NZ734260B2 - Substituted triazoles and methods relating thereto - Google Patents

Substituted triazoles and methods relating thereto

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Publication number
NZ734260B2
NZ734260B2 NZ734260A NZ73426016A NZ734260B2 NZ 734260 B2 NZ734260 B2 NZ 734260B2 NZ 734260 A NZ734260 A NZ 734260A NZ 73426016 A NZ73426016 A NZ 73426016A NZ 734260 B2 NZ734260 B2 NZ 734260B2
Authority
NZ
New Zealand
Prior art keywords
compound
methyl
alkyl
difluorophenyl
triazolyl
Prior art date
Application number
NZ734260A
Other versions
NZ734260A (en
Inventor
Neil J Ashweek
Manisha Moorjani
Deborah Slee
John P Williams
Original Assignee
Neurocrine Biosciences Inc
Filing date
Publication date
Application filed by Neurocrine Biosciences Inc filed Critical Neurocrine Biosciences Inc
Priority claimed from PCT/US2016/015740 external-priority patent/WO2016123533A1/en
Publication of NZ734260A publication Critical patent/NZ734260A/en
Publication of NZ734260B2 publication Critical patent/NZ734260B2/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

Substituted 1,2,3-triazole compounds are disclosed which have utility in the treatment of a variety of neurological disorders. The compounds provided herein have the general structure wherein R1, R2, R3 and n are as defined herein, including stereoisomers, esters, solvates and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound provided herein in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for treating neurological disorders in a subject in need thereof.

Claims (28)

CLAIMS :
1. A compound having the following structure (A): or a solvate or pharmaceutically acceptable salt thereof, wherein: R is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert- butyl; R is C alkyl, –C(=O)OR , -C(=O)-C alkanediyl-NH , –C(=O)NR R , 2 1-4 4 1-6 2 5 5 or -C(=O)R , wherein said C alkanediyl is optionally substituted with a group selected 6 1-6 from -NH-C(=NH)NH , -CO H, -CO CH , -SH, -C(=O)NH , -NH , -SCH , 2 2 2 3 2 2 3 phenyl, -OH, -OC alkyl, 4-hydroxy-phenyl, imidazolyl, cyclohexyl, and indolyl; R at each occurrence is Cl, F, C alkyl, -OC alkyl or trifluoromethyl; 3 1-4 1-4 R is C alkyl; 4 1-4 R at each occurrence is independently H or C alkyl; 5 1-4 R is C alkyl, 5-6 member nonaromatic heterocycle, or 5-6 member heterocycleC 6 2-4 1- alkyl wherein 5-6 member heterocycleC alkyl is optionally substituted with OH, Cl, F, 4 1-4 C alkyl, -OC alkyl or trifluoromethyl; and 1-4 1-4 n is 0-3; or (ii): R and R taken together with the N to which they are attached, form a 5-6 member nonaromatic heterocycle wherein the 5-6 member nonaromatic heterocycle is substituted with 0-3 R ; R at each occurrence is Cl, F, C alkyl, -OC alkyl or trifluoromethyl; 3 1-4 1-4 R at each occurrence is C alkyl; and 4 1-4 n is 1-3; wherein each C alkyl of R , R , R , and R is optionally substituted with a group 1-4 2 3 4 5 40 40 selected from halo, cyano, and -OR , where each R is hydrogen.
2. The compound of claim 1, wherein n is 1 or 2.
3. The compound of claim 1 or claim 2, wherein R is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.
4. The compound of any one of claims 1 to 3, wherein R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, –C(=O)OR , -C(=O)NR R , or -C(=O)R 4 5 5 6 or R is -C(=O)-C alkanediyl-NH , wherein the C 6alkanediyl is optionally substituted 2 1-6 2 1- with a group selected from -NH-C(=NH)NH , -CO H, - CO CH , -SH, -C(=O)NH , -NH , 2 2 2 3 2 2 -SCH3, phenyl, -OH, -OC1-4alkyl, 4-hydroxy-phenyl, cyclohexyl, imidazolyl, and indolyl.
5. The compound of any one of claims 1 to 3, wherein R and R are both methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.
6. The compound of any one of claims 1 to 5, wherein R is C alkyl or -OC alkyl. 3 1-4 1-4
7. The compound of any one of claims 1 to 5, wherein n is 1 or 2, and R is Cl, F, or trifluoromethyl.
8. The compound of claim 1, wherein: R is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert- butyl; and R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, –C(=O)OR , -C(=O)-C alkanediyl-NH , –C(=O)NR R , or -C(=O)R , wherein said 4 1-6 2 5 5 6 C alkanediyl is optionally substituted with a group selected from -NH-C(=NH)NH , - 1-6 2 CO H, -CO CH , -SH, -C(=O)NH , -NH , -SCH , phenyl, -OH, -OC alkyl, 4-hydroxy- 2 2 3 2 2 3 1-4 phenyl, imidazolyl, cyclohexyl, and indolyl.
9. The compound of any one of claims 1 to 4 and 6 to 8, wherein R is a 5-6 member nonaromatic heterocycle.
10. The compound of any one of claims 1 to 4 and 6 to 8, wherein R is a 5-6 member heterocycleC alkyl wherein 5-6 member heterocycleC alkyl is optionally substituted 1-4 1-4 with OH, Cl, F, C alkyl, -OC alkyl or trifluoromethyl. 1-4 1-4
11. The compound of claim 1, wherein R and R are taken together to form a heterocycle, and the compound has the following structure (B):
12. The compound of claim 11, wherein n is 1 or 2.
13. The compound of claim 11 or claim 12, wherein R3 is F.
14. The compound of claim 11 or claim 12, wherein R is C alkyl, -OC alkyl, 3 1-4 1-4 trifluoromethyl, or Cl.
15. The compound of any one of claims 11 to 14, wherein the heterocycle formed by R and R taken together is piperidine or morpholine.
16. The compound of any one of claims 11 to 14, wherein the heterocycle formed by R and R taken together is piperazine, oxazolidine, or pyrrolidine.
17. The compound of any one of claims 11 to 16, wherein R is methyl or ethyl.
18. The compound of claim 1, wherein the compound is: (2S)amino-N-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazolyl} phenylpropanamide; (2R)amino-N-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazolyl} phenylpropanamide; (3S)-N-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazolyl}morpholine carboxamide; (3R)-N-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazolyl}morpholine carboxamide; (2R)amino-N-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazolyl} methoxypropanamide; (2R)amino-N-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazolyl} hydroxypropanamide; N-[1-(2,6-difluoro-benzyl)-1H-[1,2,3]triazolyl]pyridinyl-propionamide; 3-(3-chlorophenyl)-N-{1-[(4-fluorophenyl)methyl]-1H-1,2,3-triazol yl}propanamide; (2S)-N-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazolyl}(2-oxopyrrolidin- 1-yl)butanamide; [1-(2,6-difluoro-benzyl)-1H-[1,2,3]triazolyl]-dimethyl-amine; [1-benzyl-1H-[1,2,3]triazolyl]-dimethyl-amine; 4-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazolyl}morpholine; 1-[(2,6-difluorophenyl)methyl](pyrrolidinyl)-1H-1,2,3-triazole; 1-[(2,6-difluorophenyl)methyl]-N-methyl-1H-1,2,3-triazolamine; 1-[(2,6-difluorophenyl)methyl]-N-ethyl-1H-1,2,3-triazolamine; 2-({1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazolyl}amino)ethanol; 1-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazolyl}pyrrolidinone; 3-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazolyl}-1,3-oxazolidinone; or 1-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazolyl}imidazolidinone; or a solvate, or pharmaceutically acceptable salt thereof.
19. The compound of claim 18, wherein the compound is (2S)amino-N-{1-[(2,6- difluorophenyl)methyl]-1H-1,2,3-triazolyl}phenylpropanamide, or a solvate or pharmaceutically acceptable salt thereof.
20. The compound of claim 18, wherein the compound is (3R)-N-{1-[(2,6- difluorophenyl)methyl]-1H-1,2,3-triazolyl}morpholinecarboxamide, or a solvate or pharmaceutically acceptable salt thereof.
21. The compound of claim 18, wherein the compound is [1-(2,6-difluoro-benzyl)-1H- [1,2,3]triazolyl]-dimethyl-amine, or a solvate or pharmaceutically acceptable salt thereof.
22. The compound of claim 18, wherein the compound is 4-{1-[(2,6- difluorophenyl)methyl]-1H-1,2,3-triazolyl}morpholine, or a solvate or pharmaceutically acceptable salt thereof.
23. The compound of claim 18, wherein the compound is 1-[(2,6- difluorophenyl)methyl](pyrrolidinyl)-1H-1,2,3-triazole, or a solvate or pharmaceutically acceptable salt thereof.
24. The compound of claim 18, wherein the compound is 1-[(2,6- difluorophenyl)methyl]-N-methyl-1H-1,2,3-triazolamine, or a solvate or pharmaceutically acceptable salt thereof.
25. A pharmaceutical composition comprising a compound of any one of claims 1 to 24, or a solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
26. Use of a compound of any one of claims 1 to 24, or a solvate or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 25, in the manufacture of a medicament for treating a neurological condition, wherein the condition is essential tremor, epilepsy, status epilepticus, or nerve agent exposure.
27. The use of claim 26, wherein the condition is essential tremor.
28. A method of manufacture of a pharmaceutical composition, comprising mixing a compound of any one of claims 1 to 24, or a solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient to form the pharmaceutical composition.
NZ734260A 2016-01-29 Substituted triazoles and methods relating thereto NZ734260B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201562110415P 2015-01-30 2015-01-30
US201562259314P 2015-11-24 2015-11-24
PCT/US2016/015740 WO2016123533A1 (en) 2015-01-30 2016-01-29 Substituted triazoles and methods relating thereto

Publications (2)

Publication Number Publication Date
NZ734260A NZ734260A (en) 2024-01-26
NZ734260B2 true NZ734260B2 (en) 2024-04-30

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