WO2012089123A1 - Certains inhibiteurs de la dipeptidylpeptidase - Google Patents

Certains inhibiteurs de la dipeptidylpeptidase Download PDF

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WO2012089123A1
WO2012089123A1 PCT/CN2011/084824 CN2011084824W WO2012089123A1 WO 2012089123 A1 WO2012089123 A1 WO 2012089123A1 CN 2011084824 W CN2011084824 W CN 2011084824W WO 2012089123 A1 WO2012089123 A1 WO 2012089123A1
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alkyl
pharmaceutically acceptable
compound
substituted
acceptable salt
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PCT/CN2011/084824
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English (en)
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Weibo Wang
Xingdong ZHAO
Ming Lei
Huajie Zhang
Longcheng Wang
Jian Zhang
Bo FANG
Xia Liu
Zuwen ZHOU
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Shanghai Fochon Pharmaceutical Co Ltd
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Publication of WO2012089123A1 publication Critical patent/WO2012089123A1/fr

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems

Definitions

  • R 6 are each independently selected from
  • aryl and cycloalkyl are each independently unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, Ci_ 6 alkyl, and Ci_ 6 alkoxy, wherein alkyl and alkoxy are each independently unsubstituted or substituted with one to five halogens; or R 5 and R 6 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, and morpholine wherein the heterocyclic ring is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, Ci_ 6 alkyl, and Ci_ 6 alkoxy, wherein alkyl and alkoxy are each independently unsubstituted or substituted with one to five halogens; m is selected from 0, 1 and 2; and
  • naphthylidene a corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene.
  • Aryl does not encompass or overlap in any way with heteroaryl, separately defined below. Hence, if one or more carbocyclic aromatic rings are fused with a heterocyclic aromatic ring, the resulting ring system is heteroaryl, not aryl, as defined herein.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • the total number of S and O atoms in the heteroaryl group exceeds 1 , those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • heteroaryl groups include but are not limited to pyrrolyl, isothiazolyl, triazinyl, pyrazinyl, pyridazinyl, indolyl, benzotriazolyl, quinoxalinyl, and isoquinolinyl,.
  • heteroaryl is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl.
  • Bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylidene.
  • Heteroaryl does not encompass or overlap with aryl as defined above.
  • the heterocycle can be substituted by oxo.
  • the point of the attachment may be carbon or heteroatom in the heterocyclic ring, provided that attachment results in the creation of a stable structure.
  • the heterocyclic ring has substituents, it is understood that the substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results.
  • Suitable heterocycles include, for example (as numbered from the linkage position assigned priority 1), 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, and 2,5-piperazinyl.
  • Morpholinyl groups are also contemplated, including 2-morpholinyl and 3-morpholinyl (numbered wherein the oxygen is assigned priority 1).
  • substitution of alkyl, cycloalkyl, heterocyclyl, aryl, and/or heteroaryl refers to substitution of each of those groups individually as well as to substitutions of combinations of those groups.
  • salts derived from inorganic bases may be selected, for example, from aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, and zinc salts. Further, for example, the pharmaceutically acceptable salts derived from inorganic bases may be selected from ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in one or more crystal structures, and may also be in the form of hydrates.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases may be selected, for example, from salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, ⁇ , ⁇ '-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, and tripropylamine, tromethamine.
  • salts may be prepared using at least one pharmaceutically acceptable non-toxic acid, selected from inorganic and organic acids.
  • acid may be selected, for example, from acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, and p-toluenesulfonic acids.
  • such acid may be selected, for example, from citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.
  • carboxy-protecting group refers to a substituent of the carboxy group that blocks or protects the carboxy functionality.
  • Common carboxy-protecting groups include --CH 2 CH 2 SO 2 PI1, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl and the like.
  • protecting groups and their use see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
  • administering at least one compound and/or at least one pharmaceutically acceptable salt should be understood to mean providing at least one compound and/or at least one pharmaceutically acceptable salt thereof to the individual in recognized need of treatment.
  • the term "effective amount” means the amount of the at least one compound and/or at least one pharmaceutically acceptable salt that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • composition is intended to encompass a product comprising the active ingredient (s), and the inert ingredient (s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pharmaceutically acceptable it is meant compatible with the other ingredients of the formulation and not unacceptably deleterious to the recipient thereof.
  • Ar is aryl unsubstituted or substituted with one to five R substituents
  • Ci_6 alkyl wherein alkyl is unsubstituted or substituted with one to five halogens, and Ci_6 alkoxy, wherein alkoxy is unsubstituted or substituted with one to five halogens;
  • X and Y are each independently selected from CR 2 R 3 , and NR 4 ;
  • R 2 and R 3 are each independently selected from
  • Ci_6 alkyl wherein alkyl is unsubstituted or substituted with one to five halogens, and Ci_6 alkoxy, wherein alkoxy is unsubstituted or substituted with one to five halogens;
  • R 4 is independently selected from
  • Ci_6 alkyl wherein alkyl is unsubstituted or substituted with one to five substituents independently selected from halogen and hydroxy,
  • (CH 2 ) n -C3_6 cycloalkyl wherein cycloalkyl is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, cyano, C0 2 H, Ci_ 6 alkyloxycarbonyl, Ci_ 6 alkyl, and Ci_ 6 alkoxy, wherein alkyl and alkoxy are each independently unsubstituted or substituted with one to five halogens,
  • any individual methylene (CH 2 ) carbon atom in (CH 2 ) n is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, Ci_6 alkyl, and Ci_ 6 alkoxy, wherein alkyl and alkoxy are each independently unsubstituted or substituted with one to five halogens;
  • R 5 and R 6 are each independently selected from:
  • alkyl is unsubstituted or substituted with one to five substituents independently selected from halogen and hydroxy,and
  • aryl and cycloalkyl are each independently unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, Ci_ 6 alkyl, and Ci_ 6 alkoxy, wherein alkyl and alkoxy are each independently unsubstituted or substituted with one to five halogens; or R 5 and R 6 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, and morpholine wherein the heterocyclic ring is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, Ci_ 6 alkyl, and Ci_ 6 alkoxy, wherein alkyl and alkoxy are each independently unsubstituted or substituted with one to five halogens;
  • n 0, 1 and 2;
  • n is selected from 0, 1, 2, and 3.
  • Ar is phenyl substituted with one to five R 1 substituents.
  • R 1 is halogen
  • Ar is selected from 2,4,5-trifluorophenyl and 2,5- difluorophenyl. In some embodiments, Ar is 2,4,5-trifluorophenyl. In some embodiments, Ar is 2,5-difiuorophenyl.
  • X is CR 2 R 3 and Y is CR 2 R 3 . In some embodiments, X is NR 4 and Y is CR 2 R 3 . In some embodiments, X is CR 2 R 3 and Y is NR 4 .
  • R 2 and R 3 are hydrogen.
  • R 4 is selected from hydrogen, Ci_ 6 alkyl , (CH 2 ) n -COCi_6 alkyl, (CH 2 ) n -C0 2 Ci_6 alkyl, (CH2) n -CONR 5 R 6 , (CH 2 ) n -S(0) m R 6 , and (CH 2 ) n -S0 2 NR 5 R 6 , wherein n is 0 and m is 2.
  • R 4 is selected from H, CH 3 , COCH 3 , C0 2 CH 3 , CONH 2 , S0 2 CH 3 , and S0 2 NH 2 .
  • X is NR 4 and Y is CR 2 R 3
  • Ar is 2,4,5-trifluorophenyl, wherein R 2 and R 3 are hydrogen, and R 4 is selected from H, C3 ⁇ 4, COCH 3 , C0 2 CH 3 , CONH 2 , S0 2 C3 ⁇ 4, and S0 2 NH 2 .
  • Also provided is a method of treating a condition responsive to inhibition of dipeptidyl peptidase-IV enzyme comprising administering to a patient in recognized need thereof an effective amount of the at least one compound and/or at least one pharmaceutically acceptable salt described herein.
  • Also provided is a method of treating a condition selected from insulin resistance, hyperglycemia, and Type II diabetes comprising administering to a patient in recognized need thereof an effective amount of the at least one compound and/or at least one pharmaceutically acceptable salt described herein.
  • pharmaceutically acceptable salt thereof described herein can be useful in a method of inhibiting the dipeptidyl peptidase-IV enzyme in a patient such as a mammal in recognized need of such inhibition comprising the administration of an effective amount of the at least one compound and/or at least one pharmaceutically acceptable salt described herein. Also provided is the use of the at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein as inhibitors of dipeptidyl peptidase-IV enzyme activity.
  • mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated.
  • the method can also be practiced in other species, such as avian species (e. g., chickens).
  • composition comprising the at least one compound and/or at least one pharmaceutically acceptable salt described herein and at least one pharmaceutically acceptable carrier.
  • Also provided is a method for the manufacture of a medicament for inhibiting dipeptidyl peptidase-IV enzyme activity in humans and animals comprising combining at least one compound and/or at least one pharmaceutically acceptable salt described herein with at least one pharmaceutically acceptable carrier.
  • the patient is a mammal, such as a human being, male or female, in whom inhibition of dipeptidyl peptidase-IV enzyme activity is desired.
  • the pharmaceutical compositions described herein encompass any composition made by admixing at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.
  • Dipeptidyl peptidase-IV enzyme is a cell surface protein that has been implicated in a wide range of biological functions. It has a broad tissue distribution (intestine, kidney, liver, pancreas, placenta, thymus, spleen, epithelial cells, vascular endothelium, lymphoid and myeloid cells, serum), and distinct tissue and cell-type expression levels. DPP-IV is identical to the T cell activation marker CD26, and it can cleave a number of
  • the compounds and/or pharmaceutically acceptable salts described herein can be useful in a method for the treatment of the following diseases, disorders and conditions.
  • Type II Diabetes and Related Disorders It is well established that the incretins GLP- 1 and GIP are rapidly inactivated in vivo by DPP-IV. Studies with DPP-IV ( / _) -deficient mice and preliminary clinical trials indicate that DPP-IV inhibition increases the steady state concentrations of GLP-1 and GIP, resulting in improved glucose tolerance. By analogy to GLP-1 and GIP, it is likely that other glucagon family peptides involved in glucose regulation are also inactivated by DPP-IV (eg. PACAP). Inactivation of these peptides by DPP-IV may also play a role in glucose homeostasis.
  • DPP-IV eg. PACAP
  • DPP-IV inhibitors described hereintherefore may have utility in the treatment of type II diabetes and in the treatment of the numerous conditions that often accompany Type II diabetes, including but being not limited to Syndrome X (also known as Metabolic Syndrome), reactive hypoglycemia, and diabetic dyslipidemia.
  • Syndrome X also known as Metabolic Syndrome
  • Obesity is another condition that can be often found with Type II diabetes that may respond to treatment with the DPP-IV inhibitors described herein.
  • the compounds and/or pharmaceutically acceptable salts described herein may have utility in treating one or more of the following conditions or diseases: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (1 1) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, (16) other inflammatory conditions, (17) pancreatitis, (18) abdominal obesity, (19) neurodegenerative disease, (20) retinopathy, (21) nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarian hyperandrogenism (polycystic ovarian syndrome), (25) Type II diabetes, (26) growth hormone deficiency, (27) neutropenia, (28) neuronal disorders,
  • DPP-IV inhibitors described herein may be useful for the treatment of obesity. This is based on the observed inhibitory effects on food intake and gastric emptying of GLP-1 and GLP-2.
  • DPP-IV inhibition may be useful for the treatment of growth hormone deficiency, based on the hypothesis that growth-hormone releasing factor (GRF), a peptide that stimulates release of growth hormone from the anterior pituitary, is cleaved by the DPP-IV enzyme in vivo (WO 00/56297).
  • GRF growth-hormone releasing factor
  • GRF can be an endogenous substrate: (1) GRF is efficiently cleaved in vitro to generate the inactive product GRF [3-44] (BBA 1122: 147-153 (1992) ) ; (2) GRF is rapidly degraded in plasma to GRF [3-44]; this is prevented by the DPP-IV inhibitor diprotin A; and (3) GRF [3-44] is found in the plasma of a human GRF transgenic pig (J. Clin. Invest., 83: 1533-1540 (1989)).
  • DPP-IV inhibitors may be useful for the same spectrum of indications which have been considered for growth hormone secretagogues.
  • Intestinal Injury The potential for using DPP-IV inhibitors for the treatment of intestinal injury can be suggested by the results of studies indicating that glucagon-like peptide-2 (GLP-2), a likely endogenous substrate for DPP-IV, may exhibit trophic effects on the intestinal epithelium (Regulatory Peptides. 90: 27-32 (2000) ).
  • GLP-2 glucagon-like peptide-2
  • DPP-IV inhibition may be useful for modulation of the immune response, based upon studies implicating the DPP-IV enzyme in T cell activation and in chemokine processing, and efficacy of DPP-IV inhibitors in in vivo models of disease.
  • DPP-IV has been shown to be identical to CD26, a cell surface marker for activated immune cells.
  • the expression of CD26 can be regulated by the differentiation and activation status of immune cells. It is for example accepted that CD26 functions as a co-stimulatory molecule in in vitro models of T cell activation.
  • a number of chemokines contain proline in the penultimate position, presumably to protect them from degradation by non-specific aminopeptidases.
  • cleavage can result in an altered activity in chemotaxis and signaling assays.
  • N- terminally truncated forms of a number of chemokines have been identified in in vitro cell culture systems, including the predicted products of DPP-IV hydrolysis.
  • DPP-IV inhibitors have been shown to be efficacious immunosuppressants in animal models of transplantation and arthritis.
  • Prodipine Pro-Pro-diphenyl-phosphonate
  • DPP-IV inhibitors have been tested in collagen and alkyldiamine-induced arthritis in rats and showed a statistically significant attenuation of hind paw swelling in this model [Int. J. Immunopharmacology, 19: 15-24 (1997) and Immunopharmacology, 40: 21-26 (1998)].
  • DPP-IV is upregulated in a number of autoimmune diseases including rheumatoid arthritis, multiple sclerosis, Graves' disease, and Hashimoto's thyroiditis (Immunology Today, 20: 367-375 (1999)).
  • DPP-IV inhibition may be useful for the treatment of EGV infection or AIDS because a number of chemokines which inhibit HIV cell entry are potential OC substrates for DPP-IV (Immunology Today 20: 367-375 (1999)).
  • SDF-1 alpha cleavage decreases antiviral activity (PNAS, 95: 6331-6 (1998)).
  • PNAS, 95: 6331-6 (1998) stabilization of SDF-1 alpha through inhibition of DPP-IV would be expected to decrease HTV infectivity.
  • DPP-IV inhibition may be useful for the treatment of
  • DPP-IV may be involved in hematopoiesis.
  • DPP-IV inhibition may be useful for the treatment of various neuronal or psychiatric disorders because a number of peptides implicated in a variety of neuronal processes are cleaved in vitro by DPP-IV.
  • a DPP-IV inhibitor thus may have a therapeutic benefit in the treatment of neuronal disorders.
  • Endomorphin-2, beta-casomorphin, and substance P have all been shown to be in vitro substrates for DPP-IV.
  • a DPP-IV inhibitor showed a significant effect that was independent of the presence of exogenous endomorphin-2 (Brain Research, 815: 278-286
  • DPP-IV inhibitors were also evidenced by the inhibitors' ability to protect motor neurons from excitotoxic cell death, to protect striatal innervation of dopaminergic neurons when administered concurrently with MPTP, and to promote recovery of striatal innervation density when given in a therapeutic manner following MPTP treatment [see Yong-Q. Wu, et al., "Neuroprotective Effects of Inhibitors of Dipeptidyl Peptidase-IV in vitro and in vivo, "Int. Conf. On Dipeptidyl Aminopeptidases: Basic Science and Clinical Applications, September 26-29, 2002 (Berlin, Germany)].
  • DPP-IV deficient mice also have an anxiolytic phenotype using the Porsolt and light/dark models.
  • DPP-IV inhibitors described herein may prove useful for treating anxiety and related disorders.
  • GLP-1 agonists can be active in models of learning (passive avoidance, Morris water maze) and neuronal injury (kainate-induced neuronal apoptosis) as demonstrated by During et al. (Nature Med. 9: 1173-1 179 (2003) ). The results may suggest a physiological role for GLP-1 in learning and neuroprotection. Stabilization of GLP-1 by DPP-IV inhibitors are expected to show similar effects.
  • DPP-IV inhibition may be useful for the treatment of tumor invasion and metastasis because an increase or decrease in expression of several ectopeptidases including DPP-IV has been observed during the transformation of normal cells to a malignant phenotype (J. Exp. Med., 190: 301-305 (1999)). Up-or down-regulation of these proteins appears to be tissue and cell-type specific. For example, increased CD26/DPP-IV expression has been observed on T cell lymphoma, T cell acute lymphoblastic leukemia, cell- derived thyroid carcinomas, basal cell carcinomas, and breast carcinomas. Thus, DPP-IV inhibitors may have utility in the treatment of such carcinomas.
  • Benign Prostatic Hypertrophy DPP-IV inhibition may be useful for the treatment of benign prostatic hypertrophy because increased DPP-IV activity was noted in prostate tissue from patients with BPH (Eur. J. Clin. Chem. Clin. Biochem., 30: 333-338 (1992)).
  • DPP-IV inhibition may be useful for the altering sperm motility and for male contraception because in seminal fluid, prostatosomes, which are prostate derived organelles important for sperm motility, possess very high levels of DPP-IV activity (Eur. J. Clin. Chem. Clin. Biochem., 30: 333-338 (1992)).
  • DPP-IV inhibition may be useful for the treatment of gingivitis because DPP-IV activity was found in gingival crevicular fluid and in some studies correlated with periodontal disease severity (Arch. Oral Biol., 37: 167-173 (1992)).
  • Osteoporosis DPP-IV inhibition may be useful for the treatment of osteoporosis because GIP receptors are present in osteoblasts.
  • the compounds and/or pharmaceutically acceptable salts thereof described herein may be further useful in a method for the treatment of the aforementioned diseases, disorders and conditions in combination with other agents.
  • the compounds and/or pharmaceutically acceptable salts thereof described herein may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of Formula I and/or pharmaceutically acceptable salts thereof or the other drugs may have utility, particularly where the combination of the drugs together are safer or more effective than either drug alone.
  • Such other drug (s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with at least one compound of Formula I and/or at least one pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition in unit dosage form containing such at least one drug and the at least one compound of Formula I and/or at least one pharmaceutically acceptable salt thereof may be desired.
  • the combination therapy may also include therapies in which the at least one compound of Formula I and/or at least one pharmaceutically acceptable salt thereof and one or more other drugs are administered on different overlapping schedules.
  • the compound(s) described herein and the other active ingredients may be used in lower doses than when each is used singly.
  • the pharmaceutical compositions described herein include but are not limited to those that contain one or more other active ingredients, in addition to at least one compound of Formula I and/or at least one pharmaceutically acceptable salt thereof.
  • Examples of other active ingredients that may be administered in combination with at least one compound of Formula I and/or at least one pharmaceutically acceptable salt thereof, and either administered separately or in the same pharmaceutical composition include, but are not limited to: (a) other dipeptidyl peptidase IV (DPP-IV) inhibitors; (b) insulin sensitizers including (i) PPARy agonists such as the glitazones (e.
  • troglitazone pioglitazone, englitazone, MCC-555, rosiglitazone, balaglitazone, and the like
  • other PPAR ligands including PPARa/ ⁇ dual agonists, such as KRP-297 and muraglitazar, and PPARa agonists such as fenofibric acid derivatives (e.g., gemfibrozil, clofibrate, fenofibrate and bezafibrate), (ii) biguanides such as metformin and phenformin, and (iii) protein tyrosine phosphatase- IB (PTP- 1B) inhibitors; (c) insulin or insulin mimetics; (d) sulfonylureas and other insulin secretagogues, such as tolbutamide glyburide, glipizide, glimepiride, and meglitinides, such as nateglinide
  • Dipeptidyl peptidase-IV inhibitors that can be combined with at least one compound of formula I and/or at least one pharmaceutically acceptable salt thereof include but are not limited to those described in WO 03/004498; WO 03/004496; EP 1 258 476; WO
  • Neuropeptide Y5 antagonists that can be combined with at least one compound of formula I and/or at least one pharmaceutically acceptable salt thereof include but are not limited to those described in U. S. Patent No. 6,335, 345 and WO 01/14376; and exemplary mention can be made of GW 59884A; GW 569180A ; LY366377; and CGP-71683A.
  • Melanocortin receptor agonists that can be combined with at least one compound of formula I and/or at least one pharmaceutically acceptable salt thereof include but are not limited to those described in WO 03/009847; WO 02/068388; WO 99/64002; WO 00/74679; WO 01/70708; and WO 01/70337 as well as those described in J. D. Speake et al.,"Recent advances in the development of melanocortin-4 receptor agonists, "Expert Opin. Ther. Patents, 12: 1631-1638 (2002).
  • compositions described herein include but are not limited to those that also contain one or more other active ingredients, in addition to at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein.
  • the at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein may be administered by oral, parenteral (e. g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of
  • compositions for the administration of the at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy.
  • the at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein is brought into association with the carrier which constitutes one or more accessory ingredients.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents, for example, corn starch, and alginic acid; binding agents, for example starch, gelatin, and acacia, and lubricating agents, for example magnesium stearate, stearic acid, and talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate, and glyceryl distearate may be employed. They may also be coated by the techniques described in the U. S. Patent Nos. 4,256,108;
  • DPP-IV inhibitors described herein are provided as solid dosage forms, such as capsules and 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.
  • 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.
  • the at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein 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 at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • the at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein 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.
  • materials that supplement the desired action such as antacids, H2 blockers, and diuretics.
  • 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.
  • Exemplary examples of flavoring agents that may be used 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, for example, encapsulated in a gelatin capsule.
  • Such solutions, and the preparation and encapsulation thereof, are described in U.S. Patent Nos.
  • 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 at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein by parenteral administration generally characterized by injection, either subcutaneous ly, 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.
  • the percentage of the at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein and the needs of the patient.
  • 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.
  • 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 and chelating agents, and other
  • antimicrobial agents examples include phenols and cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride.
  • Unit-dose parenteral preparations may be packaged in an ampoule, a vial or a syringe with a needle.
  • AU preparations for parenteral administration should be sterile, as is known and practiced in the art.
  • the at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein may optionally be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product.
  • 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 lyophilized powders may also be formulated as solids or gels.
  • the at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein is added to the resulting mixture, for example, above room temperature, such as 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 a single dosage or multiple dosages of the at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein.
  • the at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein 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, emulsion, or the like and is 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 at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein may be formulated as aerosols for topical application, such as by inhalation (see, U.S. Patent Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivery of a steroid useful for treatment inflammatory diseases, particularly asthma).
  • These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a micro fine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of the formulation will for example have median diameters of less than 50 microns, such as less than 10 microns.
  • the at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein 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 intracisternal 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 at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein alone or in combination with other pharmaceutically acceptable excipients can also be administered.
  • bases examples include cocoa butter (theobroma oil), glycerin-gelatin, carbowax,
  • 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
  • an appropriate dosage level will generally be about 0.1 to 1000 mg per day which can be administered in single or multiple doses.
  • the dosage level will be about 0.1 to about 250 mg per day; such as from about 0.5 to about 100 mg per day.
  • a suitable dosage level may be about 0.1 to 1000 mg per day, about 0.5 to 500 mg per day, or about 1 to 50 mg per day. Within this range the dosage may be 0.1 to 0.5, 0.5 to 5 or 5 to 50 mg per day.
  • the compositions are for example provided in the form of tablets containing 1.0 to 1000 mg of the at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein, such as 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 mg of the at least one compound and/or at least one
  • pharmaceutically acceptable salt thereof described herein may be administered on a regimen of 1 to 4 times per day, such as once or twice per day.
  • the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein employed, the metabolic stability and length of action of that at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
  • Inhibition constants may, for example, be determined as follows.
  • a continuous fiuorometric assay is employed with the substrate Gly-Pro-AMC, which is cleaved by DPP-IV to release the fluorescent AMC leaving group.
  • a typical reaction contains approximately 50 pM enzyme, 50 ⁇ Gly-Pro-AMC, and buffer (100 mM HEPES, pH 7.5, 0.1 mg/ml BSA) in a total reaction volume of 100 ⁇ L ⁇ .
  • Liberation of AMC is monitored continuously in a 96-well plate fluorometer using an excitation wavelength of 360 nm and an emission wavelength of 460 nm. Under these conditions, approximately 0.8 ⁇ AMC is produced in 30 minutes at 25 degrees C.
  • the enzyme used in these studies was soluble (transmembrane domain and cytoplasmic extension excluded) human protein produced in a baculovirus expression system (Bac-To-Bac, Gibco BRL).
  • the kinetic constants for hydrolysis of Gly-Pro-AMC and GLP-1 were found to be in accord with literature values for the native enzyme.
  • solutions of the at least one compound and/or at least one pharmaceutically acceptable salt thereof described herein in DMSO were added to reactions containing enzyme and substrate (final DMSO concentration is 1%). All experiments were conducted at room temperature using the standard reaction conditions described above.
  • To determine the dissociation constants (Ki) reaction rates were fit by non-linear regression to the Michaelis-Menton equation for competitive inhibition. The errors in reproducing the dissociation constants are typically less than two-fold.
  • the at least one compound of formula (I) can also be prepared as a
  • a pharmaceutically acceptable base addition salt of the at least one compound of formula (I) can be prepared by, for example, reacting the free acid form of the at least one 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 of formula (I) are set forth in the definitions section of this Application.
  • salt forms of the compounds of formula (I) can be prepared using salts of the starting materials or intermediates.
  • the free acid or free base forms of the compounds of formula (I) can be prepared from the corresponding base addition salt or acid addition salt form.
  • a compound of formula (I) in an acid addition salt form can be converted to the corresponding free base thereof by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like).
  • a suitable base e.g., ammonium hydroxide solution, sodium hydroxide, and the like.
  • a compound of formula (I) in a base addition salt form can be converted to the
  • N-oxides of the at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof 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 of formula (I) with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-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, meta-chloroperoxybenzoic acid, or the like
  • a suitable inert organic solvent e.g., a halogenated hydrocarbon such as dichloromethane
  • the N-oxides of the compounds of formula (I) can be prepared from the N-oxide of an appropriate starting material.
  • Compounds of formula (I) in an unoxidized form can be prepared from N-oxides of compounds of formula (I) by, for example, treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, and the like) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, and the like) at 0 to 80 °C.
  • a reducing agent e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, and the like
  • an inert organic solvent e.g., acetonitrile, ethanol, aqueous dioxane, and the like
  • stereoisomers by reacting a racemic mixture of the compounds 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, for example, by separation/resolution techniques based upon differences in solubility.
  • optically rC50C 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).
  • the at least one compound of formula I and/or at least one pharmaceutically acceptable salt thereof 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.
  • the compound of formula I of the present invention may be prepared from intermediates such as those of formula III and amino-heteroarene such as II using standard condensation conditions followed by reduction and chiral resolution.
  • Compounds of formula I may be prepared by condensation reactions from intermediate Ilia and intermediate II, which are either known in the literature or may be prepared by a variety of methods familiar to those skilled in the art (Scheme 2).
  • Intermediate 5 may be prepared by reacting intermediates Ilia and II in solvents such as ethanol under elevated temperature. Reduction of the nitro group of 5 with reducing agents (for example, zinc dust in a solvent such as acetic acid) provides the compound of formula I.
  • reducing agents for example, zinc dust in a solvent such as acetic acid
  • Coupling of compound I with Z ) -mandelic acid provides amides 6a and 6b as a mixture of two diasteromers. Amide 6a was separated from 6b by recrystallization in solvent such as dichloromethane.
  • the compound of formula I or synthetic intermediates illustrated in the above schemes may be further modified, for example, by manipulation of substituents on X or Y. These manipulations may include, but are not limited to, oxidation, alkylation, arylation, acylation, and hydrolysis reactions that are commonly known to those skilled in the art.
  • Amine 8 may be prepared by reaction of Ilia and 2-amino-pyrazine using conditions described in Scheme 2. Protection of amine in 8 with amino protecting group such as Boc gives compound 9. Hydrogenation of 9 with Pd/C provides amine 10. Treatment of 10 with CDI in solvent such as toluene followed by reaction with NaOMe gives methyl carbamate 11. Deprotection of Boc group in 11 with an acid such as hydrogen chloride in a solvent such as ethyl acetate provides compound 12.
  • 1,3,3-Trimethoxybutane was dropped slowly into a heated distilling flask containing 0.1 g of potassium bisulfate.
  • the 1 ,3,3-trimethoxy compound was added at such a rate that approximately 20 g was present in the flask.
  • the temperature of the flask was maintained at 140 °C to cause steady distillation of the decomposition products, . e., methyl alcohol and 2- methoxybuta-l ,3-diene.
  • the decomposition products were collected in 5% potassium carbonate solution and by further washing with potassium carbonate solution followed by drying and distilling. From 70 g of the 1 ,3,3-trimethoxy compound there was obtained in this manner 23 g of 2-methoxybuta-l ,3-diene (58% conversion).
  • Step C 1 ,2,4-Trifluoro-5-(3-methoxy-6-nitrocvclohex-3-enyl)benzene
  • Step A 7-nitro-8-(2,4,5-trifluorophenyl)-6,7,8,9-tetrahydrobenzo[4,51imidazo[l,2- alpyrazine
  • Step B 8-(2,4,5-trifluoroDhenyl)-6,7,8,9-tetrahydrobenzo[4,51imidazo[l ,2-alpyrazin-7- amine
  • Step C ( ⁇ )-2-hvdroxy-2-phenyl-N-((7i?,8 t S r )-8-(2.4.5-trifluorophenyl)-6.7.8.9- tetrahydrobenzo[4.51imidazo[1.2-alpyrazin-7-yl)acetamide
  • Step D (7 t S',8i?)-8-(2.4.5-trifluorophenyl)-6.7.8.9-tetrahvdrobenzor4.51imidazori .2- alpyrazin-7-amine
  • Step A fe -Butyl ((7 t y,8i?)-8-(2.4.5-trifluorophenyl)-6.7.8.9- tetrahydrobenzo[4,51imidazo[l ,2-alpyrazin-7-yl)carbamate
  • Step B fe -Butyl ((7£8i?)-8-(2.4.5-trifluorophenyl)-l .2.3.4.6.7.8.9- octahydrobenzo[4,51imidazo[ 1 ,2-alpyrazin-7-yl)carbamate
  • Step C (7S,8R)-met y ⁇ 7-((?gr?-butoxycarbonyl)amino)-8-(2.4.5-trifluorophenyl)- 3,4,6,7, 8,9-hexahydrobenzo[4,51imidazo[l ,2-alpyrazine-2(lH)-carboxylate
  • Step D (75.8RVMethyl 7-amino-8-(2.4.5-trifluorophenyl)-3.4.6.7.8.9- hexahydrobenzo[4,51imidazo[l ,2-alpyrazine-2(lH)-carboxylate bis-hydrochloric acid salt
  • Step A fe -Butyl ((75.8RV8-(2.4.5-trifluorophenvn- 1.2.3.4.6.7.8.9- octahydrobenzo[4,51imidazo[l,2-alpyrimidin-7-yl)carbamate
  • Step B l-((7 t y,8i?)-7-amino-8-(2.4.5-trifluorophenyl)-3.4.6.7.8.9- hexahydrobenzo[4,51imidazo[ 1 ,2-alpyrimidin- 1 (2H)-yl)ethanone [0199]
  • This compound was prepared by following the procedure in Example 6, replacing ieri-butyl ((7»S',Sii)-8-(2,4,5-trifluorophenyl)- 1,2,3,4,6,7, 8,9-octahydrobenzo[4,5]imidazo[ 1 ,2- a]pyrazin-7-yl)carbamate (from EXAMPLE 3, Step B) with fe -butyl ((7 t S , ,8i?V8-(2.4.5- trifluorophenyl)-l, 2,3,4,6,7, 8,9-octahydrobenzo[4,51imidazo[l ,2-alpyrimidin
  • This compound was prepared by following the procedures in Example 3, Steps C and D, by replacing fe -butyl ((7£8ifl-8-(2A5-trifluorophenyl)-1.23A6.7.8.9- octahydrobenzo[4,51imidazo[ 1 ,2-alpyrazin-7-yl)carbamate (from Example 3, Step B) with tert- butyl ((7 t S',8 ⁇ )-8-(2.4.5-trifluorophenyl)-1.2.3.4.6.7.8.9-octahvdrobenzor4.51imidazori.2- alpyrimidin-7-yl)carbamate (Example 10, Step A). MS-ESI (m/z): 381 [M+l] + .
  • Step A (7 t S',8 ⁇ )-8-(2.4.5-trifluorophenyl)-1.2.3.4.6.7.8.9-octahvdrobenzor4.51imidazori .2- alpyrimidin-7-amine [0202]
  • This compound was prepared by substituting 2-amino-pyrazine with 2-amino- pyrimidine in Example 1, following steps A to D.
  • Step B (7 t S , ,8i?V8-(2.4.5-trifluorophenylV1.2.3.4.6.7.8.9-octahvdrobenzor4.51imidazori.2- alpyrimidin-7-amine
  • DPP-IV Assay Solution of test compounds in varying concentrations (10 ⁇ 5 mol/L, 10 "6 mol/L, 10 "7 mol/L, 10 “8 mol/L, 10 “9 mol/L, 10 "10 mol/L, 10 "11 mol/L, and 10 "12 mol L) were prepared in dimethyl sulfoxide (DMSO) and then diluted into assay buffer comprising: 10 mM Tris-HCl pH 8.0, 0.2 M NaCl, and 0.1% BSA.
  • DMSO dimethyl sulfoxide
  • Recombinant human DPP-IV (7.8 ng/ml final concentration) was added to the dilutions and pre-incubated for 30 min at room temperature before the reaction was initiated with H-Ala-Pro-AFC (50 ⁇ final concentration). The total volume of the reaction mixture was 100 ul.

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Abstract

La présente invention a pour objet certains inhibiteurs de la dipeptidylpeptidase, leurs compositions pharmaceutiques, et leurs méthodes d'utilisation.
PCT/CN2011/084824 2010-12-29 2011-12-28 Certains inhibiteurs de la dipeptidylpeptidase WO2012089123A1 (fr)

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CN1798556A (zh) * 2003-06-06 2006-07-05 麦克公司 作为治疗或者预防糖尿病的二肽基肽酶抑制剂的稠合吲哚

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1798556A (zh) * 2003-06-06 2006-07-05 麦克公司 作为治疗或者预防糖尿病的二肽基肽酶抑制剂的稠合吲哚

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