WO2013049289A1 - Monoacylglycerol lipase inhibitors for the treatment of metabolic diseases and related disorders - Google Patents
Monoacylglycerol lipase inhibitors for the treatment of metabolic diseases and related disorders Download PDFInfo
- Publication number
- WO2013049289A1 WO2013049289A1 PCT/US2012/057465 US2012057465W WO2013049289A1 WO 2013049289 A1 WO2013049289 A1 WO 2013049289A1 US 2012057465 W US2012057465 W US 2012057465W WO 2013049289 A1 WO2013049289 A1 WO 2013049289A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- compound
- formula
- subject
- fluoro
- Prior art date
Links
- 0 *C(N(C1)CC1N(CC1)CCN1C(*)=O)=O Chemical compound *C(N(C1)CC1N(CC1)CCN1C(*)=O)=O 0.000 description 3
- IVOACCSOISMVBL-UHFFFAOYSA-N O=C(c1ncc[s]1)N(CC1)CCN1C(C1)CN1C(c(cc1)cc(cc2)c1[n]2-c(cc1)ccc1F)=O Chemical compound O=C(c1ncc[s]1)N(CC1)CCN1C(C1)CN1C(c(cc1)cc(cc2)c1[n]2-c(cc1)ccc1F)=O IVOACCSOISMVBL-UHFFFAOYSA-N 0.000 description 2
- RKBLAXHVQYRXFV-UHFFFAOYSA-N CCCN(C)C(OC(C)(C)C)=O Chemical compound CCCN(C)C(OC(C)(C)C)=O RKBLAXHVQYRXFV-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N c1ccncc1 Chemical compound c1ccncc1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- MGL Monoglyceride Lipase
- MGL inhibitors are potentially useful for the treatment of pain, inflammation, and CNS disorders.
- MGL is expressed in adipocytes, where it functions together with hormone-sensitive lipase (LIPE) to hydrolyze intracellular triglyceride stores, and in the intestine, where it is largely responsible for cleaving
- LIPE hormone-sensitive lipase
- MGL-ko mice MGL knockout mice
- MGL-ko mice Fasted MGL- ko mice exhibited reduced plasma glycerol and triacylglycerol, as well as liver triacylglycerol levels indicative of impaired lipolysis. MGL-ko mice receiving a high- fat diet showed significantly improved glucose tolerance and insulin sensitivity in comparison to wild-type controls. These observations implicate MGL in metabolic diseases and suggest that MGL inhibitors will have beneficial effects on metabolic disorders, including obesity, hyperphagia and diabetes.
- MGL inhibitors It is an object of the present invention to provide MGL inhibitors. It is also an object of the invention to provide a method of treating, ameliorating or preventing metabolic disorders, such as obesity, hyperphagia and diabetes, by the administration of a compound of formula (I). It is also an object of the invention to provide a method of reducing food consumption and/or weight gain of a subject, by the administration of a compound of formula (I). And, it is an object of the invention to provide a
- composition comprising a compound of formula (I), useful for treating, ameliorating or preventing metabolic disorders.
- the present invention is directed to a method for treating, ameliorating, or preventing metabolic diseases; comprising, consisting of, and /or consisting essentially of administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I)
- Y is a heteroaryl selected from the group consisting of thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, isoxazolyl, triazolyl, and [l,2,3]thiadiazolyl; wherein Y is optionally substituted with one substituent selected from the group consisting of fluoro, chloro, bromo, Ci- 4 alkyl, cyano, and trifluoromethyl;
- Z is a heteroaryl selected from the group consisting of indolyl, indazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, lH-pyrrolo[3,2-b]pyridin-5- yl, lH-thieno[2,3-c]pyrazol-5-yl, lH-pyrrolo[2,3-b]pyridin-5-yl, lH-pyrazolo[3,4- b]pyridin-5-yl, furo[2,3-b]pyridin-2-yl, quinazolinyl, and benzimidazolyl;
- Z is optionally independently substituted with one to two substitutents selected from the group consisting of chloro, fluoro, Ci- 4 alkyl, Ci- 4 alkoxy, and trifluoromethyl; and Z is substituted with one additional substituent that is
- a heteroaryl selected from the group consisting of pyrimidinyl, thienyl, quinolinyl, pyridinyl, isoxazolyl, thiazolyl, benzimidazolyl, pyrrolyl, furanyl, pyrimidinyl, and pyrazolyl;
- phenyl and heteroaryl substituents of Z are optionally independently substituted with one to two substituents selected from the group consisting of Ci- 4 alkyl; Ci- 4 alkoxy; one to three fluoro or chloro substituents;
- the present invention is further directed to the use of a compound of formula (I) as herein defined for the preparation of a medicament or a pharmaceutical composition for the treatment, amelioration and / or prevention of metabolic diseases, including obesity, hyperphagia, and diabetes, in a subject in need thereof.
- the present invention is further directed to the use of a compound of formula (I) as herein defined for the preparation of a medicament or a pharmaceutical composition for reducing food consumption and/or weight gainin a subject in need thereof.
- alkyl refers to straight and branched carbon chains having 1 to 8 carbon atoms. Therefore, designated numbers of carbon atoms (e.g., C 1-8 ) refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl-containing substituent.
- substituent groups with multiple alkyl groups such as (Ci_ 6 alkyl) 2 amino- the Ci- 6 alkyl groups of the dialkylamino may be the same or different.
- alkoxy refers to an -O-alkyl group, wherein the term “alkyl” is as defined above.
- alkenyl and alkynyl refer to straight and branched carbon chains having 2 or more carbon atoms, wherein an alkenyl chain contains at least one double bond and an alkynyl chain contains at least one triple bond.
- aryl refers to an unsaturated, aromatic monocyclic or bicyclic ring of 6 to 10 carbon members. Examples of aryl rings include phenyl and naphthalenyl.
- heteroaryl refers to an aromatic monocyclic or bicyclic aromatic ring system having 5 to 10 ring members and which contains carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S. Included within the term heteroaryl are aromatic rings of 5 or 6 members wherein the ring consists of carbon atoms and has at least one heteroatom member. Suitable heteroatoms include nitrogen, oxygen, and sulfur. In the case of 5 membered rings, the heteroaryl ring preferably contains one member of nitrogen, oxygen, or sulfur and, in addition, up to 3 additional nitrogens. In the case of 6 membered rings, the heteroaryl ring preferably contains from 1 to 3 nitrogen atoms.
- heteroaryl is bicyclic, at least one heteroatom is present in at least one ring.
- heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, indazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, and benzothienyl.
- the heteroaryl is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
- halogen or halo refers to fluorine, chlorine, bromine and iodine.
- alkyl or aryl or either of their prefix roots appear in a name of a substituent (e.g., arylalkyl, alkylamino) the name is to be interpreted as including those limitations given above for "alkyl” and "aryl.”
- Designated numbers of carbon atoms e.g., C ⁇ -Ce refer independently to the number of carbon atoms in an alkyl moiety, an aryl moiety, or in the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
- the designated number of carbon atoms includes all of the independent members included within a given range specified.
- Ci_6 alkyl would include methyl, ethyl, propyl, butyl, pentyl and hexyl individually as well as sub-combinations thereof (e.g., C1-2, Ci_ 3, Ci_4, Ci_5 ; C2-6, C3_6, C 4 _6, C5-6, C 2- 5 ; etc.).
- a "Q-C6 alkylcarbonyl" substituent refers to a group of the formula:
- R at a stereocenter designates that the stereocenter is purely of the R-configuration as defined in the art; likewise, the term “S” means that the stereocenter is purely of the ⁇ -configuration.
- S means that the stereocenter is purely of the ⁇ -configuration.
- the terms “*R” or “*S” at a stereocenter are used to designate that the stereocenter is of pure but unknown configuration.
- RS refers to a stereocenter that exists as a mixture of the R- and ⁇ -configurations.
- *RS or “*SR” refer to a stereocenter that exists as a mixture of the R- and ⁇ -configurations and is of unknown configuration relative to another stereocenter within the molecule.
- Unlabeled stereocenters drawn without stereo bond designations are a mixture of the R- and ⁇ -configurations.
- the absolute stereochemistry is as depicted.
- subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
- terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
- composition is intended to encompass a product comprising the specified ingredients in therapeutically effective amounts, as well as any product that results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
- treating include the management and care of a subject or patient (preferably mammal, more preferably human) for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present invention to prevent the onset of the symptoms or complications, alleviate the symptoms or complications, or eliminate the disease, condition, syndrome, or disorder.
- preventing and prevention include (a) reduction in the frequency of one or more symptoms; (b) reduction in the severity of one or more symptoms; (c) the delay or avoidance of the development of additional symptoms; and / or (d) delay or avoidance of the development of the disease, disorder, syndrome, or condition.
- a subject in need of thereof includes any subject (preferably a mammal, more preferably a human) who has experienced or exhibited at least one symptom of the disorder, disease, syndrome, or condition to be prevented.
- a subject in need thereof may additionally be a subject (preferably a mammal, more preferably a human) who has not exhibited any symptoms of the disorder, disease, syndrome, or condition to be prevented, but who has been deemed by a physician, clinician, or other medical professional to be at risk of developing said disorder, disease, syndrome, or condition.
- the subject may be deemed at risk of developing a disorder, disease, syndrome, or condition (and therefore in need of prevention or preventive treatment) as a consequence of the subject's medical history, including, but not limited to, family history, pre-disposition, co-existing (comorbid) disorders or conditions, genetic testing, and the like.
- MGL inhibitor is intended to encompass a compound that interacts with MGL to substantially reduce or eliminate its catalytic activity, thereby increasing the concentrations of its substrate(s).
- MGL-modulated is used to refer to the condition of being affected by the modulation of the MGL enzyme including the condition of being affected by the inhibition of the MGL enzyme, such as, for example, metabolic diseases including obesity and diabetes
- fect or "affected” (when referring to a disease, syndrome, condition or disorder that is affected by inhibition of MGL) as used herein, unless otherwise noted, implies a reduction in the frequency and / or severity of one or more symptoms or manifestations of said disease, syndrome, condition or disorder; and / or imply the prevention of the development of one or more symptoms or manifestations of said disease, syndrome, condition or disorder or the development of the disease, condition, syndrome or disorder.
- Compounds of formula (I) are useful in methods for treating, ameliorating and / or preventing metabolic diseases or a disorder that causes such diseases by the inhibition of MGL. Such methods comprise, consist of and/or consist essentially of administering to a subject, including an animal, a mammal, and a human in need of such treatment, amelioration and / or prevention, a therapeutically effective amount of a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof. More particularly, a compound of formula (I) is useful for treating, ameliorating and / or preventing metabolic diseases, such as obesity, hyperphagia, and diabetes, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), as herein defined. Furthermore, a compound of formula (I) is useful for reducing weight gain of a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), as herein defined.
- metabolic disorder, syndrome, diseases or conditions include, but are not limited to, diabetes, hyperphagia, overweight, obesity, obesity-associated insulin resistance, atherosclerosis, and associated symptoms or complications thereof. They also include such conditions as IDDM (insulin-dependent diabetes mellitus), NIDDM (non insulin-dependent diabetes mellitus), IGT (Impaired Glucose Tolerance), IFG (Impaired Fasting Glucose), Syndrome X (i.,e., Metabolic Syndrome), hyperglycemia, elevated blood glucose level, and insulin resistance.
- IDDM insulin-dependent diabetes mellitus
- NIDDM non insulin-dependent diabetes mellitus
- IGT Impaired Glucose Tolerance
- IFG Impaired Fasting Glucose
- Syndrome X i.,e., Metabolic Syndrome
- hyperglycemia elevated blood glucose level
- insulin resistance i.,e., Metabolic Syndrome
- the term "obesity” refers to a condition in which there is an excess of body fat.
- the operational definition of obesity is often based on the Body Mass Index (BMI), which is calculated as body weight per height in meters squared (kg/m 2 ).
- BMI Body Mass Index
- An "obese subject” is an otherwise healthy subject with a Body Mass Index (BMI) greater than or equal to 30 kg/m2 or a subject having at least one co-morbidity with a BMI greater than or equal to 27 kg/m 2 .
- a "subject at risk of obesity” is an otherwise healthy subject with a BMI of 25 kg/m 2 to less than 30 kg/m 2 or a subject having at least one co-morbidity with a BMI of 25 kg/m 2 to less than 27 kg/m 2 .
- obesity refers to a condition whereby a subject with at least one obesity-induced or obesity-related co-morbidity, that requires weight reduction or that would be improved by weight reduction, has a BMI greater than or equal to 25 kg/m 2 .
- a "subject at risk of obesity” is a subject with a BMI of greater than 23 kg/m 2 to less than 25 kg/m 2 .
- obesity as used herein, unless otherwise noted, is meant to encompass all of the above definitions of obesity.
- Obesity-induced or obesity-related co-morbidities include, but are not limited to, diabetes, impaired glucose tolerance, insulin resistance syndrome, dyslipidemia, hypertension, hyperuricacidemia, gout, coronary artery disease, myocardial infarction, angina pectoris, sleep apnea syndrome, Pickwickian syndrome, fatty liver; cerebral infarction, cerebral thrombosis, transient ischemic attack, orthopedic disorders, arthritis deformans, lumbodynia, emmeniopathy, and infertility.
- co-morbidities include: hypertension, hyperlipidemia, dyslipidemia, glucose intolerance,
- cardiovascular disease cardiovascular disease, sleep apnea, diabetes mellitus, and other obesity-related conditions.
- Treatment of obesity and obesity-related disorders, diseases, syndromes, and conditions refer to the administration of at least one compound of the present invention for the reduction of or maintenance of the body weight of an obese subject.
- the present invention is directed to a method for treating, ameliorating, or preventing metabolic disorders, diseases, syndromes, and conditions; comprising, consisting of, and /or consisting essentially of administering to a subject in need thereof, a therapeutically effe d of formula (I)
- Y is a heteroaryl selected from the group consisting of thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, isoxazolyl, and [l,2,3]thiadiazolyl; wherein Y is optionally substituted with one substituent selected from the group consisting of fluoro, chloro, bromo, Ci- 4 alkyl, and trifluoromethyl;
- Y is a heteroaryl selected from the group consisting of thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, and isoxazolyl;
- Y is optionally substituted with one substituent selected from the group consisting of fluoro, chloro, bromo, and trifluoromethyl;
- Z is a heteroaryl selected from the group consisting of indolyl, indazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, lH-pyrrolo[3,2- b]pyridin-5-yl, lH-thieno[2,3-c]pyrazol-5-yl, lH-pyrrolo[2,3-b]pyridin-5-yl, lH-pyrazolo[3,4-b]pyridin-5-yl, furo[2,3-b]pyridin-2-yl, quinazolinyl, and benzimidazolyl;
- Z is optionally independently substituted with one to two substitutents selected from the group consisting of chloro, fluoro, Ci- 4 alkyl, Ci_ 4 alkoxy, and trifluoromethyl; and Z is substituted with one additional substituent that is
- a heteroaryl selected from the group consisting of thienyl, quinolinyl, pyridinyl, isoxazolyl, benzimidazolyl, furanyl, pyrimidinyl, and pyrazolyl; and wherein said phenyl and heteroaryl substituents of Z are optionally independently substituted with one to two substituents selected from the group consisting of Ci- 4 alkyl; Ci- 4 alkoxy; one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; cyano; carboxy; aminocarbonyl; formyl; nitro; bromo; hydroxy; and Ci- 4 alkylsulfonyl;
- Z is a heteroaryl selected from the group consisting of indazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, lH-pyrrolo[3,2-b]pyridin-5-yl, 1H- thieno[2,3-c]pyrazol-5-yl, lH-pyrrolo[2,3-b]pyridin-5-yl, quinazolinyl, and benzimidazolyl;
- Z is optionally independently substituted with one to two substitutents selected from the group consisting of chloro, fluoro, Ci- 4 alkyl, Ci_ 4 alkoxy, and trifluoromethyl; and Z is substituted with one additional substituent that is
- a heteroaryl selected from the group consisting of pyrimidinyl, thienyl, quinolinyl, pyridinyl, pyrimidinyl, and pyrazolyl;
- phenyl and heteroaryl substituents of Z are optionally independently substituted with one to two substituents selected from the group consisting of Ci- 4 alkyl; Ci- 4 alkoxy; one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; cyano; carboxy; aminocarbonyl; formyl; nitro; bromo; hydroxy; and Ci- 4 alkylsulfonyl;
- a compound of formula (I) is other than a compound wherein Y is thiazol-2-yl and Z is 5-(2-fluoropyridin-3-yl)-lH-benzimidazol-2-yl.
- the present invention is directed to a method for treating, ameliorating, or preventing metabolic disorders, diseases, syndromes, and conditions; comprising, consisting of, and /or consisting essentially of administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I)
- Y is a heteroaryl selected from the group consisting of thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, isoxazolyl, and [l,2,3]thiadiazolyl; wherein Y is optionally substituted with one substituent selected from the group consisting of fluoro, chloro, bromo, Ci- 4 alkyl, and trifluoromethyl; Z is a heteroaryl selected from the group consisting of indolyl, indazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, lH-pyrrolo[3,2- b]pyridin-5-yl, lH-thieno[2,3-c]pyrazol-5-yl, lH-pyrrolo[2,3-b]pyridin-5-yl, lH-pyrazolo[3,4-b]pyridin-5-yl,
- Z is optionally independently substituted with one to two substitutents selected from the group consisting of chloro, fluoro, C 1-4 alkyl, Ci_ 4alkoxy, and trifluoromethyl; and Z is substituted with one additional substituent that is
- a heteroaryl selected from the group consisting of thienyl, quinolinyl, pyridinyl, isoxazolyl, benzimidazolyl, furanyl, pyrimidinyl, and pyrazolyl; and wherein said phenyl and heteroaryl substituents of Z are optionally independently substituted with one to two substituents selected from the group consisting of C 1-4 alkyl; one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; cyano; carboxy; aminocarbonyl; formyl; nitro; bromo; hydroxy; and Ci- 4 alkylsulfonyl; with the proviso that a compound of formula (I) is other than a compound wherein Y is thiazol-2-yl and Z is 5-(2-fluoropyridin-3-yl)-lH-benzimidazol-2-yl.
- the present invention is directed to a method for treating, ameliorating, or preventing metabolic disorders, diseases, syndromes, and conditions; comprising, consisting of, and /or consisting essentially of administering to a subject in need thereof, a therapeutically effe d of formula (I)
- Y is a heteroaryl selected from the group consisting of heteroaryl selected from the group consisting of thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, and isoxazolyl; wherein Y is optionally substituted with one substituent selected from the group consisting of fluoro, chloro, bromo, and trifluoromethyl;
- Z is a heteroaryl selected from the group consisting of indazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, lH-pyrrolo[3,2- b]pyridin-5-yl, lH-thieno[2,3-c]pyrazol-5-yl, lH-pyrrolo[2,3-b]pyridin-5-yl, quinazolinyl, and benzimidazolyl;
- Z is optionally independently substituted with one to two substitutents selected from the group consisting of chloro, fluoro, C 1-4 alkyl, Ci_ 4alkoxy, and trifluoromethyl; and Z is substituted with one additional substituent that is
- a heteroaryl selected from the group consisting of pyrimidinyl, thienyl, quinolinyl, pyridinyl, pyrimidinyl, and pyrazolyl;
- phenyl and heteroaryl substituents of Z are optionally independently substituted with one to two substituents selected from the group consisting of C 1-4 alkyl; one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; cyano; carboxy; aminocarbonyl; formyl; nitro; bromo; hydroxy; and Ci- 4 alkylsulfonyl; with the proviso that a compound of formula (I) is other than a compound wherein Y is thiazol-2-yl and Z is 5-(2-fluoropyridin-3-yl)-lH-benzimidazol-2-yl.
- An embodiment of the present invention is directed to a method for treating, ameliorating, or preventing metabolic disorders, diseases, syndromes, and conditions, including obesity and diabetes; comprising, consisting of, and /or consisting essentially of administering to a subject in need thereof, a therapeutically effective amount of 1-(1- ⁇ [3 -chloro-6-(trifluoromethyl)- 1 -benzothiophen-2-yl]carbonyl ⁇ azetidin-3-yl)-4-( 1,3- thiazol-4-ylcarbonyl)piperazine (Compound 1);
- the present invention is directed to a method for reducing food consumption and/or weight gain of a subject comprising, consisting of, and /or consisting essentially of administering to the subject in need thereof, a therapeutically effective amount of a compound of formula (I)
- Y is a heteroaryl selected from the group consisting of thienyl, furanyl,
- thiazolyl isothiazolyl, oxazolyl, pyrrolyl, isoxazolyl, and [l,2,3]thiadiazolyl; wherein Y is optionally substituted with one substituent selected from the group consisting of fluoro, chloro, bromo, C 1-4 alkyl, and trifluoromethyl; b) Y is a heteroaryl selected from the group consisting of thienyl, furanyl,
- Y is optionally substituted with one substituent selected from the group consisting of fluoro, chloro, bromo, and trifluoromethyl;
- Z is a heteroaryl selected from the group consisting of indolyl, indazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, lH-pyrrolo[3,2- b]pyridin-5-yl, lH-thieno[2,3-c]pyrazol-5-yl, lH-pyrrolo[2,3-b]pyridin-5-yl, lH-pyrazolo[3,4-b]pyridin-5-yl, furo[2,3-b]pyridin-2-yl, quinazolinyl, and benzimidazolyl;
- Z is optionally independently substituted with one to two substitutents selected from the group consisting of chloro, fluoro, C 1-4 alkyl, Ci_ 4alkoxy, and trifluoromethyl; and Z is substituted with one additional substituent that is
- a heteroaryl selected from the group consisting of thienyl, quinolinyl, pyridinyl, isoxazolyl, benzimidazolyl, furanyl, pyrimidinyl, and pyrazolyl; and wherein said phenyl and heteroaryl substituents of Z are optionally independently substituted with one to two substituents selected from the group consisting of Ci-4alkyl; Ci-4alkoxy; one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; cyano; carboxy; aminocarbonyl; formyl; nitro; bromo; hydroxy; and Ci- 4 alkylsulfonyl;
- Z is a heteroaryl selected from the group consisting of indazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, lH-pyrrolo[3,2-b]pyridin-5-yl, 1H- thieno[2,3-c]pyrazol-5-yl, lH-pyrrolo[2,3-b]pyridin-5-yl, quinazolinyl, and benzimidazolyl;
- Z is optionally independently substituted with one to two substitutents selected from the group consisting of chloro, fluoro, C 1-4 alkyl, Ci_ 4alkoxy, and trifluoromethyl; and Z is substituted with one additional substituent that is
- a heteroaryl selected from the group consisting of pyrimidinyl, thienyl, quinolinyl, pyridinyl, pyrimidinyl, and pyrazolyl;
- phenyl and heteroaryl substituents of Z are optionally independently substituted with one to two substituents selected from the group consisting of one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; cyano; carboxy; aminocarbonyl; formyl; nitro; bromo; hydroxy; and Ci- 4 alkylsulfonyl;
- a compound of formula (I) is other than a compound wherein Y is thiazol-2-yl and Z is 5-(2-fluoropyridin-3-yl)-lH-benzimidazol-2-yl.
- the present invention is directed to a method for reducing food consumption and/or weight gain of a subject comprising, consisting of, and /or consisting essentially of administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I)
- Y is a heteroaryl selected from the group consisting of thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, isoxazolyl, and [l,2,3]thiadiazolyl; wherein Y is optionally substituted with one substituent selected from the group consisting of fluoro, chloro, bromo, C 1-4 alkyl, and trifluoromethyl;
- Z is a heteroaryl selected from the group consisting of indolyl, indazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, lH-pyrrolo[3,2- b]pyridin-5-yl, lH-thieno[2,3-c]pyrazol-5-yl, lH-pyrrolo[2,3-b]pyridin-5-yl, lH-pyrazolo[3,4-b]pyridin-5-yl, furo[2,3-b]pyridin-2-yl, quinazolinyl, and benzimidazolyl;
- Z is optionally independently substituted with one to two substitutents selected from the group consisting of chloro, fluoro, C 1-4 alkyl, Ci_ 4alkoxy, and trifluoromethyl; and Z is substituted with one additional substituent that is
- a heteroaryl selected from the group consisting of thienyl, quinolinyl, pyridinyl, isoxazolyl, benzimidazolyl, furanyl, pyrimidinyl, and pyrazolyl; and wherein said phenyl and heteroaryl substituents of Z are optionally independently substituted with one to two substituents selected from the group consisting of C 1-4 alkyl; one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; cyano; carboxy; aminocarbonyl; formyl; nitro; bromo; hydroxy; and Ci- 4 alkylsulfonyl; with the proviso that a compound of formula (I) is other than a compound wherein Y is thiazol-2-yl and Z is 5-(2-fluoropyridin-3-yl)-lH-benzimidazol-2-yl.
- the present invention is directed to a method for reducing food consumption and/or weight gain of a subject comprising, consisting of, and /or consisting essentially of administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I)
- Y is a heteroaryl selected from the group consisting of heteroaryl selected from the group consisting of thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, and isoxazolyl;
- Y is optionally substituted with one substituent selected from the group consisting of fluoro, chloro, bromo, and trifluoromethyl;
- Z is a heteroaryl selected from the group consisting of indazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, lH-pyrrolo[3,2- b]pyridin-5-yl, lH-thieno[2,3-c]pyrazol-5-yl, lH-pyrrolo[2,3-b]pyridin-5-yl, quinazolinyl, and benzimidazolyl;
- Z is optionally independently substituted with one to two substitutents selected from the group consisting of chloro, fluoro, C 1-4 alkyl, Ci 4alkoxy, and trifluoromethyl; and Z is substituted with one additional substituent that is
- phenyl or (ii) a heteroaryl selected from the group consisting of pyrimidinyl, thienyl, quinolinyl, pyridinyl, pyrimidinyl, and pyrazolyl;
- phenyl and heteroaryl substituents of Z are optionally independently substituted with one to two substituents selected from the group consisting of C 1-4 alkyl; one to three fluoro or chloro substituents; trifluoromethyl; trifluoromethoxy; cyano; carboxy; aminocarbonyl; formyl; nitro; bromo; hydroxy; and Ci- 4 alkylsulfonyl; with the proviso that a compound of formula (I) is other than a compound wherein Y is thiazol-2-yl and Z is 5-(2-fluoropyridin-3-yl)-lH-benzimidazol-2-yl.
- the present invention is directed to a method for reducing food consumption and/or weight gain of a subject comprising, consisting of, and /or consisting essentially of administering to a subject in need thereof, a therapeutically effective amount of
- salts of a compound of formula (I) refer to non-toxic "pharmaceutically acceptable salts.”
- Other salts may, however, be useful in the preparation of a compound of formula (I) or of its pharmaceutically acceptable salts thereof.
- Suitable pharmaceutically acceptable salts of a compound of formula (I) include acid addition salts which can, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
- suitable pharmaceutically acceptable salts thereof may include alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and salts formed with suitable organic ligands, such as quaternary ammonium salts.
- representative pharmaceutically acceptable salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,
- hexylresorcinate hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N- methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.
- methanesulfonic acid naphthalene-2-sulfonic acid, naphthalene- 1,5-disulfonic acid, 1- hydroxy -2 -naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4- amino-salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; and bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylened
- Embodiments of the present invention include prodrugs of a compound of formula (I).
- prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound.
- administering encompasses the treatment or prevention of the various diseases, conditions, syndromes and disorders described with the compound specifically disclosed or with a compound that may not be specifically disclosed, but which converts to the specified compound in vivo after administration to a patient.
- crystalline forms for a compound of formula (I) may exist as polymorphs and as such are intended to be included in the present invention.
- some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
- solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
- the term compound as used herein, is meant to include solvated compounds of formula (I).
- any of the processes for preparation of a compound of formula (I) of the various embodiments of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, Second Edition, J.F.W. McOmie, Plenum Press, 1973; T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, 1999.
- the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
- a compound of formula (I) and the embodiments of the present invention can be administered alone, they will generally be administered in admixture with a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient and/or a pharmaceutically acceptable diluent selected with regard to the intended route of administration and standard pharmaceutical or veterinary practice.
- a pharmaceutically acceptable carrier e.g., a pharmaceutically acceptable sulfate, a pharmaceutically acceptable sulfate, or a pharmaceutically acceptable diluent selected with regard to the intended route of administration and standard pharmaceutical or veterinary practice.
- particular embodiments of the present invention are directed to pharmaceutical and veterinary compositions comprising a compound of formula (I) and at least one pharmaceutically acceptable carrier, pharmaceutically acceptable excipient, and/or pharmaceutically acceptable diluent.
- a compound of formula (I) may be admixed with any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilizing agent(s), and combinations thereof.
- Solid oral dosage forms such as tablets or capsules, containing the compounds of the present invention may be administered in at least one dosage form at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations.
- Additional oral forms in which the present inventive compounds may be administered include elixirs, solutions, syrups, and suspensions; each optionally containing flavoring agents and coloring agents.
- a compound of formula (I) can be administered by inhalation
- intratracheal or intranasal or in the form of a suppository or pessary, or it may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
- a cream comprising, consisting of, and/or consisting essentially of an aqueous emulsion of polyethylene glycols or liquid paraffin.
- It can also be incorporated, at a concentration of between about 1 % and about 10 % by weight of the cream, into an ointment comprising, consisting of, and/or consisting essentially of a white wax or white soft paraffin base together with any stabilizers and preservatives as may be required.
- An alternative means of administration includes transdermal administration by using a skin or transdermal patch.
- compositions of the present invention can also be injected parenterally, for example intracavernosally, intravenously, intramuscularly, subcutaneously, intradermally or intrathecally.
- the compositions will also include at least one of a suitable carrier, a suitable excipient, and a suitable diluent.
- compositions of the present invention are best used in the form of a sterile aqueous solution that may contain other substances, for example, enough salts and monosaccharides to make the solution isotonic with blood.
- compositions of the present invention may be administered in the form of tablets or lozenges, which can be formulated in a conventional manner.
- compositions containing a compound of formula (I) as the active ingredient can be prepared by mixing a compound of formula (I) with a pharmaceutically acceptable carrier, a
- diluent a pharmaceutically acceptable diluent
- excipient a pharmaceutically acceptable excipient according to conventional pharmaceutical compounding techniques.
- the carrier, excipient, and diluent may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral, etc.).
- suitable carriers, excipients and diluents include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
- suitable carriers, excipients and diluents include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
- Solid oral preparations also may be optionally coated with substances, such as, sugars, or be enterically -coated so as to modulate the major site of absorption and
- the carrier, excipient and diluent will usually include sterile water, and other ingredients may be added to increase solubility and preservation of the composition.
- injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives, such as solubilizers and preservatives.
- a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition thereof includes a dose range from about 0.1 mg to about 3000 mg, or any particular amount or range therein, in particular from about 1 mg to about 1000 mg, or any particular amount or range therein, or, more particularly, from about 10 mg to about 500 mg, or any particular amount or range therein, of active ingredient in a regimen of about 1 to about 4 times per day for an average (70 kg) human; although, it is apparent to one skilled in the art that the therapeutically effective amount for a compound of formula (I) will vary as will the diseases, syndromes, conditions, and disorders being treated.
- a pharmaceutical composition is preferably provided in the form of tablets containing about 0.01, about 10, about 50, about 100, about 150, about 200, about 250, and about 500 milligrams of a compound of formula (I).
- a compound of formula (I) may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three and four times daily.
- Optimal dosages of a compound of formula (I) to be administered may be readily determined and will vary with the particular compound used, the mode of administration, the strength of the preparation and the advancement of the disease, syndrome, condition or disorder.
- factors associated with the particular subject being treated including subject gender, age, weight, diet and time of administration, will result in the need to adjust the dose to achieve an appropriate therapeutic level and desired therapeutic effect.
- the above dosages are thus exemplary of the average case. There can be, of course, individual instances wherein higher or lower dosage ranges are merited, and such are within the scope of this invention.
- a compound of formula (I) may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever use of a compound of formula (I) is required for a subject in need thereof.
- a compound of formula (I) is useful in methods for treating and preventing a disease, a syndrome, a condition or a disorder in a subject, including an animal, a mammal and a human in which the disease, the syndrome, the condition or the disorder is affected by the modulation of the MGL enzyme.
- Such methods comprise, consist of and/or consist essentially of administering to a subject, including an animal, a mammal, and a human in need of such treatment or prevention a therapeutically effective amount of a compound of formula (I).
- a compound of formula (I) is useful for preventing or treating metabolic diseases, including obesity and diabetes.
- a compound of formula (I) is useful for reducing food consumption and/or weight gain.
- Scheme A illustrates a route for the synthesis compounds of formula (I), wherein Y and Z are as defined herein.
- a compound of formula Al wherein PG is a conventional amino protecting group such as, Boc, Fmoc, Cbz, and the like, is either commercially available or may be prepared by known methods described in the scientific literature.
- a compound of formula Al in the presence of a non-nucleophilic base such as, pyridine, may be treated with trifluoroacetic anhydride to afford a compound of formula hi. Removal of the protecting group (PG) by conventional methods affords a compound of formula A3.
- a compound of formula A3 may be treated with a compound of formula A4 in the presence of a hindered amine base such as, DIPEA, to afford a compound of formula A5.
- a compound of formula A6 may be coupled with a carboxylic acid of formula A7 wherein Q is hydroxy, in the presence of an appropriate coupling agent such as, HATU, DCC, EDC, HBTU, PyBrOP, and the like; optionally in the presence of a base such as DIPEA, to afford an amide of formula A8.
- an acid chloride of formula A7 wherein Q is chloro may be used to effect the acylation of a compound of formula A6.
- a non-nucleophilic base such as pyridine may be added to afford an amide of formula A8.
- Removal of the trifluoroacetyl group of a compound of formula A8 may be accomplished by the action of potassium carbonate or TEA in the presence of an alcoholic solvent such as, methanol, to afford a compound of formula A9.
- a compound of formula A9 may be acylated with a carboxylic acid or acid chloride of formula A10, wherein Q is hydroxy or chloride, respectively.
- a coupling agent such as, HATU, DCC, EDC, HBTU, PyBrOP, and the like
- a base such as, DIPEA
- the acylation is effected by the addition of the corresponding acid chloride
- the addition of a non-nucleophilic base such as pyridine affords a compound of formula (I).
- Scheme B illustrates an alternate route for the synthesis compounds of formula
- a compound of formula Al may be acylated with a compound of formula A10 using methods and reagents previously described in Scheme A to afford a compound of formula Bl.
- a compound of formula B2 may be treated with a compound of formula A4 in the presence of a hindered amine base such as, DIPEA, using the methods described in Scheme A to afford a compound of formula B3.
- a hindered amine base such as, DIPEA
- Treatment of a compound of formula B3 with 1- chloroethyl chloroformate followed by methanolysis affords the corresponding amine of formula B4.
- An acylation reaction with a compound of formula A7 using the methods described in Scheme A affords the corresponding compound of formula (I).
- a compound of formula B2 may be treated with a ketone of formula CI in the presence of decaborane or a reducing agent such as, sodium triacetoxyborohydride, to afford a compound of formula C2. Removal of the Boc-amino protecting group, using conventional reagents and methods, affords a compound of formula B4. Coupling with a compound of formula A7 as described herein provides a compound of formula (I).
- Scheme D illustrates a route for the synthesis compounds of formula (I), wherein Y and Z are as defined herein.
- a compound of formula Al may be treated with a compound of formula A4 to afford a compound of formula Dl.
- a compound of formula D2 may be coupled with a compound of formula AlO (wherein Q is OH) in the presence of a coupling agent such as, HATU, DCC, EDC, HBTU, PyBrOP, and the like; optionally in the presence of a base such as, DIPEA, to afford a compound of formula B3.
- a coupling agent such as, HATU, DCC, EDC, HBTU, PyBrOP, and the like
- DIPEA a base
- the acylation is effected by the addition of the corresponding acid chloride
- a non nucleophilic base such as pyridine affords a compound of formula B3.
- Removal of the benzhydryl group as described herein, followed by acylation with a compound of formula A7 affords a compound of formula (I).
- Scheme E illustrates a route for the synthesis compounds of formula (I)-E, wherein Y is as defined herein, and Z is a heteroaryl group, substituted with an optionally substituted phenyl or heteroaryl group, as defined herein.
- a compound of formula CI may be deprotected using conventional methods to afford the corresponding free amine of formula El.
- a ketone of formula E3 may undergo a reductive amination with a compound of formula Al in the presence of decaborane, sodium triacetoxyborohydride, and the like, to afford a compound of formula E4.
- the free amine of formula E5 may be acylated with a compound of formula A10 as described herein to afford a compound of formula E6.
- the substituted Ar E substituent of formula E6 may be treated with an appropriately substituted Ar E i- boronic acid or ester (E7), or an appropriately substituted trialkyltin reagent, trialkylsilane, and the like (wherein Ar E i is an optionally substituted phenyl or heteroaryl as defined herein), using one of a variety of coupling reactions (e.g., Suzuki, Stille, and Hiyama reactions) that are well known to those versed in the art; in the presence of a suitable catalyst; and in the presence of a base such as, cesium carbonate, sodium bicarbonate, potassium fluoride, and the like; to afford a compound of the formula (I)-E.
- an appropriately substituted Ar E i- boronic acid or ester E7
- an appropriately substituted trialkyltin reagent, trialkylsilane, and the like wherein Ar E i is an optionally substituted phenyl or heteroaryl as defined herein
- reaction mixture was diluted with ethyl ether, washed with aq NaHC03 and aq NaCl, dried over Na 2 S0 4 and concentrated. Purification by flash column chromatography (silica gel, 3% MeOH/CH 2 Cl 2 ) gave 2h (290 mg).
- IC50 values for compounds of formula (I) were determined using a spreadsheet, i.e., Excel® from Microsoft, from a fit of the equation to the
- percent vehicle (2-AG accumulation in the presence of compound/2-AG accumulation in vehicle) x 100.
- ThermoFluor (TF) assay is a 384-well microplate-based binding assay that measures thermal stability of proteins 1 ' 2 .
- the experiments were carried out using ThermoFluor instruments available from Johnson & Johnson Pharmaceutical Research & Development, LLC. TF dye used in all experiments was 1,8-ANS (Invitrogen: A- 47).
- Screening compound plates contained 100% DMSO compound solutions at a single concentration.
- compounds were arranged in a pre-dispensed plate (Greiner Bio-one: 781280), wherein compounds were serially diluted in 100% DMSO across 11 columns within a series. Columns 12 and 24 were used as DMSO reference and contained no compound.
- the compound aliquots 46 nL were robotically predispensed directly into 384-well black microplates (Abgene: TF-0384/k) using the Hummingbird liquid handler.
- protein and dye solutions were added to achieve the final assay volume of 3 ⁇ .
- the assay solutions were overlayed with 1 ⁇ ⁇ of silicone oil (Fluka, type DC 200: 85411) to prevent evaporation.
- Bar-coded microplates were robotically loaded onto a thermostatically controlled PCR-type thermal block and then heated from 40 to 90 °C degrees at a ramp- rate of 1 °C/min for all experiments. Fluorescence was measured by continuous illumination with UV light (Hamamatsu LC6), supplied via fiber optics and filtered through a band-pass filter (380-400 nm; > 6 OD cutoff). Fluorescence emission of the entire 384-well plate was detected by measuring light intensity using a CCD camera (Sensys, Roper Scientific) filtered to detect 500 ⁇ 25 nm, resulting in simultaneous and independent readings of all 384 wells.
- Rats were fed ad libitum with a standard diet (Rodent Diet 5001, PMI Nutrition International, Indiana).
- a compound of formula (I) was administered orally by metal gavage needle to male and female rats (5 per group) for 5 consecutive days at 0, 15, and 50 mg/kg/day. Rats were weighed predose and on days 1 and 4. Clinical observations were recorded prior to dosing, at 2 hours post-dose each day. Rats were fasted overnight on Day 4 and blood was collected on Day 5 from the retro-orbital sinus following anesthesia with a 70/30% carbon dioxide/oxygen mixture. Blood was collected into tubes containing tripotassium EDTA for hematology panel and no additive for serum chemistry determinations. Rats were euthanized by CO 2 inhalation and thoracic and abdominal cavities were examined and weights of liver determined.
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP12775378.8A EP2760450A1 (en) | 2011-09-30 | 2012-09-27 | Monoacylglycerol lipase inhibitors for the treatment of metabolic diseases and related disorders |
KR1020147011424A KR20140068243A (en) | 2011-09-30 | 2012-09-27 | Monoacylglycerol lipase inhibitors for the treatment of metabolic diseases and related disorders |
CA2849782A CA2849782A1 (en) | 2011-09-30 | 2012-09-27 | Monoacylglycerol lipase inhibitors for the treatment of metabolic diseases and related disorders |
JP2014533705A JP2014528428A (en) | 2011-09-30 | 2012-09-27 | Monoacylglycerol lipase inhibitors for the treatment of metabolic disorders and related disorders |
MX2014003879A MX2014003879A (en) | 2011-09-30 | 2012-09-27 | Monoacylglycerol lipase inhibitors for the treatment of metabolic diseases and related disorders. |
CN201280059367.XA CN103957916A (en) | 2011-09-30 | 2012-09-27 | Monoacylglycerol lipase inhibitors for the treatment of metabolic diseases and related disorders |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161541394P | 2011-09-30 | 2011-09-30 | |
US61/541,394 | 2011-09-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2013049289A1 true WO2013049289A1 (en) | 2013-04-04 |
Family
ID=47046854
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2012/057465 WO2013049289A1 (en) | 2011-09-30 | 2012-09-27 | Monoacylglycerol lipase inhibitors for the treatment of metabolic diseases and related disorders |
Country Status (10)
Country | Link |
---|---|
US (1) | US8987247B2 (en) |
EP (1) | EP2760450A1 (en) |
JP (1) | JP2014528428A (en) |
KR (1) | KR20140068243A (en) |
CN (1) | CN103957916A (en) |
AR (1) | AR088208A1 (en) |
CA (1) | CA2849782A1 (en) |
MX (1) | MX2014003879A (en) |
TW (1) | TW201313708A (en) |
WO (1) | WO2013049289A1 (en) |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015099196A1 (en) | 2013-12-26 | 2015-07-02 | Takeda Pharmaceutical Company Limited | 4-(piperrazin-1-yl)-pyrrolidin-2-one compounds as monoacylglycerol lipase (magl) inhibitors |
WO2017170830A1 (en) | 2016-03-31 | 2017-10-05 | 武田薬品工業株式会社 | Heterocyclic compound |
WO2017171100A1 (en) | 2016-03-31 | 2017-10-05 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
US10106556B2 (en) | 2015-03-30 | 2018-10-23 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
WO2019065791A1 (en) | 2017-09-29 | 2019-04-04 | 武田薬品工業株式会社 | Heterocyclic compound |
WO2021160602A1 (en) * | 2020-02-10 | 2021-08-19 | Janssen Pharmaceutica Nv | Monoacylglycerol lipase modulators |
US11505546B2 (en) | 2020-03-26 | 2022-11-22 | Janssen Pharmaceutica Nv | Azaspirocycles as monoacylglycerol lipase modulators |
US11512059B2 (en) | 2020-03-26 | 2022-11-29 | Janssen Pharmaceutica Nv | Aminocyclobutanes as monoacylglycerol lipase modulators |
US11787798B2 (en) | 2020-03-26 | 2023-10-17 | Janssen Pharmaceutica Nv | Aryl piperidines as monoacylglycerol lipase modulators |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102011556B1 (en) * | 2016-07-19 | 2019-08-16 | 연세대학교 산학협력단 | Composition for preventing, improving or treating hepatic steatosis or nonalcoholic fatty liver comprising enzyme degrading 2-monoacylglycerol |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008145843A1 (en) * | 2007-04-18 | 2008-12-04 | Sanofi-Aventis | Triazolopyridine carboxamide derivatives and triazolopyrimidine carboxamide derivatives, preparation thereof and therapeutic use thereof |
WO2009117444A1 (en) * | 2008-03-17 | 2009-09-24 | Northeastern University | Inhibitors of fatty acid amide hydrolase and monoacylglycerol lipase for modulation of cannabinoid receptors |
WO2010124082A1 (en) * | 2009-04-22 | 2010-10-28 | Janssen Pharmaceutica Nv | Azetidinyl diamides as monoacylglycerol lipase inhibitors |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2421535A1 (en) * | 2009-04-22 | 2012-02-29 | Janssen Pharmaceutica N.V. | Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitors |
-
2012
- 2012-09-27 WO PCT/US2012/057465 patent/WO2013049289A1/en active Application Filing
- 2012-09-27 JP JP2014533705A patent/JP2014528428A/en not_active Withdrawn
- 2012-09-27 US US13/628,428 patent/US8987247B2/en active Active
- 2012-09-27 KR KR1020147011424A patent/KR20140068243A/en not_active Application Discontinuation
- 2012-09-27 MX MX2014003879A patent/MX2014003879A/en unknown
- 2012-09-27 CN CN201280059367.XA patent/CN103957916A/en active Pending
- 2012-09-27 CA CA2849782A patent/CA2849782A1/en not_active Abandoned
- 2012-09-27 EP EP12775378.8A patent/EP2760450A1/en not_active Withdrawn
- 2012-09-28 TW TW101135711A patent/TW201313708A/en unknown
- 2012-10-01 AR ARP120103650A patent/AR088208A1/en not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008145843A1 (en) * | 2007-04-18 | 2008-12-04 | Sanofi-Aventis | Triazolopyridine carboxamide derivatives and triazolopyrimidine carboxamide derivatives, preparation thereof and therapeutic use thereof |
WO2009117444A1 (en) * | 2008-03-17 | 2009-09-24 | Northeastern University | Inhibitors of fatty acid amide hydrolase and monoacylglycerol lipase for modulation of cannabinoid receptors |
WO2010124082A1 (en) * | 2009-04-22 | 2010-10-28 | Janssen Pharmaceutica Nv | Azetidinyl diamides as monoacylglycerol lipase inhibitors |
Non-Patent Citations (15)
Title |
---|
"Design of Prodrugs", 1985, ELSEVIER |
BARBA ET AL., THE LANCET, vol. 363, 2004, pages 157 - 162 |
BUETTNER R. ET AL., OBESITY (SILVER SPRING, vol. 15, 2007, pages 798 - 808 |
CHON ET AL., FASEB, vol. 22, 2008, pages 807 - 12 |
DINH ET AL., PROC. NAT. ACAD. SCI., vol. 99, 2002, pages 10819 - 10824 |
J.F.W. MCOMIE: "Protective Groups in Organic Chemistry", 1973, PLENUM PRESS |
MATULIS, D.; KRANZ, J. K.; SALEMME, F. R.; TODD, M. J., BIOCHEMISTRY, vol. 44, 2005, pages 5258 - 66 |
PANTOLIANO, M. W; PETRELLA, E. C; KWASNOSKI, J. D; LOBANOV, V. S; MYSLIK, J; GRAF, E; CARVER, T; ASEL, E; SPRINGER, B. A; LANE, P, JBIOMOL SCREEN, vol. 6, 2001, pages 429 - 40 |
SCHLOSSBURG ET AL., NAT. NEUROSCI., vol. 13, no. 9, September 2010 (2010-09-01), pages 1113 - 9 |
SOERHEDE-WINZELL, M., DIABETES, vol. 53, no. 3, December 2004 (2004-12-01), pages S215 - S219 |
T.W. GREENE; P.G.M. WUTS: "Protective Groups in Organic Synthesis", 1991, JOHN WILEY & SONS |
T.W. GREENE; P.G.M. WUTS: "Protective Groups in Organic Synthesis", 1999, JOHN WILEY & SONS |
TASCHLER ET AL., JBC, vol. 286, no. 20, 2011, pages 17467 - 77 |
VAN HEEK, M. ET AL., J CLIN INVEST, vol. 99, 1997, pages 385 - 390 |
WALL ET AL., VIRUS RES., vol. 52, 1997, pages 152 - 167 |
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2017502957A (en) * | 2013-12-26 | 2017-01-26 | 武田薬品工業株式会社 | 4- (Piperazin-1-yl) -pyrrolidin-2-one compounds as monoacylglycerol lipase (MAGL) inhibitors |
US9624170B2 (en) | 2013-12-26 | 2017-04-18 | Takeda Pharmaceutical Company Limited | 4-(piperrazin-1-yl)-pyrrolidin-2-one compounds as monoacylglycerol lipase (MAGL) inhibitors |
WO2015099196A1 (en) | 2013-12-26 | 2015-07-02 | Takeda Pharmaceutical Company Limited | 4-(piperrazin-1-yl)-pyrrolidin-2-one compounds as monoacylglycerol lipase (magl) inhibitors |
US10106556B2 (en) | 2015-03-30 | 2018-10-23 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
US10610520B2 (en) | 2016-03-31 | 2020-04-07 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
WO2017171100A1 (en) | 2016-03-31 | 2017-10-05 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
US10323026B2 (en) | 2016-03-31 | 2019-06-18 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
WO2017170830A1 (en) | 2016-03-31 | 2017-10-05 | 武田薬品工業株式会社 | Heterocyclic compound |
WO2019065791A1 (en) | 2017-09-29 | 2019-04-04 | 武田薬品工業株式会社 | Heterocyclic compound |
US11274101B2 (en) | 2017-09-29 | 2022-03-15 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
WO2021160602A1 (en) * | 2020-02-10 | 2021-08-19 | Janssen Pharmaceutica Nv | Monoacylglycerol lipase modulators |
US11708359B2 (en) | 2020-02-10 | 2023-07-25 | Janssen Pharmaceutica Nv | Monoacylglycerol lipase modulators |
US11505546B2 (en) | 2020-03-26 | 2022-11-22 | Janssen Pharmaceutica Nv | Azaspirocycles as monoacylglycerol lipase modulators |
US11512059B2 (en) | 2020-03-26 | 2022-11-29 | Janssen Pharmaceutica Nv | Aminocyclobutanes as monoacylglycerol lipase modulators |
US11787798B2 (en) | 2020-03-26 | 2023-10-17 | Janssen Pharmaceutica Nv | Aryl piperidines as monoacylglycerol lipase modulators |
US11897872B2 (en) | 2020-03-26 | 2024-02-13 | Janssen Pharmaceutica Nv | Azaspirocycles as monoacylglycerol lipase modulators |
US11919870B2 (en) | 2020-03-26 | 2024-03-05 | Janssen Pharmaceutica Nv | Aminocyclobutanes as monoacylglycerol lipase modulators |
Also Published As
Publication number | Publication date |
---|---|
KR20140068243A (en) | 2014-06-05 |
US20130085129A1 (en) | 2013-04-04 |
US8987247B2 (en) | 2015-03-24 |
CA2849782A1 (en) | 2013-04-04 |
TW201313708A (en) | 2013-04-01 |
AR088208A1 (en) | 2014-05-14 |
JP2014528428A (en) | 2014-10-27 |
EP2760450A1 (en) | 2014-08-06 |
MX2014003879A (en) | 2014-09-01 |
CN103957916A (en) | 2014-07-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8987247B2 (en) | Monoacylglycerol lipase inhibitors for the treatment of metabolic diseases and related disorders | |
ES2871821T3 (en) | Heteroaryl inhibitors of PDE4 | |
WO2011007819A1 (en) | Pharmaceutical product containing lactam or benzene sulfonamide compound | |
NO20171941A1 (en) | Methods of treating a neurogenerative disease | |
WO2010123139A1 (en) | Arylcarboxamide derivative having sulfamoyl group | |
TWI495637B (en) | Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitors | |
RU2434851C1 (en) | Cyclic n,n'-diarylthioureas or n,n'-diarylureas - antagonists of androgen receptors, anti-cancer medication, method of obtaining and application | |
WO1997012615A1 (en) | Benzimidazole derivatives as 15-lo inhibitors | |
EP2925129A1 (en) | Pro-neurogenic compounds | |
WO2010126002A1 (en) | Pharmaceutical product containing heterocyclic sulfonamide compound | |
CN103080103A (en) | Oxopiperazine-azetidine amides and oxodiazepine-azetidine amides as monoacylglycerol lipase inhibitors | |
TR201815342T4 (en) | Use of benzimidazole-proline derivatives. | |
US9375430B2 (en) | Monoacylglycerol lipase inhibitors for the treatment of metabolic diseases and related disorders | |
WO2010085799A2 (en) | Compositions and method for the treatment of parkinson's disease | |
WO2016015159A1 (en) | Azaindoline compounds as granzyme b inhibitors | |
US6638951B1 (en) | Benzamide derivatives and drugs containing the same | |
CN1162151C (en) | Patassium channel activators | |
JP2021127289A (en) | Condensed pyrimidine derivative | |
JP2018087173A (en) | Anti-malignant brain tumor therapeutic agent | |
CN102993186B (en) | A kind of novel bridged piperazine derivatives | |
KR100556559B1 (en) | 2-4-4-4,5-dichloro-2-methylimidazol-1-ylbutyl-1-piperazinyl-5-fluoropyrimidine, preparation and therapeutic use | |
EA016869B1 (en) | COMBINATION OF TRIAZINE DERIVATIVES AND PPARa AGONISTS | |
TW200827367A (en) | A therapeutic agent for irritable bowel syndrome |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 12775378 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2849782 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2014533705 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2014/003879 Country of ref document: MX |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 20147011424 Country of ref document: KR Kind code of ref document: A |
|
REEP | Request for entry into the european phase |
Ref document number: 2012775378 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2012775378 Country of ref document: EP |