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JP-7855509-B2 - Novel functionalized lactone as a regulator of the 5-hydroxytryptamine receptor 7 and its method of use

JP7855509B2JP 7855509 B2JP7855509 B2JP 7855509B2JP-7855509-B2

Inventors

  • キャニー， ダニエル ジェイ．
  • ブラス， ベンジャミン イー．
  • ブラットナー， ケビン エム．
  • ピピン， ダグラス エー．

Assignees

  • テンプル・ユニバーシティ－オブ・ザ・コモンウェルス・システム・オブ・ハイアー・エデュケイション
  • プレベンティックス， エルエルシー

Dates

Publication Date
20260508
Application Date
20201112
Priority Date
20191113

Claims (20)

  1. A compound having a structure that conforms to general formula (I*), This includes the enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts thereof. During the ceremony, R 1N is selected from the group consisting of imidazole, oxazole, and isoxazole. Each of R AA is independently a C1 - C7 linear alkyl group. Each of R2a is independently a halogen, an unsubstituted C1 - C7 alkyl, a C1 - C7 perhaloalkyl, an unsubstituted C1 - C7 alkoxy, a C1 - C7 perhaloalkoxy, or a CN. a is 0, 1, or 2, and aa is 1 or 2. compound.
  2. A compound having a structure that conforms to general formula (I*), This includes the enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts thereof. During the ceremony, R 1N is, And in the formula, R 4a and R 4b are each hydrogen or C1 - C7 alkyl, or R 4a and R 4b , together with the atom to which they are bonded, optionally form a ring containing 3-7 atoms, which optionally contains oxygen. R 5 includes C1 - C7 alkyl, C3 - C7 cycloalkyl, C1-C7 alkoxy, C3 - C7 cycloalkoxy, C1 - C7 haloalkyl, C3- C7 cyclohaloalkyl, C1 - C7 haloalkoxy, C3 - C7 cyclohaloalkoxy, C6 - C10 aryl, 5-membered-to- 10 -membered heteroaryl, CN, NR 8a R 8b , SO₂ R 8c , NR 8d SO₂ R 8e , NR 8i COOR 8j , NHCONNR 8f , NR 8g COOR 8h , and Selected from the group consisting of, R8a , R8b , R8d , R8g , and R8i are each selected from the group consisting of hydrogen, C1 - C7 alkyl, and C3 - C7 cycloalkyl, or R8a and R8b optionally, together with the atom to which they are bonded, form a heterosille containing 3-7 atoms, which optionally contains a group selected from oxygen, sulfur, and NR9 . R8c , R8e , R8f , and R8h are each C1 - C7 alkyl or C3 - C7 cycloalkyl, R 8j is selected from the group consisting of C1 - C7 alkyl, C3 - C7 cycloalkyl, C6 - C10 aryl, and 5-membered-to-10-membered heteroaryl groups, or if both R 4a and R 8a are present, or if both R 4a and R 8g are present, these groups optionally combine with the atoms to which they are bonded to form a ring containing 4-7 atoms. R9 is selected from the group consisting of hydrogen, C1 - C7 alkyl, and C3 - C7 cycloalkyl. Each of R AA is independently a C1 - C7 linear alkyl group. Each of R2a is independently a halogen, an unsubstituted C1 - C7 alkyl, a C1 - C7 perhaloalkyl, an unsubstituted C1 - C7 alkoxy, a C1 - C7 perhaloalkoxy, or a CN. a is either 1 or 2, aa is 1 or 2, and y 1 is 0, 1 or 2. compound.
  3. A compound having a structure that conforms to general formula (I*), This includes the enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts thereof. During the ceremony, R 1N is, And in the formula, R 4a and R 4b are each hydrogen or C1 - C7 alkyl, or R 4a and R 4b , together with the atom to which they are bonded, optionally form a ring containing 3-7 atoms, which optionally contains oxygen. R 5 includes C1 - C7 alkyl, C3 - C7 cycloalkyl, C1-C7 alkoxy, C3 - C7 cycloalkoxy, C1 - C7 haloalkyl, C3- C7 cyclohaloalkyl, C1 - C7 haloalkoxy, C3 - C7 cyclohaloalkoxy, C6 - C10 aryl, 5-membered-to- 10 -membered heteroaryl, CN, NR 8a R 8b , SO₂ R 8c , NR 8d SO₂ R 8e , NR 8i COOR 8j , NHCONNR 8f , NR 8g COOR 8h , and Selected from the group consisting of, R8a , R8b , R8d , R8g , and R8i are each selected from the group consisting of hydrogen, C1 - C7 alkyl, and C3 - C7 cycloalkyl, or R8a and R8b optionally, together with the atom to which they are bonded, form a heterosille containing 3-7 atoms, which optionally contains a group selected from oxygen, sulfur, and NR9 . R8c , R8e , R8f , and R8h are each C1 - C7 alkyl or C3 - C7 cycloalkyl, R 8j is selected from the group consisting of C1 - C7 alkyl, C3 - C7 cycloalkyl, C6 - C10 aryl, and 5-membered-to-10-membered heteroaryl groups, or if both R 4a and R 8a are present, or if both R 4a and R 8g are present, these groups optionally combine with the atoms to which they are bonded to form a ring containing 4-7 atoms. R9 is selected from the group consisting of hydrogen, C1 - C7 alkyl, and C3 - C7 cycloalkyl. Each of R AA is independently a C1 - C7 linear alkyl group. Each of R2a is independently a halogen, an unsubstituted C1 - C7 alkyl, a C1 - C7 perhaloalkyl, an unsubstituted C1 - C7 alkoxy, a C1 - C7 perhaloalkoxy, or a CN. a is either 1 or 2, aa is 1 or 2, and y 1 is 1 or 2. compound.
  4. R 1N is, The compound according to claim 2.
  5. R 1N is the compound according to claim 3: In the formula, R 8a and R 8b are each independently H or an unsubstituted C1 - C7 alkyl group. In the formula, R 8d is independently H or an unsubstituted C1 - C7 alkyl, and R 8e is an unsubstituted C1 - C7 alkyl. In the formula, R 4a and R 8g are each independently H or an unsubstituted C1 - C7 alkyl, and R 8h is an unsubstituted C1 - C7 alkyl. In the formula, R 8h is an unsubstituted C1 - C7 alkyl, In the formula, R 8a , R 8b , and R 8g are each independently H or an unsubstituted C1 - C7 alkyl, and R 8h is an unsubstituted C1 - C7 alkyl. In the formula, R 8j is selected from the group consisting of C1 - C7 alkyl, C3 - C7 cycloalkyl, C6 - C10 aryl, and 5-membered to 10-membered heteroaryl. In the formula, R 8a and R 8b are each independently H or an unsubstituted C1 - C7 alkyl group. In the formula, R 8g is independently H or an unsubstituted C1 - C7 alkyl, and R 8h is independently an unsubstituted C1 - C7 alkyl. or
  6. R 1N is, The compound according to claim 3.
  7. R 1N is, The compound according to claim 1.
  8. A compound having a structure that conforms to the general formula (I**), The formula includes the enantiomer, diastereomer, hydrate, solvate, and pharmaceutically acceptable salt thereof, in which, R aa and R bb are each selected from the group consisting of hydrogen, C1 - C7 alkyl, and C3 - C7 branched alkyl. Each of R AA is independently a C1 - C7 linear alkyl group. Each of R2a is independently a halogen, an unsubstituted C1 - C7 alkyl, a C1 - C7 perhaloalkyl, an unsubstituted C1 - C7 alkoxy, a C1 - C7 perhaloalkoxy, or a CN. A compound in which aa is 1 or 2, and a' is 1 or 2.
  9. The compound according to claim 8, wherein R aa and R bb are each ethyl.
  10. The compound according to claim 1, wherein a is 0 or 1.
  11. The compound according to claim 1, wherein a is 1 or 2, and R AA is methyl.
  12. The compound according to claim 2, wherein R and AA are each methyl.
  13. The compound according to claim 3, wherein R, AA , and each are methyl.
  14. The compound according to claim 8, wherein R, AA , and each are methyl.
  15. The compound according to claim 1, wherein each of R 2a is independently a halogen.
  16. The compound according to claim 2, wherein each of R 2a is independently a halogen.
  17. The compound according to claim 3, wherein each of R 2a is independently a halogen.
  18. The compound according to claim 15, wherein each of R 2a is independently -F or -Cl.
  19. The compound according to claim 16, wherein each of R 2a is independently -F or -Cl.
  20. The compound according to claim 17, wherein each of R 2a is independently -F or -Cl.

Description

Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 62/934,985, filed on 13 November 2019, which is incorporated by reference in its entirety. Statement on research funded by the federal government This invention was made possible with government support under grant number 2R44DK115254-02A1 from the National Institute of Diabetes, Digestive and Kidney Disease. The government reserves certain rights to this invention. Serotonin, discovered in the late 1940s, is present in both the peripheral and central nervous systems [Physiol. Res, 60 (2011) 15-25; Psychopharmacology 213 (2011) 167-169]. Serotonin, also known as 5-hydroxytryptamine (5-HT), is an indolealkylamine monoamine neurotransmitter that acts at the synapses of nerve cells. Seven distinct families of serotonin receptors have been identified, and at least 20 subpopulations have been cloned based on sequence similarity, signal transduction binding, and pharmacological properties. The seven families of 5-HT receptors are named 5- HT1 , 5- HT2 , 5- HT3 , 5- HT4 , 5- HT5 , 5- HT6 , and 5- HT7 , and each of these receptors further comprises subfamilies or subpopulations. The signaling mechanisms of all seven families have been studied, and it has been found that activation of 5- HT1 and 5- HT5 receptors leads to a decrease in intracellular cAMP, while activation of 5- HT2 , 5- HT3 , 5 -HT4, 5- HT6 , and 5- HT7 results in an increase in intracellular IP3 and DAG. The 5-HT pathway in the brain is an important target for drug development in the field of CNS disorders. This neurotransmitter binds to G protein-coupled receptors and is particularly involved in cognition, mood, anxiety, attention, appetite, cardiovascular function, vasoconstriction, sleep (ACS Medical Chemistry Letters, 2011, 2, 929-932; Physiological Research, 2011, 60, 15-25), inflammatory bowel disease (IBD) and colitis (International Publication No. 2012058769, Khan, W.I., et al. Journal of Immunology, 2013, 190, 4795-4804), epilepsy, paroxysmal disorders (Epilepsy Research (2007) 75, 39), drug addiction and alcohol addiction (Hauser, S.R. et al. Frontiers) It is involved in a wide variety of behaviors, including those described in Neuroscience (2015, 8, 1-9). This specification describes novel selective modulators of the 5- HT7 receptor. These selective compounds may be useful in the treatment of CNS and non-CNS symptoms. The compounds described herein may be selective in targeting the 5-HT7 receptor by selectively targeting the 5- HT7 receptor compared to other receptors and/or the 5- HT7 receptor expressed in specific tissues or organs, thereby exhibiting effective selectivity through a specific partitioning profile of the 5- HT7 modulator. International Publication No. 2012058769 Physiol. Res, 60 (2011) 15-25Psychopharmacology 213 (2011) 167-169ACS Medicinal Chemistry Letters, 2011, 2, 929-932Physiological Research, 2011, 60, 15-25Khan, W. I. , et al. Journal of Immunology, 2013, 190, 4795-4804Epilepsy Research (2007) 75, 39Hauser, S. R. et al. Frontiers in Neuroscience, 2015, 8, 1-9 Definitions All technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art in which this disclosure pertains, unless otherwise specified. Any methods and materials similar or equivalent to those described herein may be used in carrying out or testing the present invention, but exemplary methods, apparatus and materials are described herein. All technical and patent documents referenced herein are incorporated herein by reference in their entirety. Nothing herein should be construed as meaning that the present invention is not considered to have prior rights on the grounds of prior inventions. Throughout this specification, where a composition is described as having, containing, or comprising certain components, or where a method is described as having, containing, or comprising certain steps of a particular method, the compositions of this instruction are intended to consist essentially of the listed components, and the methods of this instruction are also intended to consist essentially of the listed steps of a particular method. Throughout this application, where it is stated that an element or component is included in and/or selected from the enumerated list of elements or components, it should be understood that the element or component may be any one of the enumerated elements or components, or may be selected from a group consisting of two or more of the enumerated elements or components. In this specification, the use of the singular form includes the plural form unless otherwise specified (and vice versa). Furthermore, when the term "approximately" is used before a quantitative value, this instruction includes that specific quantitative value itself unless otherwise specified. It should be understood that the order or sequence of steps for performing a particular action is no