Patent Application
20240293370
The present invention relates to the field of medicine, and in particular to a use of compounds in inhibiting or killing mites and treating xerophthalmia.
Mite-induced diseases (for example, eye diseases and skin diseases) have not been paid enough attention in clinical practice, and are often misdiagnosed as bacterial diseases; however, conventional antibacterial treatment often has no obvious effect.
To overcome the deficiencies of the prior art, the present invention provides a use of a compound, a salt, a stereoisomer, and a solvate thereof in the preparation of products for inhibiting and/or killing mites.
In one embodiment of the present invention, the compound is of the following formula:
Specifically, the ring A may be a five-membered or six-membered heteroaryl including 1, 2, or 3 heteroatoms selected from N, O, or S atoms
In one embodiment of the present invention, the ring A is
wherein, X1, X2, X3, X4, and X5 are independently selected from CRj4 or N;
Specifically, the ring A may be selected from
each Rj4 is independently selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2.
In one example of the present invention, Rj4 is H.
In another embodiment of the present invention, the ring A is
Y1, Y2, Y3, and Y4 are independently selected from CRj5 or N; Y5 is selected from O, S, NRj5 or CRj5Rj6;
Rj5 and Rj6 are independently of each other selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2
Specifically, the ring A may be selected from
In one example of the present invention, Rj5 is H.
Specifically, Rj1 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rj1 is Cl.
Specifically, Rj2 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rj2 is H.
Specifically, Rj3 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rj3 is H.
In one embodiment of the pre sent invention, the above compound hay the following structure:
Specifically, the above compound has the following structure:
More specifically, the above compound has the following structure
In one example of the present invention, the above compound has the following structure:
In another embodiment of the present invention, the compound has the following structure:
Specifically, Rk1 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rk1 is H.
Specifically, Rk2 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rk2 is H.
Specifically, Rk3 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rk3 is H.
Specifically, Rk4 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rk4 is H.
Specifically, Rk5 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; specifically, R5 is OH or O(C1-8 alkyl), such as OCH3, O(C2 alkyl), O(C3 alkyl), O(C4 alkyl) O(C5 alkyl), O(C6 alkyl), O(C7 alkyl), O(C8 alkyl); in one example of the present invention, Rk5 is OCH3.
In one example of the present invention, is a single bond.
Specifically, Rk7 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; more specifically, Rk7 is OH or O(C1-8 alkyl), such as OCH3, O(C2 alkyl), O(C3 alkyl), O(C4 alkyl) O(C5 alkyl), O(C6 alkyl), O(C7 alkyl)CO(C8 alkyl); in one example of the present invention, Rk7 is OH.
Specifically, m is selected from 1, 2, 3, 4, or 5; in one example of the present invention, m is 2.
Specifically, Rk8 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rk8 is H.
Specifically, Rk9 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rk9 is H.
Specifically, Rk10 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rk10 is H.
Specifically, Rk11 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rk1 is H.
Specifically, Rk12 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rk12 is H.
Specifically, Rk13 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, NO2, or C2-8 alkenyl; more specifically, Rk13 is selected from C2-8 alkenyl; in one example of the present invention, Rk13 is ethenyl.
Specifically, Rk14 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rk14 is H.
Specifically, Rk15 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rk15 is H.
Specifically, Rk16 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rk16 is H.
Specifically, Rk17 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rk17 is H.
In one embodiment of the present invention, the above compound has the following structure:
In one example of the present invention, the above compound has the following structure:
In one example of the present invention, the above compound has the following structure:
In one example of the present invention, the salt of the above compound is a sulfate salt thereof.
In another embodiment of the present invention, the compound has the following structure:
Rq5, Rq6, Rq7, Rq8, and Rq9 are independently selected from H, halogen, C1-8 alkyl, O(C1-8 alkyl), S(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, C3-11 cycloalkyl, aryl, heteroaryl, C3-11 heterocycloalkyl, O(C1-8 cycloalkyl), S(C1-8 cycloalkyl), NH(C1-8 cycloalkyl), N(C1-8 cycloalkyl)(C1-8 alkyl), OH, NH2, SH, SO2(C1-8 alkyl), C2-8 alkenyl, C2-8 alkynyl, CH═CH(C1-8 alkyl), C(C1-8 alkyl)═CH2, C(C1-8 alkyl)═CH(C1-8 alkyl), C(C1-8 alkyl)═C(C1-8 alkyl)2, OC(═O)(C1-8 alkyl), C(═O)(C1-8 alkyl), (C1-8 alkyl)CO2H, CO2H, CN, CF3, CHF2, CH2F, NO2, C(═O)NH(C1-8 alkyl), C(═O)N(C1-8 alkyl)2, NHC(═O)(C1-8 alkyl), NHC(═O)(C6-18 aryl), NHC(═O)(C1-10 aralkyl), NHC(═O)(C1-10 arylalkoxy), N(C1-8 alkyl)C(═O)(C1-8 alkyl), NHC(═O)(C1-8 alkyl)NHC(═O)(C1-8 alkyl), N(C1-8 alkyl)C(═O)NH(C1-8 alkyl), N(C1-8 alkyl)C(═O)N(C1-8 alkyl)2, NHC(═O)NH(C1-8 alkyl), NHC(═O)N(C1-8 alkyl)2, NHC(═O)NH2, N(C1-8 alkyl)SO2NH(C1-8 alkyl), N(C1-8 alkyl)SO2N(C1-8 alkyl)2, NHSO2NH(C1-8 alkyl), or NHSO2N(C1-8 alkyl)2;
Specifically, Rq1 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; more specifically, Rq1 is selected from NH2, NH(C1-8 alkyl), N(C1-8 alkyl)2; in one example of the present invention, Rq1 is NH2.
Specifically, Rq2 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rq2 is H.
Specifically, m is selected from 1, 2, 3, 4, or 5; in one example of the present invention, m is 1.
Specifically, each Rq3 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rq3 is H.
Specifically, each Rq4 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rq4 is H.
Specifically, Rq5 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rq5 is H.
Specifically, Rq6 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rq6 is H.
Specifically, Rq7 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, NHC(═O)(C1-8 alkyl), NHC(═O)(C6-18 aryl), NHC(═O)(C1-10 aralkyl), NHC(═O)(C1-10 arylalkoxy), OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rq7 is H.
Specifically, Rq8 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rq8 is H.
Specifically, Rq9 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rq9 is H.
Specifically, the above compound has the following structure:
In one embodiment of the present invention, the above compound has the following structure:
In one example of the present invention, the above compound has the following structure:
In one example of the present invention, the above compound has the following structure:
In one example of the present invention, the salt of the above compound is a hydrochloride salt thereof.
In another embodiment of the present invention, the compound has the following structure:
Further, the compound has
Specifically, Rs1 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, NO2, C2-8 alkenyl, or C2-8 alkynyl; in one example of the present invention, Rs1 is H.
Specifically, Rs2 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, NO2, C2-8 alkenyl, or C2-8 alkynyl; in one example of the present invention, Rs2 is H.
Specifically, Rs3 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, NO2, C2-8 alkenyl, or C2-8 alkynyl; in one example of the present invention, Rs3 is H.
Specifically, Rs4 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, NO2, C2-8 alkenyl, or C2-8 alkynyl; in one example of the present invention, Rs4 is H.
Specifically, Rs5 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, NO2, C2-8 alkenyl, or C2-8 alkynyl; further, Rs5 is selected from NH(C1-8 alkyl); in one example of the present invention, Rs5 is NHCH3.
Specifically, Rs6 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, NO2, C2-8 alkenyl, or C2-8 alkynyl; in one example of the present invention, Rs6 is H.
Specifically, Rs7 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, NO2, C2-8 alkenyl, or C2-8 alkynyl; in one example of the present invention, Rs7 is H.
Specifically, Rs8 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, NO2, C2-8 alkenyl, or C2-8 alkynyl; in one example of the present invention, Rs8 is H.
Specifically, Rs9 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, NO2, C2-8 alkenyl, or C2-8 alkynyl; in one example of the present invention, Rs9 is H.
Specifically, Rs10 is selected from H, halogen, C1-8 alkyl, O(C1-8 alkyl), S(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, C3-11 cycloalkyl, aryl, heteroaryl, C3-11 heterocycloalkyl, O(C1-8 cycloalkyl), S(C1-8 cycloalkyl), NH(C1-8 cycloalkyl), N(C1-8 cycloalkyl)(C1-8 alkyl), OH, NH2, SH, SO2(C1-8 alkyl), C2-8 alkenyl, or C2-8 alkynyl;
Specifically, Rs11 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, NO2, C2-8 alkenyl, or C2-8 alkynyl; Further, Rs11 is H, F, Cl, Br, or I; in one example of the present invention, Rs11 is C1.
Specifically, Rs12 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, NO2, C2-8 alkenyl, or C2-8 alkynyl.
Further, Rs12 is H, F, Cl, Br, or I; in one example of the present invention, Rs12 is C1.
Specifically, Rs13 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, NO2, C2-8 alkenyl, or C2-8 alkynyl; in one example of the present invention, Rs13 is H.
Specifically, Rs14 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, NO2, C2-8 alkenyl, or C2-8 alkynyl; in one example of the present invention, Rs14 is H.
Specifically, Rs15 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, NO2, C2-8 alkenyl, or C2-8 alkynyl; in one example of the present invention, Rs15 is H.
In one embodiment of the present invention, the above compound has the following structure:
In one example of the present invention, the above compound has the following structure:
In one example of the present invention, the above compound has the following structure:
In one example of the present invention, the salt of the above compound is a hydrochloride salt thereof.
In another embodiment of the present invention, the compound has the following structure:
Specifically, Rw1 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rw1 is F.
Specifically, Rw2 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rw2 is H.
Specifically, Rw3 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rw3 is H.
Specifically, Rw4 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rw4 is H.
Specifically, Rw5 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rw5 is H.
Specifically, Rw6 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rw6 is H.
Specifically, Rw7 and Rw8 are independently selected H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rw7 is H; in one example of the present invention, Rw8 is H.
Specifically, Rw9 and Rw10 are independently selected H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rw9 is H; in one example of the present invention, Rw10 is H.
Specifically, Rw11 and Rw12 are independently selected H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rw11 is H; in one example of the present invention, Rw12 is H.
Specifically, m1 is selected from 1, 2, 3, 4, or 5; in one example of the present invention, m1 is 1.
In one embodiment of the present invention, XW is NRw13; Rw13 may be selected from H, C1-8 alkyl, or C3-11 cycloalkyl; in one example of the present invention, Xw is NH.
In one embodiment of the present invention, Yw is O.
In one embodiment of the present invention, Zw1 is O.
In one embodiment of the present invention, Zw2 is CRw13Rw14; wherein, Rw13 and Rw14 may be independently selected from H, halogen, C1-8 alkyl, C3-11 cycloalkyl, aryl, or heteroaryl; in one example of the present invention, Zw2 is CH2.
In one embodiment of the present invention, Zw3 is O.
In one embodiment of the present invention, the above compound has the following structure:
More specifically, the above compound has the following structure:
More specifically, the above compound has the following structure:
In one example of the present invention, the above compound has the following structure:
In one example of the present invention, the above compound has the following structure:
In one example of the present invention, the salt of the above compound is a hydrochloride salt thereof.
In another embodiment of the present invention, the compound has the following structure:
Specifically, each Rt1 is independently selected H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rt1 is H.
Specifically, Rt2 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; Specifically, Rt2 is selected from H, C1-3 alkyl (for example, methyl, ethyl, n-propyl, or isopropyl), CF3, CHF2, or CH2F; in one example of the present invention, Rt2 is methyl.
Specifically, Rt3 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rt3 is H.
Specifically, Rt4 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rt4 is H.
Specifically, Rt5 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rt5 is H.
Specifically, Rt6 is selected from H, F, Cl, Br, I, C1-8 alkyl, O(C1-8 alkyl), NH(C1-8 alkyl), N(C1-8 alkyl)2, OH, NH2, SH, CO2H, CN, CF3, CHF2, CH2F, or NO2; in one example of the present invention, Rt6 is H.
Specifically, Rt7 and Rt8 are independently selected from H and C1-3 alkyl (for example, methyl, ethyl, or N-propyl); in one example of the present invention, Rt7 is methyl; in one example of the present invention, Rt8 is methyl.
Specifically, Yt is selected from CH2, 0, S, or NH; more specifically, Yt is 0 or S; in one example of the present invention, Yt is O.
Specifically, Zt is C1-6 alkylene, in particular, C1-3 alkylene, such as —CH2—, —CH2CH2—, or —CH2CH2CH2—; in one example of the present invention, Zt is —CH2CH2—.
In some examples of the present invention, the above compound has the following structure:
More specifically, the above compound has the following structure:
In one example of the present the above compound has the following structure:
In one example of the present invention, the salt of the above compound is a citrate salt thereof.
Specifically, the above salts, stereoisomers, and solvates are pharmaceutically acceptable salts, stereoisomers, and solvates.
Specifically, the above compounds, or salts, stereoisomers, and solvates thereof may be used as the sole active ingredient or in combination with other same or different active ingredients for inhibiting or killing mites.
Specifically, the above acaricidal products according to the present invention can be used for therapeutic and/or prophylactic purposes as well as for non-therapeutic and/or prophylactic purposes.
Specifically, the above mites of the present invention may be one or more of Demodex, dust mites, mange mites, or the like. In an embodiment of the present invention, the above mites of the present invention are Demodex, such as Demodex folliculorum and Demodex brevis.
In an embodiment of the present invention, the above products for inhibiting and/or killing mites of the present invention are pharmaceutical compositions.
Specifically, the above pharmaceutical composition further includes a pharmaceutically acceptable excipient.
Specifically, the above pharmaceutical composition of the present invention can be used for the prevention and/or treatment of diseases caused by mite infection.
In one embodiment of the present invention, the above use is the use of the compound, or the salt, stereoisomer, and solvate thereof in the preparation of drugs for preventing and/or treating diseases caused by mite infections.
Specifically, the above diseases may be eye diseases, skin diseases, allergic diseases, or the like.
Specifically, the above eye diseases may be one or more of blepharitis, blepharial keratoconjunctivitis, meibomian gland dysfunction, eyelash shedding, abnormal eyelash arrangement, conjunctivitis, or blepharioconjunctivitis, pterygium, keratitis, basal cell carcinoma of eyelid, xerophthalmia, chalazion, or the like; it may have one or more symptoms selected from red itching of eyes, dry eyes, burning sensation of eyes, foreign body sensation, photophobia, increased eye secretion, drop of eyelashes, blurred vision, decreased vision, or the like.
Specifically, the above skin diseases may be one or more of seborrheic dermatitis, acne, rosacea, pityriasis folliculitis, perioral dermatitis, Demodex diseases, scabies, basal cell carcinoma, or the like.
Specifically, the allergic diseases may be one or more of allergic asthma, allergic rhinitis, allergic dermatitis, allergic conjunctivitis, or the like.
Specifically, the pharmaceutical compositions may be in any form suitable for administration, such as topical preparations, in particular ophthalmic preparations, topical dermatological preparations, or the like.
Specifically, the above ophthalmic preparations may be eye drops, eye ointments, ophthalmic gels, ophthalmic emulsions, ophthalmic suspensions, ophthalmic films, ophthalmic solutions, intraocular injections, or the like.
Specifically, the above topical dermatological preparations may be aerosols, powders, lotions, tinctures, liniments, films, ointments, gels, pastes, emulsions, or the like.
Specifically, various dosage forms of the above pharmaceutical compositions of the present invention can be prepared according to a conventional production method in the pharmaceutical field.
Specifically, the above pharmaceutical compositions of the present invention may contain 0.01 to 99.5% (specifically, for example, 0.01%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% 99%, or 99.5%) by weight of the active ingredient.
Specifically, the above pharmaceutical compositions can be used in humans, as well as veterinary uses in non-human animals, for example, non-human mammals, for example, pet animals (for example, dogs, cats, rabbits, mice, or the like), or livestock animals (for example, horses, cows, sheep, pigs, or the like).
In another embodiment of the present invention, the above acaricidal product of the present invention is cosmetic.
Specifically, the above cosmetics also include cosmetically acceptable excipients.
Specifically, the above cosmetic of the present invention may be a cosmetic for the face, such as a facial wash, a soap, a toner, a toner, a skincare cream, a gel, a facial cream, a sunscreen cream, an essence, a pack, a gel, a foundation, a frosting cream, or the like.
Specifically, the cosmetic of the present invention may be a cosmetic for other parts than the face, such as a neck cream, a shampoo, a body wash, a perfumed soap, a hair conditioner, a body lotion, a frosting cream, or the like.
Specifically, the above cosmetic of the present invention may also be cosmetic for eyes and periocular, such as an eye cream, a mascara, an eyeliner powder, an eyeliner cream, an eyeliner pen, an eye shadow powder, an eye shadow cream, an eyebrow pen, an eyebrow powder, or the like.
Specifically, various forms of the above cosmetics of the present invention can be prepared according to a conventional production method in the field of cosmetics.
Specifically, the cosmetic of the present invention may contain the active ingredient in an amount of 0.01 to 99.5% by weight (specifically, 0.01%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% 10% 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 99.5%). In another embodiment of the present invention, the above acaricidal product of the present invention is an acaricide, which can be used for killing and inhibiting mites that may colonize an article (for example, pillowcase, pillow core, bed sheet, bedding, mattress, clothing, carpet, cushion, sofa, summer sleeping mat, plush toy, air conditioner, or the like) in a living environment.
Specifically, the acaricides described above may contain any suitable excipient that can achieve the desired properties.
Specifically, the above acaricide may be in the form of a spray, a lotion, a patch, a small package, or the like.
Specifically, various forms of the above acaricide of the present invention can be prepared according to a conventional production method in the daily care product field.
Specifically, the above acaricide of the present invention may contain 0.01 to 99.5% by weight (specifically, 0.01%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 99.5%) of the active ingredient.
The present invention also provides a method of preventing and/or treating diseases caused by mite infection, including the step of administering to a subject in need thereof the above compound of the present invention or salts, stereoisomers and solvates thereof, and pharmaceutical compositions.
Specifically, in the above method, the diseases, the compounds, or salts, stereoisomers, and solvates thereof, and the pharmaceutical compositions have the above corresponding definitions of the present invention.
Specifically, the above subjects can be any animal receiving the prevention and/or treatment, especially mammals, such as humans, cats, dogs, rabbits, mice, horses, cattle, sheep, pigs, or the like. In an embodiment of the present invention, the subject is a human; in another embodiment of the present invention, the subject is a non-human animal.
Specifically, the amount of the above compound, or salts, stereoisomers and solvates thereof, or pharmaceutical composition administered may vary depending on such factors as the route of administration, age, weight of the subject, and types and severity of the disease to be treated.
The present invention also provides a cosmetic method including the step of administering to a subject in need thereof a compound shown in formula I-A, I-B, I-C, I-D, I-E, or I-F, or a salt, stereoisomer, and solvate thereof to ameliorate skin problems such as skin roughness, increased dandruff, or itching caused by mites in the subject.
Specifically, in the method, the subject is a human.
Specifically, the compound has the above corresponding definitions of the present invention.
The present invention also provides The use of the compound shown in formula I-A, I-B, I C, I-D, I-E, or I-F, and a salt, stereoisomer, and solvate thereof in the preparation of drugs for preventing and/or treating xerophthalmia.
Specifically, the compound shown in formula I-A, I-B, I-C, I-D, I-E, or I-F and the salt, stereoisomer, and solvate thereof have the above corresponding definitions of the present invention.
Specifically, the compound shown in formula I-A, I-B, I-C, I-D, I-E, or I-F and the salt, stereoisomer, and solvate thereof may be used as the sole active ingredient or in combination with other same or different active ingredients for the prevention and/or treatment of xerophthalmia.
Specifically, xerophthalmia has one or more symptoms selected from eye itching, foreign body sensation, burning sensation, photophobia, blurred vision, fluctuated vision, dry eyes, easy fatigue of eyes, thick secretions, sensitivity to topical stimuli, redness and swelling of eyes, congestion, keratinization, broken corneal epithelium with filamentous adhesion, or the like.
In an embodiment of the present invention, the xerophthalmia described above is xerophthalmia caused by infection with mites or related to mite infection.
Specifically, the drugs described above can be used in humans, as well as veterinary uses in non-human animals, for example, non-human mammals, for example, pet animals (for example, dogs, cats, rabbits, mice, or the like), livestock animals (for example, horses, cows, sheep, pigs, or the like).
Specifically, the above drugs may also include suitable pharmaceutically acceptable excipients.
Specifically, the drug may be in any form suitable for administration, such as an topical preparation, particularly an ophthalmic preparation, or the like.
Specifically, the above ophthalmic preparations may be eye drops, eye ointments, ophthalmic gels, ophthalmic emulsions, ophthalmic suspensions, ophthalmic films, ophthalmic solutions, intraocular injections, or the like.
The present invention also provides a method of preventing and/or treating xerophthalmia, including the step of administering to a subject in need thereof the above compound shown in formula I-A, I-B, I-C, I-D, I-E, or I-F, and the salt, stereoisomer, and solvate thereof, and the drugs.
Specifically, in the above method, xerophthalmia, the above compound shown in formula I A, I-B, I-C, I-D, I-E, or I-F, and the salt, stereoisomer, and solvate thereof, and the drugs have the above corresponding definitions of the present invention.
Specifically, the above subjects can be any animal receiving the prevention and/or treatment, especially mammals, such as humans, cats, dogs, rabbits, mice, horses, cattle, sheep, pigs, or the like. In an embodiment of the present invention, the subject is a human; in another embodiment of the present invention, the subject is a non-human animal.
Specifically, the amount of the above compound shown in formula I-A, I-B, I-C, I-D, I-E, or I-F, and the salt, stereoisomer, and solvate thereof, or the drugs to be administered may vary depending on factors such as the route of administration, age, weight of the subject, and types and severity of the disease to be treated.
Through extensive experiments, the inventors have found that the above compound shown in formula I-A, I-B, I-C, I-D, I-E, or I-F, and the salt, stereoisomer, and solvate thereof (especially the compound of formula V) can be used for mite inhibition and killing, can effectively shorten the survival time of demodex, and can be used for mite killing and inhibiting products (such as drugs, cosmetics, daily necessities, or the like). In addition, the inventors have discovered that the above compound shown in formula I-A, I-B, I-C, I-D, I-E, or I-F, and the salt, stereoisomer, and solvate thereof (especially the compound of formula V-A) are also useful for treating, effectively alleviating, and ameliorating symptoms of xerophthalmia.
Unless defined otherwise, all scientific and technical terms used herein have the same meaning as commonly understood by the ordinarily skilled in the art to which the present invention belongs.
The term “alkyl” refers to a hydrocarbon chain radical which is straight or branched and containing no unsaturation bonds, and which is attached to the rest of the molecule by a single bond. C1-8 alkyl includes C1 alkyl (that is, methyl), C2 alkyl (that is, ethyl), C3 alkyl (for example, n-propyl, and isopropyl), C4 alkyl (for example, n-butyl, isobutyl, and t-butyl), C5 alkyl, C6 alkyl, C7 alkyl, and C8 alkyl.
The term “alkenyl” refers to a straight or branched hydrocarbon chain radical containing at least two carbon atoms and at least one unsaturated bond, and which is attached to the rest of the molecule by a single bond. C2-8 alkenyl includes C2 alkenyl (that is, ethenyl), C3 alkenyl (for example, 1-propenyl, 2-propenyl, and 1-methyl-ethenyl), C4 alkenyl (for example, 1-butenyl, 2-butenyl, and 3-butenyl), C5 alkenyl, C6 alkenyl, C7 alkenyl, and C8 alkenyl.
The term “alkynyl” refers to a straight or branched hydrocarbon chain radical containing at least two carbon atoms and at least one carbon-carbon triple bond, and which is attached to the rest of the molecule by a single bond. C2-8 alkynyl includes C2 alkynyl (that is, ethynyl), C3 alkynyl (for example, 1-propynyl and 2-propynyl), C4 alkynyl (for example, 1-butynyl, 2-butynyl, and 3-butynyl), C5 alkynyl, C6 alkynyl, C7 alkynyl, and C8 alkynyl.
The term “cycloalkyl” refers to an alicyclic hydrocarbon such as cyclopropyl, cyclohexyl, adamantyl, or the like.
The term “aryl” refers to a monocyclic or polycyclic radical, including polycyclic radicals containing a monoaryl group and/or a fused aryl group, such as phenyl, naphthyl, biphenyl, indenyl, phenanthrenyl, anthracenyl, or the like.
The term “heterocyclic group” includes heteroaromatic and heteroalicyclic groups containing 1 to 3 monocyclic and/or fused rings and 3 to about 18 ring atoms, and the heterocyclic groups of the present invention containing 1, 2, or 3 heteroatoms selected from N, O, or S atoms. Heteroaryl includes, but are not limited to, coumarin, including 8-coumarin, quinolinyl, including 8-quinolinyl, isoquinolinyl, pyridinyl, pyrazinyl, pyrazolyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indolizinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl and the like; heteroalicyclic groups include, for example, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, oxathianyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxiranyl, thietanyl, azepinyl, oxazepinyl, diazepinyl, triazepinyl, 1,2,3,6-tetrahydropyridyl, 2-pyrrolidinyl, 3-pyrrolidinyl, dihydroindole, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxopentyl, pyrazolyl, dithiyl, dithiopentyl, dihydropyranyl, dihydrothiophene, pyrazolyl, imidazolyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indole, quinazinyl, or the like.
Such groups may be substituted at one or more available positions with one or more suitable groups.
The term “halogen” includes fluorine, chlorine, bromine, and iodine.
The term “salt” shall be understood to mean any form of a compound used in accordance with the present invention, where the compound is in ionic form or is charged and coupled to an ion (cation or anion) with an opposite charge or in solution. Also included in the definition are quaternary ammonium salts and complexes of the molecule with other molecules and ions, particularly complexes formed by ionic interactions. The definition includes physiologically acceptable salts; the term is to be understood as equivalent to “pharmacologically acceptable salts” or “pharmaceutically acceptable salts”.
Specifically, the pharmaceutically acceptable salts include acid addition salts and base addition salts.
Acid addition salts include, but are not limited to, salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphonic acids, and salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Thus, these salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, iodate, formate, acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, tosylate, phenyl acetates, citrates, lactates, maleates, tartrates and methanesulfonates, or also salts of amino acids such as arginate, glutamate, glycinate, gluconate, galacturonate, or the like. Acid addition salts can be prepared by contacting the free base form with enough amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.
Base addition salts are formed with metals or amines, such as hydroxides of alkali and alkaline earth metals, or with organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Examples of suitable amines include, but are not limited to, N,N′-dibenzylethylene diamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucamine, and procaine. Base addition salts can be prepared by contacting the free acid form with amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner.
In one embodiment of the present invention, the pharmaceutically acceptable salt is a hydrochloride salt, such as paroxetine hydrochloride.
The term “solvate” is to be understood as meaning any form of the compound according to the present invention in which the compound is attached to another molecule via a non-covalent bond (usually a polar solvent) and includes in particular, hydrates and alcoholates, for example, methanolates. Preferred solvates are hydrates.
Any compound referred to herein is intended to represent such specific compound and certain variations or forms thereof. Specifically, the compounds referred to herein may have asymmetric centers and thus exist in different enantiomeric or diastereomeric forms. Thus, any given compound referred to herein represents any one of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof. Likewise, stereoisomers or geometric isomers of double bonds may also be present, whereby in some cases the molecule may exist as an (E)-isomer or as a (7)-isomer (trans and cis isomers). If a molecule contains multiple double bonds, each double bond will have its own stereoisomerism, which may be the same as or different from the stereoisomerism of the other double bonds of the molecule. In addition, compounds referred to herein may exist as atropisomers. All stereoisomers of the compounds referred to herein, including enantiomers, diastereomers, geometric isomers and atropisomers, and mixtures thereof, are within the scope of the present invention.
Unless otherwise indicated, the compounds of the present invention also include isotopically-labeled forms, that is, compounds which differ only in the presence of one or more isotopically-enriched atoms. For example, compounds having the present structures except for the replacement of at least one hydrogen atom with deuterium or tritium, or the replacement of at least one carbon with a 13C- or 14C-enriched carbon, or the replacement of at least one nitrogen with a 15N-enriched nitrogen are within the scope of the present invention.
The term “xerophthalmia” refers to a variety of factors caused by dry eyes as the main symptom of tear secretion disorders, often accompanied by itching, foreign body sensation, burning sensation in both eyes, photophobia, blurred vision, vision fluctuations, and other manifestations. Common symptoms include dry eyes, easy fatigue, eye itching, foreign body sensation, pain and burning sensation, thick secretions, fear of wind and light, and sensitivity to topical stimuli; sometimes the eyes are too dry and lack basic tears, instead of stimulating reflex tear secretion, resulting in frequent lacrimation; in the more serious cases, the eyes will be red and swollen, congestion, keratinization, corneal epithelium broken and filiform substance adhesion, and the long-term damage can cause corneal and conjunctival lesions and affect vision. The xerophthalmia of the present invention includes keratoconjunctivitis sicca (KCS) and further includes any one type of xerophthalmia of reduced tear secretion type and hyper-evaporative tear type.
The xerophthalmia with reduced tear secretion is classified into xerophthalmia with Sjogren's syndrome and xerophthalmia without Sjogren's syndrome. The xerophthalmia with a Sjogren's syndrome type, includes congenital anacryadenopathy, sarcoidosis, graft versus host (GVHD) disease resulting from bone marrow transplantation; accompanied by ocular pemphigus, Stevens-Johnson syndrome, trachoma, or the like; diabetes, laser (-assisted) in Situ Keratomileusis (LASIK), or the like are causes of decreased reflex secretion.
In addition, the xerophthalmia with hyper-evaporative tear type may include a condition accompanied by a decrease in the oil layer due to meibomian gland insufficiency, blepharitis, or the like; accompanied by blink insufficiency or eyelid closure insufficiency due to eyeball protrusion, rabbit eye, or the like; with decreased tear stability due to contact lens wear; accompanied by decreased mucin secretion from embryonic cells; conditions accompanied by VDT operation, or the like.
The term “prevention” or “treatment” includes therapeutic or prophylactic treatments or measures, the goal being to prevent or slow down a targeted pathological condition or disorder. A subject is successfully “prevented” or “treated” if, following administration of a therapeutically effective amount of a CYP450 inhibitor, pharmaceutical composition, or drug of the present invention according to the methods of the present invention, the subject exhibits an observable and/or measurable reduction or disappearance of one or more signs and symptoms of a particular disease.
In the present invention, the term “animal” generally refers to vertebrates, particularly mammals, including humans. The term “non-human animal” refers to any vertebrate animal other than a human, particularly a mammal. In some embodiments of the present invention, the non human animal of the present invention is a domesticated animal, that is, an animal that has been raised and domesticated by humans and whose reproduction can be controlled artificially, for functions such as eating, labor, fur, pets, experimentation, for example, commercial animals, pet animals, laboratory animals, or the like. Economic animals include such as domestic animals, for example, pigs, cattle, sheep, horses, donkeys, foxes, raccoon dogs, mink, camels, or the like. Pet animals include such as dogs, cats, rabbits, mice (for example, guinea pigs, hamsters, gerbils, chinchillas, squirrels, or the like), or the like. Experimental animals include such as monkeys, dogs, rabbits, cats, and mice (for example, rats or murine), or the like.
The disclosures of the various publications, patents, and published patent specifications cited herein are hereby incorporated by reference in their entirety.
The technical solutions in the embodiments of the present invention are clearly and completely described below with reference to FIGS. 1 to 9, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present application, all other embodiments obtained by those skilled in the art without an inventive step shall fall within the protection scope of the present application.
This study strictly followed the ethical principles of the Declaration of Helsinki, and Ethical Guidelines for Biomedical Research Involving Human Subjects. In this study, Demodex was collected from patients diagnosed with ocular Demodex infection. Those meeting the inclusion criteria would be enrolled after an informed conversation and signing an informed consent form.
Demodex detection was performed according to the conventional eyelash microscopic examination method. 3 eyelashes were extracted from each eyelid, and a total of 12 eyelashes were extracted. The extracted eyelashes were immediately placed on a glass slide, and one piece of each three eyelashes was placed under an ordinary light microscope for observation. Demodex at all stages were counted and classified according to morphology (specific criteria were: Demodex brevis at a head-to-body ratio of 1:1 and Demodex folliculorum at a head-to-body ratio of 1:3 to 1:4). Only adults that were fully exposed to the field of view were taken as subjects (larvae and eggs were not considered as subjects since they were more fragile in early life).
Based on the above detection of Demodex, 50 μl of different solutions were added to each slide, and the survival of the worms was observed every 1 hour. The death was judged by observing whether the worms were active (body, limbs, or the like) under a microscope. Two skilled Demodex-related experimenters observed and judged separately during the experiment. If the judgment results were different, the third skilled experimenter was asked to make an independent judgment. The culture in vitro was performed in a climate chamber at 20° C. and 96% humidity. Slides were transported in a humid chamber under observation and the solution was added appropriately to ensure high humidity before vacuoles appeared on solution evaporation.
The results are shown in Table 1.
1. Case inclusion criteria
2. Case exclusion criteria
3. Shedding and elimination criteria:
Before treatment and weekly after treatment, the patient had ocular surface discomfort score, general ophthalmologic examination (visual acuity, intraocular pressure, and slit lamp examination), three tests for dry eye (conjunctival hyperemia score, BUT test, and Schirmer I test), ocular surface disease index (OSDI) score, dry eye analyzer, and ocular Demodex examination.
Considering that dry eye was a common ocular surface disease in the clinic, the positive rate of ocular Demodex reached 23.8% to 90.0%. Using the formula of sample size calculation for the validity test of quantitative data, it was concluded that there were 30 cases in the experimental group and 30 cases in the control group.
SPSS20.0 software and Excel were used for statistical processing. Paired sample t-test was used for normal distribution data of count data, the χ2 test was used for measurement data, and the non-parametric test was used for non-normal distribution data. The results were expressed as mean±standard deviation (x+s), with P<0.05 as the difference.
The above is only a preferred example of the present invention and is not intended to limit the present invention, and any modifications, equivalent substitutions, or the like made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.
The foregoing examples and methods described in the present invention may vary based on the ability, experience, and preferences of the skilled in the art.
The mere listing of the steps of the method in a certain order in the present invention does not constitute any limitation on the order of the steps of the method.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202110649315.9 | Jun 2021 | CN | national |
| 202110649319.7 | Jun 2021 | CN | national |
| 202110653692.X | Jun 2021 | CN | national |
| 202110653838.0 | Jun 2021 | CN | national |
| 202110659857.4 | Jun 2021 | CN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2022/097672 | 6/8/2022 | WO |
