2 and X 3 is S, one is C and one is C or N. Within this subset of compounds, all other variables are as defined with respect to formula I.
- a subset of compounds that is of interest relates to compounds of formula I wherein one of X 1 , X 2 and X 3 is S, and the other two are C.
- all other variables are as defined with respect to formula I.
- each R 1 is H or is selected from the group consisting of: a) halo, OH, CO 2 H, CN, NH 2, S(O) 0-2 R 6 , C(O)R 6 , OC(O)R 6 and CO 2 R" , wherein R e is or phenyl, each being optionally substituted with 1-3 groups, 1-3 of which are halo or Ci -3 alkyl, and 1-2 of which are selected from OCi -3 alkyl, haloC ⁇ alkyl, haloC ]-3 alkoxy, OH, NH 2 and NHCi -3 alkyI; b) Ci.
- each R 1 is H or is selected from the group consisting of: a) halo or OH; b) and each optionally substituted with 1-3 halo groups; c) phenyl or a 5-6 membered heteroaryl group optionally substituted with 1-3 groups, 1- 3 of which are selected from halo, Ci. 3 alkyl and haloCi_ 3 alky] groups, and 1-2 of which are selected from
- an aspect of the invention that is of interest relates to a compound of formula I wherein each R 1 is H or is selected from the group consisting of: a) halo or OH; O b) Ci. 3 alkyl and OCi -3 alkyl; c) phenyl or pyridyl, each optionally substituted with 1-3 groups, 1-3 of which are selected from halo, 1-2 of which are Ci -3 alkyl, haloC ]-3 alkyl, OCi -3 alkyl and haloOCi -3 alkyl, and 0-1 of which is OH;
- all other variables are as defined with respect to formula I.
- Another subset of compounds that is of interest relates to a compound of formula I wherein R 2 and R 3 are independently H, Ci. 3 alkyl or haloCi -3 alkyl. Within this subset of compounds, all other variables are as defined with respect to formula I. More particularly, a subset of compounds that is of interest relates to a compound of formula I wherein R 2 and R 3 are independently H or methyl. Within this subset of compounds, all other variables are as defined with respect to formula I.
- n represents an integer of from 2 or 4.
- all other variables are as defined with respect to formula I.
- a subset of compounds that is of interest relates to a compound of formula I wherein n is 2. Within this subset of compounds, all other variables are as defined with respect to formula L More particularly, a subset of compounds that is of interest relates to a compound of formula I wherein n is 4. Within this subset of compounds, all other variables are as defined with respect to formula I.
- a subset of compounds that is of interest relates to a compound of formula I wherein each R 4 is H or is independently selected from C ⁇ alkyl, Cl, CN and SCi -2 alkyl.
- each R 4 is H or is independently selected from C ⁇ alkyl, Cl, CN and SCi -2 alkyl.
- all other variables are as defined with respect to formula I.
- a subset of the invention that is of interest relates to compounds of formula I or a pharmaceutically acceptable salt or solvate thereof wherein: ring A is a phenyl or naphthyl group, or a 5-6 membered monocyclic heteroaryl group; one of X 1 , X 2 and X 3 is S, one is C and one is C or N; each R 1 is H or is selected from the group consisting of: a) halo, OH, CN, NH 2 , S(O) 0-2 R 6 , C(O)R e , OC(O)R' and CO 2 R e , wherein R e is C ⁇ alkyl or phenyl, each being optionally substituted with 1-3 groups, 1-3 of which are halo or Ci.
- Ci -6 alkyl and and alkyl portion being optionally substituted with 1-3 groups, 1-3 of which are halo and 1-2 of which are selected from: OH, CO 2 H, CO 2 C w alkyl, CO 2 C M haloalkyI, OCO 2 Ci_ 4 alkyl, NH 2 , NHC M alkyl, N(C M alkyl) 2 , Hetcy and CN; and c) phenyl or a 5-6 membered heteroaryl or a Hetcy group attached at any available ring atom and each being optionally substituted with 1-3 groups, 1-3 of which are selected from halo, Q.
- R 2 and R 3 are independently H or C 1 .3a.kyl; n represents the integer 2 or 4; and
- R 4 is H or is independently selected from halo, Within this subset of compounds, all other variables are as defined with respect to formula I.
- chiral compounds possessing one stereocenter of general formula I may be resolved into their enantiomers in the presence of a chiral environment using methods known to those skilled in the art.
- Chiral compounds possessing more than one stereocenter may be separated into their diastereomers in an achiral environment on the basis of their physical properties using methods known to those skilled in the art.
- Single diastereomers that are obtained in racemic form may be resolved into their enantiomers as described above.
- racemic mixtures of compounds may be separated so that individual enantiomers are isolated.
- the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds of Formula I to an enantiomerically pure compound to form a diastereomeric mixture, which is then separated into individual diastereomers by standard methods, such as fractional crystallization or chromatography.
- the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
- the diasteromeric derivatives may then be converted to substantially pure enantiomers by cleaving the added chiral residue from the diastereomeric compound.
- racemic mixture of the compounds of Formula I can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
- enantiomers of compounds of the general Formula I may be obtained by stereoselective synthesis using optically pure starting materials or reagents.
- tautomers which have different points of attachment for hydrogen accompanied by one or more double bond shifts.
- a ketone and its enol form are keto-enol tautomers.
- a 2-hydroxyquinoline can reside in the tautomeric 2-quinolone form. The individual tautomers as well as mixtures thereof are included.
- the dosages of compounds of formula I or a pharmaceutically acceptable salt or solvate thereof vary within wide limits.
- the specific dosage_regimen and levels for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the patient's condition. Consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective orprophylactically effective dosage amount needed to prevent, counter, or arrest the progress of the condition.
- the compounds will be administered in amounts ranging from as low as about 0.01 mg/day to as high as about 2000 mg/day, in single or divided doses.
- a representative dosage is about 0.1 mg/day to about 1 g/day. Lower dosages can be used initially, and dosages increased to further minimize any untoward effects. It is expected that the compounds described herein will be administered on a daily basis for a length of time appropriate to treat or prevent the medical condition relevant to the patient, including a course of therapy lasting months, years or the life of the patient.
- additional active agents may be administered with the compounds described herein.
- the additional active agent or agents can be lipid modifying compounds or agents having other pharmaceutical activities, or agents that have both lipid-modifying effects and other pharmaceutical activities.
- additional active agents which may be employed include but are not limited to HMG-CoA reductase inhibitors, which include statins in their lactonized or dihydroxy open acid forms and pharmaceutically acceptable salts and esters thereof, including but not limited to lovastatin (see US Patent No. 4,342,767), simvastatin (see US Patent No. 4,444,784), dihydroxy open-acid simvastatin, particularly the ammonium or calcium salts thereof, pravastatin, particularly the sodium salt thereof (see US Patent No.
- HMG-CoA synthase inhibitors include squalene epoxidase inhibitors; squalene synthetase inhibitors (also known as squalene synthase inhibitors), acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors including selective inhibitors of ACAT-I or ACAT-2 as well as dual inhibitors of ACAT-I and -2; microsomal triglyceride transfer protein (MTP) inhibitors; endothelial lipase inhibitors; bile acid sequestrants; LDL receptor inducers; platelet aggregation inhibitors, for example glycoprotein ⁇ b/HIa fibrinogen receptor antagonists and aspirin; human peroxisome proliferator activated receptor gamma (PPAR-gamma) agonists including the compounds commonly referred to as glitazones for example pioglitazone and rosiglitazone and, including those compounds included within the structural
- Cholesterol absorption inhibitors can also be used in the present invention. Such compounds block the movement of cholesterol from the intestinal lumen into enterocytes of the small intestinal wall, thus reducing serum cholesterol levels.
- Examples of cholesterol absorption inhibitors are described in U.S. Patent Nos. 5,846,966, 5,631,365, 5,767,115, 6,133,001, 5,886,171, 5,856,473, 5,756,470, 5,739,321, 5,919,672, and in PCT application Nos. WO 00/63703, WO 00/60107, WO 00/38725, WO 00/34240, WO 00/20623, WO 97/45406, WO 97/16424, WO 97/16455, and WO 95/08532.
- ezetimibe also known as l-(4- fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone, described in U.S. Patent Nos. 5,767,115 and 5,846,966.
- Therapeutically effective amounts of cholesterol absorption inhibitors include dosages of from about 0.01 mg/kg to about 30 mg/kg of body weight per day, preferably about 0.1 mg/kg to about 15 mg/kg.
- the compounds used in the present invention can be administered with conventional diabetic medications.
- a diabetic patient receiving treatment as described herein may also be taking insulin or an oral antidiabetic medication.
- an oral antidiabetic medication useful herein is metformin.
- niacin receptor agonists induce some degree of vasodilation
- the compounds of formula I may be co-dosed with a vasodilation suppressing agent. Consequently, one aspect of the methods described herein relates to the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in combination with a compound that reduces flushing.
- Conventional compounds such as aspirin, ibuprofen, naproxen, indomethacin, other NSAIDs, COX-2 selective inhibitors and the like are useful in this regard, at conventional doses.
- DP antagonists are useful as well.
- Doses of the DP receptor antagonist and selectivity are such that the DP antagonist selectively modulates the DP receptor without substantially modulating the CRI ⁇ 2 receptor.
- the DP receptor antagonist ideally has an affinity at the DP receptor (i.e., K ⁇ ) that is at least about 10 times higher (a numerically lower Kj value) than the affinity at the CRTH2 receptor. Any compound that selectively interacts with DP according to these guidelines is deemed "DP selective". This is in accordance with US Published Application No. 2004/0229844A1 published on November 18, 2004, incorporated herein by reference.
- Dosages for DP antagonists as described herein, that are useful for reducing or preventing the flushing effect in mammalian patients, particularly humans, include dosages ranging from as low as about 0.01 mg/day to as high as about 100 mg/day, administered in single or divided daily doses. Preferably the dosages are from about 0.1 mg/day to as high as about 1.0 g/day, in single or divided daily doses.
- the compound of formula I or a pharmaceutically acceptable salt or solvate thereof and the DP antagonist can be administered together or sequentially in single or multiple daily doses, e.g., bid, tid or qid, without departing from the invention.
- sustained release such as a sustained release product showing a release profile that extends beyond 24 hours, dosages may be administered every other day.
- single daily doses are preferred.
- morning or evening dosages can be utilized.
- Salts and solvates of the compounds of formula I are also included in the present invention, and numerous pharmaceutically acceptable salts and solvates of nicotinic acid are useful in this regard.
- Alkali metal salts in particular, sodium and potassium, form salts that are useful as described herein.
- alkaline earth metals in particular, calcium and magnesium, form salts that are useful as described herein.
- Various salts of amines, such as ammonium and substituted ammonium compounds also form salts that are useful as described herein.
- solvated forms of the compounds of formula I are useful within the present invention. Examples include the hemihydrate, mono-, di-, tri- and sesquihydrate.
- the heterocyclic acid compounds of the invention also include esters of formula I that are pharmaceutically acceptable, as well as those that are metabolically labile.
- Metabolically labile esters include Ci -4 alkyl esters , preferably the ethyl ester.
- Many prodrug strategies are known to those skilled in the art. One such strategy involves engineered amino acid anhydrides possessing pendant nucleophiles, such as lysine, which can cyclize upon themselves, liberating the free acid. Similarly, acetone-ketal diesters, which can break down to acetone, an acid and the active acid, can be used.
- the compounds used in the present invention can be administered via any conventional route of administration.
- the preferred route of administration is oral.
- compositions described herein are generally comprised of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, in combination with a pharmaceutically acceptable carrier.
- suitable oral compositions include tablets, capsules, troches, lozenges, suspensions, d ⁇ spersible powders or granules, emulsions, syrups and elixirs.
- carrier ingredients include diluents, binders, disintegrants, lubricants, sweeteners, flavors, colorants, preservatives, and the like.
- diluents include, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate and sodium phosphate.
- granulating and disintegrants include corn starch and alginic acid.
- binding agents include starch, gelatin and acacia.
- lubricants include magnesium stearate, calcium stearate, stearic acid and talc.
- the tablets may be uncoated or coated by known techniques. Such coatings may delay disintegration and thus, absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a compound of formula I or a pharmaceutically acceptable salt or solvate thereof is combined with another therapeutic agent and the carrier to form a fixed combination product.
- This fixed combination product may be a tablet or capsule for oral use.
- a compound of formula I or a pharmaceutically acceptable salt or solvate thereof (about 1 to about 1000 mg) and the second therapeutic agent (about 1 to about 500 mg) are combined with the pharmaceutically acceptable carrier- providing a tablet or capsule for oral use.
- Sustained release over a longer period of time may be particularly important in the formulation.
- a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
- the dosage form may also be coated by the techniques described in the U.S. Patent Nos. 4,256,108; 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for controlled release.
- Typical ingredients that are useful to slow the release of nicotinic acid in sustained release tablets include various cellulosic compounds, such as methylcellulose, ethylcellulose, propylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, starch and the like.
- Various natural and synthetic materials are also of use in sustained release formulations. Examples include alginic acid and various alginates, polyvinyl pyrrolidone, tragacanth, locust bean gum, guar gum, gelatin, various long chain alcohols, such as cetyl alcohol and beeswax.
- a tablet as described above, comprised of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, and further containing an HMG Co-A reductase inhibitor, such as simvastatin or atorvastatin.
- This particular embodiment optionally contains the DP antagonist as well.
- Typical release time frames for sustained release tablets in accordance with the present invention range from about 1 to as long as about 48 hours, preferably about 4 to about 24 hours, and more preferably about 8 to about 16 hours.
- Hard gelatin capsules constitute another solid dosage form for oral use. Such capsules similarly include the active ingredients mixed with carrier materials as described above.
- Soft gelatin capsules include the active ingredients mixed with water-miscible solvents such as propylene glycol, PEG and ethanol, or an oil such as peanut oil, liquid paraffin or olive oil.
- Aqueous suspensions are also contemplated as containing the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients include suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and acacia; dispersing or wetting agents.e.g., lecithin; preservatives, e.g., ethyl, or n-propyl para-hydroxybenzoate, colorants, flavors, sweeteners and the like.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredients in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
- a dispersing or wetting agent e.g., kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, ka
- Syrups and elixirs may also be formulated.
- a pharmaceutical composition that is of interest is a sustained release 5 tablet that is comprised of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, and a DP receptor antagonist that is selected from the group consisting of compounds A through AJ in combination with a pharmaceutically acceptable carrier.
- compositions that is of more interest are comprised of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof and a DP antagonist 0 compound selected from the group consisting of compounds A, B, D, E, X, AA, AF, AG, AH, Al and AJ, in combination with a pharmaceutically acceptable carrier.
- a DP antagonist 0 compound selected from the group consisting of compounds A, B, D, E, X, AA, AF, AG, AH, Al and AJ, in combination with a pharmaceutically acceptable carrier.
- compositions that is of more particular interest relate to a sustained release tablet that is comprised of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, a DP receptor antagonist selected from the group consisting of compounds A, B, 5 D, E, X, AA, AF, AG, AH, AI and AJ, and simvastatin or atorvastatin in combination with a pharmaceutically acceptable carrier.
- a DP receptor antagonist selected from the group consisting of compounds A, B, 5 D, E, X, AA, AF, AG, AH, AI and AJ
- simvastatin or atorvastatin in combination with a pharmaceutically acceptable carrier.
- composition in addition to encompassing the pharmaceutical compositions described above, also encompasses any product which results, directly or indirectly, from the combination, complexation or aggregation of any two or more of the ingredients, active or excipient, or ;0 from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical composition of the present invention encompasses any composition made by admixing or otherwise combining the compounds, any additional active ingredient(s), and the pharmaceutically acceptable excipients.
- Another aspect of the invention relates to the use of a compound of formula I or a >5 pharmaceutically acceptable salt or solvate thereof and a DP antagonist in the manufacture of a medicament.
- This medicament has the uses described herein.
- another aspect of the invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, a DP antagonist and an HMG Co-A reductase inhibitor, such as simvastatin, in the manufacture of a medicament.
- This medicament has the ⁇ 0 uses described herein.
- the present invention thus relates to the treatment, prevention or reversal of atherosclerosis and the other diseases 35 and conditions described herein, by administering a compound of formula I or a pharmaceutically acceptable salt or solvate in an amount that is effective for treating, preventin or reversing said condition. This is achieved in humans by administering a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective to treat or prevent said condition, while preventing, reducing or minimizing flushing effects in terms of frequency and/or severity.
- One aspect of the invention that is of interest is a method of treating atherosclerosis in a human patient in need of such treatment comprising administering to the patient a compound of formula I * or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for treating atherosclerosis in the absence of substantial flushing.
- Another aspect of the invention that is of interest relates to a method of raising serum
- HDL levels in a human patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is ) effective for raising serum HDL levels.
- Another aspect of the invention that is of interest relates to a method of treating dyslipidemia in a human patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for treating dyslipidemia.
- Another aspect of the invention that is of interest relates to a method of reducing serum
- VLDL or LDL levels in a human patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for reducing serum VLDL or LDL levels in the patient in the absence of substantial flushing.
- Another aspect of the invention that is of interest relates to a method of reducing serum triglyceride levels in a human patient in need of such treatment, comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for reducing serum triglyceride levels.
- Another aspect of the invention that is of interest relates to a method of reducing serum Lp(a) levels in a human patient in need of such treatment, comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for reducing serum Lp(a) levels.
- Lp(a) refers to lipoprotein (a).
- Another aspect of the invention that is of interest relates to a method of treating diabetes, and in particular, type 2 diabetes, in a human patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is effective for treating diabetes.
- Another aspect of the invention that is of interest relates to a method of treating metabolic syndrome in a human patient in need of such treatment comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in an amount that is 5 effective for treating metabolic syndrome.
- Another aspect of the invention that is of particular interest relates to a method of treating atherosclerosis, dyslipidemias, diabetes, metabolic syndrome or a related condition in a human patient in need of such treatment, comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt or solvate thereof and a DP receptor antagonist, said combination being administered in an amount that is effective to treat atherosclerosis, dyslipidemia, diabetes or a related condition in the absence of substantial flushing.
- Another aspect of the invention that is of particular interest relates to the methods described above wherein the DP receptor antagonist is selected from the group consisting of compounds A through AJ and the pharmaceutically acceptable salts and solvates thereof.
- TEMPO 2,2,6,6-tetramethyl-l-piperidinyloxy, free radical
- NCS is N-chlorosuccinimide
- NMO is N-methylmorpholine N-oxide
- TBS is tert-butyldimethylsilyl
- THF is tetrahydrofuran
- DMF is dimethylformamide
- TFA is trifluoroacetic acid
- DMSO is dimethyl sulfoxide.
- PMBOH is p-methoxybenzyl alcohol and PMBO is para methoxybenzyloxy.
- the yellow oil was diluted into toluene (3mL), and combined with the requisite thiophene amino ester (52mg, 0.33mmol) as shown in Scheme 1.
- the reaction mixture was heated (microwave, 300W) for lOmin at 150 0 C, cooled, concentrated in vacuo, and the residue purified by preparative RPHPLC.
- the methyl ester (34mg, 0.1 mmol) was saponified at room temperature using excess IN aqueous lithium hydroxide in (3:1 :1) THF-methanol-water.
- the solution was filtered, and the solvent was removed in vacuo to obtain the saturated ester.
- the methoxy naphthyl ester (5.73 g) was treated with NCS (0.82g, 6.11 mmol, 1.1 eq) in DMF solvent at room temperature, and the solution was stirred for 16 h. Removal of the DMF in vacuo provided a residue which was recrystalized from methanol/methylene chloride to obtain the chlorinated intermediate.
- the racemic mixture of this chloride (1.5 g, 3.69 mmol) was separated into its single enantiomers using chiral HPLC with a Chiralcel OJ column, and isocratic elution with 35% isopropanol-heptane.
- the ethyl ester intermediate (65 mg, 0.21 mmol) was dissolved in (1:1) acetic acid-HCl (2 mL) and heated to 110 0 C for 10 min. Then 5 mL of water was added, and the solution cooled to 0 0 C to obtain the acid intermediate after filtration. Oxalyl chloride (0.3 mmol) was then added to a CH 2 CI 2 (2 mL) solution of this acid intermediate (45 mg, 0.1 mmol), and one drop of DMF was added at 0 0 C. The solvent was removed in vacuo after the solution was sirred for 1 h at room temperature.
- reaction mixture was heated at 100 0 C for 15 h in a sealed tube under an argon atmosphere, then cooled, partitioned between water and ethyl acetate, the precipitate collected, and purified by column chromatography (SiO 2 , ethyl acetate-hexane).
- this enoate intermediate was hydrogenated under a balloon OfH 2 gas, followed by saponification with lithium hydroxide, and the saturated acid converted to the thiophene amide product under oxalyl chloride mediated activation.
- the product was obtained after BBr 3 -mediated demethylation of the ether as in the Examples above, and the product purified by preparative RPHPLC.
- N-chlorosuccinimide (105 mg, 0.793 ⁇ unol) was added to the commercially available thiophene aminoester (204 mg, 0.793 mmol) in tetrahydrofuran (8 mL). The reaction mixture was stirred overnight, and the solvent was removed. The chloride intermediate was purified by silica gel chromatography. This chloro aminoester was acylated and saponified under conditions described in the Examples above to provide EXAMPLE 24.
- EXAMPLE 26 was prepared under conditions similar to those described in the Examples above, and illustrated in Scheme 7. 1 HNMR (DMSOd 6 , 500 MHz) ⁇ 8.28 (s, IH), 7.86-7.82 (m, 3H), 7.70 (s, 1 H), 7.48-7.42 (m, 3H), 3.12 (t, 2H), 2.90 (t, 2H); LCMS m/z 350 (M-I).
- EXAMPLE 28 1 H NMR (500 MHz, CD 3 OD) ⁇ 7.81-7.76 (m. 3H), 7.71 (s, IH) 5 7.45-7.37 (m,3H), 3.21 (t, 2H), 2.98 (t, 2H), 2.59 (s, 3H).
- EXAMPLE 29 1 H NMR (DMSOd 6 , 500 MHz) ⁇ 7.87-7.83 (m, 12H), 7.74 (s, IH), 7.48-7.43(3H), 3.06 (t, 2H), 2.89 (t,
- niacin receptor affinity and function The activity of the compounds of the present invention regarding niacin receptor affinity and function can be evaluated using the following assays: 0
- Membrane preps are stored in liquid nitrogen in:
- Ia (human): Dilute in Binding Buffer. -0
- Ib. (human+ 4% serum): Add 5.7% of 100% human serum stock (stored at -20 0 C) for a final concentration of 4%.
- Ic. (mouse): Dilute in Binding Buffer.
- wash buffer and dilution buffer Make 10 liters of ice-cold Binding Buffer: S 5 20 mM HEPES, pH 7.4
- the compounds of the invention generally have an IC 5 O in the 3 H-nicotinic acid competition binding assay within the range of 1 nM to about 25 ⁇ M.
- 3S S-GTP ⁇ S binding assay :
- Membranes prepared from Chinese Hamster Ovary (CHO)-Kl cells stably expressing the niacin receptor or vector control (7 ⁇ g/assay) were diluted in assay buffer (100 mM HEPES, 100 mM NaCl and 10 mM MgCl 2 , pH 7.4) in Wallac Scintistrip plates and pre-incubated with test compounds diluted in assay buffer containing 40 ⁇ M GDP (final [GDP] was 10 uM) for ⁇ 10 minutes before addition of 35 S-GTP ⁇ S to 0.3 nM. To avoid potential compound precipitation, all compounds were first prepared in 100% DMSO and then diluted with assay buffer resulting in a final concentration of 3% DMSO in the assay.
- assay buffer 100 mM HEPES, 100 mM NaCl and 10 mM MgCl 2 , pH 7.4
- Binding was allowed to proceed for one hour before centrifuging the plates at 4000 rpm for 15 minutes at room temperature and subsequent counting in a TopCount scintillation counter. Non-linear ) regression analysis of the binding curves was performed in GraphPad Prism.
- CHO-Kl cell culture medium F-12 Kaighn's Modified Cell Culture Medium with 10% FBS, 2 mM L- Glutamine, 1 mM Sodium Pyruvate and 400 ⁇ g/ml G418
- Guanosine 5 '-diphosphate sodium salt (GDP, Sigma-Aldrich Catalog #87127)
- Binding Buffer 20 mM HEPES, pH 7.4 10O mM NaCl 10 mM MgCl 2 GDP Buffer: binding buffer plus GDP, ranging from 0.4 to 40 ⁇ M, make fresh before assay
- total assay volume 100 ⁇ well
- the compounds of the invention generally have an EC 50 in the functional in vitro GTP ⁇ S binding assay within the range of about less than 1 ⁇ M to as high as about 100 ⁇ M.
- mice Male C57B16 mice ( ⁇ 25g) are anesthetized using 10mg/ml/kg Nembutal sodium. When antagonists are to be administered they are co-injected with the Nembutal anesthesia. After ten minutes the animal is placed under the laser and the ear is folded back to expose the ventral side. The laser is positioned in the center of the ear and focused to an intensity of 8.4-9.0 V (with is generally ⁇ 4.5cm above the ear). Data acquisition is initiated with a 15 by 15 image format, auto interval, 60 images and a 20sec time delay with a medium resolution. Test compounds are administered following the 10th image via injection into the peritoneal space.
- Images 1-10 are considered the animal' s-baseline and data is normalized to an average of the baseline mean intensities.
- Materials and Methods - Laser Doppler Pir ⁇ med P ⁇ mll; Niacin (Sigma); Nembutal (Abbott labs).
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- 2007-04-06 EP EP07774860A patent/EP2010512A4/en not_active Withdrawn
- 2007-04-06 AU AU2007238879A patent/AU2007238879A1/en not_active Abandoned
- 2007-04-06 US US12/226,050 patent/US20090170891A1/en not_active Abandoned
- 2007-04-06 WO PCT/US2007/008584 patent/WO2007120575A2/en active Application Filing
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WO2009021740A2 (en) | 2007-08-15 | 2009-02-19 | Sanofis-Aventis | Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments |
AU2009269178B2 (en) * | 2008-07-08 | 2012-09-06 | Daiichi Sankyo Company, Limited | Nitrogen-containing aromatic heterocyclyl compound |
WO2010004972A1 (en) | 2008-07-08 | 2010-01-14 | 第一三共株式会社 | Nitrogen-containing aromatic heterocyclyl compound |
EP2308838A1 (en) * | 2008-07-08 | 2011-04-13 | Daiichi Sankyo Company, Limited | Nitrogen-containing aromatic heterocyclyl compound |
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US9150563B2 (en) | 2008-07-08 | 2015-10-06 | Daiichi Sankyo Company, Limited | Nitrogen-containing aromatic heterocyclyl compound |
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US8648103B2 (en) | 2008-07-08 | 2014-02-11 | Daiichi Sankyo Company, Limited | Nitrogen-containing aromatic heterocyclyl compound |
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WO2013037390A1 (en) | 2011-09-12 | 2013-03-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
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Also Published As
Publication number | Publication date |
---|---|
JP2009533436A (en) | 2009-09-17 |
US20090170891A1 (en) | 2009-07-02 |
AU2007238879A1 (en) | 2007-10-25 |
EP2010512A2 (en) | 2009-01-07 |
WO2007120575A3 (en) | 2008-10-09 |
EP2010512A4 (en) | 2010-02-24 |
CA2648642A1 (en) | 2007-10-25 |
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