WO2008064107A2 - 7,8-dihydro-1,6-naphthyridin-5(6h)-ones and related bicyclic compounds as inhibitors of dipeptidyl peptidase iv and methods - Google Patents
7,8-dihydro-1,6-naphthyridin-5(6h)-ones and related bicyclic compounds as inhibitors of dipeptidyl peptidase iv and methods Download PDFInfo
- Publication number
- WO2008064107A2 WO2008064107A2 PCT/US2007/084927 US2007084927W WO2008064107A2 WO 2008064107 A2 WO2008064107 A2 WO 2008064107A2 US 2007084927 W US2007084927 W US 2007084927W WO 2008064107 A2 WO2008064107 A2 WO 2008064107A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- alkyl
- aryl
- compound according
- amino
- Prior art date
Links
- 0 *c1c(*)nc(CC#N)c(C(OC=*)=O)c1* Chemical compound *c1c(*)nc(CC#N)c(C(OC=*)=O)c1* 0.000 description 3
- LJFOBAXGBZLDLB-UHFFFAOYSA-N Cc(nc1CCN2)c(CN)c(-c(c(Cl)c3)ccc3Cl)c1C2=O Chemical compound Cc(nc1CCN2)c(CN)c(-c(c(Cl)c3)ccc3Cl)c1C2=O LJFOBAXGBZLDLB-UHFFFAOYSA-N 0.000 description 2
- MLAXTRGOAHHIDA-UHFFFAOYSA-N CCOC(c1c(-c(c(Cl)c2)ccc2Cl)c(C(OCc2ccccc2)=O)c(C)nc1CCl)=O Chemical compound CCOC(c1c(-c(c(Cl)c2)ccc2Cl)c(C(OCc2ccccc2)=O)c(C)nc1CCl)=O MLAXTRGOAHHIDA-UHFFFAOYSA-N 0.000 description 1
- WSMUWHGCMHHZER-UHFFFAOYSA-N Cc(nc(CCOC)c(C(OC)=O)c1-c(c(Cl)c2)ccc2Cl)c1C#N Chemical compound Cc(nc(CCOC)c(C(OC)=O)c1-c(c(Cl)c2)ccc2Cl)c1C#N WSMUWHGCMHHZER-UHFFFAOYSA-N 0.000 description 1
- OMSQVGZDJQPGNM-UHFFFAOYSA-N Cc(nc1CCN2)c(C(O)=O)c(-c(c(Cl)c3)ccc3Cl)c1C2=O Chemical compound Cc(nc1CCN2)c(C(O)=O)c(-c(c(Cl)c3)ccc3Cl)c1C2=O OMSQVGZDJQPGNM-UHFFFAOYSA-N 0.000 description 1
- CMVFRFJWHPDMIQ-UHFFFAOYSA-N Cc(nc1CCN2CC(N(CC3)CCC3N(CCCC3)C3=O)=O)c(CN)c(-c(c(Cl)c3)ccc3Cl)c1C2=O Chemical compound Cc(nc1CCN2CC(N(CC3)CCC3N(CCCC3)C3=O)=O)c(CN)c(-c(c(Cl)c3)ccc3Cl)c1C2=O CMVFRFJWHPDMIQ-UHFFFAOYSA-N 0.000 description 1
- MVBGHNWFBKZVKZ-UHFFFAOYSA-N Cc(nc1CCN2CC(N)=O)c(CN)c(-c(ccc(Cl)c3)c3Cl)c1C2=O Chemical compound Cc(nc1CCN2CC(N)=O)c(CN)c(-c(ccc(Cl)c3)c3Cl)c1C2=O MVBGHNWFBKZVKZ-UHFFFAOYSA-N 0.000 description 1
- LVTHXSQLBBBEBH-UHFFFAOYSA-N Cc(nc1CCN2c(cccc3)c3OC)c(CN)c(-c(c(Cl)c3)ccc3Cl)c1C2=O Chemical compound Cc(nc1CCN2c(cccc3)c3OC)c(CN)c(-c(c(Cl)c3)ccc3Cl)c1C2=O LVTHXSQLBBBEBH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/12—Ophthalmic agents for cataracts
-
- 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
-
- 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
-
- 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
-
- 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
-
- 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
- A61P9/12—Antihypertensives
Definitions
- the present invention relates to 7,8-dihydro-l,6-naphthyridin-5(6H)-ones and related bicyclic compounds which are inhibitors of dipeptidyl peptidase IV (DPP- 4), and to a method for treating diabetes and related diseases or disorders by employing such compounds alone, or in combination with another type of therapeutic agent.
- DPP- 4 dipeptidyl peptidase IV
- Dipeptidyl peptidase IV is a membrane bound non-classical serine aminodipeptidase which is located in a variety of tissues (intestine, liver, lung, kidney) as well as on circulating T-lymphocytes (where the enzyme is known as CD- 26). It is responsible for the metabolic cleavage of certain endogenous peptides (GLP-l(7-36), glucagon) in vivo and has demonstrated proteolytic activity against a variety of other peptides (GHRH, NPY, GLP-2, VIP) in vitro.
- GLP-l(7-36) is a 30 amino-acid peptide derived by post-translational processing of proglucagon in the small intestine.
- GLP-l(7-36) has multiple actions in vivo including the stimulation of insulin secretion, inhibition of glucagon secretion, the promotion of satiety, and the slowing of gastric emptying. Based on its physiological profile, the actions of GLP-l(7-36) are expected to be beneficial in the prevention and treatment of Type II diabetes and potentially obesity.
- exogenous administration of GLP-l(7-36) continuously infusion in diabetic patients has demonstrated efficacy in this patient population.
- GLP- 1(7-36) is degraded rapidly in vivo and has been shown to have a short half-life in vivo (tl/2 «1.5 min).
- DPP-4 has been shown to be the primary degrading enzyme of GLP-l(7-36) in vivo.
- GLP- 1(7-36) is degraded by DPP-4 efficiently to GLP- 1(9-36), which has been speculated to act as a physiological antagonist to GLP- 1(7-36).
- inhibition of DPP-4 in vivo should potentiate endogenous levels of GLP- 1(7-36) and attenuate formation of its antagonist GLP-l(9-36) and thus serve to ameliorate the diabetic condition.
- R 1 is selected from the group consisting of hydrogen (H), halogen, CF 3 , cyano (CN), amino, substituted amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl, cycloalkenyl, aryl, heteroaryl, and cycloheteroalkyl, wherein any such functional group may optionally be substituted with 1 to 3 or more substituents selected from the group consisting of hydrogen, halo, alkyl, polyhaloalkyl, alkoxy, aryl, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, bicycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, heteroaryl, cycloheteroalkylalky
- R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl and aryl;
- R 4 is selected from the group consisting of hydrogen, alkyl and aryl;
- A is selected from the group consisting of hydrogen (H), alkyl, alkenyl, alkynyl, cycloalkyl, bicycloalkyl, cycloalkenyl, aryl, heteroaryl, cycloheteroalkyl, 0-R 1 , cyano, amino, -C(O)-OH, -C(O)-NR 6 R 7 , -C(O)-OR 6 , S(O) m -R 6 , -S(O) 2 NR 6 R 7 , -NR 6 R 7 ,-NR 6 -C(O)R 7 and -NR 6 -SO 2 R 7 , wherein any such functional group may optionally be substituted with one to three or more substituents selected from the group consisting of hydrogen, halo, alky
- Ri is selected from the group consisting of hydrogen, alkyl, and aryl;
- R 6 and R 7 are (i) each independently selected from the group consisting of hydrogen (H), alkyl, alkenyl, alkynyl, cycloalkyl, bicycloalkyl, alkylthioalkyl, arylalkylthioalkyl, cycloalkenyl, aryl, heteroaryl, heteroarylalkyl, and cycloheteroalkyl, wherein either functional group may optionally be substituted with one to three or more substituents selected from the group consisting of hydrogen, halo, alkyl, polyhaloalkyl, alkoxy, aryl, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, bicycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino
- R 6 and R 7 in NR 6 R 7 may be taken together to form a 5- or 6- membered saturated or partially unsaturated ring system selected from the group consisting of cycloheteroalkyl and heteroaryl; wherein such ring system may optionally be substituted with one to three or more substituents selected from the group consisting of hydrogen, halo, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl,
- the compounds of formula I possess activity as inhibitors of DPP-4 in vivo and are useful in the treatment of diabetes, especially Type II diabetes, and the micro- and macrovascular complications of diabetes such as retinopathy, neuropathy, nephropathy, and wound healing. Such diseases and maladies are also sometimes referred to as "diabetic complications”.
- the present invention provides for compounds of formula I, pharmaceutical compositions employing such compounds and for methods of using such compounds.
- the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, alone or in combination with a pharmaceutically acceptable carrier.
- a method for treating or delaying the progression or onset of diabetes especially Type II diabetes, including complications of diabetes, including retinopathy, neuropathy, nephropathy and delayed wound healing, and related diseases such as insulin resistance (impaired glucose homeostasis), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, hyperlipidemia including hypertriglyceridemia, Syndrome X, atherosclerosis and hypertension, and for increasing high density lipoprotein levels, wherein a therapeutically effective amount of a compound of formula I is administered to a mammalian, e.g., human, patient in need of treatment.
- a mammalian e.g., human
- the compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more other agent(s) active in the therapeutic areas described herein.
- a method for treating diabetes especially Type II diabetes, and related diseases as defined above and hereinafter, wherein a therapeutically effective amount of a combination of a compound of formula I and at least one other type of therapeutic agent, such as an antidiabetic agent and/or a hypolipidemic agent, is administered to a human patient in need of treatment.
- a therapeutically effective amount of a combination of a compound of formula I and at least one other type of therapeutic agent such as an antidiabetic agent and/or a hypolipidemic agent
- Preferred are compounds of formula I wherein b represents a single bond; n is 1; R 1 is alkyl; X is CHR 3 or C O; R 2 is H;
- Y is phenyl, halophenyl, or dihalophenyl;
- A is H, z-propylcarbonylmethyl, aminocarbonylmethyl, methylaminocarbonylmethyl, diethylaminocarbonylmethyl, pyrrolidino- carbonylmethyl, piperidinocarbonyl, 2-oxo- 1 ,4'-bipiperidinylcarbonylmethyl, morpholinylcarbonylmethyl, methyl, tetrahydrofuranylmethyl, methoxyethyl, hydroxyethyl, phenyl, or methoxyphenyl.
- the compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis.
- the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety by reference.
- the novel compounds of formula I may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected.
- reaction conditions including solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art.
- One skilled in the art of organic synthesis understands that the functionality present on various portions of the edict molecule must be compatible with the reagents and reactions proposed. Not all compounds of formula I falling into a given class may be compatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents, which are compatible with the reaction conditions, will be readily apparent to one skilled in the art and alternate methods must be used.
- a chloroketone of formula (1) (where R a is alkyl), obtained from commercial sources, is condensed with aldehyde (2) under a variety of conditions, such as under mild acidic catalysis, to form the conjugated ester (3).
- One preferred set of conditions involves reacting (1) and (2) in an alcoholic solvent, such as isopropanol, at ambient or elevated temperature, in the presence of benzylamine and acetic acid.
- Enamines of formula (4) can be obtained from commercial sources or can be prepared by reaction of the corresponding acetoacetate with ammonia. In some cases, the dihydropyridines (5) can be conveniently prepared in one pot by addition of enamine (4) directly to the reaction mixture in which (1) and (2) are condensed to give (3). Oxidation of dihydropyridine (5) to pyridine (6) can be performed by a variety of reagents, such as with Mn ⁇ 2 , HNO3, DDQ, or other methods known in the art.
- a preferred method involves treating (5) with 70% aqueous nitric acid in acetic acid as solvent to afford pyridine (6).
- Reaction of chloromethylpyridine (6) with potassium cyanide or sodium cyanide, in a solvent such as ethanol or N,N- dimethylformamide, at elevated temperature, can produce the nitrile (7), in which an additional carbon atom has been introduced.
- Reduction of the nitrile (7) can be accomplished by a variety of procedures known to those skilled in the art.
- a preferred procedure is catalytic hydrogenation using a catalyst such as Pd/C, in a solvent such as methanol or ethanol, which gives a primary amine.
- This primary amine can then undergo intramolecular ring closure, which can be spontaneous or can be facilitated by heating in a suitable solvent, such as methanol or ethanol, to afford the lactam (8).
- a suitable solvent such as methanol or ethanol
- catalytic hydrogenation will afford a carboxylic acid (where R b is H).
- the acid (8) can be converted to an activated ester such as a mixed anhydride, using a base such as triethylamine and then ethyl chloroformate, and then reduced with a reagent such as NaBH 4 .
- the acid (8) can be converted to the acid chloride with oxalyl chloride or thionyl chloride and then reduced with a suitable reducing agent, such as NaBH 4 , LiAlH 4 or lithium tri-tert-butoxy aluminum hydride.
- the resulting alcohol (9) can then be converted to a mesylate or chloride using reagents such as CH3SO 2 CI, in solvents such methylene chloride or tetrahydrofuran, and in the presence of a base such as triethylamine.
- reagents such as CH3SO 2 CI
- solvents such as methylene chloride or tetrahydrofuran
- a base such as triethylamine.
- the desired primary amines (10) can then be obtained by reaction of the precursor chloride or mesylate with NH 3 /Me0H under thermal or microwave heating conditions.
- Scheme 2 provides an alternative route to prepare aminomethyl 7,8- dihydro-l,6-naphthyridin-5(6H)-ones of formula (IA').
- a ketoester of formula (11) obtained from commercial sources or prepared by procedures known to those skilled in the art, can be condensed with aldehyde (2) under mild acidic catalysis, as described in Scheme 1, to form the conjugated ester (12).
- reaction of enamine (13) with ester (12) affords the dihydropyridine of formula (14).
- Enamines of formula (13) can be obtained from commercial sources or can be prepared by reaction of the corresponding ketoester or ketonitrile with ammonia.
- Oxidation of dihydropyridine (14) to pyridine (15) can be performed with Mn ⁇ 2 , HNO3, or other methods known in the art.
- a preferred method involves treating (14) with 70% aqueous nitric acid in acetic acid as solvent to afford pyridine (15).
- Demethylation of the methyl ether can be accomplished with BBr 3 under standard literature conditions to afford the alcohol (16).
- Heating alcohol (16) directly with an ammonia source, such as with ammonium hydroxide, in a sealed tube at elevated temperature or under microwave conditions, can afford the 7,8-dihydro-l,6- naphthyridin-5(6H)-ones (17).
- the alcohol (16) can be used in a variety of ways to prepare additional compounds of this invention, as shown in Scheme 3. Under certain conditions, such as acidic conditions, for example by direct concentration of the reaction mixture of the BBr3-mediated methoxy demethylation in Scheme 2, the alcohol (16) can close onto the ester to form the lactone (19). The alcohol (16) can also be activated by converting it into a leaving group, such as the mesylate (20). Under certain conditions, such as by exposure to basic conditions, an elimination can occur to afford the olefins (21). Each of these materials, compounds (19), (20), and (21) can be used to prepare additional compounds of this invention.
- the lactone (19), mesylate (20) and olefin (21) can each be treated with an appropriate primary amine A-NH 2 , for example glycine derivatives or alkylamines, typically under heating or microwave conditions and also typically in the presence of a suitable base, such as triethylamine, to afford 7,8- dihydro-l,6-naphthyridin-5(6H)-ones (22).
- a suitable base such as triethylamine
- the 7,8-dihydro-l,6-naphthyridin-5(6H)-ones (17) can also be further functionalized by methods described in Scheme 5.
- Scheme 6 describes an additional strategy for functionalizing the lactam.
- Compound (IA') readily available as described in earlier schemes, can be protected by a wide variety of N-protecting groups which are well known to those skilled in the art, such as BOC, bis-BOC, CBZ, etc., to afford N-protected compounds (29).
- N-protecting groups which are well known to those skilled in the art, such as BOC, bis-BOC, CBZ, etc.
- a ketoester of formula (32) (where R c is alkyl), obtained from commercial sources or prepared by procedures known to those skilled in the art, can be reacted with aldehyde (2) as described previously to form the conjugated ester (33), which after reacting with enamine (13) can yield a dihydropyridine of formula (34).
- Enamines of formula (13) can be obtained from commercial sources or can be prepared by reaction of the corresponding ketoester or ketonitrile with ammonia.
- Oxidation of dihydropyridine (34) to pyridine (35) can be performed with Mn ⁇ 2 , HNO3, or other methods known in the art, as described previously. Heating (35) directly with an appropriate amine A-NH 2 , such as with ammonium hydroxide or an alkylamine or arylamine, in a sealed tube at elevated temperature or under microwave conditions, can afford the l,6-naphthyridine-5,7(6H,8H)-diones (36).
- the desired aminomethyl l,6-naphthyridine-5,7(6H,8H)-diones (IC) of the present invention can be obtained following the procedures described in Schemes 1 and 2.
- ID 5,6-dihydro-l,6-naphthyridin-7(8H)-ones
- Z is CH 2
- n is 1.
- Selective de-esterification of the diester (35) to give the monocarboxylic acid (38) can be readily accomplished when R a and R c are different, as will be appreciated by one skilled in the art. For example, if R a is methyl and R c is tert-butyl, saponification with a base such as lithium hydroxide will provide (38).
- the aldehyde (39) from Scheme 8 can be treated with a variety of organometallic agents R 4 -M, such as alkyl or aryl
- This benzylamine can add in an intramolecular fashion to the ester functionality CC ⁇ R 0 to form the lactam (43), the ring-closure either occurring spontaneously, or under conditions such as heating in an appropriate solvent.
- Selective de-esterification of the diester (35) to give the monocarboxylic acid (45) can be readily accomplished when R a and R c are different, as will be appreciated by one skilled in the art (see Greene, T. and Wuts, P.G.M., Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc., New York, NY (1991) and references therein).
- the resulting alcohol can be oxidized to the aldehyde (46) by a variety of procedures, as described previously, such as by treatment with Mn ⁇ 2 or by Swern oxidation.
- organometallic agents R 3 -M such as alkyl or aryl Grignard reagents and the like
- solvents such as THF and ether
- Scheme 11 provides a route to compounds of the present invention where n is 2.
- Ester (50) represents intermediates useful for preparation of compounds of the present invention as described in Schemes 1 to 10.
- A is H
- X is CH 2
- R 2 is H
- the bond b is single
- compound (50) represents compound (8) which can be prepared as described in Scheme 1.
- De-esterification of ester (50) can be readily accomplished in a variety of ways depending on the nature of R to provide a carboxylic acid. These methods are well known to those skilled in the art (see Greene, T.
- the acid functionality can be readily reduced to the alcohol (51), such as by treatment with borane in a solvent such as THF, or by formation of a mixed anhydride with ethyl chloro formate and a base such as triethylamine, followed by reduction of the mixed anhydride with a reducing agent such as sodium borohydride.
- a solvent such as THF
- a mixed anhydride with ethyl chloro formate and a base such as triethylamine
- the alcohol (51) can then be converted to a mesylate or chloride using reagents such as CH3SO2CI or SOCI2 in solvents such methylene chloride or tetrahydrofuran, and with or without a base such as triethylamine.
- reagents such as CH3SO2CI or SOCI2 in solvents such methylene chloride or tetrahydrofuran, and with or without a base such as triethylamine.
- the nitrile (52) can be reduced by a variety of procedures, such as by catalytic hydrogenation using catalysts such as Raney nickel or Pd/C, or by treating the nitrile with a reducing agent such as sodium borohydride in the presence of a catalyst such as MQ 2 or C0CI 2 , to afford compounds of the present invention (IF), where n is 2.
- Scheme 12 provides a route to additional compounds of the present invention.
- Scheme 13 provides a route to compounds of the present invention where bond b is double.
- compound (47) from Scheme 10 can be treated with an appropriate amine A-NH 2 , which can form an imine/enamine intermediate, which upon heating can condense onto the ester functionality CO 2 R a to provide compound (61), where bond b is double.
- Compound (61) can be used to prepare compounds of the invention employing the procedures of Schemes 1 and 2.
- All product amines that exist as atropisomers can be separated into individual enantiomers using methods known in the art. For example, resolution by crystallization of diastereomeric salts (tartaric acid, N-protected amino acids, etc; see for example, Eliel, Ernest L.; Wilen, Samuel H.; Doyle, Michael P., Basic Organic Stereochemistry, Wiley, (2001)), chiral preparative HPLC, use of enzymes, use of chiral derivatizing agents (see for example, J. Org. Chem., 48(15):2520-2527 (1983)), or preparation and chromatographic separation of diastereomeric derivatives.
- diastereomeric salts tartaric acid, N-protected amino acids, etc; see for example, Eliel, Ernest L.; Wilen, Samuel H.; Doyle, Michael P., Basic Organic Stereochemistry, Wiley, (2001)
- chiral preparative HPLC use of enzymes
- use of chiral derivatizing agents see for example,
- alkyl or “alk” as used herein alone or as part of another group includes both branched and straight-chain saturated aliphatic hydrocarbon radicals/groups having the specified number of carbon atoms.
- Alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain, preferably having from 1 to 40 carbon atoms, more preferably 1 to 10 carbon atoms, even more preferably 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tert-butyl, n-hexyl, n-octyl, n-decyl, n- dodecyl, 2-ethyldodecyl, tetradecyl, and the like, unless otherwise indicated.
- alkyl groups can optionally be substituted with one, two or three or more substituents selected from a member of the group consisting of halo, alkyl, alkoxy, aryl, aryloxy, aryl(aryl) or diaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, hydroxy, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl and/or alkylthio.
- cycloalkyl saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclic alkyl, bicyclic alkyl (or bicycloalkyl) and tricyclic alkyl, containing a total of 3 to 20 carbons forming the ring, preferably 3 to 10 carbons, forming the ring and which may be fused to 1 or 2 aromatic rings as described for aryl, which includes, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl,
- Aryl or “Ar” as used herein alone or as part of another group refers to an unsaturated aromatic carbocyclic group of from 5 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl).
- Representative examples include, but are not limited to, aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.
- such aryl groups can optionally be substituted with one to three or more substituents selected from a member of the group consisting of hydrogen, halo, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, cyano, amino, any of the alkyl substituents described herein, or substituted amino wherein the amino includes 1 or 2 substituents
- cycloheteroalkyl refers to a saturated or unsaturated group having a single ring, multiple condensed rings or multiple covalently joined rings, from 1 to 40 carbon atoms and from 1 to 10 hetero ring atoms, preferably 1 to 4 hetero ring atoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen.
- Heterocycle or “Heterocyclic group” means a stable 5 to 7 membered monocyclic or bicyclic or 7 to 10 membered bicyclic heterocyclic ring that may be saturated, partially unsaturated, or aromatic, and that comprises carbon atoms and from 1 to 4 heteroatoms independently selected from a member of the group consisting of nitrogen, oxygen and sulfur and wherein the nitrogen and sulfur heteroatoms are optionally be oxidized and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
- heterocyclic groups may be substituted on carbon or on a nitrogen, sulfur, phosphorus, and/or oxygen heteroatom, such as, but not limited to, 1 to 3 or more substituents described for alkyl or aryl herein, so long as the resulting compound is stable.
- nitrogen, sulfur, phosphorus, and/or oxygen heteroatom such as, but not limited to, 1 to 3 or more substituents described for alkyl or aryl herein, so long as the resulting compound is stable.
- Heteroaryl as used herein alone or as part of another group embraces unsaturated heterocyclic radicals.
- heteroaryl radicals include unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-l,2,4-triazolyl, IH-1, 2,3 -triazolyl, 2H-l,2,3-triazolyl, etc.) tetrazolyl (e.g., lH-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensed heterocyclyl group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, in
- heteroaryl groups can optionally be substituted with one to three or more substituents, such as those described for alkyl or aryl herein.
- alkenyl as used herein alone or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 1 to 8 carbons in the normal chain, which include one to six double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3- heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl
- alkenyl group may be substituted with one to three or more substituents, such as those substituents disclosed for alkyl.
- alkynyl refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons and more preferably 2 to 8 carbons in the normal chain, which include one triple bond in the normal chain, such as 2-propynyl, 3-butynyl, 2- butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4- heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl,3-undecynyl, 4-dodecynyl and the like.
- alkynyl group may be substituted with one to three or more substituents, such as those substituents disclosed for alkyl.
- cycloalkenyl as employed herein alone or as part of another group refers to partially unsaturated cyclic hydrocarbons containing 3 to 12 carbons, preferably 5 to 10 carbons and 1 or 2 double bonds.
- exemplary cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, and cycloheptadienyl.
- said cycloalkenyl group may be substituted with one to three or more substituents, such as those substituents disclosed for alkyl.
- bicycloalkyl as employed herein alone or as part of another group includes saturated bicyclic ring groups such as, without limitation, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, and so forth.
- polycycloalkyl as employed herein alone or as part of another group includes two or more cycloalkyl ring systems, as defined herein, wherein at least one carbon atom is a part of at least two separately identifiable ring systems.
- the polycycloalkyl group may contain bridging between two carbon atoms, for example, bicyclo[1.1.0]butyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, tricycl[2.2.1.0.sup. l ]heptyl, norbornyl and pinanyl.
- the polycycloalkyl group may contain one or more fused ring systems, for example, decalinyl (radical from decalin) and perhydroanthracenyl.
- the polycycloalkyl group may contain a spiro union, in which a single atom is the only common member of two rings, for example, spiro[3.4]octyl, spiro[3.3]heptyl and spiro[4.5]decyl.
- halogen or "halo” as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine as well as CF3.
- alkoxy or "alkyloxy” as used herein alone or as part of another group, refers to an alkyl group, as defined herein, appended to a parent molecular moiety through an alkyl group, as defined herein.
- haloalkoxy as used herein alone or as part of another group refers to alkoxy radicals, as defined herein, further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy radicals. Examples include, without limitation, fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoromethoxy, fluoroethoxy and fluoropropoxy.
- acyl as employed herein by itself or part of another group, as
- acyl groups include a substituent group attached to a carbonyl, such as alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl, cycloalkanoyl, cycloheteroalkanoyl and the like.
- cycloalkylalkyl refers to a cycloalkyl, an aryl, a cyclohetero, a bicycloalkyl or heteroaryl group, as defined herein, appended to a parent molecular moiety through an alkyl group, as defined herein.
- arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and the like.
- cycloheteroalkylalkyl refers to a cycloheteroalkyl group as defined herein, linked through a C atom or heteroatom to a (CH2) r chain, where "r” can be 1 to 10.
- polyhaloalkyl refers to an "alkyl” group as defined above, having 2 to 9, preferably from 2 to 5, halo substituents, such as CF 3 CH 2 , CF 3 or CF 3 CF 2 CH 2 .
- polyhaloalkoxy refers to an "alkoxy” or “alkyloxy” group as defined above having 2 to 9, preferably from 2 to 5, halo substituents, such as CF 3 CH 2 O-, CF 3 O- or CF 3 CF 2 CH 2 O-.
- thiol or “thio” as used herein alone or as part of another group, refers to (-S) or (-S-).
- alkylthio or “arylalkylthio” refers to an alkyl group or and arylalkyl group, as defined herein, linked to a parent molecular moiety through a thiol group.
- alkylthioalkyl or "arylalkylthioalkyl” refers to an alkylthio group or and arylalkylthio group, as defined herein, linked to a parent molecular moiety through an alkyl group.
- hydroxy refers to a -OH group.
- hydroxyalkyl refers to a hydroxyl group, as defined herein, appended to a parent molecular moiety through a alkyl group, as defined herein.
- cyano as used herein alone or as part of another group, refers to a -CN group.
- nitro refers to a --NO 2 group.
- sulfinyl whether used alone or linked to other terms such as alkylsulfinyl, denotes respectively divalent radicals -S(O)-.
- alkylsulfinyl refers to an alkyl group, as defined herein, appended to a parent molecular moiety through a sulfinyl group, as defined herein.
- sulfonyl refers to an SO 2 group.
- alkylsulfonyl or “aminosulfonyl”, as used herein, refer to an alkyl or amino group, as defined herein, appended to a parent molecular moiety through a sulfonyl group, as defined herein.
- amino refers to an -NH3 group or an amine linkage: -NR 3 -, wherein Ra may be as described below in the definition for
- substituted amino refers to amino substituted with one or two substituents.
- R a and Rb may be the same or different and are, for example chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkylalkyl, haloalkyl, hydrooxyalkyl, alkoxyalkyl or thioalkyl.
- substituents may optionally be further substituted with any of the alkyl substituents as set out above.
- amino substituents may be taken together with the nitrogen atom to which they are attached to form 1-pyrrolidinyl, 1 -piperidinyl, 1- azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-lpiperazinyl, 4- arylalkyl-lpiperazinyl, 4-diarylalkyl-l-piperazinyl, 1-pyrrolindinyl, 1 -piperidinyl, or
- dialkylamino refers to a substituted amino group having two alkyl substituents.
- NR a Rb wherein R a and Rb are each an alkyl group, as defined herein.
- carbonyl refers to a -C(O)- group.
- aminocarbonyl alkylcarbonyl
- alkoxycarbonyl alkoxycarbonyl
- arylcarbonyl refers to an amino group, alkyl group, alkoxy group, aryl group, alkynylamino group, alkylamino group or an alkenylamino group, as defined herein, appended to a parent molecular moiety through a carbonyl group, as defined herein.
- alkylaminocarbonylamino or “alkoxycarbonylamino” as used herein, refers to a heteroaryl, aryl, alkyl, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, alkylaminocarbonyl or alkoxycarbonyl group as defined herein, appended to a parent molecular moiety through an amino group, as defined herein.
- sulfonamido refers to -S(O) 2 -NR a R b , wherein R a and R b are as defined above for "substituted amino".
- alkylcarbonyloxy refers to an "alkyl-CO-O-" group, wherein alkyl is as defined above.
- Optional or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes, without limitation, instances where said event or circumstance occurs and instances in which it does not.
- optionally substituted alkyl means that alkyl may or may not be substituted by those groups enumerated in the definition of substituted alkyl.
- Substituted as used herein, whether express or implied and whether preceded by “optionally” or not, means that any one or more hydrogen on the designated atom (C, N, etc.) is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
- prodrug esters as employed herein includes esters and carbonates formed by reacting one or more hydroxyls of compounds of formula I with alkyl, alkoxy, or aryl substituted acylating agents employing procedures known to those skilled in the art to generate acetates, pivalates, methylcarbonates, benzoates and the like.
- prodrugs are well known in the art. A comprehensive description of prodrugs and prodrug derivatives are described in: a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al, Ch.
- abetic complications include retinopathy, neuropathy and nephropathy, erectile dysfunction, delayed wound healing, and other known complications of diabetes.
- An administration of a therapeutic agent of the invention includes administration of a therapeutically effective amount of the agent of the invention.
- therapeutically effective amount refers to an amount of a therapeutic agent to treat or prevent a condition treatable by administration of a composition of the invention. That amount is the amount sufficient to exhibit a detectable therapeutic or preventative or ameliorative effect. The effect may include, for example, treatment or prevention of the conditions listed herein.
- other type of therapeutic agents includes, but is not limited to one or more antidiabetic agents (other than DPP-IV inhibitors of formula I), one or more anti-obesity agents, one or more anti-hypertensive agents, one or more anti-platelet agents, one or more anti-atherosclerotic agents and/or one or more lipid-lowering agents (including anti-atherosclerosis agents).
- the compounds of the present invention possess activity as inhibitors of the dipeptidyl peptidase IV which is found in a variety of tissues, such as the intestine, liver, lung and kidney of mammals. Via the inhibition of dipeptidyl peptidase IV in vivo, the compounds of the present invention possess the ability to potentiate endogenous levels of GLP- 1(7-36) and attenuate formation of its antagonist
- the compounds of the present invention can be administered to mammals, preferably humans, for the treatment of a variety of conditions and disorders, including, but not limited to, treating or delaying the progression or onset of diabetes(preferably Type II, impaired glucose tolerance, insulin resistance, and diabetic complications, such as nephropathy, retinopathy, neuropathy and cataracts), hyperglycemia, hyperinsulinemia, hypercholesterolemia, elevated blood levels of free fatty acids or glycerol, hyperlipidemia, hypertriglyceridemia, obesity, wound healing, tissue ischemia, atherosclerosis and hypertension.
- the compounds of the present invention may also be utilized to increase the blood levels of high density lipoprotein (HDL).
- HDL high density lipoprotein
- the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, a therapeutically effective amount of at least one of the compounds of formula I, alone or in combination with a pharmaceutical carrier or diluent.
- a pharmaceutical carrier or diluent e.g., a pharmaceutically acceptable carrier or diluent.
- compounds of the present invention can be used alone, in combination with other compounds of the invention, or in combination with one or more other therapeutic agent(s), e.g., an antidiabetic agent or other pharmaceutically active material.
- therapeutic agent(s) suitable for combination with the compound of the present invention include, but are not limited to, known therapeutic agents useful in the treatment of the aforementioned disorders including: anti-diabetic agents; anti-hyperglycemic agents; hypolipidemic/lipid lowering agents; anti-obesity agents; anti-hypertensive agents, and appetite suppressants.
- Additional therapeutic agents suitable for combination with the compound of the present invention include agents for treating infertility, agents for treating polycystic ovary syndrome, agents for treating a growth disorder and/or frailty, an anti-arthritis agent, agents for preventing inhibiting allograft rejection in transplantation, agents for treating autoimmune disease, an anti-AIDS agent, agents for treating inflammatory bowel disease/syndrome, agents for treating anorexia nervosa and an anti-osteoporosis agent.
- Suitable anti-diabetic agents for use in combination with the compound of the present invention include biguanides (e.g., metformin or phenformin), glucosidase inhibitors (e.g., acarbose or miglitol), insulins (including insulin secretagogues or insulin sensitizers), meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, gliclazide, chlorpropamide and glipizide), biguanide/glyburide combinations (e.g., Glucovance ® ), thiazolidinediones (e.g., troglitazone, rosiglitazone and pioglitazone), PPAR-alpha agonists, PPAR-gamma agonists, PPAR alpha/gamma dual agonists, PPARdelta agonists,
- Suitable thiazolidinediones include Mitsubishi's MCC-555 (disclosed in U.S. Patent No. 5,594,016), Glaxo- Wellcome's GL-262570, englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer, isaglitazone (MIT/J&J), JTT- 501 (JPNT/P&U), L-895645 (Merck), R-119702 (Sankyo/WL), NN-2344 (Dr. Reddy/NN), or YM-440 (Yamanouchi).
- Examples of PPAR-alpha agonists, PPAR-gamma agonists, PPARdelta agonists, and PPAR alpha/gamma dual agonists include muraglitazar, peliglitazar, AR-HO39242 (Astra/Zeneca), GW-409544 (Glaxo- Wellcome), GW-501516 (Glaxo- Wellcome), LY-919818 (Lilly/Ligand), KRP297 (Kyorin Merck) as well as those disclosed by Murakami et al, "A Novel Insulin Sensitizer Acts As a Coligand for Peroxisome Proliferation - Activated Receptor Alpha (PPAR alpha) and PPAR gamma.
- Suitable aP2 inhibitors include those disclosed in U.S. application Serial No. 09/391,053, filed September 7, 1999, and in U.S. application Serial No. 09/519,079, filed March 6, 2000, employing dosages as set out herein.
- Suitable other DPP4 inhibitors include saxagliptin, those disclosed in WO99/38501, WO99/46272, WO99/67279 (PROBIODRUG), WO99/67278 (PROBIODRUG), WO99/61431 (PROBIODRUG), NVP-DPP728A (l-[[[2-[(5- cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine) (Novartis) as disclosed by Hughes et al, Biochemistry, 38(36), 11597-11603, 1999, TSL-225 (tryptophyl-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (disclosed by Yamada et al., Bioorg.
- Suitable meglitinides include nateglinide (Novartis) or KAD 1229 (PF/Kissei).
- glucagon-like peptide- 1 examples include glucagon-like peptide- 1 (GLP-I), such as GLP-l(l-36) amide, GLP-l(7-36) amide, GLP-l(7-37) (as disclosed in U.S. Patent No. 5,614,492), as well as exenatide (Amylin/Lilly), LY-315902 (Lilly), MK- 0431 (Merck), liraglutide (NovoNordisk), ZP-10 (Zealand Pharmaceuticals A/S), CJC-1131 (Conjuchem Inc), and the compounds disclosed in WO 03/033671.
- GLP-I glucagon-like peptide- 1
- hypolipidemic/lipid lowering agents for use in combination with the compound of the present invention include one or more MTP inhibitors, HMG CoA reductase inhibitors, squalene synthetase inhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors, ileal Na /bile acid co-transporter inhibitors, up-regulators of LDL receptor activity, bile acid sequestrants, cholesterol ester transfer protein (e.g., CETP inhibitors, such as CP-529414 (Pfizer) and JTT-705 (Akros Pharma)), PPAR agonists (as described above) and/or nicotinic acid and derivatives thereof.
- MTP inhibitors e.g., HMG CoA reductase inhibitors, squalene synthetase inhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors, ileal Na
- MTP inhibitors which may be employed as described above include those disclosed in U.S. Patent No. 5,595,872, U.S. Patent No. 5,739,135, U.S. Patent No. 5,712,279, U.S. Patent No. 5,760,246, U.S. Patent No. 5,827,875, U.S. Patent No. 5,885,983 and U.S. Patent No. 5,962,440.
- the HMG CoA reductase inhibitors which may be employed in combination with one or more compound of formula I include mevastatin and related compounds, as disclosed in U.S. Patent No. 3,983,140, lovastatin (mevinolin) and related compounds, as disclosed in U.S. Patent No.
- HMG CoA reductase inhibitors which may be employed herein include, but are not limited to, fluvastatin, disclosed in U.S. Patent No. 5,354,772, cerivastatin, as disclosed in U.S. Patent Nos. 5,006,530 and 5,177,080, atorvastatin, as disclosed in U.S. Patent Nos.
- Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin and ZD-4522.
- phosphinic acid compounds useful in inhibiting HMG CoA reductase such as those disclosed in GB 2205837, are suitable for use in combination with the compound of the present invention.
- the squalene synthetase inhibitors suitable for use herein include, but are not limited to, ⁇ -phosphono-sulfonates disclosed in U.S. Patent No. 5,712,396, those disclosed by Biller et al., J. Med. Chem., 31(10): 1869-1871 (1988), including isoprenoid (phosphinyl-methyl)phosphonates, as well as other known squalene synthetase inhibitors, for example, as disclosed in U.S. Patent No.
- squalene synthetase inhibitors suitable for use herein include the terpenoid pyrophosphates disclosed by P. Ortiz de Montellano et al, J. Med. Chem., 20:243-249 (1977), the farnesyl diphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs as disclosed by Corey and Volante, J. Am. Chem.
- fibric acid derivatives which may be employed in combination the compound of formula I include fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like, probucol, and related compounds, as disclosed in U.S. Patent No.
- bile acid sequestrants such as cholestyramine, colestipol and DEAE-Sephadex (Secholex ® , policexide ® ), as well as lipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402), tetrahydrolipstatin (THL), istigmastanylphos-phorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide (Sumitomo), Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinic acid, acipimox, acifran, neomycin, p-aminosalicylic
- the ACAT inhibitor which may be employed in combination the compound of formula I include those disclosed in Drugs of the Future, 24:9-15 (1999) (Avasimibe); Nicolosi et al., "The ACAT inhibitor, Cl-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters", Atherosclerosis (Shannon, Irel), 137(l):77-85 (1998); Ghiselli, Giancarlo, "The pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoBlOO-containing lipoprotein", Cardiovasc. Drug Rev., 16(l): 16-30 (1998); Smith, C.
- the hypolipidemic agent may be an up-regulator of LD2 receptor activity, such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).
- suitable cholesterol absorption inhibitor for use in combination with the compound of the invention include SCH48461 (Schering- Plough), as well as those disclosed in Atherosclerosis, 115:45-63 (1995) and J. Med. Chem., 41 :973 (1998).
- ileal Na /bile acid co-transporter inhibitors for use in combination with the compound of the invention include compounds as disclosed in Drugs of the Future, 24:425-430 (1999).
- the lipoxygenase inhibitors which may be employed in combination the compound of formula I include 15-lipoxygenase (15-LO) inhibitors, such as benzimidazole derivatives, as disclosed in WO 97/12615, 15-LO inhibitors, as disclosed in WO 97/12613, isothiazolones, as disclosed in WO 96/38144, and 15-LO inhibitors, as disclosed by Sendobry et al., "Attenuation of diet-induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties", Brit.
- Suitable anti-hypertensive agents for use in combination with the compound of the present invention include beta adrenergic blockers, calcium channel blockers (L-type and T-type; e.g., diltiazem, verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone,
- Dual ET/AII antagonist e.g., compounds disclosed in WO 00/01389
- neutral endopeptidase (NEP) inhibitors neutral endopeptidase (NEP) inhibitors
- vasopepsidase inhibitors dual NEP-ACE inhibitors
- omapatrilat and gemopatrilat e.g., omapatrilat and gemopatrilat
- Suitable anti-obesity agents for use in combination with the compound of the present invention include a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta drug, 5HT2C agonists, (such as Arena APD-356); MCHRl antagonists such as Synaptic SNAP-7941 and Takeda T-226926, melanocortin receptor (MC4R) agonists, melanin- concentrating hormone receptor (MCHR) antagonists (such as Synaptic SNAP-7941 and Takeda T-226926), galanin receptor modulators, orexin antagonists, CCK agonists, NPYl or NPY5 antagonist, NPY2 and NPY4 modulators, corticotropin releasing factor agonists, histamine receptor-3 (H3) modulators, 11 -beta-HSD- 1 inhibitors, adinopectin receptor modulators
- beta 3 adrenergic agonists which may be optionally employed in combination with compound of the present invention include AJ9677 (Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer,) or other known beta 3 agonists, as disclosed in U.S. Patent Nos. 5,541,204, 5,770,615, 5,491,134, 5,776,983 and 5,488,064.
- Examples of lipase inhibitors which may be optionally employed in combination with compound of the present invention include orlistat or ATL-962 (Alizyme).
- the serotonin (and dopoamine) reuptake inhibitor (or serotonin receptor agonists) which may be optionally employed in combination with a compound of the present invention may be BVT-933 (Biovitrum), sibutramine, topiramate (Johnson &
- thyroid receptor beta compounds which may be optionally employed in combination with the compound of the present invention include thyroid receptor ligands, such as those disclosed in WO97/21993 (U. CaI SF), WO99/00353
- the monoamine reuptake inhibitors which may be optionally employed in combination with compound of the present invention include fenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, sertraline, chlorphentermine, cloforex, clortermine, picilorex, sibutramine, dexamphetamine, phentermine, phenylpropanolamine or mazindol.
- the anorectic agent which may be optionally employed in combination with the compound of the present invention include topiramate (Johnson & Johnson), dexamphetamine, phentermine, phenylpropanolamine or mazindol.
- the compound of formula I will be employed in a weight ratio to biguanide within the range from about
- the compound of formula I will be employed in a weight ratio to the glucosidase inhibitor within the range from about 0.01 : 1 to about 100: 1, preferably from about 0.5: 1 to about 50: 1.
- the compound of formula I will be employed in a weight ratio to the sulfonyl urea in the range from about 0.01: 1 to about 100: 1, preferably from about
- the compound of formula I will be employed in a weight ratio to the thiazolidinedione in an amount within the range from about 0.01 : 1 to about 100: 1, preferably from about 0.2: 1 to about 10: 1.
- the thiazolidinedione anti-diabetic agent may be employed in amounts within the range from about 0.01 to about 2000 mg/day which may be administered in single or divided doses one to four times per day.
- the sulfonyl urea and thiazolidinedione may be incorporated in a single tablet with the compound of formula I in amounts of less than about 150 mg.
- metformin or salt thereof may be employed in amounts within the range from about 500 to about 2000 mg per day which may be administered in single or divided doses one to four times daily.
- GLP-I peptides may be administered in oral buccal formulations, by nasal administration or parenterally as described in U.S. Patent Nos.
- the compound of formula I will be employed in a weight ratio to the meglitinide, PPAR-gamma agonist, PPAR-alpha/gamma dual agonist, PPARdelta agonists, PPARalpha/gamma/delta triple agonist, aP2 inhibitor or other DPP4 inhibitor within the range from about 0.01 : 1 to about 100: 1, preferably from about
- the compound of formula I of the invention will be generally be employed in a weight ratio to the hypolipidemic agent (were present), within the range from about 500: 1 to about 1 :500, preferably from about 100: 1 to about 1 : 100.
- MTP inhibitor for oral administration, a satisfactory result may be obtained employing the MTP inhibitor in an amount within the range of from about 0.01 mg/kg to about
- a preferred oral dosage form such as tablets or capsules, will contain the
- MTP inhibitor in an amount of from about 1 to about 500 mg, preferably from about 2 to about 400 mg, and more preferably from about 5 to about 250 mg, one to four times daily.
- an HMG CoA reductase inhibitor in an amount within the range of from about 1 to 2000 mg, and preferably from about 4 to about 200 mg.
- a preferred oral dosage form such as tablets or capsules, will contain the HMG CoA reductase inhibitor in an amount from about 0.1 to about 100 mg, preferably from about 5 to about 80 mg, and more preferably from about 10 to about 40 mg.
- the squalene synthetase inhibitor may be employed in dosages in an amount within the range of from about 10 mg to about 2000 mg and preferably from about 25 mg to about 200 mg.
- a preferred oral dosage form such as tablets or capsules will contain the squalene synthetase inhibitor in an amount of from about 10 to about 500 mg, preferably from about 25 to about 200 mg.
- the compound of the formula I can be administered for any of the uses described herein by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents.
- suitable means for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.
- a pharmaceutical composition will be employed containing one or more of the compound of formula I, with or without other antidiabetic agent(s) and/or antihyperlipidemic agent(s) and/or other type therapeutic agents in association with a pharmaceutical vehicle or diluent.
- the pharmaceutical composition can be formulated employing conventional solid or liquid vehicles or diluents and pharmaceutical additives of a type appropriate to the mode of desired administration, such as pharmaceutically acceptable carriers, excipients, binders and the like.
- the compound can be administered to mammalian species including humans, monkeys, dogs, etc.
- a typical injectable preparation may be produced by aseptically placing 250 mg of compound of formula I into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline, to produce an injectable preparation.
- DPP-4 inhibitory activity of the compounds of the present invention may be determined by use of an in vitro assay system which measures the degree in inhibition of DPP-4-mediated cleavage of an appropriate substrate or pseudo- substrate.
- Inhibition constants (Ki values) for the DPP-4 inhibitors of the invention may be determined by the method described in the experimental section below.
- PCR Red-tag polymerase, Sigma was performed on Human cDNA from placenta (Clontech) using two primers, ACGCCGACGATGAAGACA and AGGTAAAGAGAAACATTGTT, based on the nucleotide sequence of the human clone (accession number M74777). PCR products were cloned into the pcDN4/HisMax TOPO vector (Invitrogene). For stable transfection of CHO-DG44 cells, DPP4 was rePCRed using primers GGTACCAGCGCAGAGGCTT and CTCGAGCTAAGGTAAAGAGAAACATTG to generate Kpnl and Xhol sites.
- the Kpnl and Xhol sites were used to extract the N- terminal His tagged gene.
- the His tag which could be cleaved and removed by Enterokinase, was included to allow purification using the TALON affinity column.
- the gene was then ligated into the Kpnl and Xhol sites of the pD16 vector for stable transfection.
- Stable cell lines were generated by transfecting the expression vector into Chinese hamster ovary (CHO-DG44) cells using electroporation.
- the CHO- DG44 cell line was grown in PFCHO media supplemented with HT (glycine, hypoxanthine and thymidine, Invitrogene), glutamine and Recombulin (ICN).
- IxIO 7 cells/ml were collected, transfected with 60 ⁇ g of DNA using electroporation at 300V, and then transferred to a T75 flask.
- the HT supplement was removed and selection was initiated with methotrexate (MTX, 10 nM, ICN). After a further 10 days the cells were plated into individual wells of 96 well plates. Every 10 days the concentration of MTX was increased two to three fold, up to a maximum of 400 nM. Final stable cell line selection was based on yield and activity of the expressed protein.
- Ki /G ⁇ 50
- vi and v ⁇ are the steady state velocities measured in the presence and absence of inhibitor, E enzyme concentration.
- Ph phenyl
- Cbz carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl
- LiBH 4 lithium borohydride
- DIBAL-H diisobutylaluminum hydride
- HPLC high performance liquid chromatography
- PrepHPLC preparative HPLC
- Solvent A (Prep HPLC): 90 % H 2 O/10 % MeOH + 0.1 % TFA
- Example 1C A mixture of stock solution of Example IB (25 mL, 13 mmol) and Example IA (2.8 g, 14.5 mmol) in isopropyl alcohol (3 mL) was allowed to stir at ambient temperature for 18 h. The reaction was quenched with concentrated HCl (8 mL), and the mixture stirred at ambient temperature for 2 h. The reaction was concentrated in vacuo, diluted with diethyl ether, filtered and evaporated. The residue was purified by flash chromatography (12O g column, EtOAc/Hexanes) to give Example 1C (4.2 g, 65 % yield) as a yellow, sticky oil.
- Example 1C (4.1 mg, 8.2 mmol) was dissolved in acetic acid (3OmL) and 70 % nitric acid/water (25 mL). The reaction mixture was allowed to stir at ambient temperature for 18 h. The crude product (4.2 g) was purified by flash chromatography (120 g column, 0-100 % EtOAc/Hex) to give Example ID (2.7 g, 68 % yield) as a pale yellow oil.
- Example ID 980 mg, 2.0 mmol
- KCN 143 mg, 2.2 mmol
- Ethano I/water 20 ml
- Example IE (1.06g, 2.2 mmol), 10% Pd/C (424 mg) and 2 drops of concentrated HCl aq. solution in 40 mL of methanol was stirred under H 2 (latm, maintained by balloon) overnight at ambient temperature. The mixture was filtered through a pad of Celite and concentrated. The residue was purified by flash chromatography (elution with 1:5 MeOH/l,2-dichloromethane) to afford 540 mg (62%) of Example lF as an solid. LRMS (ESI): 397.1/399.0 [M + H] + .
- Example IG 4-(2,4-Dichlorophenyl)-2-methyl-5-oxo-5,6,7,8-tetrahydro-l,6- naphthyridine-3-carboxylic acid
- Example IF A mixture of Example IF (540 mg, 1.36 mmol) and t-BuONa (197 mg, 2.05 mmol) was irradiated in a sealed tube in a microwave reactor at 120 0 C for 20 min. The volatiles were removed in vacuo. The crude product was purified by flash chromatography (elution with 0-20% MeOH / CH 2 Cl 2 ) to afford 412 mg (87% ) of Example IG as a solid. . LRMS (ESI): 351.0/353.0 [M + H] + .
- Example IH 4-(2,4-Dichlorophenyl)-3-(hydroxymethyl)-2-methyl-7,8-dihydro- l,6-naphthyridin-5(6H)-one
- Example IG To a mixture of Example IG (412 mg, 1.18 mmol) and triethylamine (0.20 ml, 1.41 mmol) in THF (10 mL) was added ethyl chloroformate (153 mg, 1.41 mmol) dropwise at 0 0 C. The reaction mixture was stirred for 10 min. To the reaction mixture, NaBH4 (445 mg, 11.8 mmol) in 5 mL of water was added at 0 0 C. The reaction was stirred for 15 min. The reaction was quenched with IM HCl aq solution.
- Example IH To a solution of Example IH (395 mg, 1.18 mmol) and triethylamine (1.3 ml, 9.4 mmol) in THF (20 mL) was added mesyl chloride (1.0 g, 9.4 mmol) dropwise. The reaction mixture was allowed to stir at ambient temperature overnight. The volatiles were removed in vacuo. The crude product was purified by flash chromatography (elution with 0-100% EtOAc/hexane to afford 302 mg (72% for 2 steps ) of Example II as a solid. LRMS (ESI): 355.1/357.1 [M + H] + .
- Example II 150 mg, 0.42 mmol
- Ammonia (2M in MeOH) 5 mL
- Ammonia (2M in MeOH) was irradiated in a sealed tube in a microwave reactor at 120 0 C for 20 min.
- the volatiles were removed in vacuo.
- the crude product was purified by flash chromatography (elution with 0-20% MeOH/ CH 2 CI 2 ) to afford an oil, which was treated with 4M HCl in MeOH to yield 32 mg (21% ) of Example 1 as a solid.
- Example 2A (33.1 g, 87.1 mmol) was dissolved in acetonitrile (15OmL) and 70 % nitric acid (30 mL). The reaction mixture was allowed to stir at ambient temperature for 30 min. The reaction was diluted with EtOAc, washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash chromatography (elution with 0-20% EtOAc/hexane) to afford 31.8 g (74%) of Example 2B as an oil.
- Example 2B To Example 2B (6.76 g, 17.9 mmol) in 350 mL of CH 2 Cl 2 , BBr 3 (IM in CH 2 Cl 2 , 18.8 mmol) was added dropwise at 0 0 C. After the addition, the reaction was stirred at ambient temperature for 60 min. The reaction was washed with water and brine, dried (MgSO 4 ) and concentrated. The residue was purified by flash chromatography (elution with 0-100% EtOAc/hexane) to afford 4.68 g (72%) of Example 2C as an oil.
- BBr 3 IM in CH 2 Cl 2 , 18.8 mmol
- Example 2C A suspension of Example 2C (1.34 g, 6.42 mmol) in 8 mL of ammonium hydroxide and 15 mL of MeOH was irradiated in a sealed tube in a microwave reactor at 150 0 C for 2.5 h. The reaction was diluted with EtOAc and washed with water and brine, dried (MgSO 4 ) and concentrated. The residue was purified by flash chromatography (elution with 0-10% MeOH/ CH 2 Cl 2 ) to afford 1.42 g (66%) of Example 2D as a solid.
- Example 2D (1.06 g, 3.2 mmol) dropwise in 30 mL of DMF. After the addition, the reaction was stirred for 10 min. Then there was added 2-chloro-N,N- dimethylacetamide (0.78 g, 6.4 mmol), and the reaction was stirred at room temperature for 3 h. The reaction was diluted with EtOAc, washed with water and brine, dried (MgSO 4 ) and concentrated.
- Example 2E was purified by flash chromatography (elution with 0-100% EtOAc/hexane) to afford 695 mg (72%) of Example 2E as an oil.
- 1 H NMR 500 MHz, CDCl 3 ) ⁇ 7.49 (s, IH), 7.37 (d, IH), 7.16 (d, IH), 4.50 and 4.10 (ABq, 2H), 3.76-3.70 (m, 2H), 3.46-3.32 (m, 2H), 2.95 (s, 3H), 2.93 (s, 3H), 2.85 (s, 3H).
- Example 2 and Example 3 (S)-2-(3-(Aminomethyl)-4-(2,4-dichlorophenyl)-2- methyl-5-oxo-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)-N,N-dimethylacetamide TFA salt (Example 2), and (S)-2-(3-(Aminomethyl)-4-(2-chlorophenyl)-2-methyl- 5-oxo-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)-N,N-dimethylacetamide TFA salt (Example 3)
- Example 2F-1 A suspension of Example 2F-1, the faster-moving atropisomer, (293 mg, 0.70 mmol) and wet RaNi (Grade 2400, -150 mg) in 15 mL of MeOH was stirred under H 2 (latm, maintained by balloon) overnight at ambient temperature. The reaction was filtered through Celite and concentrated, the residue was purified by prep HPLC (Phenomenex, 10 min gradient, 20 to 100% B) and lyophilized to dryness overnight to afford 44 mg of Example 2 as a TFA salt.
- Example 4 and Example 5 were prepared using the same method described above for Example 2 and Example 3 with the exception that starting material Example 2F-1 was replaced with the slower-moving atropisomer, Example 2F-2.
- Example 2C To Example 2C (7.85 g, 21.56 mmol) and triethylamine (5.0 ml, 32.3 mmol) in 220 mL of CH 2 Cl 2 , methanesulfonyl chloride (1.8 mL, 23.7 mmol) was added dropwise at 0 0 C. After the addition, the reaction was refluxed for 30 min. The reaction was concentrated. The residue was purified by flash chromatography (elution with 0-10% EtOAc/hexane) to afford 5.35 g (72%) of Example 6A as a solid.
- Example 6B 2-(3-Cyano-4-(2,4-dichlorophenyl)-2-methyl-5-oxo-7,8-dihydro- l,6-naphthyridin-6(5H)-yl)acetic acid
- Example 6A A mixture of Example 6A (2.65 g, 7.66 mmol), glycine (0.63 g, 8.42 mmol) and Hunig's base (1.1 g, 8.42 mmol) in 20 ml of MeOH/MeCN (1 : 1) was irradiated in a sealed tube in a microwave reactor at 150 0 C for 30 min. The volatiles were removed in vacuo. The residue was purified by flash chromatography (elution with 0-15% MeOH/ CH 2 Cl 2 ) to afford 2.48 g (83%) of Example 6B as a foam.
- Atropisomer 6C- 1 Atropisomer 6C-2 Fast-moving Slow-moving
- Example 6C-1 A mixture of Example 6C-1, the fast-moving atropisomer, (98 mg, 0.25 mmol), 1-hydroxybenzotriazole (41 mg, 0.30 mmol) and EDC (58 mg, 0.30 mmol), in 2 ml of 4M NH3 in MeOH was stirred at ambient temperature for 2 h. The volatiles were removed in vacuo.
- Example 7 was prepared from Example 6C-1, the fast-moving atropisomer, using the same method described above for Example 6 with the exception that ammonia was replaced with methylamine.
- LRMS (ESI): 408.1/410.1 [M + H] + .
- Example 8 was prepared from Example 6C-1, the fast-moving atropisomer, using the same method described above for Example 6 with the exception that ammonia was replaced with diethylamine.
- 1 H NMR 500 MHz, CD 3 OD
- LRMS (ESI): 449.2 [M + H] + .
- Example 9 was prepared from Example 6C-1, the fast-moving atropisomer, using the same method described above for Example 6 with the exception that ammonia was replaced with pyrrolidine.
- 1 H NMR 500 MHz, CD 3 OD
- LRMS ESI
- Example 10 was prepared from Example 6C-1, the fast-moving atropisomer, using the same method described above for Example 6 with the exception that ammonia was replaced with piperidine.
- 1 H NMR 500 MHz, CD 3 OD
- LRMS 481.2 [M + H
- Example 11 was prepared from Example 6C-1, the fast-moving atropisomer, using the same method described above for Example 6 with the exception that ammonia was replaced with 4-(N-delta-valerolactam)piperidine hydrochloride.
- Example 12 was prepared from Example 6C-1, the fast-moving atropisomer, using the same method described above for Example 6 with the exception that ammonia was replaced with morpholine.
- 1 H NMR 500 MHz, CD 3 OD
- LRMS (ESI): 463.2 [M + H] + .
- Example 13A 4-(2,4-Dichlorophenyl)-2-methyl-5-oxo-7,8-dihydro-5H- pyrano[4,3-b]pyridine-3-carbonitrile
- Example 2B (7.6 g, 20 mmol) in 400 mL of CH 2 Cl 2 , BBr 3 (20 mL of IM in CH 2 Cl 2 , 20 mmol) was added dropwise at 0° C. After the addition, the reaction was stirred at ambient temperature for 60 min. The reaction was concentrated in vacuo and the residue was purified (ISCO, elution with 0-10% MeOH/CH 2 Cl 2 ) to afford 6.2 g (92%) of Example 13A as a light brown solid.
- Example 13A 120 mg, 0.36 mmol
- methylamine 24 g, 0.72 mmol
- Hunig's base 93 mg, 0.72 mmol
- the crude product was purified by flash chromatography (elution with 0-15% MeOH/ CH 2 Cl 2 ) to afford an oil, which was dissolved in 10 mL of 2M NH3 in MeOH and hydrogenated under 60 psi with -200 mg wet RaNi overnight.
- Example 13 as a TFA salt.
- Example 14 was prepared from Example 13A using the same method described above for Example 13 with the exception that methylamine was replaced with (S)-(+)-tetrahydrofurfurylamine.
- 1 H NMR 500 MHz, CD 3 OD
- Example 15 was prepared from Example 13A using the same method described above for Example 13 with the exception that methylamine was replaced with 2-methoxyethylamine.
- 1 H NMR 500 MHz, CD 3 OD
- Example 15 To Example 15 (41 mg, 0.104 mmol) in 2 mL of CH 2 Cl 2 , BBr 3 (IM in CH 2 Cl 2 , 115 uL, 0.11 mmol) was added dropwise at 0°C. After the addition, the reaction was stirred at ambient temperature for 2 h. The reaction was filtered over Celite and concentrated. The residue was purified by prep HPLC (Phenomenex, 10 min gradient, 20 to 100% B) and lyophilized to dryness overnight to afford 11 mg (21%) of Example 16 as a TFA salt.
- BBr 3 IM in CH 2 Cl 2 , 115 uL, 0.11 mmol
- Example 2D A mixture of Example 2D (126 mg, 0.38 mmol), iodobenzene (85 g, 0.42 mmol), copper iodide (16 mg, 0.08 mmol), N,N-dimethylethylenediamine (7 mg, 0.08 mmol) and CS2CO3 (248 mg, 0.76 mmol) in 4 mL of MeOH was irradiated in a sealed tube in a microwave reactor at 100 0 C for 4 h.
- Example 18 was prepared from Example 2D using the same method described above for Example 17 with the exception that iodobenzene was replaced with 2-iodoanisole.
- LRMS ESI: 442.3/444.3 [M + H] + .
- Example 19A A mixture of Example 19A (407 mg, 87 mmol) and MnO 2 in 10 mL of CH 2 Cl 2 was irradiated in a sealed tube in a microwave reactor at 100 0 C for 1 h and 120 0 C for 3 h. The reaction was filtered through Celite, concentrated and purified by flash chromatography (elution with 0-40% EtOAc/hexane) to afford 288 mg (71%) of Example 19B as an oil.
- Example 19B 120 mg, 0.31 mmol
- ammonium hydroxide/MeOH (1 : 1) was irradiated in a sealed tube in a microwave reactor at 150 0 C for 60 min.
- the reaction was concentrated in vacuo, the residue was dissolved in 10 mL of MeOH and hydrogenated under 60 psi with -200 mg wet RaNi (Grade 2400) overnight.
- the mixture was filtered through Celite and concentrated, the residue was purified by prep HPLC (Phenomenex, 10 min gradient, 20 to 100% B) and lyophilized to dryness overnight to afford 13 mg (12% for 2 steps) of Example 19 as a TFA salt.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Ophthalmology & Optometry (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Biomedical Technology (AREA)
- Vascular Medicine (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Child & Adolescent Psychology (AREA)
- Dermatology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES07864519T ES2382486T3 (en) | 2006-11-20 | 2007-11-16 | 7,8-Dihydro-1,6-naphthyridine-5 (6H) -ones and related bicyclic compounds such as dipeptidyl peptidase IV inhibitors and procedures |
AT07864519T ATE549334T1 (en) | 2006-11-20 | 2007-11-16 | 7,8-DIHYDRO-1,6-NAPHTHYRIDINE-5(6H)-ONE AND RELATED BICYCLIC COMPOUNDS AS DIPEPTIDYL-PEPTIDASE IV INHIBITORS AND METHODS |
JP2009538461A JP2010510317A (en) | 2006-11-20 | 2007-11-16 | 7,8-Dihydro-1,6-naphthyridin-5 (6H) -one and related bicyclic compounds as inhibitors of dipeptidyl peptidase IV, and methods |
EP07864519A EP2086975B1 (en) | 2006-11-20 | 2007-11-16 | 7,8-dihydro-1,6-naphthyridin-5(6h)-ones and related bicyclic compounds as inhibitors of dipeptidyl peptidase iv and methods |
CN2007800501380A CN101595109B (en) | 2006-11-20 | 2007-11-16 | 7,8-dihydro-1,6-naphthyridin-5(6h)-ones and related bicyclic compounds as inhibitors of dipeptidyl peptidase IV and methods |
NO20091938A NO20091938L (en) | 2006-11-20 | 2009-05-19 | 7,8-dihydro-1,6-naphthyridin-5 (6H) -ones and related bicyclic compounds as inhibitors of dipeptidyl peptidases IV and methods |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US86020206P | 2006-11-20 | 2006-11-20 | |
US60/860,202 | 2006-11-20 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2008064107A2 true WO2008064107A2 (en) | 2008-05-29 |
WO2008064107A3 WO2008064107A3 (en) | 2008-07-10 |
Family
ID=39283892
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2007/084927 WO2008064107A2 (en) | 2006-11-20 | 2007-11-16 | 7,8-dihydro-1,6-naphthyridin-5(6h)-ones and related bicyclic compounds as inhibitors of dipeptidyl peptidase iv and methods |
Country Status (8)
Country | Link |
---|---|
US (1) | US7723355B2 (en) |
EP (1) | EP2086975B1 (en) |
JP (1) | JP2010510317A (en) |
CN (1) | CN101595109B (en) |
AT (1) | ATE549334T1 (en) |
ES (1) | ES2382486T3 (en) |
NO (1) | NO20091938L (en) |
WO (1) | WO2008064107A2 (en) |
Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009021740A2 (en) | 2007-08-15 | 2009-02-19 | Sanofis-Aventis | Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments |
EP2308847A1 (en) | 2009-10-09 | 2011-04-13 | EMC microcollections GmbH | Substituted pyridines as inhibitors of dipeptidyl peptidase IV and their application for the treatment of diabetes and related diseases |
WO2011107494A1 (en) | 2010-03-03 | 2011-09-09 | Sanofi | Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof |
WO2011157827A1 (en) | 2010-06-18 | 2011-12-22 | Sanofi | Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases |
WO2011161030A1 (en) | 2010-06-21 | 2011-12-29 | Sanofi | Heterocyclic substituted methoxyphenyl derivatives having an oxo group, method for producing same, and use thereof as gpr40 receptor modulators |
WO2012004269A1 (en) | 2010-07-05 | 2012-01-12 | Sanofi | (2-aryloxy-acetylamino)-phenyl-propionic acid derivatives, method for producing same and use thereof as pharmaceuticals |
WO2012004270A1 (en) | 2010-07-05 | 2012-01-12 | Sanofi | Spirocyclically substituted 1,3-propane dioxide derivatives, methods for the production thereof and use of the same as medicament |
WO2012010413A1 (en) | 2010-07-05 | 2012-01-26 | Sanofi | Aryloxy-alkylene substituted hydroxyphenyl hexynoic acids, methods for the production thereof and use of the same as medicament |
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 |
WO2013045413A1 (en) | 2011-09-27 | 2013-04-04 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
WO2014064215A1 (en) | 2012-10-24 | 2014-05-01 | INSERM (Institut National de la Santé et de la Recherche Médicale) | TPL2 KINASE INHIBITORS FOR PREVENTING OR TREATING DIABETES AND FOR PROMOTING β-CELL SURVIVAL |
WO2016151018A1 (en) | 2015-03-24 | 2016-09-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Method and pharmaceutical composition for use in the treatment of diabetes |
US11661422B2 (en) | 2020-08-27 | 2023-05-30 | Incyte Corporation | Tricyclic urea compounds as JAK2 V617F inhibitors |
US11691971B2 (en) | 2020-06-19 | 2023-07-04 | Incyte Corporation | Naphthyridinone compounds as JAK2 V617F inhibitors |
US11753413B2 (en) | 2020-06-19 | 2023-09-12 | Incyte Corporation | Substituted pyrrolo[2,1-f][1,2,4]triazine compounds as JAK2 V617F inhibitors |
US11767323B2 (en) | 2020-07-02 | 2023-09-26 | Incyte Corporation | Tricyclic pyridone compounds as JAK2 V617F inhibitors |
US11780840B2 (en) | 2020-07-02 | 2023-10-10 | Incyte Corporation | Tricyclic urea compounds as JAK2 V617F inhibitors |
US11919908B2 (en) | 2020-12-21 | 2024-03-05 | Incyte Corporation | Substituted pyrrolo[2,3-d]pyrimidine compounds as JAK2 V617F inhibitors |
US11958861B2 (en) | 2021-02-25 | 2024-04-16 | Incyte Corporation | Spirocyclic lactams as JAK2 V617F inhibitors |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CZ20031125A3 (en) * | 2000-10-23 | 2003-10-15 | Smithkline Beecham Corporation | Novel compounds |
AR053346A1 (en) * | 2005-03-25 | 2007-05-02 | Glaxo Group Ltd | COMPOSITE DERIVED FROM 8H -PIRIDO (2,3-D) PIRIMIDIN -7 ONA 2,4,8- TRISUSTITUTED PHARMACEUTICAL COMPOSITION AND USE TO PREPARE A COMPOSITION FOR TREATMENT AND PROFILXIS OF A DISEASE MEDIATED BY KINASE CSBP / RK / P38 |
EA200702073A1 (en) * | 2005-03-25 | 2008-12-30 | Глэксо Груп Лимитед | Method of producing pyrido [2,3-d] pyrimidine-7-bp and 3,4-dihidropyrimido [4,5-d] pyrmidin-2 (1h) -onovy derivatives |
US8477028B2 (en) * | 2010-09-24 | 2013-07-02 | T-Mobile Usa, Inc. | Misplaced device recovery |
JP6258937B2 (en) * | 2012-08-24 | 2018-01-10 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | New bicyclic pyridine derivatives |
CN104548096B (en) * | 2013-10-09 | 2019-09-10 | 深圳翰宇药业股份有限公司 | A kind of pharmaceutical composition and preparation method thereof containing GLP-1 analog and DPP-4 inhibitor |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6900224B2 (en) * | 2002-07-31 | 2005-05-31 | The Procter & Gamble Company | Antimicrobial quinolones, their compositions and uses |
MXPA05001786A (en) * | 2002-08-13 | 2005-04-25 | Warner Lambert Co | Azaisoquinoline derivatives as matrix metalloproteinase inhibitors. |
GB0413389D0 (en) * | 2004-06-16 | 2004-07-21 | Astrazeneca Ab | Chemical compounds |
WO2006019965A2 (en) * | 2004-07-16 | 2006-02-23 | Takeda San Diego, Inc. | Dipeptidyl peptidase inhibitors |
GB0420970D0 (en) * | 2004-09-21 | 2004-10-20 | Smithkline Beecham Corp | Novel triazoloquinoline compounds |
WO2006065842A2 (en) * | 2004-12-13 | 2006-06-22 | Synta Pharmaceuticals Corp. | 5,6,7,8-tetrahydroquinolines and related compounds and uses thereof |
-
2007
- 2007-11-16 CN CN2007800501380A patent/CN101595109B/en not_active Expired - Fee Related
- 2007-11-16 ES ES07864519T patent/ES2382486T3/en active Active
- 2007-11-16 WO PCT/US2007/084927 patent/WO2008064107A2/en active Application Filing
- 2007-11-16 JP JP2009538461A patent/JP2010510317A/en not_active Withdrawn
- 2007-11-16 EP EP07864519A patent/EP2086975B1/en active Active
- 2007-11-16 US US11/941,181 patent/US7723355B2/en active Active
- 2007-11-16 AT AT07864519T patent/ATE549334T1/en active
-
2009
- 2009-05-19 NO NO20091938A patent/NO20091938L/en not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
GREENE, T.; WUTS, P.G.M.: "Protecting Groups in Organic Synthesis", 1991, JOHN WILEY & SONS, INC. |
Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009021740A2 (en) | 2007-08-15 | 2009-02-19 | Sanofis-Aventis | Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments |
EP2308847A1 (en) | 2009-10-09 | 2011-04-13 | EMC microcollections GmbH | Substituted pyridines as inhibitors of dipeptidyl peptidase IV and their application for the treatment of diabetes and related diseases |
WO2011107494A1 (en) | 2010-03-03 | 2011-09-09 | Sanofi | Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof |
WO2011157827A1 (en) | 2010-06-18 | 2011-12-22 | Sanofi | Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases |
WO2011161030A1 (en) | 2010-06-21 | 2011-12-29 | Sanofi | Heterocyclic substituted methoxyphenyl derivatives having an oxo group, method for producing same, and use thereof as gpr40 receptor modulators |
WO2012004269A1 (en) | 2010-07-05 | 2012-01-12 | Sanofi | (2-aryloxy-acetylamino)-phenyl-propionic acid derivatives, method for producing same and use thereof as pharmaceuticals |
WO2012004270A1 (en) | 2010-07-05 | 2012-01-12 | Sanofi | Spirocyclically substituted 1,3-propane dioxide derivatives, methods for the production thereof and use of the same as medicament |
WO2012010413A1 (en) | 2010-07-05 | 2012-01-26 | Sanofi | Aryloxy-alkylene substituted hydroxyphenyl hexynoic acids, methods for the production thereof and use of the same as medicament |
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 |
WO2013045413A1 (en) | 2011-09-27 | 2013-04-04 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
WO2014064215A1 (en) | 2012-10-24 | 2014-05-01 | INSERM (Institut National de la Santé et de la Recherche Médicale) | TPL2 KINASE INHIBITORS FOR PREVENTING OR TREATING DIABETES AND FOR PROMOTING β-CELL SURVIVAL |
WO2016151018A1 (en) | 2015-03-24 | 2016-09-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Method and pharmaceutical composition for use in the treatment of diabetes |
US11691971B2 (en) | 2020-06-19 | 2023-07-04 | Incyte Corporation | Naphthyridinone compounds as JAK2 V617F inhibitors |
US11753413B2 (en) | 2020-06-19 | 2023-09-12 | Incyte Corporation | Substituted pyrrolo[2,1-f][1,2,4]triazine compounds as JAK2 V617F inhibitors |
US11767323B2 (en) | 2020-07-02 | 2023-09-26 | Incyte Corporation | Tricyclic pyridone compounds as JAK2 V617F inhibitors |
US11780840B2 (en) | 2020-07-02 | 2023-10-10 | Incyte Corporation | Tricyclic urea compounds as JAK2 V617F inhibitors |
US11661422B2 (en) | 2020-08-27 | 2023-05-30 | Incyte Corporation | Tricyclic urea compounds as JAK2 V617F inhibitors |
US11919908B2 (en) | 2020-12-21 | 2024-03-05 | Incyte Corporation | Substituted pyrrolo[2,3-d]pyrimidine compounds as JAK2 V617F inhibitors |
US11958861B2 (en) | 2021-02-25 | 2024-04-16 | Incyte Corporation | Spirocyclic lactams as JAK2 V617F inhibitors |
Also Published As
Publication number | Publication date |
---|---|
EP2086975B1 (en) | 2012-03-14 |
CN101595109A (en) | 2009-12-02 |
WO2008064107A3 (en) | 2008-07-10 |
US20090149492A1 (en) | 2009-06-11 |
NO20091938L (en) | 2009-06-08 |
ES2382486T3 (en) | 2012-06-08 |
EP2086975A2 (en) | 2009-08-12 |
ATE549334T1 (en) | 2012-03-15 |
JP2010510317A (en) | 2010-04-02 |
US7723355B2 (en) | 2010-05-25 |
CN101595109B (en) | 2012-09-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2086975B1 (en) | 7,8-dihydro-1,6-naphthyridin-5(6h)-ones and related bicyclic compounds as inhibitors of dipeptidyl peptidase iv and methods | |
US7521557B2 (en) | Pyrrolopyridine-based inhibitors of dipeptidyl peptidase IV and methods | |
US7635699B2 (en) | Azolopyrimidine-based inhibitors of dipeptidyl peptidase IV and methods | |
US7589088B2 (en) | Pyrimidine-based inhibitors of dipeptidyl peptidase IV and methods | |
US8415386B2 (en) | Azolopyrrolone melanin concentrating hormone receptor-1 antagonists | |
US7488725B2 (en) | Pyrrolidinyl beta-amino amide-based inhibitors of dipeptidyl peptidase IV and methods | |
US20060079556A1 (en) | N-sulfonylpiperidine cannabinoid receptor 1 antagonists | |
KR20100044824A (en) | Non-basic melanin concentrating hormone receptor-1 antagonists and methods | |
EP2346872B1 (en) | Azolotriazinone melanin concentrating hormone receptor-1 antagonists | |
CN101228164A (en) | Pyrrolopyridine-based inhibitors of dipeptidyl peptidase IV and methods |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200780050138.0 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 07864519 Country of ref document: EP Kind code of ref document: A2 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 3254/DELNP/2009 Country of ref document: IN Ref document number: 2007864519 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2009538461 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |