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  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
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  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/52—Two oxygen atoms
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Definitions

• the invention relates to compounds that may be used to inhibit dipeptidyl peptidases as well as compositions of matter and kits comprising these compounds.
• the present invention also relates to methods for inhibiting dipeptidyl peptidases as well as treatment methods using compounds according to the present invention.
• Dipeptidyl Peptidase IV (IUBMB Enzyme Nomenclature EC.3.4.14.5) is a type II membrane protein that has been referred to in the literature by a wide a variety of names including DPP4, DP4, DAP-rV, FAP ⁇ , adenosine deaminase complexing protein 2, adenosine deaminase binding protein (ADAbp), dipeptidyl aminopeptidase IV; Xaa-Pro- dipeptidyl-aminopeptidase; Gly-Pro naphthylamidase; postproline dipeptidyl aminopeptidase IV; lymphocyte antigen CD26; glycoprotein GP110; dipeptidyl peptidase IN; glycylproline aminopeptidase; glycylproline aminopeptidase; X-prolyl dipeptidyl aminopeptidase; pep X; leukocyte antigen CD26; glycy
• DPP-IV Dipeptidyl Peptidase IV is referred to herein as "DPP-IV.”
• DPP-IV is a non-classical serine aminodipeptidase that removes Xaa-Pro dipeptides from the amino terminus ( ⁇ -terminus) of polypeptides and proteins. DPP-IV dependent slow release of dipeptides of the type X-Gly or X-Ser has also been reported for some naturally occurring peptides.
• DPP-IV is constitutively expressed on epithelial and endothelial cells of a variety of different tissues (intestine, liver, lung, kidney and placenta), and is also found in body fluids. DPP-IV is also expressed on circulating T-lymphocytes and has been shown to be synonymous with the cell-surface antigen, CD-26. DPP-IV has been implicated in a number of disease states, some of which are discussed below.
• DPP-IV is responsible for the metabolic cleavage of certain endogenous peptides (GLP-1 (7-36), glucagon) in vivo and has demonstrated proteolytic activity against a variety of other peptides (GHRH, ⁇ PY, GLP-2, VIP) in vitro.
• GLP-1 (7-36) is a 29 amino-acid peptide derived by post-translational processing of proglucagon in the small intestine.
• GLP-1 (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.
• DPP-TV has been shown to be the primary degrading enzyme of GLP-1 (7-36) in vivo.
• GLP-1 (7-36) is degraded by DPP-TV efficiently to GLP-1 (9-36), which has been speculated to act as a physiological antagonist to GLP-1 (7-36).
• Inhibiting DPP-TV in vivo is therefore believed to be useful for potentiating endogenous levels of GLP-1 (7-36) and attenuating the formation of its antagonist GLP-1 (9-36).
• DPP-TV inhibitors are believed to be useful agents for the prevention, delay of progression, and/or treatment of conditions mediated by DPP-TV, in particular diabetes and more particularly, type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (TFG), metabolic acidosis, ketosis, appetite regulation and obesity.
• diabetes in particular diabetes and more particularly, type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (TFG), metabolic acidosis, ketosis, appetite regulation and obesity.
• ITT impaired glucose tolerance
• TSG impaired fasting plasma glucose
• ketosis ketosis
• DPP-TV inhibitors based on boroProline, (Flentke, G. R., et al., Proc. Nat. Acad. Sci.
• CD45 is known to be an integral component of the T-cell signaling apparatus. It has been reported that DPP-IV is essential for the penetration and infectivity of HTV-1 and HTV-2 viruses in CD4+ T-cells (Wakselman, M., Nguyen, C, Mazaleyrat, J.-P., Callebaut, C, Krust, B., Hovanessian, A. G., Inhibition of HTV-1 infection of CD 26+ but not CD 26-cells by a potent cyclopeptidic inhibitor of the DPP-TV activity of CD 26. Abstract P.44 of the 24.sup.th European Peptide Symposium 1996).
• DPP-TV has been shown to associate with the enzyme adenosine deaminase (ADA) on the surface of T-cells (Kameoka, J., et al., Science, 193, 26466).
• ADA deficiency causes severe combined immunodeficiency disease (SCID) in humans.
• SCID severe combined immunodeficiency disease
• inhibitors of DPP-TV may be useful immunosuppressants (or cytokine release suppressant drugs) for the treatment of among other things: organ transplant rejection; autoimmune diseases such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis; and the treatment of AIDS.
• lung endothelial cell DPP-TV is an adhesion molecule for lung-metastatic rat breast and prostate carcinoma cells (Johnson, R. C, et al., J. Cell. Biol, 1993, 121, 1423). DPP-TV is known to bind to fibronectin and some metastatic tumor cells are known to carry large amounts of fibronectin on their surface. Potent DPP-IV inhibitors may be useful as drugs to prevent metastases of, for example, breast and prostrate tumors to the lungs.
• DPP-IV inhibitors may be useful as agents to treat dermatological diseases such as psoriasis and lichen planus.
• High DPP-TV activity has been found in tissue homogenates from patients with benign prostate hypertrophy and in prostatosomes. These are prostate derived organelles important for the enhancement of sperm forward motility (Vanhoof, G., et al., Eur. J. Clin. Chem.
• DPP-TV inhibitors may also act to suppress sperm motility and therefore act as a male contraceptive agent.
• DPP-TV inhibitors have been implicated as novel for treatment of infertility, and particularly human female infertility due to Polycystic ovary syndrome (PCOS, Stein-Leventhal syndrome) which is a condition characterized by thickening of the ovarian capsule and formation of multiple follicular cysts. It results in infertility and amenorrhea.
• PCOS Polycystic ovary syndrome
• DPP-IV is thought to play a role in the cleavage of various cytokines (stimulating hematopoietic cells), growth factors and neuropeptides.
• Stimulated hematopoietic cells are useful for the treatment of disorders that are characterized by a reduced number of hematopoietic cells or their precursors in vivo. Such conditions occur frequently in patients who are immunosuppressed, for example, as a consequence of chemotherapy and/or radiation therapy for cancer. It was discovered that inhibitors of dipeptidyl peptidase type TV are useful for stimulating the growth and differentiation of hematopoietic cells in the absence of exogenously added cytokines or other growth factors or stromal cells.
• DPP-TV can also cleave neuropeptides and has been shown to modulate the activity of neuroactive peptides substance P, neuropeptide Y and CLIP (Mentlein, R., Dahms, P., Grandt, D., Kruger, R., Proteolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase TV, Regul. Pept., 49, 133, 1993; Wetzel, W., Wagner, T., Vogel, D., Demuth, H.-U., Balschun, D., Effects of the CLIP fragment ACTH 20-24 on the duration of REM sleep episodes, Neuropeptides, 31, 41, 1997).
• DPP-TV inhibitors may also be useful agents for the regulation or normalization of neurological disorders.
• the present invention relates to compounds that have activity for inhibiting DPP-IV. It is noted that these compounds may also have activity for inhibiting other S9 proteases and thus may be used against these other S9 proteases as well as DPP-TV.
• the present invention also provides compositions, articles of manufacture and kits comprising these compounds.
• a pharmaceutical composition that comprises a DPP-TV inhibitor according to the present invention as an active ingredient.
• Pharmaceutical compositions according to the invention may optionally comprise 0.001%- 100% of one or more DPP-TV inhibitors of this invention.
• These pharmaceutical compositions may be administered or coadministered by a wide variety of routes, including for example, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally.
• the compositions may also be administered or coadministered in slow release dosage forms.
• the invention is also directed to kits and other articles of manufacture for treating disease states associated with DPP-TV.
• a kit comprising a composition comprising at least one DPP-TV inhibitor of the present invention in combination with instructions.
• the instructions may indicate the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
• the kit may also comprise packaging materials.
• the packaging material may comprise a container for housing the composition.
• the kit may also optionally comprise additional components, such as syringes for administration of the composition.
• the kit may comprise the composition in single or multiple dose forms.
• an article of manufacture is provided that comprises a composition comprising at least one DPP-IN inhibitor of the present invention in combination with packaging materials.
• the packaging material may comprise a container for housing the composition.
• the container may optionally comprise a label indicating the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
• the kit may also optionally comprise additional components, such as syringes for administration of the composition.
• the kit may comprise the composition in single or multiple dose forms.
• the compounds, compositions, kits and articles of manufacture are used to inhibit DPP-TV.
• the compounds, compositions, kits and articles of manufacture are used to treat a disease state for which DPP-TV possesses activity that contributes to the pathology and/or symptomology of the disease state.
• a compound is administered to a subject wherein DPP- IN activity within the subject is altered, preferably reduced.
• a prodrug of a compound is administered to a subject that is converted to the compound in vivo where it inhibits DPP-IV.
• a method of inhibiting DPP-TV comprises contacting DPP-TV with a compound according to the present invention.
• a method of inhibiting DPP-TV is provided that comprises causing a compound according to the present invention to be present in a subject in order to inhibit DPP-TV in vivo.
• a method of inhibiting DPP-TV comprises administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits DPP-F in vivo.
• the compounds of the present invention may be the first or second compounds.
• a therapeutic method comprises administering a compound according to the present invention.
• a method of inhibiting cell proliferation comprises contacting a cell with an effective amount of a compound according to the present invention.
• a method of inhibiting cell proliferation in a patient comprises administering to the patient a therapeutically effective amount of a compound according to the present invention.
• a method of treating a condition in a patient which is known to be mediated by DPP-TV, or which is known to be treated by DPP-TV inhibitors comprising administering to the patient a therapeutically effective amount of a compound according to the present invention.
• a method for using a compound according to the present invention in order to manufacture a medicament for use in the treatment of disease state which is known to be mediated by DPP-TV, or which is known to be treated by DPP-TV inhibitors.
• a method for treating a disease state for which DPP-TV possesses activity that contributes to the pathology and/or symptomology of the disease state comprising: causing a compound according to the present invention to be present in a subject in a therapeutically effective amount for the disease state.
• a method for treating a disease state for which DPP-TV possesses activity that contributes to the pathology and/or symptomology of the disease state comprising: administering a first compound to a subject that is converted in vivo to a second compound such that the second compound is present in the subject in a therapeutically effective amount for the disease state.
• the compounds of the present invention may be the first or second compounds.
• a method for treating a disease state for which DPP-TV possesses activity that contributes to the pathology and/or symptomology of the disease state comprising: administering a compound according to the present invention to a subject such that the compound is present in the subject in a therapeutically effective amount for the disease state.
• a method for treating a cell proliferative disease state comprising treating cells with a compound according to the present invention in combination with an anti-proliferative agent, wherein the cells are treated with the compound according to the present invention before, at the same time, and/or after the cells are treated with the anti-proliferative agent, referred to herein as combination therapy.
• combination therapy is intended to cover when agents are administered before or after each other (sequential therapy) as well as when the agents are administered at the same time.
• diabetes more particular type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis, appetite regulation, obesity, immunosuppressants or
• the present invention is intended to encompass all pharmaceutically acceptable ionized forms (e.g., salts) and solvates (e.g., hydrates) of the compounds, regardless of whether such ionized forms and solvates are specified since it is well known in the art to administer pharmaceutical agents in an ionized or solvated form. It is also noted that unless a particular stereochemistry is specified, recitation of a compound is intended to encompass all possible stereoisomers (e.g., enantiomers or diastereomers depending on the number of chiral centers), independent of whether the compound is present as an individual isomer or a mixture of isomers.
• pharmaceutically acceptable ionized forms e.g., salts
• solvates e.g., hydrates
• prodrugs may also be administered which are altered in vivo and become a compound according to the present invention.
• the various methods of using the compounds of the present invention are intended, regardless of whether prodrug delivery is specified, to encompass the administration of a prodrug that is converted in vivo to a compound according to the present invention.
• certain compounds of the present invention may be altered in vivo prior to inhibiting DPP-TV and thus may themselves be prodrugs for another compound.
• Such prodrugs of another compound may or may not themselves independently have DPP-TV inhibitory activity.
• Figure 1 illustrates a ribbon diagram overview of the structure of DPP-TV, highlighting the secondary structural elements of the protein.
• Alicyclic means a moiety comprising a non-aromatic ring structure. Alicyclic moieties may be saturated or partially unsaturated with one, two or more double or triple bonds. Alicyclic moieties may also optionally comprise heteroatoms such as nitrogen, oxygen and sulfur. The nitrogen atoms can be optionally quaternerized or oxidized and the sulfur atoms can be optionally oxidized.
• alicyclic moieties include, but are not limited to moieties with C3 - C8 rings such as cyclopropyl, cyclohexane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene, cycloheptadiene, cyclooctane, cyclooctene, and cyclooctadiene.
• C3 - C8 rings such as cyclopropyl, cyclohexane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene, cycloheptadiene, cyclooctane, cyclooctene
• Aliphatic means a moiety characterized by a straight or branched chain arrangement of constituent carbon atoms and may be saturated or partially unsaturated with one, two or more double or triple bonds.
• Alkenyl represented by itself means a straight or branched, unsaturated, aliphatic radical having a chain of carbon atoms having at least one double bond between adjacent carbon atoms.
• C alkenyl and C ⁇ - ⁇ alkenyl are typically used where X and Y indicate the number of carbon atoms in the chain.
• C 2 - 6 alkenyl includes alkenyls that have a chain of between 2 and 6 carbons.
• Alkoxy means an oxygen moiety having a further alkyl substituent.
• the alkoxy groups of the present invention can be optionally substituted.
• Alkyl represented by itself means a straight or branched, saturated or unsaturated, aliphatic radical having a chain of carbon atoms, optionally with oxygen (See “oxaalkyl”) or nitrogen atoms (See “aminoalkyl”) between the carbon atoms.
• oxaalkyl oxygen
• nitrogen atoms See “aminoalkyl”
• - 6 alkyl includes alkyls that have a chain of between 1 and 6 carbons (e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, and the like).
• 1 and 6 carbons e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-
• Alkyl represented along with another radical means a straight or branched, saturated or unsaturated aliphatic divalent radical having the number of atoms indicated or when no atoms are indicated means a bond (e.g., (C 6 - 1 o)aryl(C 1 . 3 )alkyl includes, benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-thienylmethyl, 2-pyridinylmethyl and the like).
• "Alkylene unless indicated otherwise, means a straight or branched, saturated or unsaturated, aliphatic, divalent radical.
• Cx alkylene and C ⁇ - ⁇ alkylene are typically used where X and Y indicate the number of carbon atoms in the chain.
• Alkylidene means a straight or branched saturated or unsaturated, aliphatic radical connected to the parent molecule by a double bond.
• Cx alkylidene and C ⁇ - ⁇ alkylidene are typically used where X and Y indicate the number of carbon atoms in the chain.
• Alkynyl represented by itself means a straight or branched, unsaturated, aliphatic radical having a chain of carbon atoms having at least one triple bond between adjacent carbon atoms.
• Cx alkynyl and C ⁇ . ⁇ alkynyl are typically used where X and Y indicate the number of carbon atoms in the chain.
• C 2 . 6 alkynyl includes alkynyls that have a chain of between 2 and 6 carbons.
• amino means a nitrogen moiety having two further substituents where a hydrogen or carbon atom is attached to the nitrogen.
• representative amino groups include -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHd- 3 -alkyl, and the like.
• the compounds of the invention containing amino moieties may include protected derivatives thereof.
• Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.
• Aminoalkyl means an alkyl, as defined above, except where one or more substituted or unsubstituted nitrogen atoms (-N-) are positioned between carbon atoms of the alkyl.
• an (C 2 . 6 ) aminoalkyl refers to a chain comprising between 2 and 6 carbons and one or more nitrogen atoms positioned between the carbon atoms.
• Animal includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals (e.g., birds, and the like).
• non-human mammals e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like
• non-mammals e.g., birds, and the like.
• Aromatic means a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp hybridized and the total number of pi electrons is equal to 4n+2.
• An aromatic ring may be such that the ring atoms are only carbon atoms or may include carbon and non-carbon atoms (see Heteroaryl).
• Aryl means a monocyclic or polycyclic ring assembly wherein each ring is aromatic or when fused with one or more rings forms an aromatic ring assembly. If one or more ring atoms is not carbon (e.g., N, S), the aryl is a heteroaryl. C aryl and C ⁇ . ⁇ aryl are typically used where X and Y indicate the number of atoms in the ring.
• Bicycloalkyl means a saturated or partially unsaturated fused bicyclic or bridged polycyclic ring assembly.
• Bicycloaryl means a bicyclic ring assembly wherein the rings are linked by a single bond or fused and at least one of the rings comprising the assembly is aromatic.
• Cx bicycloaryl and C x - ⁇ bicycloaryl are typically used where X and Y indicate the number of carbon atoms in the bicyclic ring assembly and directly attached to the ring.
• “Bridging ring” as used herein refers to a ring that is bonded to another ring to form a compound having a bicyclic structure where two ring atoms that are common to both rings are not directly bound to each other.
• Non-exclusive examples of common compounds having a bridging ring include borneol, norbornane, 7- oxabicyclo[2.2.1]heptane, and the like.
• One or both rings of the bicyclic system may also comprise heteroatoms.
• Carbamoyl means the radical -OC(O)NR a R D where R a and R b are each independently two further substituents where a hydrogen or carbon atom is attached to the nitrogen.
• Carbocycle means a ring consisting of carbon atoms.
• Carbocyclic ketone derivative means a carbocyclic derivative wherein the ring contains a -CO- moiety.
• Carbonyl means the radical -CO-. It is noted that the carbonyl radical may be further substituted with a variety of substituents to form different carbonyl groups including acids, acid halides, aldehydes, amides, esters, and ketones.
• Carboxy means the radical -CO -. It is noted that compounds of the invention containing carboxy moieties may include protected derivatives thereof, i.e., where the oxygen is substituted with a protecting group. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like.
• Cyano means the radical -CN.
• Cycloalkyl means a non-aromatic, saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly.
• Cx cycloalkyl and C ⁇ . ⁇ cycloalkyl are typically used where X and Y indicate the number of carbon atoms in the ring assembly. For example, C 3 .
• cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl,
• Cycloalkylene means a divalent saturated or partially unsaturated, monocyclic or polycyclic ring assembly.
• C x cycloalkylene and C ⁇ - ⁇ cycloalkylene are typically used where X and Y indicate the number of carbon atoms in the ring assembly.
• Disease specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the "side effects" of such therapy.
• fused ring refers to a ring that is bonded to another ring to form a compound having a bicyclic structure where the ring atoms that are common to both rings are directly bound to each other.
• Non-exclusive examples of common fused rings include decalin, naphthalene, anthracene, phenanthrene, indole, furan, benzofuran, quinoline, and the like.
• Compounds having fused ring systems may be saturated, partially saturated, carbocyclics, heterocyclics, aromatics, heteroaromatics, and the like.
• Halo means fluoro, chloro, bromo or iodo.
• Halo-substituted alkyl as an isolated group or part of a larger group, means
• alkyl substituted by one or more "halo" atoms, as such terms are defined in this
• Halo-substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like (e.g. halo-substituted (C 1 - 3 )alkyl includes chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl,
• Heteroatom refers to an atom that is not a carbon atom. Particular examples of heteroatoms include, but are not limited to nitrogen, oxygen, and sulfur.
• Heteroatom moiety includes a moiety where the atom by which the moiety is attached is not a carbon.
• Heterobicycloalkyl means bicycloalkyl, as defined in this Application, provided that one or more of the atoms within the ring is a heteroatom.
• hetero(C 9 - ⁇ 2 )bicycloalkyl as used in this application includes, but is not limited to, 3-aza- bicyclo[4.1.0]hept-3-yl, 2-aza-bicyclo[3.1.0]hex-2-yl , 3-aza-bicyclo[3.1.0]hex-3-yl, and the like.
• Heterocycloalkylene means cycloalkylene, as defined in this Application, provided that one or more of the ring member carbon atoms is replaced by a heteroatom.
• Heteroaryl means a cyclic aromatic group having five or six ring atoms, wherein at least one ring atom is a heteroatom and the remaining ring atoms are carbon. The nitrogen atoms can be optionally quaternerized and the sulfur atoms can be optionally oxidized.
• Heteroaryl groups of this invention include, but are not limited to, those derived from furan, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, 1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrroline, thiazole, 1,3,4-thiadiazole, triazole and tetrazole.
• Heteroaryl also includes, but is not limited to, bicyclic or tricyclic rings, wherein the heteroaryl ring is fused to one or two rings independently selected from the group consisting of an aryl ring, a cycloalkyl ring, a cycloalkenyl ring, and another monocyclic heteroaryl or heterocycloalkyl ring.
• bicyclic or tricyclic heteroaryls include, but are not limited to, those derived from benzo[b]furan, benzo[b]thiophene, benzimidazole, imidazo[4,5-c]pyridine, quinazoline, thieno[2,3-c]pyridine, thieno[3,2- bjpyridine, thieno[2,3-b]pyridine, indolizine, imidazo[l,2a]pyridine, quinoline, isoquinoline, phthalazine, quinoxaline, naphthyridine, quinolizine, indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole, benzothiazole, imidazo[l,5-a]pyridine, pyrazolo[ 1 ,5-a]pyridine, imidazo [ 1 ,2-a]pyrimidine, imidazo [ 1 ,2-c]pyrimidine, imidazo[
• the bicyclic or tricyclic heteroaryl rings can be attached to the parent molecule through either the heteroaryl group itself or the aryl, cycloalkyl, cycloalkenyl or heterocycloalkyl group to which it is fused.
• the heteroaryl groups of this invention can be substituted or unsubstituted.
• Heterobicycloaryl means bicycloaryl, as defined in this Application, provided that one or more of the atoms within the ring is a heteroatom.
• hetero(C 4 - ⁇ o)bicycloaryl as used in this Application includes, but is not limited to, 2-amino- 4-oxo-3 ,4-dihydropteridin-6-yl, tetrahydroisoquinolinyl, and the like.
• Heterocycloalkyl means cycloalkyl, as defined in this Application, provided that one or more of the atoms forming the ring is a heteroatom selected, independently from N, O, or S.
• heterocycloalkyl examples include piperidyl, 4- morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolizinyl, 1,4-diazaperhydroepinyl, 1,3- dioxanyl, 1,4-dioxanyl and the like.
• Haldroxy means the radical -OH.
• j-minoketone derivative means a derivative comprising the moiety -C(NR)-, wherein R comprises a hydrogen or carbon atom attached to the nitrogen.
• Isomers mean any compound having an identical molecular formulae but differing in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed
• stereoisomers Stereoisomers that are not mirror images of one another are termed
• enantiomers or sometimes “optical isomers.”
• a carbon atom bonded to four nonidentical substituents is termed a “chiral center.”
• a compound with one chiral center has two enantiomeric forms of opposite chirality.
• a mixture of the two enantiomeric forms is termed a “racemic mixture.”
• a compound that has more than one chiral center has 2 n ⁇ enantiomeric pairs, where n is the number of chiral centers.
• chiral center may exist as ether an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture.”
• a stereoisomer may be characterized by the absolute configuration of that chiral center.
• Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center.
• Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog.
• Niro means the radical -NO 2 .
• Oxaalkyl means an alkyl, as defined above, except where one or more oxygen atoms (-O-) are positioned between carbon atoms of the alkyl.
• an (C 2 - 6 )oxaalkyl refers to a chain comprising between 2 and 6 carbons and one or more oxygen atoms positioned between the carbon atoms.
• Oxoalkyl means an alkyl, further substituted with a carbonyl group.
• the carbonyl group may be an aldehyde, ketone, ester, amide, acid or acid chloride.
• “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
• “Pharmaceutically acceptable salts” means salts of inhibitors of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity.
• Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartatic acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,
• Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases.
• Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide.
• Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
• Prodrug means a compound that is convertible in vivo metabolically into an inhibitor according to the present invention.
• the prodrug itself may or may not also have DPP-TV inhibitory activity.
• an inhibitor comprising a hydroxy group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxy compound.
• esters that may be converted in vivo into hydroxy compounds include acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, quinates, esters of amino acids, and the like.
• an inhibitor comprising an amine group may be administered as an amide that is converted by hydrolysis in vivo to the amine compound.
• Protected derivatives means derivatives of inhibitors in which a reactive site or sites are blocked with protecting groups. Protected derivatives are useful in the preparation of inhibitors or in themselves may be active as inhibitors. A comprehensive list of suitable protecting groups can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.
• Substituted or unsubstituted means that a given moiety may consist of only hydrogen substituents through available valencies (unsubstituted) or may further comprise one or more non-hydrogen substituents through available valencies (substituted) that are not otherwise specified by the name of the given moiety.
• isopropyl is an example of an ethylene moiety that is substituted by -CH 3 .
• a non-hydrogen substituent may be any substituent that may be bound to an atom of the given moiety that is specified to be substituted.
• substituents include, but are not limited to, aldehyde, alicyclic, aliphatic, alkyl, alkylene, alkylidene, amide, amino, aminoalkyl, aromatic, aryl, bicycloalkyl, bicycloaryl, carbamoyl, carbocyclyl, carboxyl, carbonyl group, cycloalkyl, cycloalkylene, ester, halo, heterobicycloalkyl, heterocycloalkylene, heteroaryl, heterobicycloaryl, heterocycloalkyl, oxo, hydroxy, iminoketone, ketone, nitro, oxaalkyl, and oxoalkyl moieties, each of which may optionally also be substituted or unsubstituted.
• Sulfinyl means the radical -SO-. It is noted that the sulfinyl radical may be further substituted with a variety of substituents to form different sulfinyl groups including sulfinic acids, sulfinamides, sulfinyl esters, and sulfoxides.
• Sulfonyl means the radical -SO 2 -. It is noted that the sulfonyl radical may be further substituted with a variety of substituents to form different sulfonyl groups including sulfonic acids, sulfonamides, sulfonate esters, and sulfones.
• “Therapeutically effective amount” means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.
• Thiocarbonyl means the radical -CS-. It is noted that the thiocarbonyl radical may be further substituted with a variety of substituents to form different thiocarbonyl groups including thioacids, thioamides, thioesters, and thioketones.
• Treatment means any administration of a compound of the present invention and includes: ( 1 ) preventing the disease from occurring in an animal which may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or (3) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the disease (i.e., reversing the pathology and/or symptomatology) .
• a alkyl indicates that there is one carbon atom but does not indicate what are the substituents on the carbon atom.
• a Q alkyl comprises methyl (i.e., -CH 3 ) as well as -R a R D R c where R a , R D , and R c may each independently be hydrogen or any other substituent where the atom attached to the carbon is a heteroatom or cyano.
• CF 3 , CH 2 OH and CH 2 CN for example, are all C 1 alkyls.
• the present invention relates to compounds, compositions, kits and articles of manufacture that may be used to inhibit dipeptidyl peptidases TV (referred to herein as DPP-TV).
• DPP-TV (EC.3.4.14.5 also known as DPP4, DP4, DAP-TV, adenosine deaminase complexing protein 2, adenosine deaminase binding protein (ADAbp) or CD26) is a 766 residue, 240kDa protein that is a highly specific membrane bound non-classical serine aminodipeptidase.
• DPP-TV has a serine type mechanism of protease activity, cleaving off dipeptides from the amino-terminus of peptides with proline or alanine at the penultimate position.
• the slow release of dipeptides of the type X-Gly or X-Ser is reported for some naturally occurring peptides.
• DPP-TV is constitutively expressed on epithelial and endothelial cells of a variety of different tissues (intestine, liver, lung, kidney and placenta), and is also found in body fluids. DPP-TV is also expressed on circulating T- lymphocytes and has been shown to be synonymous with the cell-surface antigen, CD-26.
• the wild-type form of full length DPP-TV is described in GenBank Accession Number NM_001935 ("Dipeptidyl peptidase TV (CD 26) gene expression in enterocyte-like colon cancer cell lines HT-29 and Caco-2.
• DPP-IV is a member of the S9 family of serine proteases, more particularly the S9B family.
• Other members of the S9 family include, but are not limited to:
• Subfamily S9A Dipeptidyl-peptidase; Oligopeptidase B (EC 3.4.21.83); Oligopeptidase B; Prolyl oligopeptidase (EC 3.4.21.26);
• Subfamily S9B Dipeptidyl aminopeptidase A; Dipeptidyl aminopeptidase B Dipeptidyl-peptidase TV (EC 3.4.14.5); Dipeptidyl-peptidase V Fibroblast activation protein alpha subunit; Seprase
• Subfamily S9C Acylaminoacyl-peptidase (EC 3.4.19.1) [0101] It is noted that the compounds of the present invention may also possess inhibitory activity for other S9 family members and thus may be used to address disease states associated with these other family members.
• FIG. 1 illustrates a ribbon diagram overview of the structure of DPP-TV, highlighting secondary structural elements of the protein.
• DPP-TV is a cylindrical shaped molecule with an approximate height of 70 A and a diameter of 60 A.
• the catalytic triad of DPP-TV (Ser642, Asp720 and His752) is illustrated in the center of the figure by a "ball and stick" representation. This triad of amino acids is located in the peptidase domain or catalytic domain of DPP-TV.
• the catalytic domain is covalently linked to the ⁇ -propeller domain.
• the catalytic domain of DPP-TV includes residues 1-67 and 511-778.
• the catalytic domain of DPP-TV adopts a characteristic ⁇ / ⁇ hydrolase fold.
• the core of this domain contains an 8-stranded ⁇ -sheet with all strands being parallel except one.
• the ⁇ - sheet is significantly twisted and is flanked by three ⁇ -helices on one side and five ⁇ - helices on the other.
• the topology of the ⁇ -strands is 1, 2, -lx, 2x and (lx) (J. S. Richardson: The anatomy and taxonomy of protein structure; (1981) Adv. Protein Chem. 269, 15076-15084.).
• a number of residues were identified that contribute to the shape and charge characteristics of the active site. Knowledge of these residues has been an important contribution to the design of DPP-IV inhibitors of the present invention.
• DPP-IN inhibitors of the present invention include compounds comprising:
• R 2 is hydrogen or selected from the group consisting of (C 1 - 1 o)alkyl, (C 3 - 12 )cycloalkyl, (C 3 - 12 )cycloalkyl(C ⁇ - 5 )alkyl, hetero(C - 12 )cycloalkyl(C 1 - 5 )alkyl, hetero(C 3 - 12 )cycloalkyl, aryl(C 1 - 1 o)alkyl, heteroaryl(C 1 - 5 )alkyl, (C 9 - 12 )bicycloaryl, hetero(C - 12 )bicycloaryl, hetero(C 4 - 12 )bicycloaryl(C 1 -5)alkyl, carbonyl (C 1 .
• R is selected from the group consisting of perhalo(C 1 - 1 rj)alkyl, amino, (C 1 - 1 o)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl (C 1 .
• l ⁇ t is hydrogen or is selected from the group consisting of halo, perhalo(C 1 - 1 o)alkyl, amino, cyano, thio, (C 1 - 10 )alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl (C 1 - 3 )alkyl, thiocarbonyl (C 1 - 3 )alkyl, sulfonyl (C ⁇ - )alkyl, sulfinyl (C 1 - 3 )alkyl, imino (C 1 - 3 )alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, and a substituted or unsubstituted 3, 4, 5, 6 or 7 membered
• DPP-IV inhibitors of the present invention include compounds comprising:
• M is N or CR- R 2 is hydrogen or selected from the group consisting of (C 1 - 10 )alkyl, (C 3 - 12 )cycloalkyl, (C 3 - ⁇ 2 )cycloa ⁇ kyl(C ⁇ - 5 )alkyl, hetero(C 3 .
• halo perhalo(C 1 - 1 o)alkyl, amino, cyano, thio, (C 1 - 1 o)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl (C 1 . 3 )alkyl, thiocarbonyl (C 1 .
• L is a linker providing 1, 2 or 3 atom separation between X and the ring to which L is attached, wherein the atoms of the linker providing the separation are selected from the group consisting of carbon, oxygen, nitrogen, and sulfur; and X is selected from the group consisting of (C 1 - 10 )alkyl, (C 3 - 12 )cycloalkyl, hetero(C 3 - 12 )cycloalkyl, axyl(C ⁇ - 10 )alkyl, heteroaryl(C 1 - 5 )alkyl, (
• DPP-TV inhibitors of the present invention comprise compounds wherein the 1, 2 or 3 atoms of L providing the separation consist of carbon atoms.
• the 1, 2 or 3 atoms of L providing the separation are selected from the group of linkers consisting of at least one oxygen or at least one nitrogen atom.
• L separates X from the ring atom by one atom.
• L is selected from the group consisting of -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -C(O)-, -CH 2 C(O)-, -C(O)CH 2 -, -CH 2 -C(O)CH 2 -, -C(O)CH 2 CH 2 -, -CH 2 CH 2 C(O)-, -O-, -OCH 2 -, -CH 2 O-, -CH 2 OCH 2 -, -OCH 2 CH 2 -, -CH 2 CH 2 O-, -N(CH 3 )-, -NHCH 2 -, -CH 2 NH-, -CH 2 NHCH 2 -, -NHCH 2 CH 2 -, -CH 2 CH 2 NH-, -NH-C(O)-, -NCH 3 -C(O)-, -C(O)NH
• L is selected from the group consisting of -CH 2 -, -C(O)-, -CH 2 C(O)-, -C(O)CH 2 -, -CH 2 -C(O)CH 2 -, -C(O)CH 2 CH 2 -, and -CH 2 CH 2 C(O)-, each substituted or unsubstituted.
• -L-X taken together is selected from the group consisting of -(CH 2 )-(2-cyano)phenyl; -(CH 2 )-(3-cyano)phenyl; - (CH 2 )-(2-hydroxy)phenyl; -(CH 2 )-(3-hydroxy)phenyl; -(CH 2 )-(2-alkenyl)phenyl; -(CH 2 )- (3-alkenyl)phenyl; -(CH 2 )-(2-alkynyl)phenyl; -(CH 2 )-(3-alkynyl)phenyl; -(CH 2 )-(2- methoxy)phenyl; -(CH 2 )-(3-methoxy)phenyl; -(CH 2 )-(2-nitro)phenyl; -(CH 2 )-(3-methoxy)phenyl; -(CH 2 )-(2-nitro)phenyl; -(CH
• DPP-TV inhibitors of the present invention include compounds comprising:
• R 3 is selected from the group consisting of perhalo(C 1 - 1 o)alkyl, amino, (C 1 - ⁇ o)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl (C 1 .
• R 4 is hydrogen or is selected from the group consisting of halo, perhalo(C 1 - 1 o)alkyl, amino, cyano, thio, (C ⁇ - 10 )alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl (C 1 - 3 )alkyl, thiocarbonyl (C ⁇ . 3 )alkyl, sulfonyl (C ⁇ - 3 )alkyl, sulfinyl (C 1 - 3 )alkyl, imino (C 1 - 3 )alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, and a substituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;
• X is a substituted or unsubstituted (C 3 - 7 )cycloalkyl.
• the invention provides compounds wherein X is a substituted or unsubstituted (C 3 - 7 )heterocycloalkyl, or wherein X is a substituted or unsubstituted aryl.
• the invention provides compounds wherein X is a substituted or unsubstituted phenyl, or wherein X is a substituted or unsubstituted heteroaryl.
• X is a ring having a non-hydrogen substituent at a 2 or 3 position of the ring.
• X is a ring having a non-hydrogen substituent at a 2 or 3 position of the ring selected from the group consisting of (C ⁇ - ⁇ o)alkyl, (C 3 .
• X is a substituted or unsubstituted halophenyl or dihalophenyl.
• X is a substituted or unsubstituted haloaryl, haloheteroaryl, dihaloaryl or dihaloheteroaryl.
• X is selected from the group consisting of (2- cyano)phenyl; (3-cyano)phenyl; (2-hydroxy)phenyl; (3-hydroxy)phenyl; (2-alkenyl)phenyl; (3-alkenyl)phenyl; (2-alkynyl)phenyl; (3-alkynyl)phenyl; (2-methoxy)phenyl; (3- methoxy)phenyl; (2-nitro)phenyl; (3-nitro)phenyl; (2-carboxy)phenyl; (3-carboxy)phenyl; - (CH 2 )-(2-carboxamido)phenyl; (3-carboxamido)phenyl; (2-sulfonamido)phenyl; (3- sulfonamido)phenyl; (2-tetrazoTyl) ⁇ henyl; (3-tetrazolyl)phenyl; (2-aminomethyl)phen
• A is S, O or NR 24 ;
• B is CR 23 or N;
• R 23 is independently selected from the group consisting of hydrogen, halo, perhalo(C 1 - ⁇ o)alkyl, amino, thio, cyano, CF 3 , nitro, (C ⁇ o)alkyl, (C 3 - ⁇ 2 )cycloalkyl, hetero(C 3 - 12 )cycloalkyl, aryl(C 1 - 1 o)alkyl, heteroaryl (Ci- 5 )alkyl, (C 9 - 12 )bicycloaryl, hetero(C 8 -i 2 )bicycloaryl, carbonyl (C 1 - 3 )alkyl, thiocarbonyl (C 1 - 3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, imino group, carbonyl group, aminosulfonyl, alkylsulf
• X is selected from the group consisting of wherein t is O, 1, 2, 3, 4 or 5; and each R is independently selected from the group consisting of halo, perhalo(C 1 - 10 )alkyl, CF 3 , (C 1 - 10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
• X is selected from the group consisting of
• each R is independently selected from the group consisting of halo, perhalo(C 1 - ⁇ o)alkyl, CF 3 , (C ⁇ - 10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
• R is independently selected from the group consisting of -cyano, -methoxy, -nitro, -carboxy, -sulfonamido, -tetrazolyl, -aminomethyl, -hydroxymethyl, -phenyl, -halo, -CONH 2 , -CONH(C 7 )alkyl, -CO (C 1 - )alkyl, -NH 2 , -OH, -(C ⁇ - 5 )alkyl, -alkenyl, -alkynyl, (C ⁇ - 5 )cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, each substituted or unsubstituted.
• DPP-IV inhibitors of the present invention include compounds comprising:
• R 3 is selected from the group consisting of perhalo(C 1 - ⁇ o)alkyl, amino, (C 1 - ⁇ 0 )alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl (C 1 - 3 )alkyl, thiocarbonyl (C 1 - 3 )alkyl, sulfonyl (C 1 - 3 )alkyl, s
• DPP-TV inhibitors of the present invention include compounds comprising: a member selected from the group consisting of
• R 3 is selected from the group consisting of perhalo(C 1 - 1 o)alkyl, amino, (C ⁇ - 10 )alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl (C 1 - 3 )alkyl, thiocarbonyl (C ⁇ - 3 )alkyl, sulfonyl (C 1 - 3 )alkyl, thiocarbonyl (C ⁇ - 3 )alkyl, sulfonyl (C 1 - 3 )alkyl, thiocarbonyl (C ⁇ - 3 )alkyl, sulfonyl (C 1
• DPP-TV inhibitors of the present invention include compounds comprising:
• Ri is hydrogen or is selected from the group consisting of halo, perhalo(C 1 - 1 o)alkyl, amino, cyano, thio, (C ⁇ - ⁇ 0 )alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl (C 1 - 3 )alkyl, thiocarbonyl (C 1 - 3 )alkyl, sulfonyl (C 1 - 3 )alkyl, sulfinyl (C 1 - 3 )alkyl, imino (C 1 - 3 )alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted; R 2 is hydrogen or selected from the group consisting of (C 1 - 1 o)
• R 3 is selected from the group consisting of perhalo(C ⁇ - ⁇ o)alkyl, amino, (C ⁇ - ⁇ o)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl (C 1 - 3 )alkyl, thiocarbonyl (C ⁇ - 3 )alkyl, sulfonyl (C 1 - 3 )alkyl, sulfinyl (C ⁇ - 3 )alkyl, imino (C ⁇ - 3 )alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted;
• R 3 is selected from the group consisting of perhalo(C ⁇ - ⁇ o)alkyl, amino, (C ⁇ -
• the 1, 2 or 3 atoms of L providing the separation consist of carbon atoms.
• the 1, 2 or 3 atoms of L providing the separation are selected from the group of linkers consisting of at least one oxygen or at least one nitrogen atom.
• L separates X from the ring atom by one atom.
• L is selected from the group consisting of -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -C(O)-, -CH 2 C(O)-, -C(O)CH 2 -, -CH 2 -C(O)CH 2 -, -C(O)CH 2 CH 2 -, -CH 2 CH 2 C(O)-, -O-, -OCH 2 -, -CH 2 O-, -CH 2 OCH 2 -, -OCH 2 CH 2 -, -CH 2 CH 2 O-, -N(CH 3 )-, -NHCH 2 -, -CH 2 NH-, -CH 2 NHCH 2 -, -NHCH 2 CH 2 -, -CH 2 CH 2 NH-, -NH-C(O)-, -NCH 3 -C(O)-, -C(O)NH
• L is selected from the group consisting of -CH 2 -, -C(O)-, -CH 2 C(O)-, -C(O)CH 2 -, -CH 2 -C(O)CH 2 -, -C(O)CH 2 CH 2 -, and -CH 2 CH 2 C(O)-, each substituted or unsubstituted.
• -L-X taken together is selected from the group consisting of ⁇ (CH 2 )-(2-cyano)phenyl; -(CH 2 )-(3-cyano)phenyl; -(CH 2 )-(2- hydroxy)phenyl; -(CH 2 )-(3-hydroxy)phenyl; -(CH 2 )-(2-alkenyl)phenyl; -(CH 2 )-(3- alkenyl)phenyl; -(CH 2 )-(2-alkynyl)phenyl; -(CH 2 )-(3-alkynyl)phenyl; -(CH 2 )-(2- methoxy)phenyl; -(CH 2 )-(3-methoxy)phenyl; -(CH 2 )-(2-nitro)phenyl; -(CH 2 )-(2-nitro)phenyl; -(CH 2 )-(2-nitro)phenyl; -(CH 2
• DPP-TV inhibitors of the present invention include compounds comprising:
• n 1, 2, or 3;
• Ri is hydrogen or is selected from the group consisting of halo, perhalo(C 1 - 10 )alkyl, amino, cyano, thio, (C ⁇ - ⁇ o)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl (C 1 - 3 )alkyl, thiocarbonyl (Ci- 3 )alkyl, sulfonyl (C ⁇ - 3 )alkyl, sulfinyl (C 1 - 3 )alkyl, imino (C ⁇ - 3 )alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sul
• each R 5 and R 6 is independently hydrogen or is selected from the group consisting of a substituted or unsubstituted (C ⁇ - ⁇ o)alkyl, a substituted or unsubstituted (C ⁇ - ⁇ o)alkoxy, cyano, and halo, or where R 5 and R 6 are taken together to form a ring;
• R 9 is hydrogen or is selected from the group consisting of a substituted or unsubstituted (C ⁇ - ⁇ o)alkyl, a substituted or unsubstituted (C ⁇ - ⁇ o)alkoxy, cyano, and halo, or where R 5 and R 6 are taken together to form a ring;
• R 9 is hydrogen or is selected from the group consisting of a substituted or unsubstituted (C ⁇ - ⁇ o)alkyl, a substituted or unsubstituted (C ⁇ - ⁇ o)alkoxy, cyano, and halo, or where R 5 and R 6 are taken together to form
• the invention provides compounds wherein X is a substituted or unsubstituted (C 3 - 7 )cycloalkyl.
• X is a substituted or unsubstituted (C 3 - )heterocycloalkyl, wherein X is a substituted or unsubstituted aryl, or wherein X is a substituted or unsubstituted phenyl.
• X is a substituted or unsubstituted heteroaryl.
• X is a ring having a non- hydrogen substituent at a 2 or 3 position of the ring. In one variation of the above compounds, X is a ring having a non-hydrogen substituent at a 2 or 3 position of the ring selected from the group consisting of ( - ⁇ 0 )alkyl, (C 3 .
• X is a substituted or unsubstituted halophenyl or dihalophenyl.
• X is a substituted or unsubstituted haloaryl, haloheteroaryl, dihaloaryl or dihaloheteroaryl.
• the present invention provides compounds wherein X is selected from the group consisting of (2-cyano)phenyl; (3-cyano)phenyl; (2- hydroxy)phenyl; (3-hydroxy)phenyl; (2-alkenyl)phenyl; (3-alkenyl)phenyl; (2- alkynyl)phenyl; (3-alkynyl)phenyl; (2-methoxy)phenyl; (3-methoxy)phenyl; (2-nitro)phenyl; (3-nitro)phenyl; (2-carboxy)phenyl; (3-carboxy)phenyl; -(CH 2 )-(2- carboxamido)phenyl; (3-carboxamido)phenyl; (2-sulfonamido)phenyl; (3- sulfonamido)phenyl; (2-tetrazolyl)phenyl; (3-tetrazolyl)phenyl; (2-amin
• A is S, O or NR 2 ;
• B is CR 23 or N;
• R 23 is independently selected from the group consisting of hydrogen, halo, perhalo(Ci- ⁇ o)alkyl, amino, thio, cyano, CF 3 , nitro, (Ci- 10 )alkyl, (C .
• R 2 is independently selected from the group consisting of hydrogen, perhalo(C 1 - 1 o)alkyl, amino, (C 1 - 10 )alkyl, (C 3 - ⁇ 2 )cycloalkyl, hetero(C 3 - 12 )cycloalkyl, aryl(C ⁇ - ⁇ o)alkyl, heteroaryl (C ⁇ - 5 )alkyl, (C 9 - ⁇ )bicycloaryl, hetero(C 8 - 12 )bicycloaryl, carbonyl (Ci- 3 )alkyl, thiocarbonyl (C
• each R is independently selected from the group consisting of halo, perhalo(C ⁇ - 1 o)alkyl, CF 3 , (C 1 - 10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
• X is selected from the group consisting of
• each R is independently selected from the group consisting of halo, perhalo(C ⁇ -io)alkyl, CF 3 , (C 1 - 1 o)alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
• R is independently selected from the group consisting of -cyano, -methoxy, -nitro, -carboxy, -sulfonamido, -tetrazolyl, -aminomethyl, -hydroxymethyl, -phenyl, -halo, -CONH 2 , -CONH(Ci- 7 )alkyl, -CO 2 (C 1 - )alkyl, -NH 2 , -OH, -(C ⁇ - 5 )alkyl, -alkenyl, -alkynyl, (C ⁇ - 5 )cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, each substituted or unsubstituted.
• DPP-IN inhibitors of the present invention include compounds comprising:
• Ri is hydrogen or is selected from the group consisting of halo, perhalo(Ci-io)alkyl, amino, cyano, thio, (Ci- ⁇ o)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl (C ⁇ - 3 )alkyl, thiocarbonyl (C ⁇ _ 3 )alkyl, sulfonyl (C ⁇ - 3 )alkyl, sulfinyl (Ci- 3 )alkyl, imino (C ⁇ - 3 )alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulf
• each R 5 and R 6 is independently hydrogen or is selected from the group consisting of a substituted or unsubstituted (C ⁇ - 10 )alkyl, a substituted or unsubstituted (C ⁇ - ⁇ o)alkoxy, cyano, and halo, or where R5 and R 6 are taken together to form a ring; each R is independently selected from the group consisting of
• R 9 is hydrogen or is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted.
• DPP-IN inhibitors of the present invention include compounds comprising: a member selected from the group consisting of
• n 1, 2, or 3;
• Ri is hydrogen or is selected from the group consisting of halo, perhalo(Ci- ⁇ o)alkyl, amino, cyano, thio, (Ci-io)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl (C ⁇ - 3 )alkyl, thiocarbonyl (C ⁇ - 3 )alkyl, sulfonyl (Ci- 3 )alkyl, sulfinyl (C 1 - 3 )alkyl, imino (C ⁇ - 3 )alkyl,
• R 3 is selected from the group consisting of perhalo(Ci-io)alkyl, amino, (Ci-io)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl,
• R 3 is selected from the group consisting of amino, (C ⁇ - ⁇ o)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl, each substituted or unsubstituted, and a substituted or unsubstituted 3, 4, 5, 6 or 7 membered ring.
• R 3 comprises the formula wherein Rio and R ⁇ are each independently selected from the group consisting of hydrogen, perhalo(Ci-io)alkyl, amino, (Ci-io)alkyl, (C 3 .
• R 3 is a substituted or unsubstituted 3, 4, 5, 6, or 7 membered ring, wherein R 3 is a substituted or unsubstituted 3, 4, 5, 6, or 7 membered cycloalkyl, or wherein R 3 is a substituted or unsubstituted 4, 5, 6, or 7 membered heterocycloalkyl.
• R 3 is a substituted or unsubstituted aryl, or wherein R 3 is a substituted or unsubstituted heteroaryl.
• R 3 is selected from the group consisting of
• each R 8 is independently selected from the group consisting of halo, perhalo(C 1 - 10 )alkyl, CF , cyano, nitro, hydroxy, alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
• R 3 is selected from the group consisting of wherein r is 0-13 and each R 8 is independently selected from the group consisting of halo, perhalo(C ⁇ - ⁇ o)alkyl, CF 3 , cyano, nitro, hydroxy, alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
• DPP-IN inhibitors of the present invention may comprise compounds wherein R 3 is a substituted or unsubstituted heteroaryl selected from the group consisting of furan, thiophene, pyrrole, pyrazole, triazole, isoxazole, oxazole, thiazole, isothiazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, imidazole, benzimidazole, indole, isoindole, quinoline, isoquinoline, cinnoline, quinazoline, naphthyridine, pyridopyridine, quinoxaline, phthalazine, and benzothiazole, each substituted or unsubstituted.
• R 3 is a substituted or unsubstituted hetero
• R 3 may be selected from the group consisting of (C 3 - 12 )cycloalkyl, hetero(C 3 - 12 )cycloalkyl, aryl(C ⁇ - ⁇ o)alkyl, heteroaryl (Ci- 5 )alkyl, (C 9 - ⁇ 2 )bicycloaryl, and hetero(C 4 - ⁇ 2 )bicycloaryl, each substituted or unsubstituted.
• R 3 is a substituted or unsubstituted (C 3 - )cycloalkyl ring, optionally comprising O, ⁇ (O), N, S, SO, SO 2 or a carbonyl group in the ring.
• R 3 may also be substituted such that R 3 comprises a substituent selected from the group consisting of a primary, secondary or tertiary amine, a heterocycloalkyl comprising a nitrogen ring atom, and a heteroaryl comprising a nitrogen ring atom.
• R 3 comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein.
• the basic nitrogen of R 3 is separated from the ring atom to which R 3 is attached by between 1-5 atoms.
• the basic nitrogen atom forms part of a primary, secondary or tertiary amine.
• the basic nitrogen atom is a nitrogen ring atom of a heterocycloalkyl or a heteroaryl.
• R 3 includes a basic nitrogen that is capable of interacting with a carboxylic acid side chain of a residue in the DP-4 active site and thus contributes to the binding affinity of the compound to DP-4. Based on co-crystal structures obtained by Applicants, the observed interaction between the basic nitrogen substituent and the carboxylic acid appears to be via hydrogen bonding or by the formation of a salt bridge.
• the basic nitrogen of R in this variation that provides the desired carboxylic acid side chain interaction is not typically directly attached to the ring atom to which R 3 is attached.
• the basic nitrogen may be viewed as a substituent of the overall R 3 moiety.
• R 3 is 3-amino-piperidinyl-l-yl
• the basic nitrogen is the 3-amino group and not the nitrogen of the piperidine ring.
• R 3 may be viewed as a substituted piperidine ring further comprising an amine as a basic nitrogen substituent.
• the basic nitrogen of R 3 is optionally separated from the ring atom to which R 3 is attached by between 1-5 atoms.
• the basic nitrogen atom moiety of R 3 may optionally be selected from the group consisting of a primary, secondary or tertiary amine, a heterocycloalkyl comprising a nitrogen ring atom, a heteroaryl comprising a nitrogen ring atom, as well as other nitrogen containing moieties where the nitrogen can act as a Lewis base.
• other Lewis bases such as oxygen with basic lone pairs, may be capable of interacting with a carboxylic acid side chain of a residue in the DP-4 active site.
• R 3 is said to be further substituted with one or more R 8 substituents.
• R 8 may comprise the basic nitrogen atom capable of providing the interaction with the carboxylic acid side chain.
• R 8 may optionally comprise a moiety selected from the group consisting of a primary, secondary or tertiary amine, a heterocycloalkyl comprising a nitrogen ring atom, a heteroaryl comprising a nitrogen ring atom, as well as other nitrogen containing moieties where the nitrogen can act as a Lewis base.
• moieties with basic nitrogens include, but are not limited to -NH 2 , -NH(C ⁇ - 5 alkyl), -N(C ⁇ - 5 alkyl) 2 , piperazine, imidazole, and pyridine.
• R 3 groups that comprise a basic nitrogen include, but are not limited to 3-amino-piperidinyl-l-yl, 3-aminomethyl-pyrrolidin-l-yl, 3- aminoazetidin-1-yl, 3-amino-3-methylpiperidin-l-yl, 3-aminocyclopent-l-yl, 3- aminomethylcyclopent- 1 -yl, 3-aminomethylcyclohex- 1-yl, 3-aminohexahydroazepin- 1 -yl, 3-amino-cyclohex-l-yl, piperazin-1-yl, homopiperazin-1-yl, 3-amino-pyrrolidin-l-yl, R-3- aminopiperidin-1-yl, R-3-amino-3-methylpiperidin-l-yl, 3-amino-cyclohex-l-yl, 3-amino- cyclopent- 1 -yl, and 3-amino-pyrrolidin
• At least one R 8 comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein.
• the basic nitrogen atom forms part of a primary, secondary or tertiary amine.
• the basic nitrogen atom is a nitrogen ring atom of a heterocycloalkyl comprising a nitrogen ring atom or a heteroaryl comprising a nitrogen ring atom.
• At least one R 8 is a primary, secondary or tertiary amine.
• at least one R 8 is a substituted or unsubstituted heterocycloalkyl comprising a nitrogen ring atom or a substituted or unsubstituted heteroaryl comprising a nitrogen ring atom.
• at least one R 8 is selected from the group consisting of -NH2, -NH(C 1 . 5 alkyl), -N(Ci-5 alkyl) 2 , piperazine, imidazole, and pyridine.
• R is selected from the group consisting of 3-amino-piperidinyl-l-yl, 3-aminomethyl-pyrrolidin-l-yl, 3- aminoazetidin-1-yl, 3-amino-3-methylpiperidin-l-yl, 3-aminocyclopent-l-yl, 3- aminomethylcyclopent- 1 -yl, 3-aminomethylcyclohex- 1 -yl, 3-aminohexahydroazepin- 1 -yl, 3-amino-cyclohex-l-yl, piperazin-1-yl, homopiperazin-1-yl, 3-amino-pyrrolidin-l-yl, R-3- aminopiperidin-1-yl, R-3-amino-3-methylpiperidin-l-yl, 3-amino-cyclohex-l-yl, 3-aminocyclopent-l-yl, and 3-amino
• the present invention provides compounds wherein M is nitrogen.
• M is CR4 and where 1 ⁇ is selected from the group consisting of
• A is S, O or NR 2 ;
• B is CR 23 or N;
• R 23 is independently selected from the group consisting of hydrogen, halo, perhalo(C ⁇ - ⁇ o)alkyl, amino, thio, cyano, CF 3 , nitro, (C 1 - ⁇ o)alkyl, (C 3 - ⁇ 2 )cycloalkyl, hetero(C 3 - 12 )cycloalkyl, aryl(Ci- ⁇ o)alkyl, heteroaryl (C ⁇ - 5 )alkyl, (C 9 - ⁇ 2 )bicycloaryl, hetero(C 8 _ 12 )bicycloaryl, carbonyl (C ⁇ - 3 )alkyl, thiocarbonyl (C ⁇ - )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, imino group, carbonyl group, aminosulfonyl, alkylsulfonyl
• the present invention provides compounds wherein M is CR 4 and where R ⁇ is selected from the group consisting of
• each R 18 is independently selected from the group consisting of halo, perhalo(C ⁇ - 10 )alkyl, CF 3 , (C 1 - 10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, alkoxy, carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
• each R 7 is independently selected from the group consisting of halo, perhalo(C ⁇ - ⁇ o)alkyl, CF 3 , (C ⁇ - ⁇ o)alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
• R 5 and R 6 are hydrogen.
• R 5 and R 6 are taken together to form a ring.
• at least one of R 5 and R 6 is a halide, such as fluorine.
• R 5 and R 6 are a substituted or unsubstituted -(C 1 - 8 )alkyleneR 13 , wherein R 13 is selected from the group consisting of (C 3 - 12 )cycloalkyl, hetero(C 4 - ⁇ 2 )cycloalkyl, (C 6 - 12 )aryl, hetero(C 5 -i 2 )aryl, (C - 12 )bicycloalkyl, hetero(C 9 - 12 )bicycloalkyl, (C 9 - ⁇ 2 )bicycloaryl and hetero(C 4 - ⁇ 2 )bicycloaryl, each substituted or unsubstituted.
• R 5 and R 6 are hydrogen, m is 1 or 2, and each R 7 is independently selected from the group consisting of halo, perhalo(C ⁇ - ⁇ o)alkyl, CF 3 , cyano, nitro, hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
• R 7 is independently selected from the group consisting of halo, perhalo(C ⁇ - ⁇ o)alkyl, CF 3 , cyano, nitro, hydroxy,
• n is 1 or 2; R 3 is selected from the group consisting of amino, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, and a substituted or unsubstituted 4, 5, 6 or 7 membered ring; and R 5 and R 6 are hydrogen.
• R 5 and R 6 are hydrogen and
• R is 2-cyano.
• n is 1.
• n is 1, 2 or 3;
• R 5 and R 6 are hydrogen; and
• R 3 is selected from the group consisting of (C 3 . 12 )cycloalkyl, hetero(C 3 - ⁇ 2 )cycloalkyl, aryl(C 1 - 1 o)alkyl, heteroaryl (C ⁇ - 5 )alkyl, (C - ⁇ 2 )bicycloaryl, and hetero(C 4 - ⁇ 2 )bicycloaryl, each substituted or unsubstituted.
• n 1, 2 or 3; R 5 and
• R ⁇ 5 are hydrogen; and each R is independently selected from the group consisting of halo, perhalo(C 1 - ⁇ o)alkyl, alkenyl, alkynyl, CF 3 , cyano, nitro, hydroxy, heteroaryl, aryloxy, heteroaryloxy, alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
• R are taken together to form a substituted or unsubstituted fused ring.
• two R are taken together to form a substituted or unsubstituted bridged ring.
• T, U, V, W and Y are taken together and substituted through available valencies to form a substituted or unsubstituted ring fused or bridged to the ring formed by T U, V, W and Y.
• R 2 is a substituted or unsubstituted (C ⁇ - 10 )alkyl.
• R 2 is a substituted or unsubstituted
• R 2 is -Y-Z wherein Y a linker providing 1, 2 or 3 atom separation between Z and the ring to which Y is attached, wherein the atoms of the linker providing the separation are selected from the group consisting of carbon, oxygen, nitrogen, and sulfur; and Z is hydrogen or selected from the group consisting of (C 1 - ⁇ 0 )alkyl, (C 3 - 12 )cycloalkyl, hetero(C 3 - ⁇ 2 )cycloalkyl, aryl(C 1 - 10 )alkyl, heteroaryl(C ⁇ - 5 )alkyl, (C 9 - 12 )bicycloaryl, hetero(C 4 - 12 )bicycloaryl, carbonyl (
• A is S, O or NR 4 ;
• B is CR 23 or N;
• R 23 is independently selected from the group consisting of hydrogen, halo, perhalo(C 1 - 1 o)alkyl, amino, thio, cyano, CF 3 , nitro, (C ⁇ - ⁇ o)alkyl, (C 3 - 12 )cycloalkyl, hetero(C 3 - 12 )cycloalkyl, aryl(C 1 - ⁇ 0 )alkyl, heteroaryl (C 1 - 5 )alkyl, (C 9 .
• R 24 is independently selected from the group consisting of hydrogen, perhalo(C ⁇ - ⁇ 0 )alkyl, amino, (C 1 - 10 )alkyl, (C 3 - 12 )cycloalkyl, hetero(C 3 - ⁇ 2 )cycloalkyl, aryl(C 1 - ⁇ o)alkyl, heteroaryl (C ⁇ - 5 )alkyl, (C
• each R 18 is independently selected from the group consisting of halo, perhalo(C ⁇ - 1 o)alkyl, CF 3 , (C 1 - 10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, alkoxy, carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
• DPP-TV inhibitors include, but are not limited to: 2-(6-Chloro-2,4-dioxo-3 ,4-dihydro-2H-pyrimidin- 1 -ylmethyTj-benzonitrile; 2-(6-Chloro-3-methyl-2,4-dioxo-3 ,4-dihydro-2H-pyrimidin- 1 -ylmethyi)- benzonitrile; 2- ⁇ 6- [3- Amino-piperidin- 1 -yl] -3-methyl-2,4-dioxo-3 ,4-dihydro-2H-pyrimidin- 1 - ylmethyl ⁇ -benzonitrile; 2- ⁇ 6-[3-Amino-piperidin- 1 -yl]-3-ethyl-2,4-dioxo-3 ,4-dihydro-2H-pyrimidin- 1 - ylmethyl ⁇ --benzonitrile; 2- ⁇ 6-[
• DPP-IN inhibitors further include: 2- ⁇ 6-[3(R)-Amino-piperidin-l-yl]-3-memyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin- 1 -ylmethyl ⁇ -benzonitrile; 2- ⁇ 6-[3(R)-Amino-piperidin-l-yl]-3-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l- ylmethyl ⁇ -benzonitrile; 2- ⁇ 6- [3 (R)- Amino-piperidin- 1 -yl] -2,4-dioxo-3 ,4-dihydro-2H-pyrimidin- 1 - ylmethyl ⁇ -benzonitrile; 2- ⁇ 6-[3(R)-Amino-piperidin-l-yl]-5-chloro-3-methyl-2,
• the present invention provides the compounds in the form of a pharmaceutically acceptable salt.
• the present invention provides the compounds present in a mixture of stereoisomers. In yet another embodiment, the present invention provides the compounds as a single stereoisomer.
• the present invention provides pharmaceutical compositions comprising the compound as an active ingredient.
• the present invention provides pharmaceutical compositions wherein the composition is a solid formulation adapted for oral administration.
• the present invention provides pharmaceutical composition wherein the composition is a tablet.
• the present invention provides the pharmaceutical composition wherein the composition is a liquid formulation adapted for oral administration.
• the present invention provides pharmaceutical composition wherein the composition is a liquid formulation adapted for parenteral administration.
• the present invention provides the pharmaceutical composition comprising the compound of the invention wherein the composition is adapted for administration by a route selected from the group consisting of orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, and intrathecally.
• the present invention provides a kit comprising a compound of the present invention and instructions which comprise one or more forms of information selected from the group consisting of indicating a disease state for which the compound is to be administered, storage information for the compound, dosing information and instructions regarding how to administer the compound.
• the present invention provides the kit that comprises the compound in a multiple dose form.
• the present invention provides an article of manufacture comprising a compound of the present invention, and packaging materials.
• the packaging material comprises a container for housing the compound.
• the invention provides the article of manufacture wherein the container comprises a label indicating one or more members of the group consisting of a disease state for which the compound is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
• the present invention provides the article of manufacture wherein the article of manufacture comprises the compound in a multiple dose form.
• the present invention provides a method of inhibiting
• DPP-IV comprising contacting DPP-TV with a compound according to the present invention.
• the present invention provides a method of inhibiting
• DPP-TV comprising causing a compound according to the present invention to be present in a subject in order to inhibit DPP-TV in vivo.
• the present invention provides a method of inhibiting
• DPP-TV comprising: administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits DPP-TV in vivo, the second compound being a compound of the present invention.
• the present invention provides therapeutic method comprising: administering a compound according to the present invention to a subject.
• the present invention provides a method of treating a disease state for which DPP-TV possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising causing a compound of the present invention to be present in a subject in a therapeutically effective amount for the disease state.
• the present invention provides a method of treating cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound according to the present invention.
• the present invention provides a method of treating a disease where the disease is type I or type II diabetes.
• the present invention provides a method of treating autoimmune disorders such as, but not limited to, rheumatoid arthritis, psoriasis, and multiple sclerosis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound according to the present invention.
• the present invention provides a method of treating cancer where the cancer treated is colorectal, prostate, breast, thyroid, skin, lung, or head and neck.
• the present invention provides a method of treating a condition characterized by inadequate lymphocyte or hemapoietic cell activation or concentration in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound according to the present invention.
• the present invention provides a method of treating HTV infection in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound according to the present invention.
• the present invention provides a method of treating a condition characterized by inadequate lymphocyte or hemapoietic cell activation or concentration in a patient in need thereof, wherein the condition is a side effect of chemotherapy or radiation therapy.
• the present invention provides a method of treating a condition characterized by inadequate lymphocyte or hemapoietic cell activation or concentration in a patient in need thereof, wherein the condition is a result of kidney failure.
• the present invention provides a method of treating a condition characterized by inadequate lymphocyte or hemapoietic cell activation or concentration in a patient in need thereof, wherein the condition is a result of a bone marrow disorder.
• the present invention provides a method of treating a condition characterized by immunodeficiency symptoms in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound according to the present invention.
• the present invention provides a process for producing a pyrimidin-dione of the formula:
• R 2 is hydrogen or selected from the group consisting of (C ⁇ - ⁇ o)alkyl, (C 3 -i 2 )cycloalkyl, (C 3 - ⁇ 2 )cycloalkyl(C 1 - 5 )alkyl, hetero(C 3 - 12 )cycloalkyl(C ⁇ - 5 )alkyl, hetero(C 3 - 1 )cycloalkyl, aryl(C 1 - 10 )alkyl, heteroaryl(Ci- 5 )alkyl, (C - ⁇ )bicycloaryl, hetero(C 4 - 12 )bicycloaryl, hetero(C 4 - 12 )bicycloaryl(C 1 - 5 )alkyl, carbonyl (C ⁇ - 3 )alkyl, thiocarbonyl (C 1 - 3 )alkyl, sulfonyl (C 1 - 3 )alkyl, sulfin
• L is a linker providing 1, 2 or 3 atom separation between X and the ring to which L is attached, wherein the atoms of the linker providing the separation are selected from the group consisting of carbon, oxygen, nitrogen, and sulfur; and X is selected from the group consisting of (C ⁇ - 10 )alkyl, (C 3 - ⁇ 2 )cycloalkyl, hetero(C 3 - ⁇ 2 )cycloalkyl, aryl(C 1 - 10 )alkyl, heteroaryl(C 1 - 5 )alkyl, (C 9
• Hal is halogen; with a compound of the formula B X— b— LG B wherein LG is a leaving group; L is a linker providing 1, 2 or 3 atom separation between X and the ring to which L is attached, wherein the atoms of the linker providing the separation are selected from the group consisting of carbon, oxygen, nitrogen, and sulfur; and X is selected from the group consisting of (C ⁇ - ⁇ o)alkyl, (C 3 - 12 )cycloalkyl, hetero(C 3 - 12 )cycloalkyl, aryl(C 1 - 10 )alkyl, heteroaryl(C ⁇ - 5 )alkyl, (C 9 . 12 )bicycloaryl, hetero(C 4 .
• R 2 is selected from the group consisting of (C ⁇ - 10 )alkyl, (C 3 - 12 )cycloalkyl, (C 3 - ⁇ 2 )cycloalkyl(C 1 - 5 )alkyl, hetero(C 3 - 12 )cycloalkyl(C 1 - 5 )alkyl, hetero(C 3 - ⁇ 2 )cycloalkyl, aryl(C 1 - 10 )alkyl, heteroaryl(C ⁇ - 5 )alkyl, (C 9 -i 2 )bicycloaryl, hetero(C 4 -i 2 )bicycloaryl, hetero(C 4 -i 2 )bicycloaryl(C !
• the pyrimidin-dione product is further converted to an acid addition salt.
• the acid addition salt is selected from the group consisting of acetate, citrate, hydrochloride, L-lactate, succinate, sulfate, p- toluenesulfonate, benzenesulfonate, benzoate, methanesulfonate, naphthylene-2-sulfonate, propionate, p-toluenesulfonate, hydrobromate, hydroiodate, R-mandelate, and L-tartrate.
• Hal is selected from the group consisting of Br, CI and F in the compound of formula A.
• the leaving group LG is selected from the group consisting of Br, CI and I.
• step (ii) further comprises the addition of a base.
• the base is potassium carbonate.
• product E is further purified before subjecting it to step (iii).
• the purification of product E is performed by solvent washes and/or by chromatography.
• R3-H is a secondary amine or an amine hydrochloride.
• R 3 -H is selected from the group consisting of
• each R 8 is independently selected from the group consisting of halo, perhalo(C 1 - 10 )alkyl, CF 3 , cyano, nitro, hydroxy, alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, or the mono- or di-hydrochloride salt.
• step iii) further comprises purifying the product by washing the product with one or more organic solvents or mixtures of solvents and/or by column chromatography.
• L is selected from the group consisting of -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -C(O)-, -CH 2 C(O)-, -C(O)CH 2 -, -CH 2 -C(O)CH 2 -, -C(O)CH 2 CH 2 -, -CH 2 CH 2 C(O)-, -O-, -OCH 2 -, -CH 2 O-, -CH 2 OCH 2 -, -OCH 2 CH 2 -, -CH 2 CH 2 O-, -N(CH 3 )-, -NHCH 2 -, -CH 2 NH-,
• L is selected from the group consisting of -CH 2 -, -C(O)-, -CH 2 C(O)-, -C(O)CH 2 -, -CH 2 -C(O)CH 2 -, -C(O)CH 2 CH 2 -, and -CH 2 CH 2 C(O)-, each substituted or unsubstituted.
• -L-X taken together is selected from the group consisting of -(CH 2 )-(2-cyano)phenyl; -(CH 2 )-(3- cyano)phenyl; -(CH 2 )-(2-hydroxy)phenyl; -(CH 2 )-(3-hydroxy)phenyl; -(CH 2 )-(2- alkenyl)phenyl; -(CH 2 )-(3-alkenyl)phenyl; -(CH 2 )-(2-alkynyl)phenyl; -(CH 2 )-(3- alkynyl)phenyl; -(CH 2 )-(2-methoxy)phenyl; -(CH 2 )-(3-methoxy)phenyl; -(CH 2 )- (2-nitro)phenyl; -(CH 2 )-(3-nitro)phenyl; -(CH 2 )- (2-nitro)phenyl; -(CH
• M is CH
• R 3 comprises the formula N / R 10
• Rio and Rn are each independently selected from the group consisting of hydrogen, perhalo(C ⁇ - ⁇ o)alkyl, amino, (C ⁇ - ⁇ o)alkyl, (C 3 - ⁇ 2 )cycloalkyl, hetero(C 3 - ⁇ 2 )cycloalkyl, aryl(C ⁇ - ⁇ o)alkyl, heteroaryl (C ⁇ - 5 )alkyl, (C 9 - ⁇ 2 )bicycloaryl, hetero(C - ⁇ 2 )bicycloaryl, carbonyl (C ⁇ - 3 )alkyl, thiocarbonyl (C ⁇ - 3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, and sulfinyl group, each substituted or unsubstituted, or Rio and Rn are taken together to form a 4, 5, 6, or 7 membered ring, each substituted or unsubstit
• M is CH and R 3 is selected from the group consisting of 3-amino-piperidinyl-l-yl, 3-aminomethyl-pyrrolidin-l-yl, 2-aminoazetidin-l-yl, 3- amino-3-methylpiperidin-l-yl, 3-aminocyclopent-l-yl, 3-aminomethylcyclopent-l-yl, 3- aminomethylcyclohex- 1 -yl, 3-aminohexahydroazepin- 1 -yl, 3-amino-cyclohex- 1 -yl, piperazin-1-yl, homopiperazin-1-yl, 3-amino-pyrrolidin-l-yl, R-3-aminopiperidin-l-yl, R- 3-amino-3-methylpiperidin-l-yl, 3-amino-cyclohex-l-yl, 3-amino-cyclopent-l-yl,
• M is CH and R is a substituted or unsubstituted (C ⁇ _ 10 )alkyl.
• the present invention provides a process for producing a pyrimidin-dione of the formula comprising: (i) admixing 6-chloro-lH-pyrimidine-2,4-dione with an aryl halide of the formula where Hal is Br, CI, or I, under conditions sufficient to produce a compound of the formula
• the process for producing a pyrimidin-dione further comprises the formation of an acid addition salt.
• the acid addition salt is a benzoate salt.
• the pyrimidin-dione is selected from the group consisting of: 2-(6-Chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl)-benzonitrile; 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pvrimidin-l-ylmethyl)- benzonitrile; 2- ⁇ 6- [3- Amino-piperidin- 1 -yl] -3 -methyl-2,4-dioxo-3 ,4-dihydro-2H-pyrimidin- 1 - ylmethyl ⁇ -benzonitrile; 2- ⁇ 6-[3-A
• the compounds of the present invention may be present and optionally administered in the form of salts, hydrates and prodrugs that are converted in vivo into the compounds of the present invention.
• the compounds of the present invention possess a free base form
• the compounds can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, e.g., hydrohalides such as hydrochloride, hydrobromide, hydroiodide; other mineral acids and their corresponding salts such as sulfate, nitrate, phosphate, etc.; and alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate; and other organic acids and their corresponding salts such as acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate and ascorbate.
• a pharmaceutically acceptable inorganic or organic acid e.g., hydrohalides such as hydrochloride, hydrobromide, hydroiodide
• other mineral acids and their corresponding salts such as sulfate, n
• Further acid addition salts of the present invention include, but are not limited to: adipate, alginate, arginate, aspartate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptaoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate, lactobionate, malate, malonate, man
• a pharmaceutically acceptable base addition salt can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
• bases include alkali metal hydroxides including potassium, sodium and lithium hydroxides; alkaline earth metal hydroxides such as barium and calcium hydroxides; alkali metal alkoxides, e.g. potassium ethanolate and sodium propanolate; and various organic bases such as ammonium hydroxide, piperidine, diethanolamine and N- methylglutamine.
• aluminum salts of the compounds of the present invention are alkali metal hydroxides including potassium, sodium and lithium hydroxides; alkaline earth metal hydroxides such as barium and calcium hydroxides; alkali metal alkoxides, e.g. potassium ethanolate and sodium propanolate; and various organic bases such as ammonium hydroxide, piperidine, diethanolamine and N- methylglutamine.
• aluminum salts of the compounds of the present invention are also included.
• Organic base salts of the present invention include, but are not limited to: copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium and zinc salts.
• Organic base salts include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, e.g., arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, iso-propylamine, lidocaine, lysine, meglumine, N
• N-oxides of compounds according to the present invention can be prepared by methods known to those of ordinary skill in the art.
• N-oxides can be prepared by treating an unoxidized form of the compound with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, met ⁇ -chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0 °C.
• an oxidizing agent e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, met ⁇ -chloroperoxybenzoic acid, or the like
• a suitable inert organic solvent e.g., a halogenated hydrocarbon such as dichloromethane
• the N-oxides of the compounds can be prepared from the N-oxide of an appropriate starting material.
• Prodrug derivatives of compounds according to the present invention can be prepared by modifying substituents of compounds of the present invention that are then converted in vivo to a different substituent. It is noted that in many instances, the prodrugs themselves also fall within the scope of the range of compounds according to the present invention.
• prodrugs can be prepared by reacting a compound with a carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate, p ⁇ r -nitrophenyl carbonate, or the like) or an acylating agent. Further examples of methods of making prodrugs are described in Saulnier et ⁇ /.(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985.
• Hydrates of compounds of the present invention may be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
• a "pharmaceutically acceptable salt”, as used herein, is intended to encompass any compound according to the present invention that is utilized in the form of a salt thereof, especially where the salt confers on the compound improved pharmacokinetic properties as compared to the free form of compound or a different salt form of the compound.
• the pharmaceutically acceptable salt form may also initially confer desirable pharmacokinetic properties on the compound that it did not previously possess, and may even positively affect the pharmacodynamics of the compound with respect to its therapeutic activity in the body.
• An example of a pharmacokinetic property that may be favorably affected is the manner in which the compound is transported across cell membranes, which in turn may directly and positively affect the absorption, distribution, biotransformation and excretion of the compound.
• the solubility of the compound is usually dependent upon the character of the particular salt form thereof, which it utilized.
• an aqueous solution of the compound will provide the most rapid absorption of the compound into the body of a subject being treated, while lipid solutions and suspensions, as well as solid dosage forms, will result in less rapid adsorption of the compound.
• DPP-TV is believed to contribute to the pathology and/or symptomology of several different diseases such that reduction of the activity of DPP-TV in a subject through inhibition may be used to therapeutically address these disease states. Examples of various diseases that may be treated using the DPP-TV inhibitors of the present invention are described herein. It is noted that additional diseases beyond those disclosed herein may be later identified as the biological roles that DPP-TV plays in various pathways becomes more fully understood.
• DPP-TV inhibitors of the present invention may be used to treat are those involving the prevention and treatment of diabetes and obesity, in particular type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis, appetite regulation and obesity.
• ITT impaired glucose tolerance
• IGF impaired fasting plasma glucose
• metabolic acidosis ketosis
• appetite regulation and obesity are those involving the prevention and treatment of diabetes and obesity, in particular type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis, appetite regulation and obesity.
• DPP-TV inhibitors of the present invention may also be used as immunosuppressants (or cytokine release suppressant drugs) for the treatment of among other things: organ transplant rejection; autoimmune diseases such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis; and the treatment of AIDS.
• immunosuppressants or cytokine release suppressant drugs
• DPP-TV inhibitors of the present invention may also be used for treating various cancers including breast cancer, lung cancer and prostate cancer.
• DPP-TV inhibitors of the present invention may also be used to treat dermatological diseases such as psoriasis, rheumatoid arthritis (RA) and lichen planus.
• dermatological diseases such as psoriasis, rheumatoid arthritis (RA) and lichen planus.
• DPP-TV inhibitors of the present invention may also be used to treat infertility and amenorrhea.
• DPP-TV inhibitors of the present invention may also be used to modulate cleavage of various cytokines (stimulating hematopoietic cells), growth factors and neuropeptides. For example, such conditions occur frequently in patients who are immunosuppressed, for example, as a consequence of chemotherapy and/or radiation therapy for cancer.
• DPP-TV inhibitors of the present invention may also be used prevent or reduce cleavage of N-terminal Tyr- Ala from growth hormone-releasing factor. Accordingly, these inhibitors may be used in the treatment of short stature due to growth hormone deficiency
• DPP-TV inhibitors of the present invention may also be used to address disease states associated with cleavage of neuropeptides and thus may be useful for the regulation or normalization of neurological disorders.
• DPP-TV inhibitors of the present invention may be used in conjunction with other agents to inhibit undesirable and uncontrolled cell proliferation.
• anti-cell proliferation agents examples include, but are not limited to, retinoid acid and derivatives thereof, 2-methoxyestradiol, ANGIOSTATINTM protein, ENDOSTATINTM protein, suramin, squalamine, tissue inhibitor of metalloproteinase-I, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor- 1, plasminogen activator inhibitor-2, cartilage-derived inhibitor, paclitaxel, platelet factor 4, protamine sulfate (clupeine), sulfated chitin derivatives (prepared from queen crab shells), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, modulators of matrix metabolism, including for example, proline analogs ((l-azetidine-2- carboxylic acid (LACA)), cishydroxyproline, d,l-3,4-dehydroproline,
• anti-angiogenesis agents include antibodies, preferably monoclonal antibodies against these angiogenic growth factors: bFGF, aFGF, FGF-5, VEGF isoforms, VEGF-C, HGF/SF and Ang-l/Ang-2.
• bFGF vascular endothelial growth factor
• aFGF vascular endothelial growth factor
• FGF-5 vascular endothelial growth factor
• VEGF isoforms VEGF-C
• HGF/SF Ang-l/Ang-2.
• Ferrara N. and Alitalo, K. "Clinical application of angiogenic growth factors and their inhibitors" (1999) Nature Medicine 5:1359-1364.
• compositions and administration methods may be used in conjunction with the DPP-TV inhibitors of the present invention.
• Such compositions may include, in addition to the DPP-TV inhibitors of the present invention, conventional pharmaceutical excipients, and other conventional, pharmaceutically inactive agents.
• the compositions may include active agents in addition to the DPP-TV inhibitors of the present invention.
• These additional active agents may include additional compounds according to the invention, and/or one or more other pharmaceutically active agents.
• compositions may be in gaseous, liquid, semi-liquid or solid form, formulated in a manner suitable for the route of administration to be used.
• routes of administration for oral administration, capsules and tablets are typically used.
• parenteral administration reconstitution of a lyophilized powder, prepared as described herein, is typically used.
• compositions comprising DPP-TV inhibitors of the present invention may be administered or coadministered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally.
• the compounds and/or compositions according to the invention may also be administered or coadministered in slow release dosage forms.
• the DPP-TV inhibitors and compositions comprising them may be administered or coadministered in any conventional dosage form.
• Co-administration in the context of this invention is intended to mean the administration of more than one therapeutic agent, one of which includes a DPP-IN inhibitor, in the course of a coordinated treatment to achieve an improved clinical outcome.
• Such co-administration may also be coextensive, that is, occurring during overlapping periods of time.
• Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may optionally include one or more of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; agents for the adjustment of tonicity such as sodium chloride or dextrose, and agents for adjusting the acidity or alkalinity of the composition, such as alkaline or acidifying agents or buffers like carbonates, bicarbonates, phosphates, hydrochloric acid, and organic acids like acetic and citric acid.
• a sterile diluent such as water for injection,
• Parenteral preparations may optionally be enclosed in ampules, disposable syringes or single or multiple dose vials made of glass, plastic or other suitable material.
• methods for solubilizing the compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as TWEE ⁇ , or dissolution in aqueous sodium bicarbonate.
• cosolvents such as dimethylsulfoxide (DMSO)
• surfactants such as TWEE ⁇
• dissolution in aqueous sodium bicarbonate such as sodium bicarbonate
• Derivatives of the compounds, such as prodrugs of the compounds may also be used in formulating effective pharmaceutical compositions.
• a solution, suspension, emulsion or the like may be formed.
• the form of the resulting composition will depend upon a number of factors, including the intended mode of administration, and the solubility of the compound in the selected carrier or vehicle.
• the effective concentration needed to ameliorate the disease being treated may be empirically determined.
• compositions according to the present invention are optionally provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, dry powders for inhalers, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of the compounds, particularly the pharmaceutically acceptable salts, preferably the sodium salts, thereof.
• the pharmaceutically therapeutically active compounds and derivatives thereof are typically formulated and administered in unit-dosage forms or multiple-dosage forms.
• Unit-dose forms refers to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art.
• Each unit- dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent.
• unit-dose forms include ampoules and syringes individually packaged tablet or capsule.
• Unit-dose forms may be administered in fractions or multiples thereof.
• a multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dose form.
• Examples of multiple-dose forms include vials, bottles of tablets or capsules or bottles of pint or gallons.
• multiple dose form is a multiple of unit-doses that are not segregated in packaging.
• the composition may comprise: a diluent such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose; a lubricant, such as magnesium stearate, calcium stearate and talc; and a binder such as starch, natural gums, such as gum acaciagelatin, glucose, molasses, polvinylpyrrolidine, celluloses and derivatives thereof, povidone, crospovidones and other such binders known to those of skill in the art.
• a diluent such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose
• a lubricant such as magnesium stearate, calcium stearate and talc
• a binder such as starch, natural gums, such as gum acaciagelatin, glucose, molasses, polvinylpyrrolidine, celluloses and derivatives thereof, povidone, crospovidones and other such binders
• Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, or otherwise mixing an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to form a solution or suspension.
• a carrier such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to form a solution or suspension.
• the pharmaceutical composition to be administered may also contain minor amounts of auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triemanolamine sodium acetate, triethanolamine oleate, and other such agents.
• auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triemanolamine sodium acetate, triethanolamine oleate, and other such agents.
• auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triemanolamine sodium acetate
• Dosage forms or compositions may optionally comprise one or more DPP-TV inhibitors according to the present invention in the range of 0.005% to 100% (weight/weight) with the balance comprising additional substances such as those described herein.
• a pharmaceutically acceptable composition may optionally comprise any one or more commonly employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose, magnesium carbonate, sodium saccharin, talcum.
• compositions include solutions, suspensions, tablets, capsules, powders, dry powders for inhalers and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparing these formulations are known to those skilled in the art.
• the compositions may optionally contain 0.01%-100% (weight/weight) of one or more DPP-TV inhibitors, optionally 0.1- 95%, and optionally 1-95%.
• Salts, preferably sodium salts, of the DPP-IV inhibitors may be prepared with carriers that protect the compound against rapid elimination from the body, such as time release formulations or coatings.
• the formulations may further include other active compounds to obtain desired combinations of properties.
• Oral pharmaceutical dosage forms may be as a solid, gel or liquid.
• solid dosage forms include, but are not limited to tablets, capsules, granules, and bulk powders. More specific examples of oral tablets include compressed, chewable lozenges and tablets that may be enteric-coated, sugar-coated or film-coated.
• capsules include hard or soft gelatin capsules. Granules and powders may be provided in non- effervescent or effervescent forms. Each may be combined with other ingredients known to those skilled in the art.
• DPP-TV inhibitors according to the present invention are provided as solid dosage forms, preferably capsules or tablets.
• the tablets, pills, capsules, troches and the like may optionally contain one or more of the following ingredients, or compounds of a similar nature: a binder; a diluent; a disintegrating agent; a lubricant; a glidant; a sweetening agent; and a flavoring agent.
• binders that may be used include, but are not limited to, microcrystalline cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste.
• Examples of lubricants that may be used include, but are not limited to, talc, starch, magnesium or calcium stearate, lycopodium and stearic acid.
• Examples of diluents that may be used include, but are not limited to, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.
• Examples of glidants that may be used include, but are not limited to, colloidal silicon dioxide.
• Examples of disintegrating agents that may be used include, but are not limited to, crosscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose.
• coloring agents examples include, but are not limited to, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate.
• sweetening agents examples include, but are not limited to, sucrose, lactose, mannitol and artificial sweetening agents such as sodium cyclamate and saccharin, and any number of spray-dried flavors.
• flavoring agents examples include, but are not limited to, natural flavors extracted from plants such as fruits and synthetic blends of compounds that produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate.
• wetting agents examples include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.
• anti-emetic coatings examples include, but are not limited to, fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates.
• film coatings examples include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.
• the salt of the compound may optionally be provided in a composition that protects it from the acidic environment of the stomach.
• the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine.
• the composition may also be formulated in combination with an antacid or other such ingredient.
• dosage unit form When the dosage unit form is a capsule, it may optionally additionally comprise a liquid carrier such as a fatty oil. In addition, dosage unit forms may optionally additionally comprise various other materials that modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents.
• Compounds according to the present invention may also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like.
• a syrup may optionally comprise, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
• the DPP-TV inhibitors of the present invention may also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics.
• active materials such as antacids, H2 blockers, and diuretics.
• Examples of pharmaceutically acceptable carriers that may be included in tablets comprising DPP-IN inhibitors of the present invention include, but are not limited to binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents.
• Enteric-coated tablets because of the enteric-coating, resist the action of stomach acid and dissolve or disintegrate in the neutral or alkaline intestines.
• Sugar- coated tablets may be compressed tablets to which different layers of pharmaceutically acceptable substances are applied.
• Film-coated tablets may be compressed tablets that have been coated with polymers or other suitable coating. Multiple compressed tablets may be compressed tablets made by more than one compression cycle utilizing the pharmaceutically acceptable substances previously mentioned. Coloring agents may also be used in tablets.
• Flavoring and sweetening agents may be used in tablets, and are especially useful in the formation of chewable tablets and lozenges.
• liquid oral dosage forms that may be used include, but are not limited to, aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
• aqueous solutions examples include, but are not limited to, elixirs and syrups.
• elixirs refer to clear, sweetened, hydroalcoholic preparations.
• pharmaceutically acceptable carriers examples include, but are not limited to solvents.
• solvents Particular examples include glycerin, sorbitol, ethyl alcohol and syrup.
• syrups refer to concentrated aqueous solutions of a sugar, for example, sucrose. Syrups may optionally further comprise a preservative.
• Emulsions refer to two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid. Emulsions may optionally be oil-in- water or water-in-oil emulsions. Examples of pharmaceutically acceptable carriers that may be used in emulsions include, but are not limited to non-aqueous liquids, emulsifying agents and preservatives.
• Examples of pharmaceutically acceptable substances that may be used in non- effervescent granules, to be reconstituted into a liquid oral dosage form, include diluents, sweeteners and wetting agents.
• Examples of pharmaceutically acceptable substances that may be used in effervescent granules, to be reconstituted into a liquid oral dosage form, include organic adds and a source of carbon dioxide.
• Coloring and flavoring agents may optionally be used in all of the above dosage forms.
• preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol.
• non-aqueous liquids that may be used in emulsions include mineral oil and cottonseed oil.
• emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate.
• suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia.
• Diluents include lactose and sucrose.
• Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as sodium cyclamate and saccharin.
• wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.
• organic acids that may be used include citric and tartaric acid.
• Sources of carbon dioxide that may be used in effervescent compositions include sodium bicarbonate and sodium carbonate.
• Coloring agents include any of the approved certified water soluble FD and C dyes, and mixtures thereof.
• flavoring agents include natural flavors extracted from plants such fruits, and synthetic blends of compounds that produce a pleasant taste sensation.
• the solution or suspension in for example propylene carbonate, vegetable oils or triglycerides, is preferably encapsulated in a gelatin capsule.
• the solution e.g., for example, in a polyethylene glycol
• a pharmaceutically acceptable liquid carrier e.g. water
• liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g. propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells.
• vegetable oils glycols, triglycerides, propylene glycol esters (e.g. propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells.
• propylene glycol esters e.g. propylene carbonate
• compositions designed to administer the DPP-IV inhibitors of the present invention by parenteral administration, generally characterized by injection, either subcutaneously, intramuscularly or intravenously.
• injectables may be prepared in any conventional form, for example as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
• excipients examples include, but are not limited to water, saline, dextrose, glycerol or ethanol.
• the injectable compositions may also optionally comprise minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.
• Implantation of a slow-release or sustained-release system such that a constant level of dosage is maintained (see, e.g., U.S. Pat. No. 3,710,795) is also contemplated herein.
• the percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject.
• Parenteral administration of the formulations includes intravenous, subcutaneous and intramuscular administrations.
• Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as the lyophilized powders described herein, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions.
• the solutions may be either aqueous or nonaqueous.
• suitable carriers include, but are not limited to physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
• PBS physiological saline or phosphate buffered saline
• thickening and solubilizing agents such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
• Examples of pharmaceutically acceptable carriers that may optionally be used in parenteral preparations include, but are not limited to aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.
• aqueous vehicles examples include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection.
• nonaqueous parenteral vehicles examples include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil.
• Antimicrobial agents in bacteriostatic or fungistatic concentrations may be added to parenteral preparations, particularly when the preparations are packaged in multiple-dose containers and thus designed to be stored and multiple aliquots to be removed. Examples of antimicrobial agents that may used include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride.
• Examples of isotonic agents that may be used include sodium chloride and dextrose.
• Examples of buffers that may be used include phosphate and citrate.
• antioxidants that may be used include sodium bisulfate.
• Examples of local anesthetics that may be used include procaine hydrochloride.
• Examples of suspending and dispersing agents that may be used include sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone.
• Examples of emulsifying agents that may be used include Polysorbate 80 (TWEEN 80).
• a sequestering or chelating agent of metal ions include EDTA.
• Pharmaceutical carriers may also optionally include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.
• concentration of a DPP-TV inhibitor in the parenteral formulation may be adjusted so that an injection administers a pharmaceutically effective amount sufficient to produce the desired pharmacological effect.
• concentration of a DPP-TV inhibitor and/or dosage to be used will ultimately depend on the age, weight and condition of the patient or animal as is known in the art.
• Unit-dose parenteral preparations may be packaged in an ampoule, a vial or a syringe with a needle. All preparations for parenteral administration should be sterile, as is know and practiced in the art.
• Injectables may be designed for local and systemic administration.
• a therapeutically effective dosage is formulated to contain a concentration of at least about 0.1 % w/w up to about 90% w/w or more, preferably more than 1 % w/w of the DPP-TV inhibitor to the treated tissue(s).
• the DPP-TV inhibitor may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment will be a function of the location of where the composition is parenterally administered, the carrier and other variables that may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data.
• concentrations and dosage values may also vary with the age of the individual treated. It is to be further understood that for any particular subject, specific dosage regimens may need to be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations. Hence, the concentration ranges set forth herein are intended to be exemplary and are not intended to limit the scope or practice of the claimed formulations.
• the DPP-TV inhibitor may optionally be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug.
• the form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle.
• the effective concentration is sufficient for ameliorating the symptoms of the disease state and may be empirically determined.
• the DPP-IV inhibitors of the present invention may also be prepared as lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures.
• the lyophilized powders may also be formulated as solids or gels.
• Sterile, lyophilized powder may be prepared by dissolving the compound in a sodium phosphate buffer solution containing dextrose or other suitable excipient. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation.
• the lyophilized powder may optionally be prepared by dissolving dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose or other suitable agent, about 1-20%, preferably about 5 to 15%, in a suitable buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, typically, about neutral pH.
• a suitable buffer such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, typically, about neutral pH.
• a DPP-IN inhibitor is added to the resulting mixture, preferably above room temperature, more preferably at about 30-35 °C, and stirred until it dissolves.
• the resulting mixture is diluted by adding more buffer to a desired concentration.
• the resulting mixture is sterile filtered or treated to remove particulates and to insure sterility, and apportioned into vials for lyophilization.
• Each vial may contain
• the DPP-TV inhibitors of the present invention may also be administered as topical mixtures. Topical mixtures may be used for local and systemic administration.
• the resulting mixture may be a solution, suspension, emulsions or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for topical administration.
• the DPP-TV inhibitors may be formulated as aerosols for topical application, such as by inhalation (see, U.S. Pat. Nos.
• compositions for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
• the particles of the formulation will typically have diameters of less than 50 microns, preferably less than 10 microns.
• the DPP-TV inhibitors may also be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracistemal or intraspinal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the DPP-TV inhibitor alone or in combination with other pharmaceutically acceptable excipients can also be administered.
• rectal administration may also be used.
• pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect.
• Rectal suppositories are used herein mean solid bodies for insertion into the rectum that melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients.
• Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point.
• bases examples include cocoa butter (theobroma oil), glycerin-gelatin, carbowax, (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the various bases may be used.
• Agents to raise the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. The typical weight of a rectal suppository is about 2 to 3 gm. Tablets and capsules for rectal administration may be manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration.
• the invention is also directed to kits and other articles of manufacture for treating diseases associated with DPP-TV. It is noted that diseases are intended to cover all conditions for which the DPP-TV possesses activity that contributes to the pathology and/or symptomology of the condition.
• a kit comprising a composition comprising at least one DPP-TV inhibitor of the present invention in combination with instructions.
• the instructions may indicate the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
• the kit may also comprise packaging materials.
• the packaging material may comprise a container for housing the composition.
• the kit may also optionally comprise additional components, such as syringes for administration of the composition.
• the kit may comprise the composition in single or multiple dose forms.
• an article of manufacture is provided that comprises a composition comprising at least one DPP-TV inhibitor of the present invention in combination with packaging materials.
• the packaging material may comprise a container for housing the composition.
• the container may optionally comprise a label indicating the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
• the kit may also optionally comprise additional components, such as syringes for administration of the composition.
• the kit may comprise the composition in single or multiple dose forms.
• the packaging material used in kits and articles of manufacture according to the present invention may form a plurality of divided containers such as a divided bottle or a divided foil packet.
• the container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule.
• a pharmaceutically acceptable material for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule.
• the container that is employed will depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle that is in
• kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral, topical, transdermal and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
• dosage forms e.g., oral, topical, transdermal and parenteral
• Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of individual tablets or capsules to be packed or may have the size and shape to accommodate multiple tablets and/or capsules to be packed. Next, the tablets or capsules are placed in the recesses accordingly and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
• kits are a dispenser designed to dispense the daily doses one at a time in the order of their intended use.
• the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen.
• a memory-aid is a mechanical counter that indicates the number of daily doses that has been dispensed.
• a memory-aid is a battery- powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
• a racemic mixture of a compound may be reacted with an optically active resolving agent to form a pair of diastereoisomeric compounds.
• the diastereomers may then be separated in order to recover the optically pure enantiomers.
• Dissociable complexes may also be used to resolve enantiomers (e.g., crystalline diastereoisomeric salts).
• Diastereomers typically have sufficiently distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) that they can be readily separated by taking advantage of these dissimilarities.
• diastereomers can typically be separated by chromatography or by separation/resolution techniques based upon differences in solubility.
• separation/resolution techniques A more detailed description of techniques that can be used to resolve stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).
• Compounds according to the present invention can also be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid.
• a pharmaceutically acceptable base addition salt of a compound can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
• Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds are set forth in the definitions section of this Application.
• the salt forms of the compounds can be prepared using salts of the starting materials or intermediates.
• the free acid or free base forms of the compounds can be prepared from the corresponding base addition salt or acid addition salt form.
• a compound in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like).
• a compound in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc).
• N-oxides of compounds according to the present invention can be prepared by methods known to those of ordinary skill in the art.
• N-oxides can be prepared by treating an unoxidized form of the compound with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, et -chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0 °C.
• an oxidizing agent e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, et -chloroperoxybenzoic acid, or the like
• a suitable inert organic solvent e.g., a halogenated hydrocarbon such as dichloromethane
• the N-oxides of the compounds can be prepared from the N-oxide of an appropriate starting material.
• Compounds in an unoxidized form can be prepared from N-oxides of compounds by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80 °C.
• a reducing agent e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like
• an inert organic solvent e.g., acetonitrile, ethanol, aqueous dioxane, or the like
• Prodrug derivatives of the compounds can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et /.(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).
• appropriate prodrugs can be prepared by reacting a non-derivatized compound with a suitable carbamylating agent (e.g., l,l-acyloxyalkylcarbonochloridate, /?ara-nitrophenyl carbonate, or the like).
• Protected derivatives of the compounds can be made by methods known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons, Inc. 1999.
• Compounds according to the present invention may be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
• Compounds according to the present invention can also be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. While resolution of enantiomers can be carried out using covalent diasteromeric derivatives of compounds, dissociable complexes are preferred (e.g., crystalline diastereoisomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities.
• the diastereomers can be separated by chromatography or, preferably, by separation/resolution techniques based upon differences in solubility.
• the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
• a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).
• g grams
• mg milligrams
• L liters
• mL milliliters
• ⁇ L microliters
• psi pounds per square inch
• M molar
• mM millimolar
• DPP-TV inhibitors according to the present invention may be synthesized according to a variety of reaction schemes. Some illustrative schemes are provided herein in the examples. Other reaction schemes could be readily devised by those skilled in the art.
• alkylation of the amine may be performed under standard conditions known in the art, including the use of a base such as NaH, LiH or the like in an organic solvent or mixture of solvents.
• the solvent may include DMSO, THF, DMF and the like, or mixtures thereof.
• additives may be used, including LiBr, Lil, Nal and the like. The mixture was evaporated and co-evaporated with water in vacuo to remove most of the DMF, and then poured into ice water (IL). The precipitate was collected by filtration.
• alkylation of the amine may be performed under standard conditions known in the art, including the use of a base such as NaH, LiH or the like in an organic solvent or mixture of solvents.
• the solvent may include DMSO, THF, DMF and the like, or mixtures thereof.
• additives may be used, including LiBr, Lil, Nal and the like.
• the alkylation can be performed using methyliodide and K s CO 3 in acetone.
• the reaction may be performed at about 15-45 °C, preferably at about 20-43 °C, and more preferably at about 35-41 °C until the reaction is complete.
• the benzonitrile may be purified in a variety of organic solvents or solvent mixtures.
• the benzonitrile can be purified by adding a mixture of dichloromethane and heptane.
• the benzonitrile may be further purified in an organic solvent or mixture of solvents such as dichloromethane, chloroform, acetonitrile, THF, ethyl acetate, isopropyl acetate and the like.
• the product is purified and washed with ethyl acetate.
• condensation with the amine or amine hydrochloride may be performed in a solvent or mixture of solvents with a base, such as potassium carbonate, sodium bicarbonate and the like, or mixtures thereof.
• the solvent may comprise both protic and aprotic solvents, or mixtures thereof.
• the solvent may comprise a mixture of isopropyl alcohol and water.
• reaction may be heated to about 30-100 °C, preferably about 35-55 °C, and more preferably about 45-50 °C until the reaction is complete.
• Solvents were decanted, and the solid was washed with Et 2 O two times to give 270 mg product as off-white powder.
• the product may be further purified by washing with an organic solvent or mixture of solvents.
• solvent or solvent mixtures include isopropyl acetate, ethyl acetate, dichloromethane, heptane, and the like.
• the product may optionally be purified by column chromatography.
• the benzonitrile product may be isolated as the free base if desired, but preferably, the product may be further converted to the corresponding acid addition salt, such as the benzoic acid salt.
• the benzonitrile product is treated with benzoic acid to form 2-[6-(3-a ⁇ m ⁇ o-piperidin-l-yl)-3-memyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin- 1 -ylmethyl] -benzonitrile benzoate (4).
• Preparation and isolation of the benzoate salt may be performed by conventional methods for the formation of acid addition salts.
• protease inhibitory activities of DPP-TV inhibitors can be readily determined by methods known to those of ordinary skill in the art since suitable in vitro assays for measuring protease activity and the inhibition thereof by test compounds are known. Examples of assays that may be used for measuring protease inhibitory activity and selectivity are set forth below.
• test compounds in varying concentrations ( ⁇ lOmM final concentration) were prepared in Dimethyl Sulfoxide (DMSO) and then diluted into assay buffer comprising: 20mM Tris, pH 7.4; 20mM KCl; and O.lmg/mL BSA.
• DMSO Dimethyl Sulfoxide
• Human DPP-TV (0.1 nM final concentration) was added to the dilutions and pre-incubated for 10 minutes at ambient temperature before the reaction was initiated with A-P-7-amido-4- trifluoromethylcoumarin (AP-AFC; 10 ⁇ M final concentration).
• the total volume of the reaction mixture was 10-100 ⁇ L depending on assay formats used (384 or 96 well plates).
• test compounds in varying concentrations ( ⁇ lOmM final concentration) were prepared in Dimethyl Sulfoxide (DMSO) and then diluted into assay buffer comprising: 20mM Tris, pH 7.4; 20mM KCl; and O.lmg/mL BSA.
• Human FAP ⁇ (2 nM final concentration) was added to the dilutions and pre-incubated for 10 minutes at ambient temperature before the reaction was initiated with A-P-7-amido-4- trifluoromethylcoumarin (AP-AFC; 40 ⁇ M final concentration).
• the total volume of the reaction mixture was 10-lOO ⁇ L depending on assay formats used (384 or 96 well plates).
• test compounds in varying concentrations ( ⁇ lOmM final concentration) were prepared in Dimethyl Sulfoxide (DMSO) and then diluted into assay buffer comprising: lOOmM Hepes, pH 7.4; 0.01% Brij35; and 10% glycerol. Tryptase (rhLung beta; 0.1 nM final concentration) was added to the dilutions and pre-incubated with compound for 10 minutes at ambient temperature. The enzymatic reaction was initiated with 25 ⁇ M Z-lys-SBzl and 400 ⁇ M DTNB. The total volume of the reaction mixture was lOO ⁇ L in Costar A 2 96 well plates.
• DMSO Dimethyl Sulfoxide

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