tetrazole compounds and methods for making and using them

专利摘要:
Tetrazole Compounds and Methods for Making and Using Them Here are described tetrazole compounds and their use in the treatment of medical disorders such as obesity. Pharmaceutical compositions and methods for making various tetrazole compounds are provided. The compounds are contemplated to have activity against methionyl aminopeptidase 2.
公开号:BR112013018771A2
申请号:R112013018771
申请日:2012-01-26
公开日:2019-09-17
发明作者:Joan Dyke Hazel；Mary Cramp Susan；David Pallin Thomas
申请人:Zafgen Inc；
IPC主号:

专利说明:

“TETRAZOL COMPOUNDS AND METHODS FOR MAKING AND USING THEM”
CROSS REFERENCE TO RELATED ORDERS
This application claims the benefit and priority of Provisional Patent Application US 61 / 436,265, filed on January 26, 2011, hereby incorporated by reference in its entirety.
FUNDAMENTALS
It is reported that more than 1.1 billion people worldwide are overweight. Obesity is estimated to affect more than 90 million people in the United States alone. Twenty-five percent of the population in the United States over the age of twenty is considered clinically obese. Although being overweight or obese presents problems (for example, restricted mobility, discomfort in tight spaces, such as theater or airplane seats, social difficulties, etc.), these conditions, in particular clinical obesity, affect other aspects of health , that is, diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being overweight or obese. The estimated mortality from obesity-related conditions in the United States is more than 300,000 per year (O'Brien et al. Amer J Surgery (2002) 184: 4S-8S; and Hill et al. (1998) Science, 280: 1371 ).
There is no curative treatment for overweight or obese. Traditional pharmacotherapies for treating an overweight or obese subject, such as serotonin and noradrenergic reuptake inhibitors, noradrenergic reuptake inhibitors, selective serotonin reuptake inhibitors, intestinal lipase inhibitors, or surgery, such as stomach reduction or gastric banding , have been shown to provide minimal short-term benefits or significant rates of recidivism, and have also shown harmful side effects to patients.
MetAP2 encodes a protein that works at least in part by enzymatically removing the amino terminal methionine residue from certain recently translated proteins, such as glyceraldehyde-3-phosphate dehydrogenase (Warder et al. (2008) J Proteome Res 7: 4807). Increased expression of the MetAP2 gene has historically been associated with various forms of cancer. Molecules that inhibit the enzymatic activity of MetAP2 have been identified and explored for their usefulness in the treatment of various types of tumor (Wang et al. (2003) Cancer Res 63: 7861) and infectious diseases, such as microsporidiosis, leishmaniasis and malaria (Zhang et al. (2002) J Biomed Sci.9: 34). Notably, inhibition of MetAP2 activity in obese and obese-diabetic animals leads to a reduction in body weight in part by increasing fat oxidation in part by reducing food consumption (Rupnick et al. (2002) Proc Natl Acad Sei USA 99 : 10730).
Such MetAP2 inhibitors may also be useful for patients with excess
2/52 adiposity and adiposity-related conditions including type 2 diabetes, fatty liver disease and cardiovascular disease (via, for example, improving insulin resistance, reducing liver lipid content and reducing cardiac workload). Thus, compounds capable of modulating MetAP2 are needed to target the treatment of obesity and related diseases as well as other diseases favorably responsive to MetAP2 modulator treatment.
SUMMARY
Described here are, for example, compounds that can be modulators of MetAP2, use of the compounds as medicinal agents, processes for preparing the compounds, pharmaceutical compositions containing one or more of the compounds as active ingredients either alone or in combination with other agents, and use of compounds in the manufacture of drugs for use in inhibiting MetAP2 activity in warm-blooded animals such as humans. In some embodiments, the compounds may be useful for the treatment of obesity, type 2 diabetes and / or other conditions associated with obesity. Pharmaceutical compositions are further provided comprising at least one disclosed compound and a pharmaceutically acceptable carrier.
In one embodiment, compounds represented by Formula I are provided here:
and pharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof, in which:
A is a ring selected from the group consisting of phenyl, heteroaryl, C ₃ . ₆ cycloalkyl, and heterocyclyl, wherein heteroaryl is a 5-6 membered ring having one, two or three heteroatoms each independently selected from N, O, or S, where heterocyclyl is a 4-7 membered ring; B is selected from the group consisting of a bond or (CR ^B1 R ^B2 );
R ¹ is selected from the group consisting of hydrogen, halogen, hydroxyl, cyan, Cq. ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ . ₆ cycloalkyl, C ^ and alkoxy, C ₃ . ₆ alkenyloxy, C ₃ . ₆ alkynyloxy, C ₃ . ₆ cycloalkoxy, Cvealkyl-S / OV where w is 0, 1, or 2, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclyl-C- | ₆ alkyl, and heterocyclyl-Cvgalkoxy, where heteroaryl is a 5-6 membered ring having one, two or three heteroatoms each independently selected from N, O, or S, where heteroaryl is optionally substituted with one or more substituents each one independently selected from R ^b , where heterocyclyl is a 4-7 membered ring optionally substituted by one or more substituents each independently selected from R ^c , and where when heterocyclyl contains an -NH- fraction, that -NH- fraction is optionally
3/52 replaced by R ^d , where C2.6alkenyl, C2.6alkenyl, C3.6alkenyloxy, and C3_6alkynyloxy are each independently optionally substituted by one or more substituents each independently selected from R ^p , where C1. ₆ alkyl and C ^ alkoxy are each independently optionally substituted by one or more substituents each independently selected from R ^p , where C ₃ . ₆ cycloalkyl and C ₃ . ₆ cycloalkoxy are each independently optionally substituted by one or more substituents each independently selected from R ^p
R ² is selected from the group consisting of halogen, hydroxyl, cyano, C ^ ealalkyl, C2. 6 alkenyl, C2.6alkynyl, C3.6cycloalkyl, Cvealoxy, C3.6alkenyloxy, C3_6 alkynyloxy, C3. 6cycloalkyloxy, C4-alkyl-CIO-C3_6cycloalkyl-C1_4alkyl-, Cs ^ cycloalkyl-C ^ alkoxy-, phenyl-C® 6alkyl-, phenyl, phenoxy, phenyl-Cvealoxy-, heteroaryl, heteroaryl-heteroaryl, heteroaryl-heteroaryl; heteroaryl-C1-6alkoxy, heterocyclyl-C1-6alkyl-, and heterocyclyl-Ch-ealcoxy-, where heteroaryl is a 5-6 membered ring having one, two or three heteroatoms each independently selected from N, O, or S, in which heteroaryl and phenyl group are each independently optionally substituted with one or more substituents each independently selected from R ^b , where heterocyclyl is a 4-7 membered ring optionally substituted by one or more substituents each independently selected from R ^c , and where when heterocyclyl contains an -NH- fraction, that -NH- fraction is optionally substituted by R ^d , where C- | _6alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ^ alkoxy, C ₃ . ₆ alkenyloxy, and C ₃ . ₆ alkynyloxy are each independently optionally substituted by one or more substituents each independently selected from halogen, hydroxyl, R ^to R ^to N-, and cyano, wherein C3_cycloalkyl, and C3.6cycloalkoxy are each independently optionally substituted by one or more substituents each independently selected from halogen, hydroxyl, R ^to R ^to N-, cyano, and C _1-6 alkyl; or
R ¹ and R ² when taken together with the carbons to which they are attached form a 5-7 membered saturated, partially unsaturated or unsaturated ring, optionally having 1.2, or 3 groups each independently selected from O, NR ^h , and S (O) _r where r is 0, 1, or 2, wherein the 5-7 membered ring is optionally substituted on a carbon by one or more groups each independently selected from R ^e ;
R ^A1 is selected, independently for each occurrence, from the group consisting of hydrogen, hydroxyl, cyano, halogen, Cvealkyl, C2.6alkenyl, C3.6alkynyl, C3.6cycloalkyl, Cvealoxy, and R ^f R ⁹ N-, where C ^ ealkyl, C2. ₆ alkenyl, C ₃ . ₆ alkynyl, C _{3 6} cycloalkyl, and C 4 alkoxy are each independently optionally substituted with one or more halogens;
R ^A2 is selected, independently for each occurrence, from the group consisting of hydrogen, hydroxyl, cyano, halogen, C ^alkyl, C2.6alkenyl, C2.6alquinyl, C36cycloalkyl, Cvealoxy, C3_6alkenyloxy, C3.6alquinyloxy, C3.6cycloalkoxy, C3.6cycloalkoxy, SIOV where w is 0, 1, or 2 R ^f R ⁹ N, R ^{f 9} N R-carbonyl, R ^f R ⁹ N-carbonyl-N (Ra) -, R ^f SO 2 N-R ⁹ , C ^ alkylcarbonyl-NtR ³ ) -, C®
4/52 alkylsulfonylN (R ^a ) -, CV6 alkoxycarbonyl-N (R ^a ) -, phenyl, phenoxy, phenyl-Cvealalkyl-, phenyl-Cvgaloxy, heteroaryl, heteroaryloxy, heterocycloxy, heteroaryl-C- | .6alkyl, heteroaryl-C-| , heterocyclylC- | _ ₆ alkyl-, and heterocyclyl-C1-alkoxy-, where heteroaryl is a 5-6 membered ring having one, two or three heteroatoms each independently selected from N, O, or S, where 5 heteroaryl is optionally substituted with one or more substituents each independently selected from R ^b , where heterocyclyl is a 4-7 membered ring optionally substituted by one or more substituents each independently selected from R ^c , where when heterocyclyl contains a fraction -NH-, that -NH- moiety is optionally substituted by R ^d , where C ^ ealalkyl and C ^ galcoxy are each independently optionally replaced by one or more groups each independently selected from R ^p , where C2.6alkenyl and C2_ and alkynyl are each independent optionally substituted by one or more substituents each independently selected from R ^p ; where C3. ₆ cycloalkyl and C ₃ . ₆ cycloalkoxy are each independently optionally substituted by one or more substituents each independently selected from R ^p ;
R ^B1 and R ^B2 are selected, independently for each occurrence, from the group consisting of hydrogen, C ^ alkoxy, halogen, C ^ alkyl, C ₂ -6 alkenyl, C ₃ . ₆ alkynyl, and C ₃ . ₆ cycloalkyl, where C ₂ . ₆ alkenyl and C ₃ . ₆ alkynyls are each independently optionally substituted by one or more groups each independently selected from R ^p , where C- | _6alkyl and Ci.6alkoxy are each independently optionally substituted by 20 one or more groups each independently selected from R ^p , where C3. ₆ cycloalkyl is optionally substituted by one or more groups each independently selected from R ^p , or R ^B1 and R ^B2 when taken together with the carbons to which they are attached form a cyclopropyl ring or 4-6 membered ring, where the 4-6 membered ring optionally has a group selected from N (R ^h ), O, or S (O) _r where r is 0, 1, or 2;
R ^a and R ^a are selected, independently for each occurrence, from the group consisting of hydrogen and Cvealquil, or R ^a and R ^a when taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, in which C ^alkyl is optionally substituted by one or more substituents each selected independently from the group consisting of halogen, oxo, and hydroxyl, and wherein the heterocyclic ring is optionally substituted by one or more substituents each selected independently of the group consisting of halogen , alkyl, oxo, or hydroxyl;
R ^b is selected, independently for each occurrence, from the group consisting of halogen, hydroxyl, cyano, C1_6alkyl, C2.6alkenyl, C2.6alkynyl, C3.6cycloalkyl, C4 alkoxy, C3.6alkenyloxy, C3.6alquinyloxy, C3.6cycloalkoxy, CV6alquil -S (O) w where w is 0, 1, or 2, Cv 35 6alquilN (Ra) -, C1_ ₆ alkyl-N (Ra) carbonyl, N- R R R R N -carbonyl-, R ^to R ^to N-carbonyl-N (R ^a ) -; R ^to R ^to N-SO2-, and C1.6alkylcarbonyl-N (R ^a ) -, where C2. ₆ alkenyl, C ₃ . ₆ alkynyl, and Cvealcoxy are each independently optionally substituted by one or more substituents each
5/52 independently selected from R ^p ; where C ₃ . ₆ cycloalkyl and C ₃ . ₆ cycloalkoxy are each independently optionally substituted by one or more substituents each independently selected from R ^p , where C 4 alkyl is optionally substituted by one or more substituents selected from R ^p ;
R ^c is selected, independently for each occurrence, from the group consisting of hydroxyl, cyano, oxo, halogen, Ci.6alkyl, C2.6alkenyl, C2_6alkynyl, C3.6cycloalkyl, fe. 6alkoxy, Cv6alkyl-S (O) w- where w is 0, 1, or 2, Cvealkyl-NR ³ -, Cv6alkylC ₃ . ₆ cycloalkyl-, C ₃ . eCycloalkyl-Cvealkyl, R ^to R ^to N-, C1.6alkylcarbonyl-N (R ^a ) -; Cvealcoxycarbonyl-NtR ³ ) -, R ^to R ^to NSO2-, R ^to R ^to N-carbonyl-, and R ^to R ^to N-carbonyl-N (R ^a ), where C ^ is alkyl, C ₂ . ₆ alkenyl, C ₂ .6 alkynyl, C ₃ . ₆ cycloalkyl, and Ci. ₆ alkoxy are each independently optionally substituted by one or more groups each independently selected from R *;
R ^d is selected, independently for each occurrence from the group consisting of Cfeealquil, Cvealquilcarbonil, and Cl - ₆ alkylsulfonyl, wherein C ^ alkyl is optionally substituted by one or more substituents each independently selected from halogen, hydroxyl, and R ^to R ^the N-;
R ^e is selected, independently for each occurrence, from the group consisting of hydroxyl, cyano, halogen, oxo, C1-4 alkyl, C2.4alkenyl, C2.4alkynyl, C3.6cycloalkyl, Cfe 4alkoxy, C3.6alkenyloxy, C3.6alquinyloxy, C3 .6cycloalkoxy, C3.6cycloalkyl-C14alkoxy-, C ^ alkylS (O) W- where w is 0, 1, or 2, R ^to R ^to N-, R ^to R ^to N-carbonyl, R ^to R ^to N-carbonyl -N (R ^a ) -, R ^a R ^to N-SO2-, Cvealkylcarbonyl-NIR ³ ) -, C1-6 alkyl-SO2-N (R ^a ) -, C ^ ealcoxycarbonyl-, and Ci.4alcoxycarbonylN (R ^a ) -, where C2.6alkenyl, and C2.6alkynyl are each independently optionally substituted by one or more substituents each independently selected from R ^p , where C4alkyl and C® alkoxy are each independently optionally substituted by one or more substituents each independently selected from R ^p , where C3. ₆ cycloalkyl and C ₃ . ₆ cycloalkoxy are each independently optionally substituted by one or more substituents each independently selected from R ^p j
R ^f and R ⁹ are selected, independently for each occurrence, from the group consisting of hydrogen, C1_4alkyl optionally substituted by one or more substituents each independently selected from R ^p , and C3. ₆ cycloalkyl optionally substituted by one or more substituents each independently selected from R ^p ”, or R ^f and R ⁹ when taken together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each selected independently from the group consisting of halogen, hydroxyl, oxo, cyan, Cvealquil, C · ,. 6alkoxy, R ^to R ^to N-, C- | .6alkylcarbonyl-N (R ^to ) -, Cvealoxycarbonyl-NIR ³ ) -, R ^to R ^to N-SO2-, R ^to R ^to Ncarbonyl-, and R ^to R ^a N-carbonyl-N (Ra), wherein C16alquil and Ci. ₄ alkoxy are each independently optionally substituted by one or more substituents each independently selected from the group consisting of R R N-, halogen, hydroxy, cyano, C _v
6/52 ₄ alkoxycarbonyl, R ^to R ^to N-carbonyl, R ^to R ^to N-SO ₂ -, C 4 alkoxy, and Ci. ₄ alkylS (O) _w - where w is 0, 1, or 2;
R ^p is selected, independently for each occurrence, from the group consisting of R ^to R ^to N-, halogen, hydroxy, cyano, CV4 alkoxycarbonyl, R ^to R ^to N-carbonyl, R ^to R ^to N-SO2-, ₄ alkoxy, and C ^ alkylSfOV where w is 0, 1, or 2;
R ^p is selected, independently for each occurrence, from the group consisting of R ^to R ^to N-, halogen, hydroxy, cyano, C ^ alkoxycarbonyl, R ^to R ^to N-carbonyl, R ^to R ^to N-SO ₂ -, C _{v 4} alkoxy, C1-4 alkylS / Ojw- where w is 0, 1, or 2, and C ₃ . ₆ cycloalkyl, where C ₃ . _s cycloalkyl is optionally substituted by one or more substituents each independently selected 10 from R ^p ”;
R ^p is selected, independently for each occurrence, from the group consisting of R ^to R ^to N-, halogen, hydroxy, cyano, CV4 alkoxycarbonyl, R ^to R ^to N-carbonyl, R ^to R ^to N-SO2-, C _{v 4} alkoxy , Ç!. ₄ alkylS (O) _w where w is 0, 1, or 2, and C ₁₆ alkyl- where C 4 alkyl is optionally substituted by one or more substituents each independently selected from R ^p ;
R 'is selected, independently for each occurrence, from the group consisting of R ^f R ⁹ N-, halogen, cyano, hydroxyl, and C- | _ ₆ alkoxy;
R ^h is selected, independently for each occurrence, from the group consisting of hydrogen; Ci.6alkyl, C3.6alkenyl and C3.6alkynyl, in which none of the carbon atoms forming an unsaturated bond is attached to N; C3_6cycloalkyl; Cvealkyl-S / O ^ -; and 016 N20 alkyl (R ^a ) carbonyl; wherein CV6alkyl is optionally substituted by one or more substituents each independently selected from R ^p ; wherein C3.6alkenyl and C3.6alkynyl are each independently optionally substituted by one or more substituents each independently selected from R ^p ; where C3. ₆ cycloalkyl is optionally substituted by one or more substituents each independently selected from R ^p .
DETAILED DESCRIPTION
The characteristics and other details of the disclosure will now be more particularly described. Prior to another description, certain terms used in the specification, examples, and attached claims are collected here. These definitions should be read in the light of the rest of the disclosure and understood by a person skilled in the art. Unless otherwise defined, all scientific and technical terms used here have the same meaning as is commonly understood by a person skilled in the art.
Definitions "Treating" includes any effect, for example, diminishing, reducing, modulating, or eliminating, which results in the improvement of the condition, disease, disorder and the like.
The term "alkenyl" as used herein refers to a straight or branched unsaturated hydrocarbon having at least one carbon-carbon double bond, such as a linear or branched group of 2-6 or 3-4 carbon atoms, referenced here for example, like C ₂ .
7/52 ₆ alkenyl, and C ₃ . ₄ alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, alii, butenyl, pentenyl, etc.
The term "alkoxy" as used here refers to a straight or branched alkyl group attached to an oxygen (alkyl-O-). Exemplary alkoxy groups include, but are not limited to, groups with an alkyl group of 1-6 or 2-6 carbon atoms, referred to herein as Cvealoxy, and C ₂ -C ₆ alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, etc.
The term "alkoxycarbonyl" as used herein refers to a straight or branched oxygen-linked alkyl group attached to a carbonyl (alkyl-O-C (O) -) group. Exemplary alkoxycarbonyl groups include, among others, alkoxycarbonyl groups of 1-6 carbon atoms, referred to herein as Cvealoxycarbonyl. Exemplary alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.
The term "alkenyloxy" used here refers to a linear or branched alkenyl group attached to an oxygen (alkenyl-O). Exemplary alkenoxy groups include, among others, groups with an alkenyl group of 3-6 carbon atoms referred to herein as C ₃ . ₆ alkenyloxy. Exemplary "alkenyloxy" groups include, but are not limited to, allyloxy, butenyloxy, etc.
The term "alkynyloxy" used here refers to a linear or branched alkynyl group attached to an oxygen (alkynyl-O)). Exemplary alkynyloxy groups include, but are not limited to, propynyloxy.
The term "alkyl" as used herein refers to a linear or branched hydrocarbon such as a linear or branched 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C | _ _s alkyl, C ₁ _ ₄ alkyl, and C 4 salkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 3-methyl- 2-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2- pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.
The term "alkylcarbonyl" as used herein refers to a straight or branched alkyl group attached to a carbonyl group (alkyl-C (O) -). Exemplary alkylcarbonyl groups include, among others, alkylcarbonyl groups of 1-6 atoms, referred to herein as C _{v 6} alkylcarbonyl groups. Exemplary alkylcarbonyl groups include, but are not limited to, acetyl, propanoyl, isopropanoyl, butanoyl, etc.
The term "alkynyl" as used here refers to a straight or branched unsaturated hydrocarbon having at least one carbon-carbon triple bond, such as a 2-6 linear or branched group, or 3-6 carbon atoms, referred to herein as C ₂ .salquinyl, and C ₃ . ₆ alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.
The term "carbonyl" as used here refers to the radical -C (O) -.
8/52
The term "cyan" as used here refers to the radical -CN.
The term "cycloalkoxy" as used here refers to a cycloalkyl group attached to an oxygen (cycloalkyl-O-).
The term "cycloalkyl" as used herein refers to a saturated or partially unsaturated monocyclic hydrocarbon group of, for example, 3-6, or 4-6 carbons, referred to here, for example, as C ₃ . ₆ cycloalkyl or C ₄ . ₆ cycloalkyl and derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl or cyclopropyl.
The terms "halo" or "halogen" as used here refer to F, Cl, Br, or I.
The terms "heteroaryl" or "heteroaromatic group" as used here refers to a 4-6 membered aromatic monocyclic ring system containing one or more heteroatoms, for example, one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, said heteroaryl ring can be attached to the adjacent radical by a carbon or nitrogen. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridyl, and pyrimidinyl.
The terms "heterocyclyl" or "heterocyclic group" are recognized in the art and refer to 4-7 membered saturated or partially unsaturated ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. A heterocycle can be fused to one or more phenyl rings, partially unsaturated, or saturated. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, and piperazine.
The term "heterocyclylalkoxy" as used herein refers to a heterocyclyl-alkyl-O- group,
The term "heterocyclyloxyalkyl" refers to a heterocyclyl-O-alkyl- group,
The term "heterocyclyloxy" refers to a heterocyclyl-O- group,
The term "heteroaryloxy" refers to a heteroaryl-O- group,
The terms "hydroxy" and "hydroxyl" as used here refer to the radical -OH.
The term "oxo" as used here refers to the radical = 0.
"Pharmaceutically or pharmacologically acceptable" includes molecular entities and compositions that do not produce an adverse, allergic, or other unwanted reaction when administered to an animal, or a human, as appropriate. For human administration, preparations must achieve sterility, pyrogenicity, safety and purity standards as required by the FDA Office of Biologies standards.
The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" as used herein refers to any and all solvents, dispersion medium, coatings, isotonic and delayed absorption agents, and the like, which are compatible with pharmaceutical administration. The use of said means and agents for substances
Pharmaceutically active 9/52 is well known in the art. The compositions can also contain other active compounds providing complementary, additional or improved therapeutic functions.
The term "pharmaceutical composition" as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
“Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, for example, domestic animals (e.g., dogs, cats, and the like), farm animals (for example, cows, sheep, pigs, horses, and the like) and laboratory animals (for example, rats, mice, guinea pigs, and the like). The treated mammal is desirably a mammal in which treatment of obesity, or weight loss, is desired. "Modulation" includes antagonism (for example, inhibition), agonism, partial antagonism and / or partial agonism.
In this specification, the term "therapeutically effective amount" means the amount of the object compound that will induce the biological or clinical response of a tissue, system, animal, or human being being sought by the researcher, veterinarian, physician, or other clinical. The compounds are administered in therapeutically effective amounts to treat a disease. Alternatively, the therapeutically effective amount of a compound is the amount required to obtain a desired therapeutic and / or prophylactic effect, such as an amount that results in weight loss.
The term "pharmaceutically acceptable salts" as used herein refers to salts of acidic or basic groups that may be present in the compounds used in the present compositions. The compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various organic and inorganic acids. The acids that can be used to prepare pharmaceutically acceptable acid addition salts of said basic compounds are those that form non-toxic acid addition salts, that is, salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate salts, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, gluconate, gluconate, gluconate , saccharate, format, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (ie 1, T-methylene-bis- (2-hydroxy-3-naphthoate)). Compounds included in the present composition that are acidic in nature are capable of
10/52 form basic salts with various pharmacologically acceptable cations. Examples of said salts include alkali metal or alkaline earth metal salts and, in particular, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present composition that include a basic or acidic fraction can furthermore form pharmaceutically acceptable salts with various amino acids. The disclosure compounds can contain both the acidic and basic groups; for example, an amino group and a carboxylic acid. In said case, the compound can exist as an acid addition salt, a zwitterion, or a basic salt.
The compounds of the disclosure may contain one or more chiral centers and / or double bonds and therefore exist as stereoisomers, as geometric isomers, enantiomers or diastereoisomers. The term "stereoisomers" when used here consists of all geometric isomers, enantiomers or diastereoisomers. These compounds can be designated by the symbols "R" or "S," depending on the configuration of substituents around the stereogenic carbon atom. Various stereoisomers of these compounds and mixtures thereof are included by this disclosure. Stereoisomers include enantiomers and diastereoisomers. Mixtures of enantiomers or diastereoisomers may be designated “(±)” in the nomenclature, but the person skilled in the art will recognize that a structure implicitly denotes a chiral center.
The disclosure compounds can contain one or more chiral centers and / or double bonds and therefore exist as geometric isomers, enantiomers or diastereoisomers. Enantiomers and diastereoisomers can be designated by the symbols “(+),” “R” or “S,” depending on the configuration of the substituents around the stereogenic carbon atom, but the person skilled in the art will recognize that a structure can denote a chiral center implicitly. Geometric isomers, the result of the arrangement of substituents around a carbon-carbon double bond or arrangement around a cycloalkyl or heterocyclic ring, may still exist in the compounds. The symbol ............ denotes a connection that can be single, double or triple as described here. Substituents around a carbon-carbon double bond are designated as being in the "Z" or "E" configuration where the terms "Z 'and" E "are used in accordance with IUPAC standards. Unless otherwise specified, structures that portray double bonds include both the "E" and "Z" isomers. Substituents around a carbon-carbon double bond may alternatively be referred to as "cis" or "trans," where "cis" represents substituents on the same side of the double bond and "trans" represents substituents on the opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring can also be referred to as "cis" or "trans." The term "cis" represents substituents on the same side of the ring and the term "trans" represents substituents on opposite sides of the ring plane. Mixtures of compounds in which the substituents are arranged on both sides and opposite sides of the
11/52 rings are called “cis / trans.”
The term "stereoisera" when used here consists of all geometric isomers, enantiomers or diastereoisomers. Various stereoisorts of these compounds and mixtures thereof are included by this disclosure.
Individual enantiomers and diasterioisomers of the compounds can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparing racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) attaching a mixture of enantiomers to an auxiliary chiral, separating the mixture resulting from diastereoisomers by recrystallization or chromatography and releasing the optically pure product from the auxiliary, (2) forming a salt using a optically active resolving agent, (3) direct separation of the mixture of optical enantiomers in liquid chromatography columns or (4) kinetic resolution using stereoselective or enzymatic chemical reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral gas phase chromatography or crystallization of the compound in a chiral solvent. Stereoselective synthesis, a chemical or enzymatic reaction in which a single reactive forms an unequal mixture of stereoisorts during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective synthesis includes both enantio- and diastereoselective transformations. For example, see Career and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.
The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In one embodiment, the compound is amorphous. In one embodiment, the compound is a polymorph. In another embodiment, the compound is in a crystalline form.
Still included are isotopically labeled compounds that are identical to those mentioned here, except that one or more atoms are replaced by an atom containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O , ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ CI, respectively. For example, a compound can have one or more H atoms replaced as deuterium.
Certain revealed isotopically labeled compounds (for example, those marked with ³ H and ¹⁴ C) are useful in tissue distribution assays of the compound and / or substrate. Tritiated (ie, ³ H) and carbon-14 (ie, ¹⁴ C) isotopes are particularly preferred for their ease of preparation and detectability. In addition, substitution with heavier 12/52 isotope as deuterium (ie ² H) can generate certain therapeutic advantages that result in greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements) and therefore may preferred in some circumstances. Isotopically labeled compounds can generally be prepared by the following procedures analogous to those disclosed in the examples herein by replacing an isotopically labeled reagent from an isotopically marketed reagent.
The term "prodrug" refers to compounds that are transformed in vivo to generate a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. Transformation can occur by various mechanisms (such as esterase, amide, phosphatase, oxidizing and / or reducing metabolism) at various locations (such as in the intestinal lumen or intestinal transit, blood, or liver). Pro-drugs are well known in the art (for example, see Rautio, Kumpulainen, et al, Nature Reviews Drug Discovery 2008, 7, 255). For example, if a compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound contains a carboxylic acid functional group, a prodrug may comprise an ester formed by replacing the hydrogen atom of each acid group with a group such as ( Cvsjalkyl, (C ₂ .i ₂ ) alkanoyloxymethyl, 1 - (alkanoyloxy) ethyl containing from 4 to 9 carbon atoms, 1-methyl-1 - (alkanoyloxy) -ethyl containing from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl containing from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl containing from 4 to 7, carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl containing from 5 to 8 carbon atoms, 20 N- (alkoxycarbonyl) aminomethyl containing 3 to 9 carbon atoms, 1- (N (alkoxycarbonyl) amino) ethyl containing from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N, N- (C ₁ - ₂ ) alkylamino (C ₂ - ₃ ) alkyl (such as β-dimethylaminoethyl), carbamoyl-CCr ^ alkyl, N, N-di (C ₁ - ₂ ) alkylcarbamoyl- (C ₁ - ₂ ) alkyl and pi peridino-, pyrrolidino- or morpholino (C ₂ - ₃ ) alkyl.
Similarly, if a compound contains an alcohol functional group, a prodrug can be formed by replacing the hydrogen atom of the alcohol group with a group such as (Cvsjalcanoyloxymethyl, l- ^ CveJalcanoyloxyJetil, 1-methyl-1 - ((C _v6 ) alkanoyloxy) ethyl (Cv ₆ ) alkoxycarbonyloxymethyl, N- (Ci. ₆ ) alkoxycarbonylaminomethyl, succinoyl, (C _{1. 6} ) alkanoyl, aaminofCv ^ alkanoyl, arylacyl and a-aminoacyl, or α-aminoacyl-a-aminoacyl, where each group □ 30 aminoacyl is independently selected from naturally occurring L-amino acids, P (O) (OH) ₂ , -P (O) (O (C ₁ - ₆ ) alkyl) ₂ or glycosyl (the radical resulting from the removal of a group hydroxyl of the hemiacetal form of a carbohydrate).
If a compound incorporates a functional amino group, a prodrug can be formed, for example, by creating an amide or carbamate, an N-acyloxyalkyl derivative, 35 a methyl derivative (oxodioxolenyl), an N-Mannich base, imine or enamine. In addition, a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can be metabolically cleaved to generate an amine
13/52 primary or secondary. For examples, see Simplício, et at., Molecules 2008, 13, 519 and references in this.
I. Tetrazole Compounds
In certain embodiments, compounds of formula I are provided:
and pharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof, in which:
A may be a ring selected from the group consisting of phenyl, heteroaryl, C ₃ . ₆ cycloalkyl, and heterocyclyl, for example, heteroaryl is a 5-6 membered ring having one, two or three heteroatoms each independently selected from N, O, or S, and where heterocyclyl can be, for example, a 4-7 membered ring;
B can be selected from the group consisting of a bond or (CR ^B1 R ^B2 );
R ¹ can be selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C1-6alkyl, C2.6alkenyl, C2.6alkynyl, C3.6cycloalkyl, C- | _6alkoxy, C3.6alkenyloxy, C3. 6alkynyloxy, C3.6cycloalkoxy, C4 alkyl-SjOjw- where w is 0, 1, or 2, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclyl-C1-alkyl, and heterocyclyl-C1-6alkoxy, where heteroaryl is a 5- 6 members having one, two or three heteroatoms each independently selected from N, O, or S, where heteroaryl is optionally substituted with one or more substituents each independently selected from R ^b , where heterocyclyl is a 4-7 ring members optionally substituted by one or more substituents each independently selected from R ^c , and where when heterocyclyl contains an -NH- fraction, that -NH fraction is optionally substituted by R ^d , where C2. ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₆ alkenyloxy, and C ₃ . ₆ alkynyloxy are each independently optionally substituted by one or more substituents each independently selected from R ^p , where C ^ alkyl and Cvealoxy are each independently optionally substituted by one or more substituents each independently selected from R ^p , where C ₃ . ₆ cycloalkyl and C ₃ . ₆ cycloalkoxy are each independently optionally substituted by one or more substituents each independently selected from R ^p ;
R ² can be selected from the group consisting of halogen, hydroxyl, cyano, C _{v 6} alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₆ cycloalkyl, C ^ and alkoxy, C ₃ . ₆ alkenyloxy, C ₃ . ₆ alkynyloxy, C ₃ . ecicloalkyloxy, C _v6 alkyl-S (O) ₂ -, C ₃ . ₆ cycloalkyl-Ci. ₄ alkyl-, C ₃ . ₆ cycloalkyl-C ₁ . ₄ alkoxy-, phenyl-Cv ₆ alkyl-, phenyl, phenoxy, phenyl-Cvealoxy-, heteroaryl, heteroaryloxy, heteroaryl-Cvealkyl, heteroarylCvealoxy, heterocyclyl-Cvealkyl-, and heterocyclyl-C ^ ealoxy-, in which heteroaryl is a ring that is heteroaryl 5-6
14/52 members containing one, two or three heteroatoms each independently selected from N, O, or S, in which the heteroaryl and phenyl group are each independently optionally substituted with one or more substituents each independently selected from R ^b , in which heterocyclyl is a 4-7 membered ring optionally substituted by one or 5 more substituents each independently selected from R ^c , and where when heterocyclyl contains an -NH- fraction, that -NH- fraction is optionally substituted by R ^d , in whereas C1_6alkyl, C2_6alkenyl, C2.6alkynyl, C4 alkoxy, C3.6alkenyloxy, and C3.6alkynyloxy are each independently optionally substituted by one or more substituents each independently selected from halogen, hydroxyl, R ^to R ^to N-, and cyano , where C3. 10 ecicloalkyl, and C ₃ . ₆ cycloalkoxy are each independently optionally substituted by one or more substituents each independently selected from halogen, hydroxyl, R ^to R ^to N-, cyano, and C ^ alkyl; or
R ¹ and R ² when taken together with the carbons to which they are attached can form a 5-7 membered saturated, partially unsaturated or unsaturated ring, having 15 optionally 1, 2, or 3 groups each independently selected from O, NR ^h , and S (O) _r where r is 0, 1, or 2, where the 5-7 membered ring is optionally substituted on a carbon by one or more groups each independently selected from R ^e ;
R ^A1 is selected, independently for each occurrence, from the group consisting of hydrogen, hydroxyl, cyano, halogen, C ^ ealalkyl, C2.6alkenyl, C3.6alkynyl, C3.6cycloalkyl, 20 Ci.6alkoxy, and R ^f R ⁹ N- , where Ci.6alkyl, C ₂ . ₆ alkenyl, C ₃ . ₆ alkynyl, C ₃ . ₆ cycloalkyl, and Ci. ₆ alkoxy are each independently optionally substituted with one or more halogens;
R ^A2 can be selected, independently for each occurrence, from the group consisting of hydrogen, hydroxyl, cyano, halogen, C ^ salkyl, C2.6alkenyl, C2_6alkynyl, C3. 6cycloalkyl, C4 galoxy, C3.6alkenyloxy, C3.6alkynyloxy, C3.6cycloalkoxy, Cvealkyl-S / OV where w 25 is 0, 1, or 2, R ^f R ⁹ N-, R ^f R ⁹ N-carbonyl-, R ^f R ⁹ N-carbonyl-N (R ^a ) -, R ^f R ⁹ N-SO2-, Cvealkyl-carbonylN (R ^a ) -, alkylsulfonylN (R ^a ) -, Cvealoxycarbonyl-NfR ³ ) -, phenyl, phenoxy , phenyl-C-i-6alkyl-, phenylC- | _6alkoxy, heteroaryl, heteroaryloxy, heterocycloxy, heteroaryl-C16alkyl, heteroaryl-Cvsalcoxi-, heterocyclyl-Cvealkyl-, and heterocyclyl-Cvealcoxy-, in which heteroaryl is a 5- ring member containing one, two or three heteroatoms each independently selected from N, O, 30 or S, where heteroaryl is optionally substituted with one or more substituents each independently selected from R ^b , where heterocyclyl is a 4-7 membered ring optionally substituted by one or more substituents each independently selected from R ^c , and where when heterocyclyl contains an -NH- fraction, that -NH- fraction is optionally substituted by R ^d , where C ^ alkyl and Cv6alkoxy are each independently 35 optionally substituted by one or more groups each independently selected from R ^p , where C ₂ . ₆ alkenyl and C ₂ . ₆ alkynyl are independently optionally substituted by one or more substituents each independently selected from R ^p; on what
15/52
C ₃ _ ₆ cycloalkyl and C ₃ . ₆ cycloalkoxy are each independently optionally substituted by one or more substituents each independently selected from R ^p ”;
R ^B1 and R ⁸² can be selected, independently for each occurrence, from the group consisting of hydrogen, C ^ ealoxy, halogen, C1_6alkyl, C2_6alkenyl, C3.6alkynyl, and C3.6cycloalkyl, where C2.6alkenyl and C3.6alkyl are each. one independently optionally substituted by one or more groups each independently selected from R ^p , where C- | _6alkyl and Cvealoxy are each optionally independently replaced by one or more groups each independently selected from R ^p , where C3_6cycloalkyl is optionally replaced by one or more groups each independently selected from R ^p , or R ^B1 and R ^B2 when taken together with the carbons to which they are attached form a cyclopropyl ring or 4-6 membered ring, where the 4- 6 members optionally have a group selected from N (R ^h ), O, or S (O) where r is 0, 1, or 2;
R ^a and R ^a can be selected, independently for each occurrence, from the group consisting of hydrogen and C ^ galquyl, or R ^a and R ^a when taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring , where C ,. ₆ alkyl is optionally substituted by one or more substituents each selected independently from the group consisting of halogen, oxo, and hydroxyl, and in which the heterocyclic ring can be optionally substituted by one or more substituents each selected independently of the group consisting of halogen, alkyl, oxo, or hydroxyl;
R ^b can be selected, independently for each occurrence, from the group consisting of halogen, hydroxyl, cyano, C ^ ealkyl, C2.6alkenyl, C2.6alkynyl, C3.6cycloalkyl, 6alkoxy, C3.6alkenyloxy, C3.6alkynyloxy, C3.6cycloalkoxy , C ^ ealkyl-S / O) '- where w is 0, 1, or 2, C- | 6alkylN (R ^a ) -, Cvealkyl-NfR ^ carbonyl, R ^to R ^to N-, R ^to R ^to N -carbonyl-, R ^to R ^to N-carbonyl-N (R ^a ) -; R ^to R ^to N-SO2-, and Ci-ealalkyl-carbonyl-NIR ³ ) -, in which C2.6alkenyl, C3.6alkynyl, and C4 galcoxy are each independently optionally substituted by one or more substituents each independently selected of R ^p ; where C3. ₆ cycloalkyl and C ₃ . ₆ cycloalkoxy are each independently optionally substituted by one or more substituents each independently selected from R ^p ”, wherein Cvealkyl is optionally substituted by one or more substituents selected from R ^p ;
R ^c can be selected, independently for each occurrence, from the group consisting of hydroxyl, cyano, oxo, halogen, Cvealkyl, C2.6alkenyl, C2.6alquinyl, C3.6cycloalkyl, Cvealoxy, Cvealquil-S / OV where w is 0, 1 , or 2, Cvealkyl-NR ³ -, CvealkylCs-ecicloalkyl-, C3. eCycloalkyl-Cvsalkyl, R ^to R ^to N-, Ci.6alkylcarbonyl-N (R ^a ) -; C1. ₆ alkoxycarbonyl-N (R ^a ) -, R ^to R ^to NSO2-, R ^to R ^to N-carbonyl-, and R ^to R ^to N-carbonyl-N (R ^a ), where C is salyl, C2. ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₆ cycloalkyl, and Cvealoxy are each independently optionally substituted by one or more groups each independently selected from R ';
R ^d can be selected, independently for each occurrence, from the group con
16/52 consisting of C ^ alkyl, C ^ alkylcarbonyl, and Ci.ealkylsulfonyl, where Cvealkyl is optionally substituted by one or more substituents each independently selected from halogen, hydroxyl, and R ^to R ^to N-;
R ^e can be selected, independently for each occurrence, from the group consisting of hydroxyl, cyano, halogen, oxo, Ci.4alkyl, C2.4alkenyl, C2.4alkynyl, C3.6cycloalkyl, C1.4alkoxy, C3.6alkenyloxy, C3.6alquinyloxy , C3.6cycloalkoxy, C3.6cycloalkyl-C-.4alkoxy-, C4 alkylS (O) W- where w is 0, 1, or 2, R ^to R ^to N-, R ^to R ^to N-carbonyl, R ^a R ^to N-carbonyl-N (R ^a ) -, R ^to R ^to N-SO2-, Ci-ealalkyl-carbonyl-NfR ³ ) -, Ci.6alkyl-SO2-N (R ^a ) -, Cvsalkoxycarbonyl-, and C1. ₄ alkoxycarbonylN (R ^a ) -, where C2.6alkenyl, and C2.6alkynyl are each independently optionally substituted by one or more substituents each independently selected from R ^p , where _Ci.6alkyl and Ο _Ί _ ₆ alkoxy are each one independently optionally substituted by one or more substituents each independently selected from R ^p , where C ₃ . scicloalkyl and C ₃ . ₆ cycloalkoxy are each independently optionally substituted by one or more substituents each independently selected from R ^p ;
R ^f and R ⁹ can be selected, independently for each occurrence, from the group consisting of hydrogen, C1.4alkyl optionally substituted by one or more substituents each independently selected from R ^p , and C3. ₆ cycloalkyl optionally substituted by one or more substituents each independently selected from R ^p , or R ^f and R ⁹ when taken together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each one selected independently from the group consisting of halogen, hydroxyl, oxo, cyano, Cv 6alkyl, Cvealoxy, R ^to R ^to N-, Cvealalkylcarbonyl-N / R ³ ) -, Ci.6alkoxycarbonyl-N (R ^a ) -, R ^to R ^to N-SO2-, R ^to R ^to N-carbonyl-, and R ^to R ^to N-carbonyl-N (R ^a ), in which C ^ alkyl and C ^ alkoxy are each independently optionally substituted by one or more substituents each selected independently from the group consisting of R ^to R ^to N-, halogen, hydroxy, cyano, Cv 4 to alkoxycarbonyl, R ^to R ^to N-carbonyl, R ^to R ^to N-SO ₂ -, Ci. ₄ alkoxy, and C ^ alkylS / Ofe where w is 0, 1, or 2;
R ^p can be selected, independently for each occurrence, from the group consisting of R ^to R ^to N-, halogen, hydroxy, cyano, C ^ alkoxycarbonyl, R ^to R ^to N-carbonyl, R ^to R ^to NSO ₂ -, C _M alkoxy, and Ci.4alkylS (O) _w - where w is 0, 1, or 2;
R ^p can be selected, independently for each occurrence, from the group consisting of R ^to R ^to N-, halogen, hydroxy, cyano, C ^ alkoxycarbonyl, R ^to R ^to N-carbonyl, R ^to R ^to NSO ₂ -, C ₁ . ₄ alkoxy, C4 alkylSfOjw- where w is 0, 1, or 2, and C ₃ . ₆ cycloalkyl, where C ₃ . ₆ cycloalkyl is optionally substituted by one or more substituents each independently selected from R ^p
R ^p can be selected, independently for each occurrence, from the group consisting of R ^to R ^to N-, halogen, hydroxy, cyano, C ^ alkoxycarbonyl, R ^to R ^to N-carbonyl, R ^to R ^to N
17/52
SO ₂ -, C4 alkoxy, C- | ₄ alkylS (O) _w where w is 0, 1, or 2, and Ci. ₆ alkyl, where C ^ alkyl is optionally substituted by one or more substituents each independently selected from R ^p ;
R ^f can be selected, independently for each occurrence, from the group consisting of R ^f R ⁹ N-, halogen, cyano, hydroxyl, and Cvealcoxy;
R ^h can be selected, independently for each occurrence, from the group consisting of hydrogen; C6 eal alkyl, C3.6 alkenyl and C3.6 alkynyl, in which none of the carbon atoms forming an unsaturated bond is attached to N; C3.6cycloalkyl; C1-6 alkyl-S (O) 2-; and C1-6 alkyl-N (R ^a ) carbonyl; wherein C _1-6 alkyl is optionally substituted by one or more substituents each independently selected from R ^p ; wherein C3.6alkenyl and C3.6alkynyl are each independently optionally substituted by one or more substituents each independently selected from R ^p ; where C3. ₆ cycloalkyl is optionally substituted by one or more substituents each independently selected from R ^p
In some embodiments, A may be phenyl.
In some embodiments, B can be a link.
In certain embodiments, R ¹ can be selected from the group consisting of hydrogen, halogen, cyano, hydroxyl, C ^ salkyl, C2.4alkenyl, C2.4alquinyl, C3.6cycloalkyl, Ci.4alkoxy, C3.4alkenyloxy, and C3.4alquinyloxy, wherein C2.4alkenyl, C2.4alkenyl, C3.4alkenyloxy, and C3. 4 alkynyloxy are each independently optionally substituted by one or more substituents each independently selected from R ^p , wherein Ci.3alkyl and Ci_ ₄ alkoxy are each independently optionally substituted by one or more substituents each independently selected from R ^p , where C ₃ . ₆ cycloalkyl is optionally substituted by one or more substituents each independently selected from R ^p .
In other embodiments, R ¹ can be selected from the group consisting of H or C _{v 3} alkyl.
In still other modalities, R ¹ can be H.
In some embodiments, R ² can be selected from the group consisting of halogen, cyano, Cvealkyl, C2_6alkenyl, C2.6alkynyl, C3.6cycloalkyl, C- | _6alkoxy, C3.6alkenyloxy, C3. 6 alkynyloxy, C3.6cycloalkyloxy, Cv6alkyl-S (O) 2-, C3_6cycloalkyl-C1_4alkyl-, and Cs-eCycloalkyl-Cv 4alkoxy-, where C1.6alkyl, C2.6alkenyl, C2.6alkyl, C2.6alkyl, C2.6alkyl, and C3. 6alquiniloxi are each independently optionally substituted by one or more substituents each independently selected from halogen, hydroxyl, R R N-, or cyano, wherein C3_ ₆ cycloalkyl and C _{3. 6} cycloalkoxy are each independently optionally substituted by one or more substituents each independently selected from halogen, hydroxyl, R ^to R ^to N-, cyano, and C ₁ . ₆ alkyl.
In other embodiments, R ² is selected from the group consisting of halogen, cyano, Ci. ₆ alkyl, C ₃ . ₆ cycloalkyl, C ^ alkoxy, _{C3. 6} cycloalkyloxy, Cs-eCicloalkyl-Cv-1-alkyl, and C ₃ .
18/52 gCYcloalkyl-C1-1 alkoxy-, and C-i.alcoxy-Cvealkyl-,
In still other modalities, R ² can be selected from the group consisting of bromine, methyl, methoxy, or cyclopropyl.
In some embodiments, R-, and R ₂ when taken together with the rings to which they are attached can form:
where * represents the connection points in Formula I.
In some embodiments, R ^A1 can be selected from the group consisting of hydrogen, halogen, C ^ alkyl, or C _V6 alkoxy, where C ₁₆ alkyl and Cvealoxy are each independently optionally substituted with one or more halogens.
In other embodiments, R ^A1 can be hydrogen.
In some embodiments, R ^A2 can be selected from the group consisting of hydrogen, halogen, C ^ alkyl, C2.6alkenyl, C3.6cycloalkyl, Cvealoxy, and C3.6alkenyloxy, where Cvealkyl and C ^ ealcoxy are each independently optionally substituted by one or more substituents each independently selected from R ^p , where C2. Alkenyl ₆ is optionally substituted by one or more substituents each independently selected from R ^p , where C ₃ . ₆ cycloalkyl is optionally substituted by one or more substituents each independently selected from R ^p .
In certain embodiments, R ^B1 and R ^B2 can be H.
Provided here are compounds that can be selected from the group consisting of N- [1 - (1 H-tetrazol-5-yl) -5,6,7,8-tetrahydronaphthalen-2-yl] -benzenesulfonamide, N- [3cyclopropyl- 2- (1H-tetrazol-5-yl) -phenyl] -benzenesulfonamide, N- [3-methoxy-2- (1H-tetrazol-5-yl) phenylj-benzenesulfonamide, N- [3-methyl-2- (1 H-tetrazol-5-yl) -phenyl] -benzenesulfonamide, N- [3bromo-2- (1H-tetrazol-5-yl) -phenyl] -benzenesulfonamide and pharmaceutically acceptable salts thereof and stereoisomers thereof.
Procedures for preparing the compounds described here are provided below with reference to Schemes 1 and 2. In the reactions described below, it may be necessary to protect reactive functional groups (such as hydroxy, amino, uncle, or carboxy groups) to avoid their unwanted participation in the reactions. The incorporation of said groups, and the methods required to introduce and remove them, are known to those skilled in the art. (For example, see Greene, Wuts, Protective Groups in Organic Synthesis. 2nd Ed. (1999)). The deprotection step can be the final step in the synthesis so that removal of the protecting groups generates a compound of formula I, as disclosed here, or as exemplified in, for example, General Formula I, below. Starting materials used in the following
These schemes can be acquired or prepared by the methods described in the chemical literature, or by adaptations thereof, using methods known to those skilled in the art. The order in which the steps are carried out may vary depending on the groups introduced and the reagents used, but it could be apparent to those skilled in the art.
Compounds of General Formula I can be prepared according to Scheme 1. Specific steps in the synthesis process are described in more detail below.
SCHEME 1
General Formula I
In Scheme 1, Step (i), an anthranilate ester 1A can be converted to a sulfonamide 1B by treatment with an appropriate sulfonyl chloride in the presence of a base (such as pyridine, triethylamine, or diisopropylethylamine) optionally in a solvent (such as dichloromethane , dimethylformamide, or N-methylpyrrolidinone) at a temperature between room temperature and the reflux temperature of the solvent.
In Scheme 1, Step (ii), a sulfonamide ester 1B can be converted to the corresponding carboxylic acid 1C. Depending on the nature of the ester this can be achieved in several ways. For example, a methyl, ethyl or benzyl ester can be treated with an aqueous base (such as sodium hydroxide or lithium hydroxide) in a solvent (such as an alcohol solvent, for example, methanol or ethanol, or an ether solvent, for example , dioxane or tetrahydrofuran) at a temperature between room temperature and the reflux temperature of the solvent or radiating in the microwave at a temperature between 120 ° C and 160 ° C for a period of between 10 minutes and 2 hours. If ester 1B is, for example, a tertiary butyl ester, conversion to carboxylic acid can be achieved by treatment with an acid in an appropriate solvent (for example, trifluoroacetic acid) optionally in a chlorinated solvent (such as dichloromethane) or a solution of hydrogen chloride in a solvent (such as dioxane). If the ester is a benzyl ester, conversion to carboxylic acid can be achieved by catalytic hydrogenation, in the presence of a metallic catalyst (such as palladium or palladium hydroxide on a solid support, for example, carbon) in a
20/52 solvent (such as dioxane or ethyl acetate).
In Scheme 1, Step (iii), a carboxylic acid 1C can be converted to the corresponding primary amide 1D. For example, carboxylic acid can be converted to acid chloride by treating the carboxylic acid with a chlorinating agent (such as oxalyl chloride or thionyl chloride) optionally in the presence of a catalyst (such as N, Ndimethylformamide) optionally in a solvent (such as dichloromethane or toluene) at a temperature between room temperature and the reflux temperature of the solvent. The acid chloride can then be treated with ammonia (gas or solution) in a solvent (such as water or tetrahydrofuran) to generate the amide.
Alternatively, in Scheme 1, Step (iii), the carboxylic acid can be treated with a coupling agent (such as 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3,3tetramethyluronium hexafluorphosphate, dicyclohexylcarbonildiimide , carbonyl-diimidazole, or other similar coupling agent) in the presence of ammonia or an ammonia source, such as an ammonium salt (eg, ammonium chloride) in a solvent (such as dichloromethane or Ν, Ν-dimethylformamide) at a temperature between room temperature and the reflux temperature of the solvent. A wide range of conditions are known to the person skilled in the art for converting a carboxylic acid to a primary amide.
In Scheme 1, Step (iv), a primary amide 1D can be converted to nitrile 1E. This can be achieved by dehydrating the amide. For example, the primary amide can be treated with a dehydrating reagent (such as thionyl chloride, phosphorus oxychloride, or phosphorus pentachloride) optionally in a solvent (such as 1,2-dichloroethane, chlorobenzene, toluene, or dimethylformamide) at a temperature between room temperature and the reflux temperature of the solvent. A wide range of conditions are known to the person skilled in the art for converting a primary amide to a nitrile.
In Scheme 1, Step (v), a nitrile 1E can be converted to a tetrazole of General Formula I. This can be achieved by treating the nitrile with an azide. For example, nitrile can be treated with sodium azide in the presence of an organo-tin halide (such as tributyltin chloride), optionally in the presence of an ammonium salt (such as tetrabutylammonium bromide) in a solvent (such as Ν, Ν-dimethylformamide) in a temperature between room temperature and the reflux temperature of the solvent or alternatively by microwave radiation at a temperature between 160 ° C and 230 ° C.
Alternatively, in Scheme 1, Step (v), nitrile can be treated with a silyl azide (such as trimethylsilyl azide) optionally in the presence of an organo-tin reagent (such as an alkyl tin oxide, for example, di-butyl tin oxide) in a solvent (such as 1,2-dichloroethane) at a temperature between room temperature and the reflux temperature of the solvent or alternatively by microwave radiation at a temperature between 120 ° C and 180 ° C.
21/52
Alternatively, in Scheme 1, Step (v), nitrile can be treated with an organo-tin azide (such as tributyltin azide) in a solvent (such as 1,2-dichlorobenzene) at an ambient temperature at a reflux temperature of the solvent or alternatively by microwave radiation at a temperature between 120 ° C and 180 ° C. A wide range of conditions are known to the specialist for the conversion of a nitrile to a tetrazole.
Alternatively, compounds of Formula
General I can also be prepared according to Scheme 2.
SCHEME 2
In Scheme 2, Step (i), a nitrobenzoic acid 2A is converted to N-phenylamide 2B. For example, carboxylic acid can be converted to acid chloride by treating the carboxylic acid with a chlorinating agent (such as oxalyl chloride or thionyl chloride) optionally in the presence of a catalyst (such as Ν, Ν-dimethylformamide) optionally in a solvent (such as dichloromethane or toluene) at a temperature between room temperature and the reflux temperature of the solvent. The acid chloride can then be treated with benzylamine in a solvent (such as dichloromethane or tetrahydrofuran) to generate the amide.
Alternatively, in Scheme 2, Step (i), the carboxylic acid can be treated with a coupling agent (for example, 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3,3tetramethyluronium hexafluorophosphate , dicyclohexylcarbonyldiide, carbonyl-diimidazole, or other similar coupling agent) in the presence of benzylamine in a solvent (such as dichloromethane or Ν, Ν-dimethylformamide) at a temperature between room temperature and the reflux temperature of the solvent. A wide range of conditions are known to the skilled person for the conversion of a carboxylic acid to a secondary amide.
In Scheme 2, Step (ii), N-benzylamide 2B is converted to an N-benzyltetrazole 2C.
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This can be achieved by treating amide with a chlorinating agent (such as phosphorus pentachloride) in a solvent (such as dichloromethane) followed by treating the generated intermediate with an azide (such as trimethylsilyl azide) at a temperature between 0 ° C and the temperature reflux of the solvent (preferably at room temperature).
In Scheme 2, Step (iii), the nitro intermediate 2C is converted to 2D aniline. This can be achieved by treating a solution of the nitro intermediate in a solvent (such as methanol, ethanol, or ethyl acetate) with a hydrogenation catalyst (such as palladium on carbon, palladium on carbon hydroxide, or platinum on carbon) in a hydrogen atmosphere at a pressure of 1 bar to 4 bar.
Alternatively, in Scheme 2, Step (iii), the nitro intermediate can be reduced to aniline, for example, by treatment with a tin salt (such as tin chloride) or a metal (such as iron or zinc) in the presence of an acid (such as acetic acid or hydrochloric acid) at a temperature between room temperature and 100 ° C. A wide range of conditions are known to the skilled person for converting a nitro compound to an aniline.
In Scheme 2, Step (iv), a 2D aniline can be converted to a 2E sulfonamide by treatment with an appropriate sulfonyl chloride in the presence of a base (such as pyridine, triethylamine, or diisopropylethylamine) optionally in a solvent (such as dichloromethane, dimethylformamide, or N-methylpyrrolidinone) at a temperature between room temperature and the reflux temperature of the solvent.
In Scheme 2, Step (v), the benzyl group can be removed from 2D to generate a compound of General Formula I. This can be achieved by treating the solution of the benzyl tetrazole in a solvent (such as methanol, ethanol, or ethyl acetate) with a hydrogenation catalyst (such as palladium on carbon, palladium hydroxide on carbon, or platinum on carbon) in a hydrogen atmosphere at a pressure of 1 bar to 4 bar.
It will be recognized by a person skilled in the art that compounds of formula I, General Formula I, or intermediates of these compounds can be further derivatized or converted to other compounds by modifications to the substituents using standard methods known as substitution, oxidation, or reduction including those interconversions described above for the preparation of compounds of General Formula I.
For example, a carbon-carbon bond can be made by reacting a compound in which one of the substituents is an appropriate group (such as bromine or trifluoromethanesulfonate) with an organometallic reagent such as boronic acid, or boronate ester in the presence of a catalyst palladium (such as palladium chloride dppf, tetrakistriphenylphosphine palladium (O), or bis-palladium tris (dibenzylidene acetone)), in the presence of a base (such as potassium carbonate or cesium carbonate) in an appropriate solvent (such as aqueous dioxane or aqueous tetrahydrofuran) at a temperature between room temperature and the reflux temperature of the solvent or by radiation in a microwave oven at a time
23/52 temperature between 100 ° C and 160 ° C.
Alternatively, a carbon-carbon bond can be formed by reacting a compound in which one of the substituents is an appropriate group (such as a bromide or a trifluoromethanesulfonate) with a stanane in the presence of a palladium catalyst (such as palladium chloride dppf) in an appropriate solvent (such as dioxane, dimethoxyethane, or tetrahydrofuran) at a temperature between room temperature and the reflux temperature of the solvent or alternatively by microwave radiation at a temperature between 100 ° C and 160 ° C.
Alternatively, a carbon-carbon bond can be formed by reacting a compound in which one of the substituents is an leaving group (such as a bromide or a trifluoromethanesulfonate) with an alkene (such as an acrylate) in the presence of a catalyst (such as a catalyst palladium, for example, tetrakis-triphenylphosphine palladium (O)) and a base or salt (such as tributylamine or potassium acetate) at a temperature between 80 ° C and 120 ° C or by microwave radiation at a temperature between 100 ° C and 160 ° C.
Alternatively, a carbon-carbon bond can be formed by reacting a compound in which one of the substituents is an appropriate group (such as a bromide or a trifluoromethanesulfonate) with an organozinc reagent in the presence of a catalyst (such as a palladium catalyst, for example , tetrakis-triphenylphosphine palladium (O)) and a base or salt (such as tributylamine or potassium acetate) in an appropriate solvent (such as dioxane or tetrahydrofuran) at a temperature between room temperature and the reflux temperature of the solvent or by radiation in a microwave at a temperature between 100 ° C and 160 ° C.
A carbon-carbon bond can alternatively be prepared by reacting a compound in which one of the substituents is an appropriate group (such as a bromide or a trifluoromethanesulfonate) with a terminal alkyl in the presence of a palladium catalyst (such as tetrakis (triphenylphosphino) ) palladium (O)) optionally in the presence of an additional copper catalyst (such as copper (I) iodide) in the presence of a base or salt (such as triethylamine or potassium acetate), in a solvent (such as tetrahydrofuran or N, Ndimethylformamide ) at a temperature between room temperature and the reflux temperature of the solvent or by microwave radiation at a temperature between 100 ° C and 160 ° C.
Examples of the formation of carbon-oxygen bonds are known to a person skilled in the art to prepare ethers. Examples of the formation of carbonoxygen bonds may involve the reaction of an intermediate in which one of the substituents is an aryl halide or aryl sulfonate (such as an aryl fluoride, bromide, or tosylate) with an alcohol or phenol. An alcohol or phenol can be deprotonated, for example, by treatment with a base (such as sodium hydride) in a solvent (such as tetrahydrofuran) and then treated with the
24/52 aryl halide or sulfonate, then stirred at a temperature between room temperature and the reflux temperature of the solvent.
Alternatively an ether can be prepared by coupling a phenol with an alcohol in the presence of a phosphine (such as triphenylphosphine) and in the presence of a dehydrating agent (such as an ester of an azodicarboxylate, for example, dimethyl, diethyl, or diisopropyl azodicarboxylate) in a solvent (such as tetrahydrofuran) at a temperature between 0 ° C and room temperature.
Other methods of forming a carbon-oxygen bond involve deprotonation of a phenol by treatment with a base (such as sodium hydride or potassium carbonate) in a solvent (such as tetrahydrofuran or dimethyl formamide) followed by reaction with an alkylating agent (such as an alkyl halide or alkyl sulfate) and stirring at a temperature between room temperature and the reflux temperature of the solvent.
Examples of the formation of carbon-nitrogen bonds are known to a person skilled in the art. For example, a carbon-nitrogen bond can be formed by the alkylation of a primary or secondary amine using a reducing alkylation process. For example, the amine can be treated with an aldehyde and a borohydride (like sodium triacetoxyborohydride, or sodium cyanoborohydride) in a solvent (like a halogenated hydrocarbon, for example, dichloromethane), or an alcohol, (for example, ethanol) and, where necessary, in the presence of an acid (such as acetic acid).
Another example of the formation of carbon-nitrogen bonds involves the treatment of a compound in which one of the substituents is a leaving group (such as a bromide or a trifluoromethanesulfonate) with an amine in the presence of a palladium catalyst (such as tetrakis-triphenylphosphine palladium (O)) in the presence of a binder (such as Xantphos) in a solvent (such as toluene) at a temperature between room temperature and the reflux temperature of the solvent or alternatively by microwave radiation at a temperature between 100 ° C and 150 ° C.
Alternatively, a carbon-nitrogen bond can be formed by reacting an aryl halide (such as an aryl fluoride or aryl bromide) or an aryl sulfonate (such as an aryl tosylate) with an amine in a solvent (such as butanol) at a temperature between room temperature and the reflux temperature of the solvent or by microwave radiation at a temperature between 120 ° C and 220 ° C.
Another example of converting one functional group to another involves the reaction in which an aryl halide can undergo halogen-metal exchange by treatment with the base (such as a lithium base, for example, n-butyl or t-butyl lithium) ) optionally at a low temperature (such as -78 ° C) in a solvent (such as tetrahydrofuran) and then quenched with an electrophile to introduce a desired substituent. Thus, for example, a formyl group can be introduced using dimethylformamide as the electrophile.
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Particular oxidation approaches include dehydrogenations and aromatization, decarboxylation and the addition of oxygen to certain functional groups. For example, aldehyde groups can be prepared by oxidizing the corresponding alcohol using conditions well known to those skilled in the art. For example, an alcohol can be treated with an oxidizing agent (such as the Dess-Martin reagent) in a solvent (such as a halogenated hydrocarbon, for example, dichloromethane).
Alternative oxidizing conditions can be used, such as treatment with oxalyl chloride and an activating amount of dimethyl sulfoxide and subsequent extinction by the addition of an amine (such as triethylamine). Such a reaction can be conducted in an appropriate solvent (such as a halogenated hydrocarbon, for example, dichloromethane) and under appropriate conditions (such as cooling below room temperature, for example, to 78 ° C followed by heating to room temperature).
In another example, sulfur atoms can be oxidized to the corresponding sulfoxide or sulfone using an oxidizing agent (such as a peroxy acid, for example, 3-chloroperoxybenzoic acid) in an inert solvent (such as a halogenated hydrocarbon, for example, dichloromethane) at a temperature between room temperature and the reflux temperature of the solvent.
Particular reduction approaches include the removal of oxygen atoms from particular functional groups, saturation (or partial saturation) of unsaturated compounds including aromatic rings. For example, primary alcohols can be generated from the corresponding ester or aldehyde by reduction, using a metal hydride (such as lithium aluminum hydride or sodium borohydride in a solvent such as tetrahydrofuran or methanol).
Alternatively, an alcohol can be generated from the corresponding carboxylic acid by reduction, using a metal hydride (such as aluminum and lithium hydride in a solvent such as tetrahydrofuran).
Salts of the compounds of Formula I can be prepared by reacting a compound of formula I with an appropriate acid or base in an appropriate solvent, or mixture of solvents (such as an ether, for example, diethyl ether, or an alcohol, for example, ethanol, or an aqueous solvent) using conventional procedures. Salts of the Formula I compound can be exchanged for other salts by treatment using ion exchange chromatography procedures.
Where it is desired to obtain a particular enantiomer of a compound of formula I, it can be produced from a corresponding mixture of enantiomers using any appropriate procedure for resolving enantiomers. For example, diastereoisomeric derivatives (like salts) can be produced by reacting a mixture of enantiomers of a compound of Formula I (like a racemate) or intermediates in the direction of compounds of Formula I and an appropriate chiral compound (like a chiral base) . The days
26/52 tereoisomers can then be separated by any conventional means (such as crystallization or chromatography) and the desired enantiomer recovered (as by treatment with an acid in the case where the diastereoisomer is a salt). Alternatively, a racemic mixture of esters can be resolved by kinetic hydrolysis using a variety of biocatalysts (for example, see Patel Steroselective Biocatalysts, Marcei Decker; New York 2000).
In another resolution process a racemate of compounds of formula I or intermediates in the direction of compounds of formula I can be separated using chiral high performance liquid chromatography. Alternatively, a particular enantiomer can be obtained using an appropriate chiral intermediate in one of the processes described above. Chromatography, recrystallization, and other conventional separation procedures can still be used with intermediate or final products where it is desired to obtain a particular geometric isomer.
II. Methods
In another aspect, methods of modulating MetAP2 activity are provided. Said methods comprise exposing said receptor to a compound described herein. In some embodiments, the compound used by one or more of the methods mentioned above is one of the generic, subgeneric, or specific compound described here, as a compound of formula I. The ability of the compounds described here to modulate or inhibit MetAP2 can be assessed by procedures known in the art and / or described herein. In another aspect, methods for treating a disease associated with MetAP2 expression or activity in a patient are provided. For example, a contemplated method includes administering a disclosed compound in an amount sufficient to establish effective intracellular MetAP2 inhibition to increase the production of thioredoxin in a patient and to induce stimulation in various organs of anti-obesity processes in the subject, for example, by administering a compound revealed in an amount insufficient to reduce angiogenesis in the patient.
In certain embodiments, a method for treating and or alleviating obesity in a patient by administering an effective amount of a disclosed compound is provided. Methods are still provided here to induce weight loss in a patient in need.
Other contemplated methods of treatment include methods for treating or ameliorating an obesity-related condition or comorbidity by administering a compound disclosed herein to a subject. For example, methods for treating type 2 diabetes in a patient in need are contemplated here.
Exemplary comorbidities include cardiac disorders, endocrine disorders, respiratory disorders, liver disorders, skeletal disorders, psychiatric disorders, metabolic disorders, and reproduction disorders.
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Exemplary cardiac disorders include hypertension, dyslipidemia, ischemic heart disease, cardiomyopathy, heart attack, stroke, venous thromboembolic disease, and pulmonary hypertension. Exemplary endocrine disorders include type 2 diabetes and latent autoimmune diabetes in adults. Exemplary respiratory disorders include obesity hypoventilation syndrome, asthma, and obstructive sleep apnea. An exemplary liver disorder is non-alcoholic fatty liver disease. Exemplary skeletal disorders include low back pain and osteoarthritis of weight-bearing joints. Exemplary metabolic disorders include Prader-Willi syndrome and polycystic ovary syndrome. Exemplary reproductive disorders include sexual dysfunction, erectile dysfunction, infertility, obstetric complications, and fetal abnormalities. Exemplary psychiatric disorders include weight-related depression and anxiety.
In particular, in certain embodiments, a method for treating the above medical indications comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of formula I, is provided.
Obesity or reference to "overweight" refers to an excess of fat in proportion to the mass of body fat. Excess fat accumulation is associated with an increase in size (hypertrophy) as well as number (hyperplasia) of adipose tissue cells. Obesity is varied in terms of absolute weight, weight: height ratio, subeutaneous fat distribution, and social and aesthetic normals. A common measure of body fat is body mass index (BMI). BMI refers to the body weight ratio (expressed in kilograms) by the square of the weight (expressed in meters). The body mass index can be precisely calculated using any of the formulas: weight (kg) / height ² (m ² ) (SI) or 703 X weight (lb) / height ² (inch ² ) (US).
According to the US Centers for Disease Control and Prevention (CDC), an overweight adult has a BMI of 25 kg / m ² to 29.9 kg / m ² , and an obese adult has a BMI of 30 kg / m ² or more. A BMI of 40 kg / m ² or greater is indicative of morbid obesity or extreme obesity. Obesity can also refer to patients with a waist circumference of about 102 cm for men and about 88 cm for women. For children, the definitions of overweight and obese take into account age and gender effects on body fat. Patients with a different genetic background may be considered "obese" at a level that differs from the general guidelines above.
The compounds are still useful for reducing the risk of secondary obesity outcomes, as well as reducing the risk of left ventricular hypertrophy. Methods to treat patients at risk of obesity, such as those who are overweight but not obese, for example with a BMI of between about 25 and 30 kg / m ² , are also contemplated. In certain modalities, a patient is a human.
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BMI does not account for the fact that excess fat can selectively occur in different parts of the body, and the development of adipose tissue may be more health-threatening in some parts of the body than in other parts of the body. For example, "central obesity", typically associated with an "apple-shaped" body, results from excess adiposity especially in the abdominal region, including abdominal fat and visceral fat, and has a higher risk of comorbidity than "peripheral obesity" , which is typically associated with a “pear-shaped” body resulting from excess adiposity especially in the hips. The measurement of waist / hip circumference (WHR) can be used as an indicator of central obesity. A minimum WHR indicative of central obesity has been variously established and a centrally obese adult typically has a WHR of about 0.85 or greater if a woman and about 0.9 or greater if a man.
Methods for determining whether a subject is overweight or obese that counts for the ratio of excess fat to lean body mass involves obtaining a subject's body composition. Body composition can be obtained by measuring the thickness of body fat in various places on the body, such as the abdominal area, the subscapular region, arms, buttocks and hips. These measures are then used to estimate total body fat with a margin of error of approximately four percentage points. Another method is bioelectrical impedance analysis (BIA), which uses the resistance of electrical flow through the body to estimate body fat. Another method is to use a large water tank to measure body buoyancy. Increased body fat will result in greater buoyancy, while greater muscle mass will result in a tendency to sink.
In another aspect, methods for treating an overweight or obese subject involving determining a level of at least one biomarker related to being overweight or obese in the subject, and administering an effective amount of a disclosed compound to obtain a target level in the subject are provided. Exemplary biomarkers include body weight, body mass index (BMI), WHR Waist / Hip ratio, plasma adipokines, and a combination of two or more of them.
In certain embodiments, the compound used by one or more of the previous methods is one of the generic, subgeneric or specific compounds described here, as a compound of formula I.
The compounds can be administered to patients (animals and humans) in need of said treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient , concomitant medication or special diets being followed by
29/52 patient, and other factors that those skilled in the art will recognize, with the appropriate dosage, finally, being at the doctor's discretion. To treat clinical conditions and diseases noted above, a compound can be administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectally in unit dosage formulations containing non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Parenteral administration may include subcutaneous, intravenous or intramuscular injections, or infusion techniques.
Treatment can be continued for a short or long period as desired. The compositions can be administered on a regimen of, for example, one to four or more times a day. An appropriate treatment period can be, for example, at least about a week, at least about two weeks, at least about a month, at least about six months, at least about 1 year, or indefinitely. A treatment period can end when a desired result, for example, a target weight loss, is achieved. A treatment regimen can include a corrective phase, during which a sufficient dose to provide weight reduction is administered, and can be followed by a maintenance phase, during which, for example, a lower enough dose to prevent weight gain is achieved. administered. An appropriate maintenance dose is possibly found in the lower parts of the dose ranges provided here, but corrective and maintenance doses can be readily established for individual subjects by those skilled in the art without undue experimentation, based on the disclosure here. Maintenance doses can be used to maintain body weight in subjects whose body weight has previously been controlled by other means, including diet and exercise, bariatric procedures such as bypass or bandage surgeries, or treatments using other pharmacological agents.
III. Pharmaceutical Compositions and Kits
In another aspect, pharmaceutical compositions comprising compounds as disclosed herein formulated together with a provided pharmaceutically acceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration rectally, vaginally, or aerosol, although the most appropriate form of administration in a given case will depend on the degree and severity of the condition being treated and the nature of the particular compound being used. For example, disclosed compositions can be formulated as a unit dose, and / or can be formulated for oral or subcutaneous administration.
Exemplary pharmaceutical compositions can be used in the form of a pre
30/52 pharmaceutical paraparation, for example, in solid, semi-solid, or liquid form, which contains one or more of the compounds, as an active ingredient, in mixture with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral applications . The active ingredient can be manipulated, for example, with the usual non-toxic pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active compound object is included in the pharmaceutical composition in an amount sufficient to produce the active effect on the processes or condition of the disease.
To prepare solid compositions such as tablets, the main active ingredient can be mixed with a pharmaceutical carrier, for example, conventional compression ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums , and other pharmaceutical diluents, for example, water to form a solid preformulation composition containing a homogeneous mixture of a compound, or a non-toxic pharmaceutically acceptable salt thereof. When referring to those preformulation compositions as homogeneous, it is understood that the active ingredient is uniformly dispersed throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
In solid dosage forms for oral administration (capsules, tablets, pills, pills, powders, granules and the like), the object composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) diluents or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions can also comprise buffering agents. Solid compositions of a similar type can also be employed as diluents in hard and soft gelatin capsules using said excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
A tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Tablets made by compression can be
31/52 prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), active or dispersing surface agent. Molded tablets can be prepared in a suitable machine from a mixture of the object composition moistened as an inert liquid diluent. Tablets, and other solid dosage forms, such as pills, capsules, pills and granules can optionally be labeled or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation technique.
Compositions for inhalation or insufflation include solutions and suspensions in, aqueous or organic solvents, or mixtures thereof, and pharmaceutically acceptable powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the object composition, liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed oils, peanuts, corn, germ, olive, castor and sesame), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and esters of sorbitan fatty acid, cyclodextrins and mixtures thereof.
Suspensions, in addition to the subject composition, may contain suspending agents such as, for example, isostearyl ethoxylated alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydride, bentonite, agar and tragacanth, and mixtures thereof.
Formulations for rectal or vaginal administration can be presented as a suppository, which can be prepared by mixing an object composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, which is solid at room temperature, but liquid at body temperature, and therefore will melt in the body cavity and release the active agent.
Dosage forms for transdermal administration of an object composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, adhesives and inhalants. The active component can be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, tampons, or propellants that may be required.
Ointments, pastes, creams and gels may contain, in addition to an object composition, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacan
32/52 to, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays may contain, in addition to an object composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may also contain usual propellants, such as chlorofluorhydrocarbons and unsubstituted volatile hydrocarbons, such as butane and propane.
The compositions and compounds can alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous suspension (for example, fluorocarbon propellant) could be used. Sonic nebulizers can be used because they minimize the shearing agent, which can result in degradation of the compounds contained in the object compositions. Ordinarily, an aqueous aerosol is formed by formulating an aqueous solution or suspending an object composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular object composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, sugar alcohols. Aerosols are usually prepared from isotonic solutions.
Pharmaceutical compositions suitable for parenteral administration comprise an object composition in combination with one or more sterile solutions, dispersions, suspensions, dispersions, suspensions or emulsions or pharmaceutically acceptable powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, which can be contain antioxidants, buffers, bacteriostats, solutes that generate the isotonic formulation with the blood of the intended container or with suspending or thickening agents.
Examples of suitable aqueous or non-aqueous carriers that can be employed in pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and appropriate mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity can be maintained, for example, by using coating materials, such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.
In another aspect, enteral pharmaceutical formulations including a disclosed compound, an enteric material; and a pharmaceutically acceptable carrier or excipient thereof are provided. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the intestinal tract (intestine) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5. Thus, enteric materials are not soluble, for example, up to a pH of about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.2 of 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0. Exemplary enteric materials include cellulose acetate phthalate (GAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellite, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate succinate, cellulose acetate succinate, cellulose acetate succinate, cellulose acetate succinate phthalate propionate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methyl methacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methyl methacrylate and methacrylic acid copolymer of methyl methyl methyl acetate and maleic anhydride). ethyl acrylate copolymer, natural resins such as zein, shellac and copai collophorium, and several commercially available enteric dispersion systems (eg Eudragit L30D55, Eudragit FS30D, Eudragit S100, Eudragit S100, Kollicoat EMM30D, Aquacaterl ). The solubility of each of the above materials is known or is readily determinable in vitro. The above is a list of possible materials, but a person skilled in the art with the benefit of the revelation could recognize that it is not comprehensive and that there are other enteric materials that can be used.
Advantageously, the kits are provided for use by, for example, a consumer in need of weight loss. Said kits include an appropriate dosage form such as those described above and instructions describing the method of using said dosage form to mediate, reduce, or prevent inflammation. The instructions could direct the consumer or medical staff to administer the dosage form according to the modes of administration known to those skilled in the art. Said kits could advantageously be packaged and sold in single or multiple unit kits. An example of a kit is called a blister pack. Blister packs are well known in the packaging industry and are being widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs usually consist of a sheet of relatively rigid material covered with a sheet of a preferably transparent plastic material. During the packaging process, the recesses are formed in the plastic sheet. The recesses have the size and shape of the tablets or capsules to be packaged. Then the
34/52 tablets are placed in the recesses and the sheet of relatively rigid material is sealed against the plastic sheet on the face that is opposite to the direction in which the recesses were formed. As a result, the tablets or capsules are in the recesses between the plastic sheet and the other. Preferably the resistance of the sheet is such that the tablets or capsules can be removed from the blister pack by applying manual pressure to the recesses through which an opening is formed in the sheet at the location of the recess. The tablet or capsule can then be removed through said opening.
It may be desirable to provide a memory aid in the kit, for example, in the form of numbers next to the tablets or capsules by the numbers corresponding to the days of the regimen that the tablets or capsules so specified should be ingested. Another example of a memory aid is a calendar printed on the card, for example, as follows “First Week, Monday, Tuesday,. . . etc. . . . Second Week, Monday, Tuesday, ... etc. Other variations of memory aids will be readily apparent. A "daily dose" can be a single pill or capsule or several pills or capsules to be taken on a given day. In addition, a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.
Also contemplated here are methods and compositions that include a second active agent, or administering a second active agent. For example, in addition to being overweight or obese, a subject or patient may also have comorbidities related to overweight or obesity, that is, diseases and other adverse health conditions associated with, exacerbated by, or precipitated by overweight or obese. Compounds are contemplated here in combination with at least one other agent that has previously been shown to treat these conditions related to overweight or obesity.
For example, type II diabetes has been associated with obesity. Certain complications of type II diabetes, for example, disability and premature death, can be prevented, alleviated, or eliminated by sustained weight loss (Astrup, A. Pub Health Nutr (2001) 4: 499-5 15). Agents administered to treat type II diabetes include sulfonylureas (for example, Chlorpropamide, Glipizide, Gliburide, Glimepiride); meglitinides (for example, Repaglinide and Nateglinide); biguanides (for example, Metformin); thiazolidinediones (Rosiglitazone, Troglitazone, and Pioglitazone); dipeptidylpeptidase-4 inhibitors (for example, Sitagliptin, Vildagliptin, and Saxagliptin); glucagon-like peptide 1 mimetics (for example, Exenatide and Liraglutide); and alpha-glucosidase inhibitors (for example, Acarbose and Miglitol.
Cardiac disorders and conditions, for example, hypertension, dyslipidemia, ischemic heart disease, cardiomyopathy, cardiac infarction, stroke, venous thromboembolic disease and pulmonary hypertension, have been related to overweight or obesity. For example,
35/52 hypertension was related to obesity due to substances secreted by excess adipose tissue that act on the kidneys, resulting in hypertension. In addition, with obesity there is usually greater amounts of insulin produced (due to the excess of adipose tissue) and this excess insulin still raises blood pressure. A primary treatment option for hypertension is weight loss. Agents administered to treat hypertension include Chlortalidone; Hydrochlorothiazide; Indapamide, Metolazone; loop diuretics (for example, Bumetanide, Ethacrylic acid, Furosemide, Lasix, Torsemide); potassium sparing agents (for example, Amiloride hydrochloride, benzamyl, Spironolactone, and Triamterene); peripheral agents (for example, Reserpine); central alpha agonists (for example, Clonidine hydrochloride, Guanabenz acetate, Guanfacine hydrochloride, and Methyldopa); alpha-blockers (for example, Doxazosin mesylate, Prazosin hydrochloride, and Terazosin hydrochloride); beta-blockers (eg Acebutolol, Atenolol, Betaxolol, Bisoprolol fumarate, Carteolol hydrochloride, Metoprolol tartrate, Metoprolol succinate, Nadolol, Penbutolol sulfate, Pindolol, Propranolol hydrochloride, and Timolol maleate); combined alpha and beta blockers (for example, Carvedilol and Labetalol hydrochloride); direct vasodilators (for example, Hydralazine hydrochloride and Minoxidil); calcium antagonists (for example, Diltiazem hydrochloride and Verapamil hydrochloride); dihydropyridines (for example, Amlodipine besylate, Felodipine, Isradipine, Nicardipine, Nifedipine, and Nisoldipine); ACE inhibitors (benazepril hydrochloride, Captopril, Enalapril maleate, Fosinopril sodium, Lisinopril, Moexipril, Quinapril hydrochloride, Ramipril, Trandolapril); Angiotensin II receptor blockers (for example, Losartan potassium, Valsartan, and Irbesartan); renin inhibitors (for example, Aliskiren); and combinations thereof. These compounds are administered in the regimens and dosages known in the art.
Carr et al. (The Journal of Clinical Endocrinology & Metabolism (2004) Vol. 89, No. 6 2601-2607) discusses a link between overweight or obese and dyslipidemia. Dyslipidemia is typically treated with statins. Statins, HMG-CoA reductase inhibitors, reduce cholesterol production in a subject and / or remove cholesterol build-up from the arteries. Statins include mevastatin, lovastatin, pravastatin, simvastatin, velostatin, dihydrocompactin, fluvastatin, atorvastatin, dalvastatin, carvastatin, crilvastatin, bevastatin, cefvastatin, rosuvastatin, pitavastatin, and glenvastatin. These compounds are administered in a regimen and in dosages known in the art. Eckel (Circulation (1997) 96: 3248-3250) discusses a relationship between overweight or obese and ischemic heart disease. Agents administered to treat ischemic heart disease include statins, nitrates (eg, Isosorbide Dinitrate and Isosorbide Mononitrate), beta-blockers, and calcium channel antagonists. These compounds are administered in regimens and in dosages known in the art.
Wong et al. (Nature Clinical Practice Cardiovascular Medicine (2007) 4: 436-443) discusses a relationship between overweight or obese and cardiomyopathy. Agents administered to treat cardiomyopathy include inotropic agents (eg, Digoxin), diuretics (eg, Furosemide), ACE inhibitors, calcium antagonists, anti-agents
36/52 arrhythmic (eg, Sotolol, Amiodarone and Disopyramide), and beta-blockers. These compounds are administered in regimens and in dosages known in the art. Yusef et al. (Lancet (2005) 366 (9497): 1640-1649) discusses a relationship between overweight or obese and cardiac infarction. Agents administered to treat cardiac infarction include ACE inhibitors, Angiotensin II receptor blockers, direct vasodilators, beta blockers, anti-arrhythmic agents and thrombolytic agents (for example, Alteplase, Retaplase, Tenecteplase, Anistreplase, and Urokinase). These compounds are administered in regimens and dosages known in the art.
Suk et al. (Stroke (2003) 34: 1586-1592) discusses a relationship between overweight or obese and stroke. Agents administered to treat stroke include antiplatelet agents (for example, Aspirin, Clopidogrel, Dipyridamol, and Ticlopidine), anticoagulant agents (for example, Heparin), and thrombolytic agents. Stein et al. (The American Journal of Medicine (2005) 18 (9): 978-980) discusses a relationship between overweight or obese and venous thromboembolic disease. Agents administered to treat venous thromboembolic disease include antiplatelet agents, anticoagulant agents, and thrombolytic agents. Sztrymf et al. (Rev Pneumol Clin (2002) 58 (2): 104-10) discusses a relationship between overweight or obese and pulmonary hypertension. Agents administered to treat pulmonary hypertension include inotropic agents, anticoagulants, diuretics, potassium (eg, K-dur), vasodilators (eg, Nifedipine and Diltiazem), Bosentan, Epoprostenol, and Sildenafil. Disorders and respiratory conditions such as obesity hypoventilation syndrome, asthma, and obstructive sleep apnea have been linked to being overweight or obese. Elamin (Chest (2004) 125: 1972-1974) discusses a relationship between overweight or obese and asthma. Agents administered to treat asthma include bronchodilators, anti-inflammatory agents, leukotriene blockers, and anti-IgE agents. Particular asthma agents include Zafirlukast, Flunisolide, Triamcinolone, Beclomethasone, Terbutaline, Fluticasone, Formoterol, Beclomethasone, Salmeterol, Theophylline, eXopenex.
Kessler et al. (Eur Respir J (1996) 9: 787-794) discusses a relationship between overweight or obese and obstructive sleep apnea. Agents administered to treat sleep apnea include Modafinil and amphetamines.
Liver disorders and conditions, such as non-alcoholic fatty liver disease, have been related to being overweight or obese. Tolman et al. (Ther Clin Risk Manag (2007) 6: 11531163) discusses a relationship between overweight or obese and non-alcoholic fatty liver disease. Agents administered to treat non-alcoholic fatty liver disease include antioxidants (for example, Vitamins E and C), insulin sensitizers (Metformin, Pioglitazone, Rosiglitazone, and Betaine), hepatoprotectors, and lipid-lowering agents.
Skeletal disorders and conditions, such as low back pain and osteoarthritis of weight-bearing joints, were related to being overweight or obese, van Saase (J Rheuma
37/52 tol (1988) 15 (7): 1152-1158) discusses a relationship between overweight or obese and osteoarthritis of weight-bearing joints. Agents administered to treat osteoarthritis of weight-bearing joints include acetaminophen, non-steroidal anti-inflammatory agents (eg, Ibuprofen, Etodolac, Oxaprozine, Naproxen, Diclofenac, and Nabumetone), COX-2 inhibitors (eg, Celecoxib), steroids, supplements (eg glucosamine and chondroitin sulfate), and artificial joint fluid.
Metabolic disorders and conditions, for example, Prader-Willi syndrome and polycystic ovary syndrome, have been related to being overweight or obese. Cassidy (Journal of Medical Genetics (1997) 34: 917-923) discusses a relationship between overweight or obese and Prader-Willi syndrome. Agents administered to treat Prader-Willi Syndrome include human growth hormone (HGH), somatropin, and weight loss agents (eg, Orlistat, Sibutramine, Methamphetamine, lonamine, phentermine, Bupropion, Diethylpropion, Phendimetrazine, Benzfetermine, and Topamax) .
Hoeger (Obstetrics and Gynecology Clinics of North America (2001) 28 (1): 85-97) discusses a relationship between overweight or obese and polycystic ovary syndrome. Agents administered to treat polycystic ovary syndrome include insulin sensitizers, synthetic estrogen and progesterone combinations, Spironolactone, Eflornithine, and Clomiphene. Reproductive disorders and conditions such as sexual dysfunction, erectile dysfunction, infertility, obstetric complications, and fetal abnormalities, have been related to being overweight or obese. Larsen et al. (Int J Obes (Lond) (2007) 8: 1189-1198) discusses a relationship between overweight or obese and sexual dysfunction. Chung et al. (Eur Urol (1999) 36 (1): 68-70) discusses a relationship between overweight or obese and erectile dysfunction. Agents administered to treat erectile dysfunction include phosphodiesterase inhibitors (for example, Tadalafil, Sildenafil citrate, and Vardenafil), prostaglandin E analogs (for example, Alprostadil), alkaloids (for example, loimbine), and testosterone. Pasquali et al. (Hum Reprod (1997) 1: 82-87) discusses a relationship between overweight or obese and infertility. Agents administered to treat infertility include Clomiphene, Clomiphene citrate, Bromocriptine, Gonadotropin-releasing hormone (GnRH), GnRH agonist, GnRH antagonist, Tamoxifen / nolvadex, gonadotropins, human chorionic gonadotropin (HCG), gonadotropin (HCG) , recombinant follicle stimulating hormone (FSH), urofolitropine, heparin, follitropin alfa, and follitropin beta.
Weiss et al. (American Journal of Obstetrics and Gynecology (2004) 190 (4): 10911097) discusses a relationship between overweight or obese and obstetric complications. Agents administered to treat obstetric complications include Bupivacaine hydrochloride, Dinoprostone PGE2, Meperidine HCI, Ferro-folic-500 / iberet-folic-500, Meperidine, Methylergonovine maleate, Ropivacaine HCI, Nalbuphine HCI, Oxymorphone HCI, Oxypholine, Rhytoxydine, Oxycodoline, Dyspramine, Dyspramine, Dyspramine, Dyspramine, Dyspramine, Dyspramine, Dyspramine, Dyspramine, Dyspramine, Dyspramine, Dyspramine, Dyspramine, Dyspramine, Dyspramine, Dyspramine, Dyspramine, Dysproxin, Dysproline, Dysproline, Dyspramine, Dyspramine, Dyspramine, Dyspramine, Dyspramine, Dyspramine, Dyspramine, Dysproline, Dysproline, Dysproline, Dysproline, Dyspramine, Dysproline, Dyspramine, Dysproxamine, , Sufentanil citrate, and Oxitocic.
38/52
Psychiatric disorders and conditions, for example, depression and anxiety associated with weight, have been related to being overweight or obese. Dixson et al. (Arch Intern Med (2003) 163: 2058-2065) discusses a relationship between overweight or obese and depression. Agents administered to treat depression include serotonin reuptake inhibitors (for example, Fluoxetine, Escitalopram, Citalopram, Paroxetine, Sertraline, and Venlafaxine); triciclic antidepressants (for example, Amitriptyline, Amoxapine, Clomipramine, Desipramine, Dosulepin hydrochloride, Doxepine, Imipramine, Iprindol, Lofepramine, Nortriptyline, Opipramol, Protriptyline, and Trimipramine); monoamine oxidase inhibitors (for example, Isocarboxazid, Moclobemide, Phenelzine, Tranylcypromine, Selegiline, Rasagiline, Nialamide, Iproniazid, Iproclozide, Toloxatone, Linazolid, Dienolide cavapirone desmethoxyiangonine, and Dextroanfetamine); psychostimulants (for example, Amphetamine, Methamphetamine, Methylphenidate, and Arecoline); antipsychotics (for example, Butyrophenones, Phenothiazines, Thioxanthenes, Clozapine, Olanzapine, Risperidone, Quetiapine, Ziprasidone, Amisulpride, Paliperidone, Simbiax, Tetrabenazine, and Cannabidiol); and mood stabilizers (for example, Lithium carbonate, valproic acid, Divalproex sodium, sodium vaiproate, Lamotrigine, Carbamazepine, Gabapentin, Oxcarbazepine, and Topiramate).
Simon et al. (Archives of General Psychiatry (2006) 63 (7): 824-830) discusses a relationship between overweight or obese and anxiety. Agents administered to treat anxiety include serotonin uptake inhibitors, mood stabilizers, benzodiazepines (eg, Alprazolam, Clonazepam, Diazepam, and Lorazepam), tricyclic antidepressants, monoamine oxidase inhibitors, and beta-blockers.
In another aspect methods to facilitate and maintain weight loss in a subject involving administering to the subject an amount of a disclosed effective compound results in weight loss in the subject and administering the therapeutically effective amount of a different weight loss agent to maintain a weight reduced in the subject are provided. Weight loss agents include serotonin reuptake inhibitors and noradrenergics; noradrenergic reuptake inhibitors; selective serotonin reuptake inhibitors; and intestinal lipase inhibitors. Particular weight loss agents include orlistat, sibutramine, methamphetamine, ionamine, phentermine, bupropion, diethylpropion, phendimetrazine, benzfetermine, bromocriptine, lorcaserin, topiramate, or agents that act to modulate food intake by blocking the action of ghrelin, inhibiting activity of ghrelin diacylglycerol acyltransferase 1 (DGAT1), inhibit stearoyl CoA desaturase 1 (SCD1) activity, inhibit neuropeptide Y receptor 1 function, activate neuropeptide Y receptor 2 or 4 function, or inhibit sodium glucose 1 or cotransporter activity 2. These compounds are administered in regimens and in dosages known in the art.
EXAMPLES
The compounds described here can be prepared in a number of basic ways
39/52 based on the teachings contained here and synthetic procedures known in the art. In describing the synthetic methods described below, it should be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work procedures, can be chosen to be the standard conditions for that reaction, unless otherwise indicated. It is understood by a specialist in the technique of organic synthesis that the functionality present in various parts of the molecule must be compatible with the proposed reagents and reactions. Substituents not compatible with the reaction conditions will be apparent to a person skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.
At least some of the compounds identified as "Intermediates" here are contemplated as active ingredients. For example, at least some of the compounds identified as "Intermediates" here may be modulators of MetAP2.
¹ H NMR spectra were recorded at room temperature using a Varian Unity Inova spectrometer (400MHz) with a 5mm triple resonance probe for example, compounds, and a Bruker Avance DRX spectrometer (400MHz) or a Bruker Avance DPX spectrometer (300MHz) for the intermediate compounds. Chemical shifts were expressed in ppm in relation to tetramethylsilane. The following abbreviations were used: br = broad sign, s = singlet. d = doublet, dd = double doublet, dt = double triple, t = triplet, q = quartet, m = multiplet.
Mass spectrometry experiments (LCMS) to determine retention times and associated mass ions were performed using the following methods:
Method A: The experiments were performed on a Waters Micromass ZQ2000 mass spectrometer with an electrospray source operating in positive and negative ion mode connected to the Waters Acquity UPLC system. Detection was achieved using a PDA UV detector. The LC column was an Acquity BEH 1.7 micron C18 100x2.1 mm. The flow rate was 0.4 mL / minute. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) and was kept constant for 0.4 minutes followed by a gradient of up to 5% solvent A and 95% solvent B in the following 6 minutes. The final solvent system was kept constant for another 0.8 minutes.
Method B: Experiments were performed on a Waters Micromass ZQ2000 quadrupole mass spectrometer with an electrospray source operating in positive and negative ion mode connected to a Hewlett Packard HP1100 LC system. Detection was achieved using a DAD UV detector and a Sedex 85 evaporative light scattering detector. The LC column was a Higgins Clipeus 5 microns C18 100x3.0mm. The flow rate was 1 mL / minute. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5%
40/52 acetonitrile containing 0.1% formic acid (solvent B) and was kept constant for 1 minute followed by a gradient of up to 5% solvent A and 95% solvent B over the next 12 minutes. The final solvent system was kept constant for another 7 minutes.
Method C: Experiments were performed on a quadrupole Waters ZMD mass spectrometer with an electrospray source operating in positive and negative ion mode connected to a Waters 1525 LC system. Detection was achieved using a Waters 996 diode array detector and a Sedex 85 evaporative light scattering detector. The LC column was Luna 3 microns C18 (2) 30x4.6mm. The flow rate was 2mL / minute. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) and was kept constant for 0.5 minutes followed by a gradient of up to 5% solvent A and 95% solvent B for the following 4 minutes. The final solvent system was kept constant for another minute.
Method D: Experiments were performed on a single quadrupole Finnigan AQA mass spectrometer with an electrospray source operating in positive ion mode connected to a Hewlett Packard 1050 LC system. Detection was achieved using a UV diode array detector and a Sedex 65 evaporative light scattering detector. The LC was Luna 3 microns C18 (2) 30x4.6mm. The flow rate was 2mL / minute. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) and was kept constant for 0.5 minutes followed by a gradient of up to 5% solvent A and 95% solvent B for the following 4 minutes. The final solvent system was kept constant for another minute.
Method E: Experiments were performed on a Waters Platform LC quadrupole mass spectrometer with an electrospray source operating in positive and negative ion mode connected to a Hewlett Packard HP1100 LC system. Detection was achieved using both a diode array detector and a Sedex 85 evaporative light scattering detector. The LC column was Phenomenex Luna 3 microns C18 (2) 30x4.6mm. The flow rate was 2 mL / minute. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) and was kept constant for 0.5 minutes followed by a gradient of up to 5% solvent A and 95% solvent B for the following 4 minutes. The final solvent system was kept constant for another minute. Microwave experiments were performed using a Biotage Initiator ™, which uses a single-mode resonator and dynamic field tuner, both of which provide reproducibility and control. Temperatures of 40-250 ° C can be achieved, and pressures up to 20 bar can be achieved. Three types of flasks are available for this process, 0.5-2.0 ml, 2.0-5.0 ml and 5.0-20 ml.
Preparative HPLC purification was conducted using a Genesis (C18) reverse phase C18 column (100 * 22.5mm with 7 micron particle size, UV detection
41/52 at 230 or 254 nm, flow 5-15 mL / min), eluting with gradients from 100-0 to 0-100% water / acetonitrile containing 0.1% formic acid. The fractions containing the required product (identified by LCMS analysis) were grouped, the organic fraction removed by evaporation, and the remaining aqueous fraction lyophilized, to generate the final product.
Compounds that required column chromatography were purified using a Biotage SP1 ™ rapid purification system with Touch Logic Control ™ or a Combiflash Companion® with pre-packaged Isolute® SPE silica gel cartridge, Biotage SNAP cartridge or Redisep® Rf cartridge respectively.
Abbreviations: AIBN: Azo-bis- (isobutyronitrile); DCM: Dichloromethane; DIPEA: Diisopropylethylamine; DMF: Ν, Ν-Dimethylformamide; HATU: 2- (7-Aza-1H-benzotriazol-1-yl) 1,1,3,3-tetramethyluronium hexafluorophosphate; NMP: 1-Methyl-2-pyrrolidone; THF: Tetrahydrofuran; Xantphos: 4,5-Bis (diphenylphosphino) -9,9-dimethylxanthene.
Example 1: N- [1 - (1 H-Tetrazol-5-yl) -5,6,7,8-tetrahydronaphthalen-2-yl] benzenesulfonamide
/
N = N
Tin tri-n-butyl chloride (0.16mL) was added to a solution of sodium azide (0.039g) in DMF (0.6mL) and the mixture was stirred for 5 minutes. Tetra-butyl ammonium bromide (0.0065g) was then added, followed by N- (1-cyano-5,6,7,8-tetrahydronaphthalen-2yl) benzenesulfonamide (Intermediate 1, 0.177g). The mixture was heated by microwave radiation at 220 ° C for 1 hour. The solution was then acidified with 1N hydrochloric acid and the products were extracted in DCM, dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness and the residue was purified by preparative HPLC (C18). Fractions containing the desired product were combined, and the solvent was removed by evaporation to generate the title compound as a beige solid (0.01 g).
LCMS (Method B) r / t 9.46min (M + H) 356.
NMR (CD ₃ OD) δ 7.04 (t, 1H), 6.99-6.85 (m, 4H), 6.76-6.68 (m, 2H), 2.32 (m, 2H) , 1.97 (m, 2H), 1.34-1.15 (m, 4H)
Example 2: N- [3-Cyclopropyl-2- (1 H-tetrazol-5-yl) -phenyl] -benzenesulfonamide
N- (2-Cyano-3-cyclopropylphenyl) -benzenesulfonamide (Intermediate 9, 0.052g), azide
42/52 trimethyl silane (0.087g) and dibutyltin oxide (0.038g) were suspended in 1,2dichloroethane (3ml). The mixture was heated by microwave radiation to 140 ° C for 45 minutes. Six other aliquots of azidotrimethylsilane (0.174g) were added and after each addition the mixture was heated by microwave radiation at 140 ° C for 60 minutes. The reaction mixture was acidified to pH 1 using 1N hydrochloric acid, and then extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was triturated with a mixture of pentane and cyclohexane and the solid was collected by filtration, to generate the title compound as a white solid (0.039g).
LCMS (Method A) r / t 3.97min (M + H) 342.
NMR (DMSO-d ₆ ) δ 9.79 (brs, 1H), 7.65-7.61 (m, 2H), 7.59 (t, 1H), 7.53-7.47 (m, 2H ), 7.26 (t, 1H), 6.86 (d, 1H), 6.82 (d, 1H), 1.49-1.39 (brm, 1H), 0.69-0.63 ( m, 2H), 0.51-0.46 (m, 2H).
Example 3: N- [3-methoxy-2- (1 H-tetrazol-5-yl) -phenyl] -benzenesulfonamide; s ^ ^{N u} H
HN N /
N = N
A mixture of N- [2- (1-benzyl-1H-tetrazol-5-yl) -3-methoxyphenyl] -benzenesulfonamide (Intermediate 12, 0.104g), ammonium formate (0.45g) and palladium hydroxide (0 , 01 g) in ethanol (10mL) was heated to reflux for 72 hours. The reaction mixture was filtered through celite and the filtrate was evaporated in vacuo. The residue was purified by flash chromatography on silica, eluting with a mixture of DCM and methanol. Fractions containing the desired product were combined and evaporated to generate the title compound as a colorless solid (0.05 g).
LCMS (Method A) r / t 4.18min (M + H) 332.
NMR (DMSO-d ₆ ) δ 10.99 (s, 1H), 7.68-7.63 (m, 2H), 7.55 (t, 1H), 7.48-7.40 (m, 3H ), 7.07 (d, 1H), 6.93 (d, 1H), 3.82 (s, 3H).
Example 4: N- [3-Methyl-2- (1 H-tetrazol-5-yl) -phenyl] -benzenesulfonamide o; s' o ^{N u} H
HN / N = N
N- [2- (1-Benzyl-1 H-tetrazol-5-yl) -3-methylphenyl] -benzenesulfonamide (Intermediate 15,
0.05g) was dissolved in ethyl acetate (10mL) in a nitrogen atmosphere. Carbon palladium (10%, 0.02g) was added and the nitrogen atmosphere was replaced with hydrogen. The mixture was stirred for 7 days and then filtered through celite and the solvent was removed by evaporation in vacuo. The residue was purified by preparative HPLC (C18). Fractions with
43/52 having the desired product were combined, and the solvent was removed by evaporation to generate the title compound as a white solid (0.08g).
LCMS (Method A) r / t 3.66min (M + H) 316.
NMR (DMSO-d ₆ ) δ 9.91 (s, 1H), 7.63-7.55 (m, 3H), 7.51-7.46 (m, 2H), 7.25 (t, 1H ), 7.13 (d, 1H), 6.88 (d, 1H), 2.02 (s, 3H).
Example 5: N- [3-Bromo-2- (1 H-tetrazol-5-yl) -phenyl] -benzenesulfonamide [only
O ^z N ^υ H hn N
HN N /
N = N
The solution of N- (3-Bromo-2-cyanophenyl) -benzenesulfonamide (Intermediate 21, 0.22g) and tributyltin azide (0.43g) in 1,2-dichlorobenzene (1.5mL) was heated by microwave radiation to 130 ° C for 2 hours. The mixture was diluted with ether and extracted with 1M aqueous sodium hydroxide. The aqueous solution was acidified with 1N hydrochloric acid at pH 1 and then extracted with ethyl acetate. The organic solution was washed with brine and then dried over sodium sulfate, filtered and the filtrate was evaporated. The residue was triturated with ether and the solid was collected by filtration to generate the title compound as a colorless solid (0.19g).
LCMS (Method A) r / t 3.76min (M + H) 381.
NMR (DMSO-d ₆ ) δ 10.03 (br s, 1H), 7.69-7.65 (m, 2H), 7.64-7.59 (m, 1H), 7.58-7, 50 (m, 3H), 7.35 (t, 1H), 7.11 (d, 1H).
Intermediate 1: N- (1-Cyano-5,6,7,8-tetrahydronaphthalen-2-yl) benzenesulfonamide
2-Benzenesulfonylamino-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid amide (Intermediate 2, 1.2g) was dissolved in dry DCM (20mL) and phosphorus pentachloride (0.9g) was added. The mixture was stirred for 3 hours then saturated aqueous sodium hydrogen carbonate was added carefully and the products were extracted in ethyl acetate. The organic solution was dried over magnesium sulfate, filtered and the solvent was removed by evaporation. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane. The fractions containing the desired product were combined and the solvent was evaporated to generate the title compound as an off-white solid.
LCMS (Method B) r / t 10.35min (M + H) 313.
NMR (DMSO-d _s ) δ 10.33 (br s 1H), 7.80-7.39 (br m, 5H), 7.28-7.12 (br m, 1H), 6,756.55 (br m, 1H), 2.80-2.50 (br m, 4H), 1.83-1.50 (br m, 4H).
Intermediate 2: 2-Benzenesulfonylamino-5,6,7,8-tetrahydronaphthalene-1 acid
44/52 carboxylic amide
2-Benzenesulfonylamino-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid (Intermediate 3, 0.5g) was suspended in DCM (10mL) and oxalyl chloride (0.15mL) was added together with DMF (one drop) . The mixture was stirred for 30 minutes, then concentrated in vacuo. The residue was dissolved in dry THF (20mL) and added slowly to a solution of ammonia in THF. After stirring for 1 hour, the solution was concentrated in vacuo and the residue was triturated with diethyl ether and the solid collected by filtration to generate the title compound as a white powder (0.48g).
NMR (CDCI ₃ ) δ 7.84-7.80 (m, 3H), 7.56 (t, 1H), 7.50-7.44 (m, 2H), 7.04-6.98 (m , 2H), 5.78 (br m, 2H), 2.75-2.67 (m, 4H), 1.78-1.68 (m, 4H).
Intermediate 3: 2-Benzenesulfonylamino-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid
2-Benzenesulfonylamino-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid methyl ester (Intermediate 4, 0.68g) was dissolved in dioxane (12ml_) and the lithium hydroxide solution (0.6g) in water (6mL) was added. The mixture was heated by microwave radiation at 160 ° C for 15 minutes then diluted with 1N hydrochloric acid. The product was extracted into DCM and the organic solution was separated, dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo to generate the title compound as a white powder.
NMR (CDCI3) δ 8.64 (br s, 1H), 7.78-7.72 (m, 2H), 7.55 (t, 1H), 7.47-7.36 (m, 3H), 7.16 (d, 1H), 2.84 (t, 2H), 2.75 (t, 2H), 1.79-1.69 (m, 4H).
Intermediate 4: 2-Benzenesulfonylamino-5,6,7,8tetrahydronaphthalene-1-carboxylic acid methyl ester
To a solution of 2-amino-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid methyl ester (Intermediate 5, 1.5g) in pyridine (20ml) was added benzenesulfonyl chloride (0.95mL). The mixture was stirred for 1 hour then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid, dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo to generate the title compound as a solid
45/52 almost white crystalline (2.4g).
NMR (CDCI ₃ ) δ 8.17 (br s, 1H), 7.69-7.65 (m, 2H), 7.52 (t, 1H), 7.44-7.37 (m, 3H) , 7.13 (d, 1H), 3.63 (s, 3H), 2.73 (t, 2H), 2.65 (t, 2H), 1.76-1.63 (m, 4H).
Intermediate 5: 2-amino-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid methyl ester
2- (Benzhydrylideneamino) -5,6,7,8-tetrahydronaphthalene-1-carboxylic acid methyl ester (Intermediate 6, 8.2g) was dissolved in THF (100mL) and 1N hydrochloric acid (100mL) was added. The mixture was stirred for 1 hour and then passed through an SCX2 SPE column. The column was washed with acetonitrile and then the desired product was eluted with a solution of 2M ammonia in methanol. Evaporation of the solvent gave the title compound as a clear oil (2.8g) which was used without further purification or analysis.
Intermediate 6: 2- (Benzhydrylideneamino) -5,6,7,8tetrahydronaphthalene-1-carboxylic acid methyl ester
Cesium carbonate (12.4g), palladium (II) acetate (0.12g), triethylamine (0.12mL) and Xantphos (0.474g) were suspended in dioxane (50mL) in nitrogen. 2-Trifluoromethanesulfonyloxy-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid methyl ester (Intermediate 7, 4.2g) and benzhydrylidenamine (5.5ml_) in dioxane (35ml_) were added and the mixture was heated to 100 ° C for 3.5 hours. The resulting mixture was partitioned between ethyl acetate and water. The organic solution was washed with water and concentrated in vacuo. The residue was recrystallized from methanol to generate the title compound as an off-white solid (8.2g).
LCMS (Method C) r / t 5.00min (M + H) 370.
Intermediate 7: 2-Trifluoromethanesulfonyloxy-5,6,7,8tetrahydronaphthalene-1-carboxylic acid methyl ester o ^z o
2-Hydroxy-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid methyl ester (Intermediate 8, 6g) was dissolved in DCM (100mL) and pyridine (6.5mL). The solution was cooled to -20 ° C and trifluoromethanesulfonium anhydride (6.5mL) was added under a drip for 15 minutes. THE
The mixture was stirred at -20 ° C for another 20 minutes, then allowed to warm to room temperature and stirred for another 60 minutes. 1-Butyl methyl ether (200mL) was added and the resulting mixture was filtered. The filtrate was washed with 2N hydrochloric acid, water and then with brine before being dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to generate the title compound as a yellow oil (9.2g).
LCMS (Method C) r / t 4.74 min (M + H) 339, (M + Na) 361.
Intermediate 8: 2-Hydroxy-5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid methyl ester
In a nitrogen atmosphere, platinum oxide (5g) was added to a solution of 2-hydroxy-naphthalene-1-carboxylic acid methyl ester (10g) in acetic acid (200mL). The nitrogen atmosphere was replaced with hydrogen, the pressure was increased to 4 bar and the mixture was stirred overnight. The resulting suspension was filtered and the filtrate was concentrated in vacuo to generate an oil. The residue was purified by chromatography on silica, eluting with DCM. Fractions containing the desired product were combined and evaporated in vacuo to generate the title compound as a colorless oil (11.7g).
LCMS (Method C) r / t 4.31min (M + H) 207.
Intermediate 9: N- (2-Cyano-3-cyclopropylphenyl) -benzenesulfonamide yl / ° zSÍ o ^{N U} H
Benzenesulfonyl chloride (0.093g) was added to a solution of 2-amino-6cyclopropyl-benzonitrile (Intermediate 10, 0.07g) in DCM (4mL) and pyridine (0.1 mL). The mixture was stirred for 5 hours, then another aliquot of benzenesulfonyl chloride (0.093g) was added along with triethylamine (0.12mL) and the mixture was stirred overnight. The reaction mixture was washed with water, and the organic solution was dried over magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane. The fractions containing the desired product were combined and evaporated to generate the title compound as a colorless oil (0.052g).
LCMS (Method D) r / t 4.07min (M + H) 299.
NMR (CDCI ₃ ) δ 7.86-7.81 (m, 2H), 7.58 (t, 1H), 7.52-7.45 (m, 3H), 7.38 (t, 1H), 7.04 (brs, 1H), 6.65 (d, 1H), 2.12-2.04 (m, 1H), 1.12-1.05 (m, 2H), 0.75-0, 68 (m, 2H).
Intermediate 10: 2-Amino-6-cyclopropylbenzonitrile
47/52
A carbon palladium paste (10%; 0.025g) in DCM (5mL) was added to a solution of 2-nitro-6-cyclopropylbenzonitrile (Intermediate 11, 0.25g) in ethanol (15ml_) under nitrogen. The nitrogen atmosphere was exchanged for hydrogen and the mixture was stirred for 48 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane. Fractions containing the desired product were combined and evaporated to generate the title compound as a colorless oil (0.082g).
NMR (CDCI ₃ ) δ 7.18 (t, 1H), 6.53 (d, 1H), 6.26 (d, 1H), 4.8-4.0 (br m, 2H), 2.20 -2.10 (m, 1H), 1.10-1.02 (m, 2H), 0.78-0.70 (m, 2H).
Intermediate 11: 2-Nitro-6-cyclopropylbenzonitrile
2-Bromo-6-nitrobenzonitrile (0.56g), cyclopropyl boronic acid (0.63g), palladium (II) acetate (0.055g), tricyclohexylphosphine (0.135g) and tribasic potassium phosphate (2.36g) were dissolved in a mixture of toluene (15ml_) and water (3mL). The mixture was heated to 100 ° C under nitrogen for 18 hours. The mixture was cooled and then partitioned between water and DCM. The organic solution was separated, dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane. Fractions containing the desired product were combined and evaporated to generate the title compound as a light yellow solid (0.51 g).
NMR (CDCI3) δ 8.05 (d, 1H), 7.64 (t, 1H), 7.27 (d, 1H), 2.52-2.45 (m, 1H), 1.33-1 , 26 (m, 2H), 0.91-0.85 (m, 2H).
Intermediate 12: N- [2- (1-Benzyl-1H-tetrazol-5-yl) -3-methoxyphenyl] -benzenesulfonamide
N ^X N / N = N .si O ^{N υ} H
2- (1-Benzyl-1H-tetrazol-5-yl) -3-methoxyphenylamine (Intermediate 13, 0.115g) was dissolved in pyridine (0.16mL) and DCM (2mL). Benzenesulfonyl chloride (0.08g) was added and the mixture was stirred overnight. The reaction mixture was diluted with DCM and washed with 1N hydrochloric acid, dried over magnesium sulfate and filtered. The filtrate was evaporated to
48/52 drying and the residue was purified by flash chromatography on silica, eluting with a mixture of DCM and methanol. Fractions containing the desired product were combined and evaporated to generate the title compound as a colorless solid (0.11g).
LCMS (Method E) r / t 3.55min (M + H) 422.
Intermediate 13: 2- (1-Benzyl-1 H-tetrazol-5-yl) -3-methoxyphenylamine
1-Benzyl-5- (2-methoxy-6-nitrophenyl) -1H-tetrazole (Intermediate 14, 0.14g) was dissolved in ethanol (5mL) in an atmosphere of nitrogen. Carbon platinum (10%, 0.01 g) was added and the nitrogen atmosphere was replaced with hydrogen. The mixture was stirred for 18 hours and then filtered through celite. The filtrate was evaporated to dryness to generate the title compound as a brown gum (0.12g).
LCMS (Method E) r / t 3.18min (M + H) 282.
Intermediate 14: 1-Benzyl-5- (2-methoxy-6-nitrophenyl) -1H-tetrazole
1-Benzyl-5- (2-fluor-6-nitrophenyl) -1H-tetrazole (Intermediate 18, 0.3g) was dissolved in DCM (4mL) and the solution of sodium methoxide in methanol (20%; 2mL) was added. The mixture was stirred for 4 hours and then the solvent was removed by evaporation in vacuo. The residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid and then brine. The organic solution was dried over sodium sulfate, filtered and the solvent was removed by evaporation in vacuo. The residue was purified by flash chromatography on silica, eluting with a mixture of DCM and methanol. Fractions containing the desired product were combined and evaporated to generate the title compound as a pale yellow solid (0.14g).
LCMS (Method E) r / t 3.30min (M + H) 312.
Intermediate 15: N- [2- (1-Benzyl-1 H-tetrazol-5-yl) -3-methylphenyl] -benzenesulfonamide
2- (1-Benzyl-1 H-tetrazol-5-yl) -3-methylphenylamine (Intermediate 16, 0.15g) was dissolved
49/52 in pyridine (5mL) and benzenesulfonyl chloride (0.07g, 0.4mmol) was added. The mixture was stirred overnight, then diluted with ethyl acetate and washed with 1N hydrochloric acid, dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness and the residue was purified by flash chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane. The fractions containing the desired product were combined and evaporated to generate the title compound as a white powder (0.16g).
LCMS (Method A) r / t 4.68min (M + H) 406.
NMR (DMSO-dg) δ 10.03 (s, 1H), 7.75 (m, 1H), 7.73 (m, 1H), 7.66-7.53 (m, 3H), 7.29 (t, 1H), 7.25-7.16 (m, 3H), 7.03 (d, 1H), 6.96-6.92 (m, 2H), 6.83 (d, 1H), 5.36 (dd, 2H), 1.46 (s, 3H).
Intermediate 16: 2- (1-Benzyl-1 H-tetrazol-5-yl) -3-methylphenylamine
N N /
N = N
II H ₂ l r
1-Benzyl-5- (2-methyl-6-nitrophenyl) -1H-tetrazole (Intermediate 17, 0.1g) was dissolved in ethyl acetate (20mL) in an atmosphere of nitrogen. Palladium on carbon (10%, 0.1 g) was added and the nitrogen atmosphere was replaced with hydrogen. The mixture was stirred for 4 hours and then filtered over celite. The solvent was removed by evaporation in vacuo to generate the title compound as a white solid (0.09g).
LCMS (Method E) r / t 3.30min (M + H) 266.
Intermediate 17: 1-Benzyl-5- (2-methyl-6-nitrophenyl) -1H-tetrazole
N N /
N = N o ₂ i r
Phosphorus pentachloride (0.42g, 2mmol) was added to a solution of N-benzyl-2methyl-6-nitrobenzamide (Intermediate 19, 0.54g) in DCM (10mL). The mixture was stirred under nitrogen for 30 minutes and then azidotrimethylsilane (0.48g) was added and the mixture was stirred for an additional 72 hours. The mixture was diluted with DCM (50mL) and water (50mL). Solid hate bicarbonate was then added to the mixture until there was no more gas evolution. The organic solution was washed with saturated aqueous sodium bicarbonate, then with 1N hydrochloric acid, dried over magnesium sulfate and filtered. The solvent was evaporated to generate an orange solid which was recrystallized from ethyl acetate to generate the title compound as a white solid (0.42g).
LCMS (Method E) r / t 3.37min (M + H) 296.
NMR (DMSO-d ₆ ) δ 8.20 (d, 1H), 7.83-7.73 (m, 2H), 7.27-7.20 (m, 3H), 7.07-7.04 (m,
50/52
2H), 5.47 (d, 2H), 1.6 (s, 3H).
In a similar manner, the following compound was prepared from the appropriate starting materials:
Intermediate 18: 1-Benzyl-5- (2-fluor-6-nitrophenyl) -1H-tetrazole
N N /
N = N ho ₂ nt
Starting from N-benzyl-2-fluor-6-nitrobenzamide (Intermediate 20) and used without further characterization.
Intermediate 19: N-Benzyl-2-methyl-6-nitrobenzamide
2-Nitro-6-methylbenzoic acid (0.91 g) and benzylamine (0.53g) were dissolved in NMP (5mL) and DIPEA (3mL). HATU (1.9g) was added and the mixture was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate and then brine. The organic solution was dried over magnesium sulfate, filtered and the solvent was removed in vacuo to generate a light brown oil (1.01g) which crystallized on standing.
NMR (DMSO-d ₆ ) δ 8.96 (t, 1H), 7.90 (d, 1H), 7.62 (d, 1H), 7.50 (t, 1H), 7.36-7, 28 (m, 5H), 4.41 (d, 2H), 2.27 (s, 3H).
In a similar manner, the following compound was prepared from the appropriate starting materials:
Intermediate 20: N-Benzyl-2-fluor-6-nitrobenzamide
Starting from 6-fluor-2-nitrobenzoic acid and used without further characterization.
Intermediate 21: N- (3-Bromo-2-cyanophenyl) -benzenesulfonamide o ^{N υ} H
51/52
Benzenesulfonyl chloride (0.53g) was added to a solution of 2-amino-6bromobenzonitrile (Intermediate 22, 0.5g) in DCM (15ml_) and pyridine (1ml_). The mixture was stirred for 2 hours, then another aliquot of benzenesulfonyl chloride (0.53g) was added and the mixture was stirred overnight. The reaction mixture was diluted with DCM, washed with 1N hydrochloric acid, and the organic solution was dried over sodium sulfate and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash chromatography on silica, eluting with a mixture of DCM and methanol. Fractions containing the desired product were combined and evaporated to generate the title compound as a white powder (0.24g).
LCMS (Method E) r / t 3.33min (M + H) 335, 337.
Intermediate 22: 2-Amino-6-bromobenzonitrile
N
2-Bromo-6-nitrobenzonitrile (5g) was dissolved in a solution of methanol (100mL) and dioxane (65mL) and heated to reflux. Powdered iron (4.6g) was added in portions for 20 minutes and the mixture was heated to reflux for 4 hours. The mixture was allowed to cool to room temperature, filtered and the filtrate was evaporated in vacuo. The residue was triturated with water and the solid was collected by filtration to generate the title compound as a light brown solid (3.8g).
LCMS (Method E) r / t 3.01 min (M + H) 197, 199.
Biological activity
The compounds are tested for their ability to inhibit the activity of recombinant human MetAP2 using the following assay.
Recombinant human Flag-MetAP2 expressed in Sf9 cells followed by affinity purification and EDTA treatment to remove the cation from the endogenous active site was dialyzed against MnCI ₂ to produce the manganese enzyme in the assay. The assay was conducted for 30 minutes at 25 ° C in 50mM HEPES buffer containing 100mM NaCI, pH 7.5 in the presence of 0.75mM substrate Methionine-Alanine-Serine (MAS) and 50pg / mL amino acid oxidase using a dilution of purified MetAP2 generating approximately 50,000 RFU of control activity. The substrate divation by MetAP2 and oxidation of free methionine by amino acid oxidase was detected and quantified using fluorescence generated by Amplex red (10-acetyl-3,7-dihydroxyphenoxazine) in combination with wild radish peroxidase that detects H ₂ O ₂ released during the oxidation step. The fluorescent signal was detected using a multi-well fluorometer. Compounds were diluted in DMSO prior to the addition of the assay buffer, the final concentration of DMSO in the assay being 1%.
IC ₅₀ is defined as the concentration at which a given compound reaches 50% control inhibition. IC ₅₀ values are calculated using the XLfit software package
52/52 (version 2.0.5).
The compounds demonstrated activity in the test for this Example as indicated in the following table, where A represents IC ₅₀ <1μΜ and B represents IC ₅₀ > 1.0μΜ.
Compound name Activity N- [1- (1H-Tetrazol-5-yl) -5,6,7,8-tetrahydronaphthalen-2-yl] -benzenesulfonamide B N- [3-Cyclopropyl-2- (1H-tetrazol-5-yl) -phenyl] -benzenesulfonamide THE N- [3-Methoxy-2- (1H-tetrazol-5-yl) -phenyl] -benzenesulfonamide THE N- [3-Methyl-2- (1H-tetrazol-5-yl) -phenyl] -benzenesulfonamide B N- [3-Bromo-2- (1H-tetrazol-5-yl) -phenyl] -benzenesulfonamide B
INCORPORATION BY REFERENCE
All publications and patents mentioned here, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent were specifically and individually incorporated by reference. In the event of a conflict, this request, including any definition here, will prevail.
EQUIVALENTS
Although specific modalities have been discussed, the specification above is illustrative and not restrictive. Many variations will become apparent to those skilled in the art when reviewing this specification. The full scope of the modalities must be determined by reference to the claims, along with their full scope of equivalents and the specification together with these variations.
Unless otherwise indicated, all numbers that express quantities of ingredients, reaction conditions and so on used in the specification and in the claims will be understood to be modified in all cases by the term "about." Thus, unless otherwise indicated, the numerical parameters established in this specification and in the attached claims are approximations that may vary depending on the desired properties sought to be obtained.

权利要求:
Claims (24)
[1]
1. Compound, CHARACTERIZED by the fact that it is represented by Formula I:

and pharmaceutically acceptable salts, stereoisomers, esters and prodrugs thereof, in which:
A is phenyl;
B is selected from the group consisting of a bond or (CR ^B1 R ^B2 );
R ¹ is hydrogen;
R ² is selected from the group consisting of halogen, hydroxyl, cyano, C1-6 alkyl, C2-6 alkenyl, C2.6 alkynyl, C3.6 cycloalkyl, C1-6 alkoxy, C3.6 alkenyloxy, C3.6 alkynyloxy, C3.6 cycloalkyloxy, C1-6 alkyl-S (O) 2_, C3.6 cycloalkyl-C1-4-alkyl-, C3.6 cycloalkyl-C1-4 alkoxy-, phenyl-C16 alkyl-, phenyl, phenoxy, phenyl-C16 alkoxy-, heteroaryl, heteroaryloxy, heteroaryl-C6 alkyl, heteroarylC1-6 alkoxy, heterocyclyl-C1-6 alkyl-, and heterocyclyl-C1-6 alkoxy-, where heteroaryl is a 5-6 membered ring having one, two or three heteroatoms, each selected independently of N, O or S, where the heteroaryl and phenyl groups are each independently optionally substituted by one or more substituents, each independently selected from R ^b , where heterocyclyl is a 4-7 membered ring optionally substituted by one or more substituents, each independently selected from R ^c , and where when the heterocyclyl contains an -NH- fraction, that f -NH- ration is optionally substituted by R ^d , where Ον6 alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, Ο _ν6 alkoxy, C ₃ . ₆ alkenyloxy r C ₃ . ₆ alkynyloxy are each independently optionally substituted by one or more substituents, each independently selected from halogen, hydroxyl, R ^to R ^to N- and cyano, where C3.6 cycloalkyl, and C3.6 cycloalkoxy are each independently optionally substituted by one or more substituents, each independently selected from halogen, hydroxyl, R ^to R ^to N-cyano, and C1-6 alkyl; or
R ¹ and R ² , when taken together with the carbons to which they are attached, form a 5-7 membered saturated, partially unsaturated or unsaturated ring, optionally having 1, 2 or 3 groups, each independently selected from O, NR ^h , and S (O) _r , where r is 0, 1 or 2, where the 5-7 membered ring is optionally substituted on a carbon by one or more groups, each independently selected from R ^e ;
R ^A1 is selected, independently for each occurrence, from the group consisting of hydrogen, hydroxyl, cyano, halogen, C1-6 alkyl, C2.6 alkenyl, C3.6 alkynyl, C3.6 cycloalkyl, Ci-6 alkoxy, and R ^f R ⁹ N-, wherein Ci_6 alkyl, C _{2. 6} alkenyl, C ₃ . ₆ alkynyl, C ₃ . ₆ cycloalkyl, and Ci_ ₆
[2]
2/7 alkoxides are each independently optionally substituted by one or more halogens;
R ^A2 is selected, independently for each occurrence, from the group consisting of hydrogen, hydroxyl, cyano, halogen, C1-6 alkyl, C2-6 alkenyl, C2.6 alkynyl, C3.6 cycloalkyl, C1-6 alkoxy, C3.6 alkenyloxy, C3.6 alkynyloxy, C3.6 cycloalkoxy, C1-6 alkyl-S (O) w-, where w is 0, 1 or 2, R ^f R ⁹ N-, R ^f R ⁹ N-carbonyl-, R R ^{f 9} N-carbonilN (Ra) -, R ^f SO 2 N-R ^9, C ₆ alkyl carbonilN (Ra) -, CH-6 alquilsulfonilN (Ra) -, alkoxycarbonyl-N (R ^a ) -, phenyl, phenoxy, phenyl-C16-alkyl-, phenylC ^-alkoxy, heteroaryl, heteroaryloxy, heterocycloxy, heteroaryl-C16-alkyl, heteroaryl-GQg alkoxy-, heterocyclyl-C16-alkyl-, and heterocyclyl-C16 alkoxy -, where heteroaryl is a 5-6 membered ring having one, two or three heteroatoms, each independently selected from N, O or S, where the heteroaryl is optionally substituted by one or more substituents, each independently selected from R ^b , where the heterocyclyl is an optionally substituted 4-7 membered ring by one or more substituents, each independently selected from R ^c , where when the heterocyclyl contains an -NH- fraction, that -NH- fraction is optionally substituted by R ^d , where alkyl and alkoxy are each independently optionally substituted by one or more groups, each independently selected from R ^p , where C2. ₆ alkenyl and C ₂ . ₆ alkynyls are each independently optionally substituted by one or more substituents, each independently selected from R ^p ; where C ₃ . ₆ cycloalkyl and C ₃ . ₆ cycloalkoxy are each independently optionally substituted by one or more substituents, each independently selected from R ^p ;
R ^B1 and R ^B2 are selected, independently for each occurrence, from the group consisting of hydrogen, C1-6 alkoxy, halogen, C1-6 alkyl, C2.6 alkenyl, C3.6 alkynyl and C3.6 cycloalkyl, where C2. 6 alkenyl and C3.6 alkynyl are each independently optionally substituted by one or more groups, each independently selected from R ^p , where alkyl and alkoxy are each independently optionally substituted by one or more groups, each independently selected from R ^p , where C3. ₆ cycloalkyl is optionally substituted by one or more groups, each independently selected from R ^p , or R ^B1 and R ^B2 , when taken together with the carbons to which they are attached, form a cyclopropyl ring or 4-6 membered ring, wherein the 4-6 membered ring optionally has a group selected from N (R ^h ), O or S (O) _r , where r is 0, 1 or 2;
R ^a and R ^a are selected, independently for each occurrence, from the group consisting of hydrogen and alkyl, or R ^a and R ^a , when taken together with the nitrogen to which they are attached, form a 4-6 membered heterocyclic ring , where C1-6 alkyl is optionally substituted by one or more substituents, each selected independently from the group consisting of halogen, oxo and hydroxyl, and where the heterocyclic ring is optionally substituted by one or more substituents, each selecting
[3]
3/7 independent of the group consisting of halogen, alkyl, oxo, or hydroxyl;
R ^b is selected, independently for each occurrence, from the group consisting of halogen, hydroxyl, cyano, C1-6 alkyl, C2-6 alkenyl, C2.6 alkynyl, C3.6 cycloalkyl, Ci-6 alkoxy, C3.6 alkenyloxy, C3.6 alkynyloxy, C3.6 cycloalkoxy, C1-6 alkyl-S (O) w-, where w is 0, 1 or 2, C1-6 alkyl-N (R ^a ) -, C1-6 alkyl-N ( R ^a ) carbonyl, R ^to R ^to N-, R ^to R ^to N-carbonyl-, R ^to R ^to N-carbonyl-N (R ^a ) -, R ^to 'R ^to N-SO2-, and Ci-6 alkylcarbonyl-N (R ^a ) -, where C2. ₆ alkenyl, C ₃ . CI _{6 6} alkynyl and alkoxy are each independently optionally substituted by one or more substituents each independently selected from R ^w, where C _{3. 6} cycloalkyl and C ₃ . ₆ cycloalkoxy are each independently optionally substituted by one or more substituents, each independently selected from R ^p , where alkyl is optionally substituted by one or more substituents selected from R ^p ;
R ^c is selected, independently for each occurrence, from the group consisting of hydroxyl, cyano, oxo, halogen, alkyl, C2.6 alkenyl, C2.6 alkynyl, C3.6 cycloalkyl, alkoxy, Cve alkyl-S (O) w- , where w is 0, 1 or 2, alkyl-NR ^a -, C3 alkyl. ₆ cycloalkyl-, C ₃ . ₆ cycloalkyl-C ₁₆ alkyl, R ^to R ^to N-, alkylcarbonyl-N (R ^a ) -; alkoxycarbonyl-N (R ^a) R ^a R ^a NSO 2 R R N-carbonyl, and R ^to R N-carbonyl-N (Ra), wherein Ci-6 alkyl, C _{2. 6} alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₆ CI - ₆ alkoxy and cycloalkyl are each independently optionally substituted by one or more groups each independently selected from R;
R ^d is selected, independently for each occurrence from the group consisting of CI - ₆ alkyl, CI - ₆ alkylcarbonyl and Cl - ₆ alkylsulfonyl, CI - ₆ alkyl that is optionally substituted by one or more substituents each independently selected from halogen, hydroxyl, and R ^to R ^to N-;
R ^c e is selected, independently for each occurrence, from the group consisting of hydroxyl, cyano, halogen, oxo, C1-4 alkyl, C2.4 alkenyl, C2.4 alkynyl, C3.6 cycloalkyl, Ci4 alkoxy, C3.6 alkenyloxy, C3.6 alkynyloxy, C3.6 cycloalkoxy, C3.6 cycloalkyl-C14 alkoxy-, alkyl-S (O) w- where w is 0, 1, or 2, R ^a R ^a N-, R ^a R ^a N-carbonyl, R ^to R ^to N-carbonyl-N (R ^a ) -, R ^to R ^to NSO2-, Cve alkyl-carbonyl-N (R ^a ) -, alkyl-SO2-N (R ^a ) -, alkoxycarbonyl - and alkoxycarbonyl-N (R ^a ) -, where C2. ₆ alkenyl and C ₂ . ₆ alkynyls are each independently optionally substituted by one or more substituents, each independently selected from R ^p , where alkyl and alkoxy are each independently optionally substituted by one or more substituents, each independently selected from R ^p , where C ₃ . ₆ cycloalkyl and C ₃ . ₆ cycloalkoxy are each independently optionally substituted by one or more substituents, each independently selected from R ^p ;
R ^f and R ⁹ are selected, independently for each occurrence, from the group consisting of hydrogen, C1-4 alkyl optionally substituted by one or more substituents, each independently selected from R ^p , and C3. ₆ cycloalkyl optionally substituted by one or more substituents, each independently selected from R ^p , or R ^f and R ⁹ ,
[4]
4/7 when taken together with the nitrogen to which they are attached, form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxy, oxo, cyano, C ₆ alkyl, C- ₆ alkoxy, R ^a R ^to N-, C ₆ alkylcarbonyl-N (R ^a ) -, C 6 alkoxycarbonyl-N (R ^a ) -, R ^a R ^to N-SO2-, R ^a ' R N-carbonyl, and R ^to R N-carbonyl-N (Ra), wherein Ci-6 alkyl , and Cl - ₄ alkoxy are each independently optionally substituted by one or more substituents each independently selected from group consisting of R ^to R ^to N-, halogen, hydroxy, cyano, alkoxycarbonyl, R ^to R ^to N-carbonyl, R ^to R ^to N-SO ₂ -, alkoxy, and C ^ alkylS (O) _w -, where W is 0, 1 or 2;
R ^p is selected, independently for each occurrence, from the group consisting of R ^to R ^to N-, halogen, hydroxy, cyano, alkoxycarbonyl, R ^to R ^to N-carbonyl, R ^to R ^to N-SO ₂ -, alkoxy, and alkylS (O) _w -, where w is 0, 1, or 2;
R ^p is selected, independently for each occurrence, from the group consisting of R ^to R ^to N-, halogen, hydroxy, cyano, alkoxycarbonyl, R ^to R ^to N-carbonyl, R ^to R ^to N-SO ₂ -, alkoxy, Cj -4 alkylS (O) _w -, where w is 0, 1 or 2, and C ₃ . ₆ cycloalkyl, where C ₃ . ₆ cycloalkyl is optionally substituted by one or more substituents, each independently selected from R ^p ;
R ^p is selected, independently for each occurrence, from the group consisting of R ^to R ^to N-, halogen, hydroxy, cyano, C1-4 alkoxycarbonyl, R ^to R ^to N-carbonyl, R ^to R ^to N-SO2-, CI - ₄ alkoxy, C1-4 alkylS (O) _w where w is 0, 1, or 2, and CI - ₆ alkyl, CI - ₆ alkyl that is optionally substituted by one or more substituents each independently selected from R ^p ;
R 'is selected, independently for each occurrence from the group consisting of R ^f R ⁹ N-, halogen, cyano, hydroxy and Cl - _C6alkoxy;
R ^h is selected, independently for each occurrence, from the group consisting of hydrogen; alkyl, C3.6 alkenyl and C3.6 alkynyl, in which none of the carbon atoms forming an unsaturated bond is attached to N; C3.6 cycloalkyl, alkyl-S (O) 2-; and alkyl-N (R ^a ) carbonyl; wherein alkyl is optionally substituted by one or more substituents, each independently selected from R ^p ; where C3. ₆ alkenyl and C ₃ . ₆ alkynyls are each independently optionally substituted by one or more substituents, each independently selected from R ^p ; where C ₃ . ₆ cycloalkyl is optionally substituted by one or more substituents, each independently selected from R ^p .
2. Compound according to claim 1, CHARACTERIZED by the fact that B is a bond.
3. Compound according to claim 1 or 2, CHARACTERIZED by the fact that R ² is selected from the group consisting of halogen, cyano, C _1-6 alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₆ cycloalkyl, C ₆ alkoxy, C _{3. 6} C ₃ alkenyloxy. ₆ alkynyloxy, C ₃ . ₆ cycloalkyloxy, C ₆ alkyl-S (O) ₂ -, C _{3. 4} CI_ ₆ cycloalkyl-alkyl, and C _{3. 6} cycloalkyl CI_ ₄ alkoxy-, wherein Cl - ₆ alkyl, C _{2. 6}
[5]
5/7 alkenyl, C ₂ . ₆ alkynyl, C® alkoxy, C ₃ . ₆ alkenyloxy and C ₃ . ₆ alkynyloxy are each independently optionally substituted by one or more substituents, each independently selected from halogen, hydroxyl, R ^to R ^to N-, or cyano, where C ₃ . ₆ cycloalkyl and C ₃ . ₆ cycloalkoxy are each independently optionally substituted by one or more substituents, each independently selected from halogen, hydroxyl, R ^to R ^to N-, cyano and C® alkyl.
A compound according to any one of claims 1 to 3, CHARACTERIZED by the fact that R ² is selected from the group consisting of halogen, cyano, C 1-6 alkyl, C ₃ . ₆ cycloalkyl, C ₆ alkoxy, C _{3. 6} cycloalkyloxy, C ₃ . ₆ CI_ ₄ -alkyl-cycloalkyl, C _{3. 6} cycloalkyl-CI - ₄ alkoxy- and alkoxy-CI - ₆ alkyl CI_ _6.
A compound according to any one of claims 1 to 4, CHARACTERIZED by the fact that R ² is selected from the group consisting of bromine, methyl, methoxy, or cyclopropyl.
[6]
6. Compound according to any one of claims 1 to 5, CHARACTERIZED by the fact that Rt and R ₂ , when taken together with the ring to which they are attached, form:
where * represents the attachment points in Formula I.
[7]
7. A compound according to any one of claims 1 to 6, characterized in that R ¹ is selected from the group consisting of hydrogen, halogen, C ₆ alkyl, or C ₆ alkoxy, wherein alkyl and Cl - ₆ CI - ₆ alkoxy are each optionally independently substituted with one or more halogens.
[8]
A compound according to any one of claims 1 to 7,
CHARACTERIZED by the fact that R ^A1 is hydrogen.
[9]
Compound according to any one of claims 1 to 8,
CHARACTERIZED by the fact that R ^A2 is selected from the group consisting of hydrogen, halogen, 0 ^ 6 alkyl, C2.6 alkenyl, C3.6 cycloalkyl, C® alkoxy and C3.6 alkenyloxy, where C® alkyl and C® alkoxy they are each independently optionally substituted by one or more substituents, each independently selected from R ^p , where C2. ₆ alkenyl is optionally substituted by one or more substituents, each independently selected from R ^p , where C ₃ . ₆ cycloalkyl is optionally substituted by one or more substituents, each independently selected from R ^p .
[10]
10. Compound according to any one of claims 1 to 9, CHARACTERIZED by the fact that R ^B1 and R ^B2 are H.
6/7
[11]
11. Compounds CHARACTERIZED for being N- [1- (1 H-tetrazol-5-yl) -5,6,7,8-tetrahydronaphthalen-2-yl] -benzenesulfonamide, N- [3-cyclopropyl-2- (1 H-tetrazol-5-yl) -phenyl] benzenesulfonamide, N- [3-methoxy-2- (1 H-tetrazol-5-yl) -phenyl] -benzenesulfonamide, N- [3-methyl-2- (1 H -tetrazol-5-yl) -phenyl] -benzenesulfonamide, N- [3-bromo-2- (1 H-tetrazol-5-yl) -phenyl] benzenesulfonamide and pharmaceutically acceptable salts thereof.
[12]
12. Use of a compound as defined in any of claims 1 to 11, CHARACTERIZED by the fact that it is in the manufacture of a medication to treat and / or control obesity in a patient who needs it.
[13]
13. Use according to claim 12, CHARACTERIZED by the fact that it comprises administering said compound in an amount sufficient to establish inhibition of intracellular MetAP2 and / or in an amount effective to induce the stimulation of multiple organs in anti-obesity processes in the individual .
[14]
14. Use according to claim 12 or 13, CHARACTERIZED by the fact that it comprises administering said compound in an amount insufficient to reduce angiogenesis in the patient.
[15]
15. Use of a compound as defined in any of claims 1 to 11, CHARACTERIZED by the fact that it is in the manufacture of a medicine to induce weight loss in a patient who needs it.
[16]
16. Use, according to claim 12 or 15, CHARACTERIZED by the fact that the patient is a human.
[17]
17. Use according to any of claims 12, 15 or 16, CHARACTERIZED by the fact that the patient has a body mass index equal to or greater than about 30 kg / m ² before administration.
[18]
18. Use according to any of claims 12, 15 or 16, CHARACTERIZED by the fact that the compound is administered orally or subcutaneously.
[19]
19. Pharmaceutical composition, CHARACTERIZED by the fact that it comprises a compound as defined in any one of claims 1 to 11, and a pharmaceutically acceptable carrier.
[20]
20. Composition, according to claim 19, CHARACTERIZED by the fact that the composition is formulated as a unit dose.
[21]
21. Composition, according to claim 19, CHARACTERIZED by the fact that the composition is formulated for oral administration.
[22]
22. Composition according to claim 19, CHARACTERIZED by the fact that the composition is formulated for intravenous or subcutaneous administration.
[23]
23. A compound according to any one of claims 1 to 3, CHARACTERIZED by the fact that R ² is selected from the group consisting of C ^ and alkyl,
7/7
C ₃ - ₆ cycloalkyl, C ₆ alkoxy, C ₃ . ₆ cycloalkyloxy, C ₃ . ₆ cycloalkyl-Ci. ₄ -alkyl-, C ₃ . ₆ cycloalkyl CI_ _4-alkoxy- and alkoxy-CI - ₆ alkyl CI_ _6.
[24]
24. Compound according to any one of claims 1 to 9, CHARACTERIZED by the fact that R ^A1 and R ^A2 are H.

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法律状态:
2020-01-14| B08K| Patent lapsed as no evidence of payment of the annual fee has been furnished to inpi [chapter 8.11 patent gazette]|Free format text: EM VIRTUDE DO ARQUIVAMENTO PUBLICADO NA RPI 2542 DE 24-09-2019 E CONSIDERANDO AUSENCIA DE MANIFESTACAO DENTRO DOS PRAZOS LEGAIS, INFORMO QUE CABE SER MANTIDO O ARQUIVAMENTO DO PEDIDO DE PATENTE, CONFORME O DISPOSTO NO ARTIGO 12, DA RESOLUCAO 113/2013. |

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2021-10-05| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US201161436265P| true| 2011-01-26|2011-01-26|

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PCT/US2012/022721|WO2012103333A1|2011-01-26|2012-01-26|Tetrazole compounds and methods of making and using same|

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