CN115315418B - Cannabidiol prodrug, and pharmaceutical composition and application thereof - Google Patents

Cannabidiol prodrug, and pharmaceutical composition and application thereof Download PDF

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CN115315418B
CN115315418B CN202280002921.4A CN202280002921A CN115315418B CN 115315418 B CN115315418 B CN 115315418B CN 202280002921 A CN202280002921 A CN 202280002921A CN 115315418 B CN115315418 B CN 115315418B
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compound
maleate
cbd
syndrome
butyl
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CN115315418A (en
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白信法
蒋王林
王文艳
孙晓琳
杨会杰
张睿
田京伟
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Shandong Luye Pharmaceutical Co Ltd
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Shandong Luye Pharmaceutical Co Ltd
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Abstract

The invention relates to a cannabidiol prodrug, a preparation method and a pharmaceutical composition thereof. Also relates to the use of compounds or pharmaceutical compositions containing the prodrugs in the manufacture of medicaments for the treatment of diseases associated with mammals or humans, including epilepsy, spasticity, encephalopathy, pain, anxiety and other mood disorders, parkinson's disease and tremor, multiple sclerosis, cancer, inflammation, and the like.

Description

Cannabidiol prodrug, and pharmaceutical composition and application thereof
Technical Field
The present invention relates to a class of prodrugs of cannabidiol suitable for use in mammals; and pharmaceutical compositions comprising cannabidiol prodrugs and their use for the treatment and prevention of diseases and disorders.
Background
Datamonitor Healthcare estimates that in 2018, the us, japan and five european union markets had 660 ten thousand active epilepsy diagnosed, and that 2038 cases will increase to 710 ten thousand. The domestic epidemiological data show that the 'lifetime prevalence rate' of epilepsy in China is about 7 per thousand, about 900 thousands of patients with epilepsy are present, wherein about 600 thousands of the patients with active epilepsy are present, and about 40 thousands of the newly-added patients with epilepsy are present every year.
From clinical symptoms and electroencephalogram, 2017ILAE determined epilepsy types to be in four broad categories, including focal, generalized, combined focal (Combined generalized and focal epilepsy), and ill-defined categories of epilepsy. Dravet syndrome and Lennox-Gastaut syndrome are generalized merged focal epileptic types and refractory epileptic types. The incidence of Dravet syndrome is 11/10 in children 3-13 years old, 4/10 in Lennox-Gastaut syndrome in children 3-13 years old, and 8/10 in seizure-accompanied tuberous sclerosis syndrome.
Refractory epilepsy refers to seizures that cannot be controlled, i.e., are not easily controlled or alleviated, by a drug, and is also referred to as controlled or drug-resistant seizures. The Door-to-Door study estimates the prevalence of refractory epilepsy at 2.7-7.1/1000 in high-income areas and 2.2-22.2/1000 in medium-low-income areas. Currently, the incidence of drug-resistant epilepsy based on a survey of large sample populations is difficult to obtain. Overall, the incidence of drug-resistant epilepsy in children and adults is 15% and 30%, respectively.
Cannabidiol (CBD) is white to light yellow resin or crystal, has melting point of 66-67 deg.C, is almost insoluble in water, and is soluble in ethanol, methanol, ether, benzene, chloroform, etcAn organic solvent.
Figure BDA0003824655900000013
Is cannabidiol oral, approved by the FDA in 2018 for marketing, and is used clinically to treat (1) Dravet syndrome-associated seizures in patients aged one or more years; (2) Lennox-Gastaut syndrome-associated seizures; approved for the treatment of seizures associated with tuberous sclerosis syndrome in 2020 (https:// www.accessdata.fda.gov/drug ftda _ docs/label/2020/210365s005s006s007lbl.pdf).
Figure BDA0003824655900000012
The specification of the preparation is as follows: 1ml:100mg; the maximum recommended maintenance dose for patients with seizures associated with the Lennox-Gastaut syndrome and Dravet syndrome in one year and older is 10mg/kg, BID; the maximum recommended maintenance dose for patients with seizures associated with tuberous sclerosis syndrome in one year of age and older is 12.5mg/kg, BID. 100ml per bottle, containing absolute ethanol (7.9% w/v), sesame oil, strawberry essence and sucralose. It is a great problem for infant patients because it contains 7.9% absolute ethanol. Meanwhile, cannabidiol has poor water solubility, the bioavailability of oral administration is only 6%, the gastrointestinal tract absorption level is unstable, and high-fat diet causes AUC 0-∞ And C max Equal PK parameters fluctuate widely (relative to fasted state C) max Increase 5 fold, increase 4 fold AUC), liver toxicity appeared (https:// www.accessdata.fda.gov/drug atfda _ docs/label/2018/210365lbl. Pdf). Based on the defects, the problem to be solved in clinic is to provide a prodrug oral preparation which improves the bioavailability, removes absolute ethyl alcohol and sesame oil in the preparation, enters the body and is quickly converted into cannabidiol.
Disclosure of Invention
In one aspect, the invention provides a compound of formula (I), a pharmaceutically acceptable salt or an enantiomer thereof,
Figure BDA0003824655900000011
wherein the content of the first and second substances,
R 1 、R 2 identical or different, each independently selected from-OH, -OC (O) -R 4 or-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )；
X is NH or O;
Y 1 is independently selected from C 2-10 Alkyl groups of (a); y is 2 Independently selected from hydrogen, C 2-10 Alkyl groups of (a); or Y 1 、Y 2 Form a ring system with the attached N atom, said ring system being an unsubstituted heterocyclyl or heteroaryl;
R 3 is C 1-10 Alkyl groups of (a); r 4 Is C 1-10 Alkyl groups of (a); n =2-10;
with the following conditions: r is 1 Or R 2 At least one of them is-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )。
In one embodiment of the compounds of formula (I),
R 1 、R 2 identical or different, each independently selected from the group consisting of-OH, -OC (O) -R 4 or-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )；
X is NH or O;
Y 1 is independently selected from C 2-6 Alkyl groups of (a); y is 2 Independently selected from hydrogen, C 2-6 Alkyl groups of (a); or Y 1 、Y 2 Form a ring system with the attached N atom, said ring system being an unsubstituted heterocyclyl or heteroaryl;
R 3 is C 1-6 Alkyl groups of (a); r 4 Is C 1-6 Alkyl groups of (a);
n =2, 3,4, 5, 6, 7, 8, 9, or 10;
with the following conditions: r 1 Or R 2 At least one of them is-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )。
In one embodiment of the compounds of formula (I),
R 1 、R 2 identical or different, each independently selected from the group consisting of-OH, -OC (O) -R 4 or-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )；
X is NH or O;
Y 1 independently selected from C 2-6 A linear or branched alkyl group;
Y 2 independently selected from hydrogen, C 2-6 A linear or branched alkyl group;
or Y 1 、Y 2 Form a ring system with the attached N atom, said ring system being an unsubstituted 3-8 membered heterocyclyl or 3-8 membered heteroaryl.
R 3 Is C 1-6 A linear or branched alkyl group;
R 4 is C 1-6 A linear or branched alkyl group;
n =2, 3,4, 5, 6, 7, 8, 9 or 10;
with the following conditions: r 1 Or R 2 At least one of them is-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )。
In one embodiment of the compounds of formula (I),
R 1 、R 2 identical or different, each independently selected from-OH, OC (O) -R 4 Or- -OC (O) - -X- - (CH) 2 )n-N(Y 1 Y 2 )；
X is NH or O;
Y 1 independently selected from ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl;
Y 2 independently selected from the group consisting of hydrogen, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl;
R 3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl;
R 4 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl;
n =2, 3,4, 5, 6, 7, 8, 9, or 10;
the conditions are as follows: r 1 Or R 2 At least one of them is-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )。
In one embodiment of the compounds of formula (I),
R 1 、R 2 identical or different, each independently selected from-OH, -OC (O) -R 4 or-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )；
X is NH or O;
Y 1 、Y 2 form a ring system with the attached N atom, said ring system being selected from
Figure BDA0003824655900000031
Figure BDA0003824655900000032
R 3 Is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl;
R 4 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl;
n =2, 3,4, 5, 6, 7, 8, 9, or 10;
with the following conditions: r 1 Or R 2 At least one ofis-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )。
In one embodiment of the compounds of formula (I),
R 1 is independently selected from
Figure BDA0003824655900000033
R 2 Independently selected from-OH, a,
Figure BDA0003824655900000034
Figure BDA0003824655900000035
R 3 Is a pentyl group.
In one embodiment of the compounds of formula (I),
R 1 is-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )；
R 2 Selected from-OH, -OC (O) -R 4 or-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )；
X is NH or O; preferably O;
Y 1 、Y 2 form a ring system with the attached N atom, said ring system being
Figure BDA0003824655900000036
R 3 Is C 1-6 Alkyl groups of (a); r is 4 Is C 1-6 Alkyl groups of (a);
n =2, 3,4 or 5.
In one embodiment of the compounds of formula (I),
R 1 is-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )；
R 2 Selected from-OH, -OC (O) -R 4 or-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )；
Y 1 、Y 2 Form a ring system with the attached N atom, said ring system being
Figure BDA0003824655900000041
X is O; r 3 Is a pentyl group; r 4 Is methyl, ethyl or propyl; n =2, 3,4 or 5, preferably n =2.
In one aspect, the invention provides a compound of formula (II), a pharmaceutically acceptable salt or an enantiomer thereof,
Figure BDA0003824655900000042
wherein the content of the first and second substances,
R 1 、R 2 identical or different, each independently selected from-OH, OC (O) -R 4 Or- -OC (O) - -X- - (CH) 2 )n-N(Y 1 Y 2 )；
X is NH or O;
Y 1 independently selected from C 2-10 Alkyl groups of (a); y is 2 Independently selected from hydrogen, C 2-10 Alkyl groups of (a); or Y 1 、Y 2 Form a ring system with the attached N atom, said ring system being an unsubstituted heterocyclyl or heteroaryl;
R 3 is C 1-10 Alkyl groups of (a); r is 4 Is C 1-10 Alkyl groups of (a); n =2-10;
with the following conditions: r 1 Or R 2 At least one of them is-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )。
In one embodiment of the compound of formula (II),
R 1 、R 2 identical or different, each independently selected from the group consisting of-OH, -OC (O) -R 4 or-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )；
X is NH or O;
Y 1 independently selected from C 2-6 Alkyl groups of (a);
Y 2 independently selected from hydrogen, C 2-6 Alkyl groups of (a);
or Y 1 、Y 2 Form a ring system with the attached N atom,said ring is an unsubstituted heterocyclyl or heteroaryl;
R 3 is C 1-6 Alkyl groups of (a); r is 4 Is C 1-6 Alkyl groups of (a);
n =2, 3,4, 5, 6, 7, 8, 9, or 10;
with the following conditions: r is 1 Or R 2 At least one of them is-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )。
In one embodiment of the compound of formula (II),
R 1 、R 2 identical or different, each independently selected from the group consisting of-OH, -OC (O) -R 4 or-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )；
X is NH or O;
Y 1 independently selected from C 2-6 A linear or branched alkyl group;
Y 2 independently selected from hydrogen, C 2-6 A linear or branched alkyl group;
or Y 1 、Y 2 Form a ring system with the attached N atom, said ring system being an unsubstituted 3-8 membered heterocyclyl or 3-8 membered heteroaryl.
R 3 Is C 1-6 A linear or branched alkyl group;
R 4 is C 1-6 A linear or branched alkyl group;
n =2, 3,4, 5, 6, 7, 8, 9 or 10;
with the following conditions: r 1 Or R 2 At least one of them is-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )。
In one embodiment of the compound of formula (II),
R 1 、R 2 identical or different, each independently selected from the group consisting of-OH, -OC (O) -R 4 or-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )；
X is NH or O;
Y 1 independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethanePropylyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl;
Y 2 independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl;
R 3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl;
R 4 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl;
n =2, 3,4, 5, 6, 7, 8, 9 or 10;
the conditions are as follows: r 1 Or R 2 At least one of them is-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )。
In one embodiment of the compound of formula (II),
R 1 、R 2 identical or different, each independently selected from-OH, -OC (O) -R 4 or-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )；
X is NH or O;
Y 1 、Y 2 form a ring system with the attached N atom, said ring system being selected from
Figure BDA0003824655900000051
Figure BDA0003824655900000052
R 3 Is methyl, ethyl, propyl or isopropylButyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl;
R 4 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl;
n =2, 3,4, 5, 6, 7, 8, 9, or 10;
with the following conditions: r 1 Or R 2 At least one of them is-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )。
In one embodiment of the compound of formula (II),
R 1 is independently selected from
Figure BDA0003824655900000061
R 2 Independently selected from-OH,
Figure BDA0003824655900000062
Figure BDA0003824655900000063
R 3 Is a pentyl group.
In one embodiment of the compound of formula (II),
R 1 is-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )；
R 2 Selected from-OH, -OC (O) -R 4 or-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )；
X is NH or O; preferably O;
Y 1 、Y 2 form a ring system with the attached N atom, said ring system being
Figure BDA0003824655900000064
R 3 Is C 1-6 Alkyl groups of (a); r 4 Is C 1-6 Alkyl groups of (a);
n =2, 3,4 or 5.
In one embodiment of the compound of formula (II),
R 1 is-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )；
R 2 Selected from-OH, -OC (O) -R 4 or-OC (O) -X- (CH) 2 )n-N(Y 1 Y 2 )；
Y 1 、Y 2 Form a ring system with the attached N atom, said ring system being
Figure BDA0003824655900000065
X is O; r 3 Is a pentyl group; r 4 Is methyl, ethyl or propyl; n =2, 3,4 or 5; preferably n =2.
In one aspect, the present invention provides the following compounds, pharmaceutically acceptable salts or enantiomers thereof:
Figure BDA0003824655900000066
Figure BDA0003824655900000071
Figure BDA0003824655900000081
in one aspect, the present invention provides a salt of any one of the compounds described above, or an enantiomer thereof, said salt being selected from the group consisting of p-toluenesulfonate, fumarate, maleate, oxalate, phosphate, hydrochloride, sulfate, malate, tartaric acid, citric acid or trifluoroacetate.
In one aspect, the invention provides the maleate, tosylate, fumarate, or hydrochloride salt of compound 25.
In one aspect, the present invention provides compound 25 maleate form I having characteristic diffraction peaks at the following 2 Θ angles in an X-ray powder diffraction pattern using Cu-ka radiation: 9.016 + -0.2 deg., 13.765 + -0.2 deg., 17.411 + -0.2 deg., 18.411 + -0.2 deg., 21.575 + -0.2 deg., 27.798 + -0.2 deg..
Figure BDA0003824655900000082
In one aspect, the compound 25 maleate form I, in an X-ray powder diffraction pattern using Cu-ka radiation, has characteristic diffraction peaks at the following 2 Θ angles: 9.016 + -0.2 deg., 13.765 + -0.2 deg., 17.411 + -0.2 deg., 18.411 + -0.2 deg., 21.575 + -0.2 deg., 23.289 + -0.2 deg., 27.798 + -0.2 deg..
In one aspect, the compound 25 maleate form I, in an X-ray powder diffraction pattern using Cu-ka radiation, has characteristic diffraction peaks at the following 2 Θ angles: 8.676 +/-0.2 degrees, 9.016 +/-0.2 degrees, 9.580 +/-0.2 degrees, 13.765 +/-0.2 degrees, 16.154 +/-0.2 degrees, 17.411 +/-0.2 degrees, 18.411 +/-0.2 degrees, 21.575 +/-0.2 degrees, 23.289 +/-0.2 degrees and 27.798 +/-0.2 degrees.
In one aspect, the compound 25 maleate form I has an X-ray powder diffraction pattern using Cu-ka radiation as shown in figure 1-1.
In one aspect, the invention provides compound 25 maleate form II having characteristic diffraction peaks at the following 2 Θ angles in an X-ray powder diffraction pattern using Cu-ka radiation: 7.868 +/-0.2 deg., 10.713 +/-0.2 deg., 12.122 +/-0.2 deg. and 18.535 +/-0.2 deg.
In one aspect, the compound 25 maleate form II, in an X-ray powder diffraction pattern using Cu-ka radiation, has characteristic diffraction peaks at the following 2 Θ angles: 7.868 + -0.2 deg., 8.892 + -0.2 deg., 9.111 + -0.2 deg., 9.760 + -0.2 deg., 10.713 + -0.2 deg., 12.122 + -0.2 deg., 18.061 + -0.2 deg., 18.535 + -0.2 deg..
In one aspect, the compound 25 maleate form II has an X-ray powder diffraction pattern using Cu-ka radiation as shown in figure 2-1.
In one aspect, the present invention provides compound 25 maleate form III having characteristic diffraction peaks at the following 2 Θ angles in an X-ray powder diffraction pattern using Cu-ka radiation: 8.730 + -0.2 deg., 10.010 + -0.2 deg., 12.578 + -0.2 deg., 15.928 + -0.2 deg., 17.679 + -0.2 deg..
In one aspect, the compound 25 maleate form III, in an X-ray powder diffraction pattern using Cu-ka radiation, has characteristic diffraction peaks at the following 2 Θ angles: 6.241 + -0.2 deg., 8.730 + -0.2 deg., 10.010 + -0.2 deg., 12.578 + -0.2 deg., 15.928 + -0.2 deg., 17.679 + -0.2 deg., 19.581 + -0.2 deg., 23.836 + -0.2 deg..
In one aspect, the compound 25 maleate salt form III having an X-ray powder diffraction pattern using Cu-ka radiation is shown in figure 3-1.
In one aspect, the present invention provides compound 25 maleate form IV having characteristic diffraction peaks at the following 2 Θ angles in an X-ray powder diffraction pattern using Cu-ka radiation: 8.004 +/-0.2 degrees, 10.575 +/-0.2 degrees, 12.151 +/-0.2 degrees, 16.137 +/-0.2 degrees, 22.366 +/-0.2 degrees and 24.308 +/-0.2 degrees.
In one aspect, compound 25 maleate form IV, having characteristic diffraction peaks at the following 2 Θ angles in an X-ray powder diffraction pattern using Cu-ka radiation: 8.004 +/-0.2 degrees, 9.600 +/-0.2 degrees, 10.575 +/-0.2 degrees, 12.151 +/-0.2 degrees, 16.137 +/-0.2 degrees, 17.008 +/-0.2 degrees, 22.366 +/-0.2 degrees, 23.296 +/-0.2 degrees and 24.308 +/-0.2 degrees.
In one aspect, the compound 25 maleate salt form IV has an X-ray powder diffraction pattern using Cu-ka radiation as shown in figure 4-1.
In one aspect, the present invention provides a crystalline form of compound 25 fumarate having characteristic diffraction peaks at the following 2 Θ angles in an X-ray powder diffraction pattern using Cu-ka radiation: 7.692 + -0.2 deg., 8.305 + -0.2 deg., 10.407 + -0.2 deg., 18.680 + -0.2 deg., 22.187 + -0.2 deg..
In one aspect, the crystalline form of compound 25 fumarate has characteristic diffraction peaks at the following 2 Θ angles in an X-ray powder diffraction pattern using Cu-ka radiation: 7.692 + -0.2 deg., 8.305 + -0.2 deg., 10.407 + -0.2 deg., 15.332 + -0.2 deg., 17.377 + -0.2 deg., 18.680 + -0.2 deg., 20.344 + -0.2 deg., 22.187 + -0.2 deg., 23.210 + -0.2 deg., 23.688 + -0.2 deg..
In one aspect, the compound 25 fumarate salt is in a crystalline form, an X-ray powder diffraction pattern using Cu-ka radiation is shown in fig. 5-1.
In one aspect, the present invention provides a crystalline form of compound 25 p-toluenesulfonate having characteristic diffraction peaks at the following 2 Θ angles in an X-ray powder diffraction pattern using Cu-ka radiation: 5.768 + -0.2 deg., 8.367 + -0.2 deg., 11.406 + -0.2 deg., 17.183 + -0.2 deg., 23.035 + -0.2 deg..
In one aspect, the compound 25 p-toluenesulfonate crystalline form having an X-ray powder diffraction pattern using Cu-ka radiation is shown in fig. 6-1.
In one aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of any one of the compounds described above, or a stereoisomer or pharmaceutically acceptable salt thereof, or a crystalline form of any one of the compounds described above, and a pharmaceutically acceptable carrier. Such carriers include auxiliary ingredients conventional in the art, such as fillers, binders, diluents, disintegrants, lubricants, colorants, flavorants, antioxidants, wetting agents and the like.
The pharmaceutical composition can be prepared into various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral liquid, suspension, granules, powder, fine granules, pills, mini-tablets, instant films, nasal sprays, transdermal patches, injections or various sustained and controlled release preparations and the like. The pharmaceutical compositions may be administered orally, transmucosally, rectally, or parenterally (including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly, and intrasternally). The administration dose may be appropriately adjusted depending on the age, sex and type of disease of the patient.
For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, liquid capsule, suspension, or liquid. The pharmaceutical compositions are preferably prepared in dosage unit form containing specific amounts of the active ingredient. For example, the pharmaceutical composition may be provided in a tablet or capsule containing the active ingredient in an amount ranging from about 0.1 to 1000mg, preferably from about 0.25 to 250mg, and more preferably from about 0.5 to 100 mg. Suitable daily dosages for humans or other mammals may vary widely depending on the condition of the patient and other factors, but can be determined using conventional methods.
In one aspect, the present invention provides the use of any one of the compounds described above, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for the treatment of a disease or condition. The diseases or symptoms include: epilepsy (including seizures, seizure-sclerosis complex, dravet syndrome, lennox-Gastaut syndrome, mycoplasmal seizures, juvenile mycoplasmal epilepsy, refractory epilepsy); spasms (including juvenile spasms, west syndrome, refractory pediatric spasms, hemifacial spasms); encephalopathy (including lethargy, attention/concentration problems, and cognitive problems); pain (including radiculopathy and neuropathy, lower back pain and fibromyalgia); neuropathic pain; numbness and/or tingling; anxiety and other mood disorders; hypertension and autonomic dysfunction; parkinson's disease and tremor (including essential tremor); insomnia; bell's paralysis and dysfunction of the facial nerves; glaucoma, and glaucoma; multiple sclerosis; cancer, including brain tumors; post-traumatic stress disorder (PTSD); trigeminal neuralgia; autism/asperger's disease; attention deficit disorder and hyperactivity disorder; social isolation; occipital neuralgia; symptoms associated with TMJ dysfunction; cognitive problems (including memory impairment); headache, (including migraine, tension); peripheral neuropathy; peripheral neuropathy; apneas, including central sleep apnea, obstructive sleep apnea syndrome, and mixed apneas; smoking cessation; arthritis, including rheumatoid arthritis; recessing; vomiting; anti-obesity; nausea; alcohol use disorder; dystonia; inflammatory bowel syndrome; neuropathic pain associated with post-herpetic neuralgia; diabetic neuropathy; herpes zoster; burn; actinic keratosis; oral ulcer; actinic keratosis; canker sores and post-ulcerous craniotomy pain; psoriasis; pruritic contact dermatitis; eczema; dermatitis bullosa; exfoliative dermatitis; fungal diseases; pemphigus; severe erythema multiforme; seborrheic dermatitis; ankylosing spondylitis; psoriatic arthritis; reiter's syndrome; gout; cartilage calcification disease; joint pain; dysmenorrhea; musculoskeletal pain; myositis; bursitis; epicondylitis osteoarthritis; synovitis; pancreatitis; other disease states and conditions will be apparent to those skilled in the art.
Definitions and explanations
As used herein, the following terms and phrases are intended to have the following meanings, unless otherwise indicated. A particular term or phrase, unless specifically defined, should not be considered as indefinite or unclear, but rather construed according to ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.
The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to any base or acid addition salt.
Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present invention.
Using wedge and dashed bonds, unless otherwise indicated
Figure BDA0003824655900000101
Representing the absolute configuration of a stereogenic centre, with
Figure BDA0003824655900000102
Showing the relative configuration of a stereocenter. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include E, Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the invention.
The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
Optically active (R) -and (S) -isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to afford the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).
The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium representative of a vehicle capable of delivering an effective amount of an active agent of the present invention, without interfering with the biological activity of the active agent, and without toxic side effects to the host or patient.
The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For oral dosage forms of the invention, an "effective amount" of one active agent in a composition is the amount required to achieve the desired effect when combined with another active agent in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in a case may be determined by a person skilled in the art in the light of routine tests.
The term "active ingredient", "active substance" or "active agent" refers to a chemical entity that is effective in treating a target disorder, disease or condition.
Unless otherwise specified, the term "alkyl" is intended to mean a straight-chain or branched-chain saturated hydrocarbon radical, which may be monosubstituted (e.g., -CH) 2 F) Or polysubstituted (e.g. -CF) 3 ) And may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). Alkyl is preferably C 1-10 Alkyl groups of (a) such as: c 1 、C 2 、C 3 、C 4 、C 5 、C 6 、C 7 、C 8 、C 9 、C 10 In (1). Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl, 1-ethylpropyl), hexyl (e.g., n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl), heptyl, octyl, nonyl, decyl, and the like.
Unless otherwise specified, the term "heterocycle" or "heterocyclyl" means a stable heteroatom or heteroatom group containing monocyclic, bicyclic, or tricyclic ring, which may be saturated, partially unsaturated, or unsaturated (aromatic), which comprises carbon atoms and 1,2,3, or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles can be fused to a benzene ring to form a bicyclic ring. The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O) p, p being 1 or 2). The nitrogen atom may be substituted or unsubstituted (i.e. N or NR, wherein R is H or other substituents already defined herein). The heterocyclic ring may be attached to any heteroatom or carbon pendant group to form a stable structure. The heterocyclic rings described herein may be substituted at the carbon or nitrogen position if the resulting compound is stable. The nitrogen atoms in the heterocycle are optionally quaternized. In a preferred embodiment, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. In another preferred embodiment, the total number of S and O atoms in the heterocycle does not exceed 1. As used herein, the term "aromatic heterocyclic group" or "heteroaryl" means a stable 5, 6, 7 membered monocyclic or bicyclic or 7, 8, 9 or 10 membered bicyclic heterocyclic group aromatic ring comprising carbon atoms and 1,2,3 or 4 ring heteroatoms independently selected from N, O and S. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents already defined herein). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O) p, p being 1 or 2). It is noted that the total number of S and O atoms on the heteroaromatic ring does not exceed 1. Bridged rings are also included in the definition of heterocyclic. Bridged rings are formed when one or more atoms (i.e., C, O, N or S) connect two non-adjacent carbon or nitrogen atoms. Preferred bridged rings include, but are not limited to: one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In bridged rings, ring substituents may also be present on the bridge.
Examples of heterocyclic compounds include, but are not limited to: azetidinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzomercaptofuranyl, benzomercaptophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4 aH-carbazolyl, carbolinyl, chromanyl, chromene, cinnolinyl decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b ] tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isoindolyl, isoindolinyl, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxy, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazine, phenothiazine, benzoxanthyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, pyridoxalinyl, tetrahydropyrrolyl, tetrahydroquinoxalinyl, pyridoxalinyl, phenoxazinyl, and phenanthrolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, isothiazolylthienyl, thienooxazolyl, thienothiazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Fused ring and spiro compounds are also included.
Unless otherwise specified, the term "aryl" means a polyunsaturated aromatic hydrocarbon substituent, which may be mono-or poly-substituted, and which may be mono-, di-or polyvalent, and which may be mono-or polycyclic (e.g., 1 to 3 rings; wherein at least one ring is aromatic), fused together or covalently linked. The term "heteroaryl" refers to an aryl (or ring) containing one to four heteroatoms. In one illustrative example, the heteroatoms are selected from B, N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atoms are optionally quaternized. The heteroaryl group may be attached to the rest of the molecule through a heteroatom. Non-limiting examples of aryl or heteroaryl groups include phenyl, naphthyl, 4-biphenyl, furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyranyl, triazinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, indolyl, benzothienyl, benzodioxolyl, benzoxazolyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, coumarinyl, cinnolinyl, quinoxalinyl. Non-limiting examples of aryl or heteroaryl groups are preferably: phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. The substituents for any of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.
The compound is made by hand or
Figure BDA0003824655900000121
The software names, and the commercial compounds are under the supplier catalog name.
Drawings
FIGS. 1-1, 1-2, 1-3, 1-4: an XRPD spectrum, a DSC spectrum, a TGA chart, a crystal form I of the maleic acid salt of the compound 25, 1 H NMR spectrum
FIGS. 2-1, 2-2, 2-3: an XRPD spectrum, a DSC/TGA spectrum, a spectrum of a crystal form II of the maleate of the compound 25, 1 H NMR spectrum
FIGS. 3-1, 3-2, 3-3: an XRPD spectrum, a DSC/TGA spectrum, a spectrum of a crystal form III of the maleate of the compound 25, 1 H NMR spectrum
FIGS. 4-1, 4-2, 4-3: are each a chemical compoundXRPD spectrogram of substance 25 maleate form IV DSC/TGA spectrum, 1 H NMR spectrum
FIGS. 5-1, 5-2, 5-3, 5-4: respectively is an XRPD spectrum, a DSC spectrum, a TGA chart of the 25 fumarate salt of the compound, 1 H NMR spectrum
FIGS. 6-1, 6-2, 6-3, 6-4: respectively is an XRPD spectrum, a DSC spectrum, a TGA chart and a, 1 H NMR spectrum
FIG. 7-1: time profile of prodrug of compound 24 and 25 hydrochloride in beagle dogs
FIG. 7-2: time profile of metabolite CBD of compound 24 and 25 hydrochloride in beagle dogs
FIGS. 7-3: compound 25 maleate and CBD dosing time profiles for CBD in high oil diet and fasted model beagle dogs
FIG. 8: prodrug drug time profile of metabolite CBD in rats
FIG. 9-1: hygroscopicity profile of compound 25 maleate form I
FIG. 9-2: XRPD spectrogram before and after hygroscopicity experiment of compound 25 maleate crystal form I
FIG. 10-1: XRPD spectrogram of room temperature competitive beating experiment of crystal form I and crystal form II of compound 25 maleate
FIG. 10-2: XRPD spectrogram of compound 25 maleate crystal form I and crystal form II high-temperature competition beating experiment
FIG. 11: XRPD spectrogram before and after tabletting experiment of compound 25 maleate crystal form I
Detailed Description
Synthesis method I
Figure BDA0003824655900000131
CBD is dissolved in solvent and added with basic catalyst, and stirred for reaction at room temperature. Adding p-nitro phenyl chloroformate, and reacting at room temperature. Quenching with water, extracting with ethyl acetate, mixing organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the organic phase under reduced pressure, and separating by column chromatography to obtain fragment 1.
Fragment 1 was dissolved in solvent, and reaction reagents were added and reacted at room temperature/heat. Quenching with water, extracting with ethyl acetate, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the organic phase under reduced pressure, and separating by high performance liquid chromatography. To obtain the product of formula (II) (i.e. R) 1 Or R 2 Products in which one is OH).
Optionally, the product of formula (II) (i.e., R) 1 Or R 2 One of which is OH) and an alkaline reagent are dissolved in a solvent, different reaction reagents are added dropwise, and the reaction is carried out at room temperature after ice bath. Quenching with water, extracting with ethyl acetate, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the organic phase under reduced pressure, and separating by high performance liquid chromatography. To obtain R 1 And R 2 Structurally different products of formula (II).
Synthesis Process II
Figure BDA0003824655900000141
CBD is dissolved in solvent and alkaline reagent is added, and the reaction is stirred at room temperature. Adding p-nitro phenyl chloroformate, and reacting at 0 ℃. Quenching with water, extracting with ethyl acetate, mixing organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the organic phase under reduced pressure, and separating by column chromatography to obtain fragment 2.
Fragment 2, the reagent and the alkaline reagent are dissolved in a solvent and heated under reflux for reaction overnight. Quenching with water, extracting with ethyl acetate, combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the organic phase under reduced pressure, and separating by high performance liquid chromatography. To obtain the product of formula (II) (i.e. R) 1 Or R 2 Products that are not OH).
The present invention will be further illustrated with reference to specific examples and test examples, but the scope of the present invention is not limited in any way.
Example 1: synthesis of fragment 1
Figure BDA0003824655900000142
The synthetic route is as follows:
Figure BDA0003824655900000143
CBD (2.0g, 6.4mmol, 1eq) was dissolved in 60mL of methylene chloride and triethylamine (1.3g, 12.8mmol, 2.0eq) was added, and the reaction was stirred at room temperature for 0.5h. Phenyl p-nitrochloroformate (1.54g, 7.68mmol, 1.2eq) was added thereto and reacted at room temperature for 2 hours. Quenched with water, then extracted with ethyl acetate (50ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate = 5:1) to give fragment 1 (1.1 g, oil), yield: 33 percent. MS m/z (ESI): 480.4[ 2 ], M +1].
Example 2: synthesis of Compound 13 trifluoroacetate salt
Figure BDA0003824655900000144
The synthesis route is as follows:
Figure BDA0003824655900000151
fragment 1 (479mg, 0.9mmol, 1.0eq) was dissolved in 10mL of dichloromethane, and ethylenediamine (108mg, 1.8mmol, 2.0eq) was added to react at room temperature for 3h. Quenched with water, then extracted with ethyl acetate (50ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, and separated by high performance liquid chromatography (Waters autopurification HPLC-system C18 50 × 250mm Wavelength 254nm water (0.1% tfa) -MeCN (0.1% tfa)). Compound 13 trifluoroacetate salt (185 mg, white solid) was obtained, yield: 40 percent. MS m/z (ESI): 401.3[ 2 ] M +1] + 。 1 H NMR(400MHz,DMSO-d 6 ):δ9.26(br,1H),8.13(br,2H),7.60(br,1H),6.45(s,1H),6.26(s,1H),5.01(s,1H),4.44(d,J＝5.2Hz,2H),3.60-3.75(m,1H),3.14-3.32(m,3H),2.86-2.89(m,2H),2.40(t,J＝8.0Hz,2H),2.20-2.40(m,1H),1.70-1.80(m,1H),1.45-1.60(m,9H),1.20-1.45(m,5H),0.86(t,J＝7.2Hz,3H).
Example 3: synthesis of Compound 17 trifluoroacetate salt
Figure BDA0003824655900000152
The synthetic route is as follows:
Figure BDA0003824655900000153
fragment 1 (479mg, 0.9mmol, 1.0eq) was dissolved in 10mL of dichloromethane, and diethylaminoethanol (320mg, 2.7mmol, 3.0eq) was added to react at room temperature for 3 hours. Quenching with water, followed by extraction with ethyl acetate (50mL. Multidot.3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the organic phase under reduced pressure, and separating by high performance liquid chromatography (Waters autopurification HPLC-system C18 50. Multidot.250mm wavelet h 254nm water (0.1. Multidot. TFA) -MeCN (0.1. Multidot. TFA)). Compound 17 trifluoroacetate salt (56.6 mg, white solid) was obtained, yield: 11 percent. MS m/z (ESI): 458.3[ M ] +1] + 。 1 H NMR(400MHz,DMSO-d 6 ):δ10.0-10.50(br,1H),9.50(s,1H),6.50(s,1H),6.38(s,1H),5.04(s,1H),4.30-4.50(m,3H),3.60-3.80(m,1H),3.06-3.30(m,5H),2.56-2.60(m,1H),2.35-2.48(m,2H),2.05-2.20(m,1H),1.81-2.00(m,1H),1.48-1.75(m,9H),1.30-1.70(m,10H),0.75-0.80(m,3H).
Example 4: synthesis of Compound 18 trifluoroacetate salt
Figure BDA0003824655900000161
The synthetic route is as follows:
Figure BDA0003824655900000162
fragment 1 (2.0 g,4.0mmol, 1eq) was dissolved in 60mL of dichloromethane, 2-morpholinoethanol (2.6 g,20.0mmol,5.0 eq) was added, and the reaction was refluxed overnight. Quenched with water, extracted with ethyl acetate (50ml × 3) and combinedThe organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by high performance liquid chromatography (Waters autopurification HPLC-system C18 50 × 250mm Wavelength 254nm water (0.1% tfa) -MeCN (0.1% tfa)). Compound 18 trifluoroacetate salt (211 mg, oil) was obtained, yield: 9 percent. MS m/z (ESI): 472.3[ 2 ] M +1] + 。 1 H NMR(400MHz,DMSO-d 6 ):δ9.42(s,1H),6.50(s,1H),6.35(s,1H),5.07(s,1H),4.45(s,2H),4.26-4.34(m,1H),4.14-4.20(m,1H),3.70-3.90(m,1H),3.60(t,J＝6.0Hz,4H),2.60-2.75(m,3H),2.41-2.50(m,6H),2.05-2.25(m,1H),1.90-2.00(m,1H),1.49-1.75(m,10H),1.30-1.45(m,5H),0.89(t,J＝8.8Hz,3H).
Example 5: synthesis of Compound 19 trifluoroacetate salt
Figure BDA0003824655900000163
The synthetic route is as follows:
Figure BDA0003824655900000164
fragment 1 (450mg, 0.94mmol, 1eq) was dissolved in 10mL of dichloromethane, and N, N-diethylethylenediamine (210mg, 1.9mmol, 2.0eq) was added to the solution and reacted at room temperature for 2 hours. Quenched with water, then extracted with ethyl acetate (50ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, and separated by high performance liquid chromatography (Waters autopurification HPLC-system C18 50 × 250mm Wavelength 254nm water (0.1% tfa) -MeCN (0.1% tfa)). Compound 19 trifluoroacetate salt (236 mg, white solid) was obtained, yield: 44 percent. MS m/z (ESI): 457.3[ M ] +1] + 。 1 H NMR(400MHz,DMSO-d 6 ):δ9.34(br,1H),9.23(s,1H),7.60(br,1H),6.43(s,1H),6.22(s,1H),5.03(s,1H),4.44(d,J＝5.2Hz,2H),3.60-3.75(m,1H),3.14-3.32(m,6H),2.60-2.80(m,1H),2.40(t,J＝8.0Hz,2H),2.20-2.40(m,1H),1.70-1.80(m,1H),1.45-1.60(m,10H),1.20-1.45(m,10H),0.86(t,J＝7.2Hz,3H).
Example 6: synthesis of Compound 21 trifluoroacetate salt
Figure BDA0003824655900000171
The synthetic route is as follows:
Figure BDA0003824655900000172
fragment 1 (450mg, 0.94mmol, 1eq) was dissolved in 10mL of dichloromethane and 2-morpholinoethylamine (227mg, 1.9mmol, 2.0eq) was added and reacted at room temperature for 2h. Quenched with water, then extracted with ethyl acetate (50ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, and separated by high performance liquid chromatography (Waters autopurification HPLC-system C18 50 × 250mm Wavelength 254nm water (0.1% tfa) -MeCN (0.1% tfa)). Compound 21 trifluoroacetate salt (242 mg, white solid) was obtained, yield: 44 percent. MS m/z (ESI): 471.3[ M ] +1] + 。 1 H NMR(400MHz,DMSO-d 6 ):δ9.95(br,1H),9.22(s,1H),7.58(br,1H),6.43(s,1H),6.25(s,1H),5.02(s,1H),4.43(d,J＝5.2Hz,2H),3.00-4.02(m,14H),2.70-2.83(br,1H),2.40(t,J＝8.0Hz,2H),2.10-2.28(m,1H),1.78-1.90(m,1H),1.45-1.60(m,10H),1.45-1.75(m,10H),1.25-1.40(m,5H),0.86(t,J＝7.2Hz,3H).
Example 7: synthesis of Compound 24 trifluoroacetate salt
Figure BDA0003824655900000173
The synthetic route is as follows:
Figure BDA0003824655900000174
compound 18 (320mg, 0.67mmol, 1eq) was dissolved in 5mL of dichloromethane in free form with triethylamine (130mg, 1.3mmol, 2eq), and was reacted with acetyl chloride (130mg, 1.3mmol,2.0 eq) dropwise over an ice bath at room temperature for 3 hours. Quench with water, then extract with ethyl acetate (50ml. X.3), combine the organic phases, dry over anhydrous sodium sulfate, filterThe organic phase was concentrated under reduced pressure and separated by high performance liquid chromatography (Waters autopurification HPLC-system C18 50 × 250mm Wavelength 254nm water (0.1% tfa) -MeCN (0.1% tfa)). Compound 24 trifluoroacetate salt (260 mg, waxy) was obtained, yield: 62 percent. MS m/z (ESI): 514.3[ mu ] M +1] + 。 1 H NMR(400MHz,DMSO-d 6 ):δ6.88(s,1H),6.80(s,1H),5.22(s,1H),4.72-4.80(m,1H),4.60(s,1H),4.50(m,1H),4.03(t,J＝6.0Hz,4H),3.58-3.62(m,1H),3.35-3.41(m,2H),3.05-3.35(m,3H),2.58-2.80(m,3H),1.95-2.35(m,12H),1.75-1.95(m,3H),1.72(s,3H),1.38-1.42(m,6H),0.95(t,J＝7.6Hz,3H).
Example 8: synthesis of fragment 2
Figure BDA0003824655900000181
The synthetic route is as follows:
Figure BDA0003824655900000182
CBD (2.0g, 6.4mmol, 1eq) was dissolved in 60mL of methylene chloride and triethylamine (1.3g, 12.8mmol, 2.0eq) was added, and the reaction was stirred at room temperature for 0.5h. Phenyl p-nitrochloroformate (5.1g, 25.5mmol, 4eq) was added and reacted at 0 ℃ for 2 hours. Quenched with water, then extracted with ethyl acetate (50ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate =10: 1) to give fragment 2 (3.2 g, oil), yield: 78 percent. MS m/z (ESI): 645.2[ M ] +1].
Example 9: synthesis of Compound 25 trifluoroacetate salt
Figure BDA0003824655900000183
The synthetic route is as follows:
Figure BDA0003824655900000191
fragment 2 (1.0 g,1.6mmol,1.0 eq), 2-morpholinoethanol (2.0 g,16.0mmol,10 eq) and triethylamine (9.39g, 9.30mmol,6 eq) were dissolved in 30mL of dichloromethane and heated under reflux overnight. Quenched with water, then extracted with ethyl acetate (50ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, and separated by high performance liquid chromatography (Waters autopurification HPLC-system C18 50 × 250mm Wavelength 254nm water (0.1% tfa) -MeCN (0.1% tfa)). Compound 25 trifluoroacetate salt (850 mg, waxy) was obtained, yield: 62 percent. MS m/z (ESI): 629.2[ M ] +1] + 。 1 H NMR(400MHz,DMSO-d 6 ):δ7.00(s,2H),5.02(s,1H),4.53-4.60(m,2H),4.40-4.53(m,3H),4.34(s,1H),3.60-4.02(br,9H),3.10-3.52(br,8H),2.55(t,J＝8.0Hz,3H),2.05-2.30(m,1H),1.90-2.00(m,1H),1.50-1.65(m,10H),1.20-1.30(m,5H),0.86(t,J＝6.8Hz,3H).
Example 10: synthesis of fragment 3
Figure BDA0003824655900000192
The synthetic route is as follows:
Figure BDA0003824655900000193
CBD (0.80g, 2.50mmol, 1eq) was dissolved in 8mL tetrahydrofuran, sodium hydride (0.091g, 3.80mmol, 1.5eq) was added, and the reaction was stirred at 0 ℃ for 0.5h. Methyl iodide (0.43g, 3.0mmol, 1.2eq) was added and reacted at 0 ℃ for 2 hours. Quenched with water, then extracted with ethyl acetate (50ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate =10: 1) to give fragment 3 (0.13 g, oil), yield: 15 percent.
Example 11: synthesis of Compound 26 trifluoroacetate salt
Figure BDA0003824655900000201
The synthesis route is as follows:
Figure BDA0003824655900000202
3- (4-Morpholinyl) propionic acid (74.5mg, 0.46mmol, 1.2eq), EDCI (113g, 0.59mmol, 1.5eq) and DMAP (60mg, 0.46mmol, 1.2eq) were dissolved in 10mL of dichloromethane and reacted at room temperature for 0.5h. Fragment 3 (130mg, 0.39mmol,1.0 eq) was added and the reaction stirred at room temperature for 3h. Quenched with water, then extracted with ethyl acetate (50ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, and separated by high performance liquid chromatography (Waters autopurification HPLC-system C18 50 × 250mm Wavelength 254nm water (0.1% tfa) -MeCN (0.1% tfa)). Compound 26 trifluoroacetate salt (75 mg, waxy) was obtained, yield: 33 percent. MS m/z (ESI): 470.3[ deg. ] M +1] + 。 1 H NMR(400MHz,DMSO_d 6 ):δ10.12(br,1H),6.68(s,1H),6.45(s,1H),5.0(s,1H),4.35-4.42(m,2H),3.05-3.99(m,11H),1.94-2.19(m,2H),1.50-1.69(m,9H),1.24-1.32(m,5H),0.85(t,J＝9Hz,3H).
Example 12: synthesis of Compound 24
Figure BDA0003824655900000203
The synthetic route is as follows:
Figure BDA0003824655900000204
compound 24 trifluoroacetate salt (628mg, 1mmol, 1.0eq) was dissolved in 10mL of water, and a saturated sodium hydrogencarbonate solution was added dropwise to adjust pH =9, and the mixture was stirred at room temperature for 1h. Extraction with ethyl acetate (50ml × 3), combining the organic phases, drying over anhydrous sodium sulfate, filtration and concentration of the organic phase under reduced pressure. Compound 24 (488 mg, oil) was obtained, yield: 95 percent. MS m/z (ESI): 514.3[ mu ] M +1] + 。 1 H NMR(600MHz,CDCl 3 -d):δ6.80(s,1H),6.73(s,1H),5.20(s,1H),4.54(s,1H),4.45(s,1H),4.35–4.43(m,1H),4.20–4.33(m,1H),3.68–3.80(m,4H),3.52–3.65(m,1H),2.63–2.77(m,3H),2.46–2.62(m,6H),2.13–2.33(m,4H),1.96–2.05(m,1H),1.76–1.83(m,1H),1.69–1.76(m,1H),1.67(s,3H),1.57–1.63(m,5H),1.28–1.35(m,4H),0.82–0.96(t,J＝7.6Hz,3H).
Example 13: synthesis of Compound 24 hydrochloride
Figure BDA0003824655900000211
The synthetic route is as follows:
Figure BDA0003824655900000212
compound 24 (514mg, 1mmol, 1.0eq) was dissolved in 10mL of ethyl acetate, and dioxane hydrochloride solution (4N) was added dropwise, adjusted to pH =3, and stirred at room temperature for 2h. The reaction mixture was concentrated under reduced pressure. Compound 24 hydrochloride (550 mg, white solid) was obtained, yield: 100 percent. MS m/z (ESI): 514.3[ mu ] M +1] + 。
Example 14: synthesis of Compound 25
Figure BDA0003824655900000213
The synthesis route is as follows:
Figure BDA0003824655900000214
compound 25 trifluoroacetate salt (857mg, 1mmol, 1.0eq) was dissolved in 10mL of water, and a saturated sodium hydrogencarbonate solution was added dropwise to adjust pH =9, and stirred at room temperature for 1h. Extraction with ethyl acetate (50ml × 3), combining the organic phases, drying over anhydrous sodium sulfate, filtration and concentration of the organic phase under reduced pressure. Compound 25 (604 mg, white solid) was obtained, yield: 96 percent. MS m/z (ESI): 629.4[ M ] +1] + 。 1 H NMR(600MHz,CDCl 3 -d):δ6.82(s,2H),5.20(s,1H),4.53(s,1H),4.44(s,1H),4.36–4.43(m,2H),4.19–4.32(m,2H),3.69–3.79(m,8H),3.60–3.66(m,1H),2.65–2.76(m,5H),2.46–2.63(m,10H),2.13–2.27(m,1H),1.95–2.02(m,1H),1.74–1.83(m,1H),1.67–1.73(m,1H),1.64–1.67(m,3H),1.57–1.63(m,5H),1.27–1.36(m,4H),0.84–0.93(t,J＝7.0Hz,3H).
Example 15: synthesis of Compound 25 hydrochloride
Figure BDA0003824655900000221
The synthesis route is as follows:
Figure BDA0003824655900000222
compound 25 (629mg, 1mmol,1.0 eq) was dissolved in 10mL of ethyl acetate, a dioxane solution (4N) hydrochloride was added dropwise, pH =3 was adjusted, a solid was precipitated, and the mixture was stirred at room temperature for 2 hours. Filtration, washing of the filter cake with ethyl acetate (5 ml × 3), collection of the filter cake and drying. Compound 25 hydrochloride (491 mg, white solid) was obtained, yield: 70 percent. MS m/z (ESI): 629.4[ M ] +1] + 。
Example 16: preparation and characterization of Compound 25 maleate form I
Figure BDA0003824655900000223
1.1 preparation of Compound 25 maleate form I
(1) 505.03mg of compound 25 was weighed, 5.0mL acetone (10 vol) was added, stirred at 20 ℃ for 5min and completely dissolved.
(2) 190.45mg maleic acid (2.0 eq) was weighed and added to 5.0mL acetone (10 vol) and stirred for 30min to completely dissolve.
(3) And (3) dropwise adding the maleic acid solution obtained in the step (2) into the compound 25 solution obtained in the step (1) (dropwise adding is completed within 5 min), and stirring for 24h until no solid is precipitated.
(4) Adding 5.0mL of methyl tert-butyl ether (dropwise addition is completed within 10 min), stirring for precipitation within 24h, continuing stirring for 24h, filtering, and vacuum drying (40 ℃) for 4 days to obtain 339.56mg of compound 25 maleate crystal form I.
1.2 characterization of Compound 25 maleate form I
1.2.1 powder X-ray diffraction (XRPD)
The X-ray diffraction patterns were obtained from a D2 Phaser type acquisition with a Brookfield instrument, the instrument parameters of which are shown in Table 1-1. The XRPD pattern is shown in figure 1-1, and the pattern analysis data is shown in table 1-2.
TABLE 1-1 XRPD apparatus parameters
Figure BDA0003824655900000231
Table 1-2 XRPD pattern analysis data for compound 25 maleate form I
Figure BDA0003824655900000232
1.2.2 Differential Scanning Calorimetry (DSC)
The method comprises the following steps: the DSC curve was obtained from a DSC model 3 acquisition of a mettler instrument. Weighing the sample into a sample tray, precisely weighing, recording the weight, and heating from 30 ℃ to 350 ℃ at a heating rate of 10 ℃/min. The nitrogen flow rate was 50mL/min. The crucible was in a sealed state during the experiment.
The results are shown in FIGS. 1-2, which indicate that Compound 25 maleate form I has an endothermic peak at 115.03 ℃.
1.2.3 thermogravimetric analysis (TGA)
The TGA curve was obtained from the collection of relaxation-resistant TG209F 3. Weigh sample into sample dish (Al) 2 O 3 ) In the above step, the weight is precisely measured and recorded. The temperature was raised from 40 ℃ to 350 ℃ at a rate of 20 ℃/min. The nitrogen flow rate was 70mL/min.
The test results are shown in figures 1-3, which indicate that compound 25 maleate form I loses 0.2% of weight in the range of endothermic peak temperature.
1.2.4 1 H NMR
The nuclear magnetic results were obtained from a 400MHz acquisition of Varian, DMSO, using a deuterated solvent.
The results are shown in fig. 1-4, which show that compound 25 maleate form I has no solvent residue, is anhydrous, and has a molar ratio of maleic acid to free base of 2.0.
Example 17: preparation and characterization of compound 25 maleate form II
1.1 preparation method
About 90mg of compound 25 maleate form I was weighed, 1.8mL of isopropyl acetate was added at 50 ℃, 0.8mL of acetone was added, and filtered. And (3) transferring the filtrate to-10 ℃, continuously stirring for 1 day, filtering, and vacuum drying the obtained solid at 50 ℃ for 4 hours to obtain the compound 25 maleate crystal form II.
1.2 characterization method:
1.2.1 XPRD and 1 HNMR: the same characterization method as in example 16.
1.2.2 TGA
The TGA profile was obtained from TGA550 acquisition by a TA instrument. Sample weighing into sample dish (Al) 2 O 3 ) In the method, the temperature is raised to 300 ℃ at a temperature rise rate of 10 ℃/min.
1.2.3 DSC
DSC curves were obtained from a DSC model 250 acquisition of a TA instrument. The sample is weighed into a sample pan, precisely weighed, and the weight is recorded. The temperature is raised from 25 ℃ to 300 ℃ at a heating rate of 10 ℃/min.
1.3 test results
1.3.1 XPRD
The XPRD spectrum is shown in FIG. 2-1, and the spectrum analysis data is shown in Table 2.
Table 2 XRPD pattern analysis data for compound 25 maleate form II
Serial number 2θ±0.2(°) Relative Strength (%) Serial number 2θ±0.2(°) Relative Strength (%)
1 7.868 100.0 7 14.239 34.7
2 8.892 44.4 8 15.898 35.9
3 9.111 47.2 9 16.632 31.9
4 9.760 42.9 10 18.061 55.7
5 10.713 33.6 11 18.535 92.8
6 12.122 98.6
1.3.2 DSC/TGA/ 1 H NMR
DSC results show that the compound 25 maleate crystal form II has an endothermic peak at 76.47 ℃; TGA results indicate that compound 25 maleate form II has no weight loss within the melting point range; 1 the H NMR results showed that compound 25 maleate form II was an anhydrous form with a molar ratio of maleic acid to free base of 2.0. The DSC/TGA spectrum is shown in figure 2-2, 1 the H NMR spectrum is shown in FIGS. 2-3.
Example 18: preparation and characterization of compound 25 maleate form III
1.1 preparation method
Weighing about 1g of compound 25 maleate crystal form I, dissolving the raw materials with 4mL of acetonitrile and 40mL of water, freezing with dry ice, and freeze-drying to obtain the compound 25 maleate amorphous. 30.64mg of compound 25 maleate is weighed to be amorphous in a sample bottle, 0.2mL of isopropanol is added, and the mixture is stirred for 3 days at the temperature of about 15 ℃ to obtain the compound 25 maleate crystal form III.
1.2 characterization method: XPRD, TGA/DSC and 1 the characterization method of HNMR was the same as that of example 17.
1.3 test results
1.3.1 XPRD
The XRPD pattern is shown in figure 3-1, and the pattern analysis data is shown in table 3.
Compound 25 maleate form III having an X-ray powder diffraction pattern using Cu-Ka radiation is shown in FIG. 3-1.
Table 3 XRPD pattern analysis data for compound 25 maleate form III
Serial number 2θ±0.2(°) Relative Strength (%) Serial number 2θ±0.2(°) Relative Strength (%)
1 6.241 16.6％ 11 19.581 42.1％
2 7.384 4.1％ 12 20.385 12.5％
3 8.730 23.5％ 13 21.894 9.6％
4 10.010 17.7％ 14 22.400 13.8％
5 12.578 44.8％ 15 23.836 28.0％
6 15.303 11.1％ 16 26.001 7.4％
7 15.928 49.5％ 17 26.435 16.2％
8 17.219 11.1％ 18 26.564 19.8％
9 17.679 100.0％ 19 27.674 9.1％
10 19.254 19.5％ 20 28.164 10.5％
1.3.2 DSC/TGA/ 1 H NMR
DSC result shows that the compound 25 maleate crystal form III has an endothermic peak at 115.31 ℃ which is the melting point of the crystal form; the TGA results indicate that compound 25 maleate form III has no weight loss over the melting point range, 1 the H NMR results indicated that compound 25 maleate form III was an anhydrous form with a molar ratio of maleic acid to free base of 2.0. The DSC/TGA spectrum is shown in FIG. 3-2, and the 1H NMR spectrum is shown in FIG. 3-3.
Example 19: preparation and characterization of compound 25 maleate form IV
1.1 preparation method
Weighing about 1g of compound 25 maleate crystal form I, dissolving the raw materials with 4mL of acetonitrile and 40mL of water, freezing with dry ice, and freeze-drying to obtain the compound 25 maleate amorphous. Weighing about 30mg of compound 25 maleate amorphous in a sample bottle, adding 0.1mL acetonitrile-methyl tert-butyl ether (1:8), and stirring at about 15 ℃ for 3 days to obtain compound 25 maleate crystal form IV.
1.2 characterization method: XPRD, TGA/DSC and 1 the characterization method of HNMR was the same as that of example 17.
1.3 test results
1.3.1 XPRD
The XRPD pattern is shown in figure 4-1, and the pattern analysis data is shown in table 4.
Table 4 XRPD pattern analysis data for compound 25 maleate form IV
Serial number 2θ±0.2(°) Relative Strength (%) Serial number 2θ±0.2(°) Relative Strength (%)
1 8.004 100 9 16.137 70.6
2 9.600 27.1 10 17.008 30.7
3 10.575 37.6 11 18.177 20.4
4 11.105 12.1 12 19.061 19.2
5 12.151 34.6 13 21.307 26.9
6 13.523 18.8 14 22.366 45.2
7 14.327 13.3 15 23.296 31.9
8 15.182 24.3 16 24.308 55.2
1.3.2 DSC/TGA/ 1 H NMR
1 The H NMR spectrum showed 0.8% (0.18 mol) acetonitrile and 1.6% methyl tert-butyl ether residue; DSC results show that two endothermic peaks can be seen before 125 ℃ in the compound 25 maleate crystal form IV; the TGA results indicated that compound 25 maleate form IV had a 3.2% weight loss before 125 ℃ and was converted to amorphous form after heating to 100 ℃. The DSC/TGA spectrum is shown in 4-2, 1 the H NMR spectrum is shown in 4-3.
Example 20: preparation and characterization of compound 25 fumarate crystalline form
1.1 preparation method
(1) 504.59mg of compound 25 was weighed, 5.0mL acetonitrile (10 vol) was added, stirred at 20 ℃ for 5min and completely dissolved.
(2) 187.45mg fumaric acid (2.0 eq) was weighed and added to 5.0mL acetone (10 vol) and stirred for 30min to completely dissolve.
(3) And dropwise adding the fumaric acid solution into the raw material solution (dropwise adding is completed within 5 min), stirring for 24h, and separating out solids.
(4) Stirring was continued for 24h, filtered and dried under vacuum (4 days at 40 ℃ C. And 2 days at 50 ℃ C.) to give 560.28mg of compound 25 fumarate as crystalline form.
1.2 characterization method: XPRD, TGA/DSC and 1 the characterization method of HNMR was the same as that of example 16.
1.3 test results
1.3.1 XPRD
The XRPD pattern is shown in figure 5-1, and the pattern analysis data is shown in table 5.
Compound 25 fumarate in crystalline form, with an X-ray powder diffraction pattern using Cu-ka radiation, as shown in figure 5-1.
Table 5 XRPD pattern analysis data for compound 25 fumarate salt form
Figure BDA0003824655900000261
Figure BDA0003824655900000271
1.3.2 DSC/TGA/ 1 H NMR
DSC results show that the crystal form of the 25 fumarate of the compound has an endothermic peak at 91.76 ℃; the TGA results indicate that compound 25 fumarate crystalline form did not lose weight until 120 ℃; 1 the H NMR result shows that the crystal form of the fumarate salt of the compound 25 has no solvent residue and is an anhydrous crystal form, and the molar ratio of fumaric acid to free base is 2.0. DSC/TGA- 1 The H NMR spectra are shown in FIG. 5-2, FIG. 5-3, and FIG. 5-4, respectively.
Example 21: preparation and characterization of compound 25 p-toluenesulfonate crystal form
1.1 preparation method
(1) 500.80mg of compound 25 was weighed, 5.0mL acetone (10 vol) was added, stirred at 20 ℃ for 5min and completely dissolved.
(2) 307.70mg p-toluenesulfonic acid (2.0 eq) was weighed and added to 5.0mL acetone (10 vol) and stirred for 30min to completely dissolve.
(3) And (4) dropwise adding the p-toluenesulfonic acid solution into the raw material solution (dropwise adding is finished within 5 min), and stirring for 24h until no solid is precipitated.
(4) Adding 5.0mL of methyl tert-butyl ether (dropwise addition is completed within 10 min), stirring for 24h to separate out, continuing stirring for 24h, filtering, and vacuum drying (40 ℃) for 4 days to obtain 533.47mg of compound 25 p-toluenesulfonate crystal form.
1.2 characterization method: XPRD, TGA/DSC and 1 the characterization method of HNMR was the same as that of example 16.
1.3 test results
1.3.1 XPRD
The XRPD pattern is shown in figure 6-1, and the pattern analysis data is shown in table 6.
Table 6 XRPD pattern analysis data for compound 25 p-toluenesulfonate crystalline form
Serial number 2θ±0.2(°) Relative Strength (%) Serial number 2θ±0.2(°) Relative Strength (%)
1 5.768 100.0 11 19.620 5.6
2 8.367 24.3 12 20.082 3.8
3 11.406 21.7 13 20.904 2.6
4 12.430 2.0 14 21.639 1.8
5 13.413 2.3 15 21.819 1.8
6 13.705 4.7 16 22.183 2.7
7 16.139 1.8 17 23.035 10.4
8 16.866 6.2 18 25.069 2.8
9 17.183 9.7 19 26.606 3.1
10 18.708 2.1 20 31.640 1.3
1.3.2DSC/TGA/ 1 H NMR
DSC results show that the crystal form of the compound 25 p-toluenesulfonate has an endothermic peak at 148.41 ℃; the TGA results indicated that compound 25 p-toluenesulfonate crystalline form had a weight loss of 0.6% before 200 ℃; 1 h NMR results showed no solvent residue for the compound 25 p-toluenesulfonate crystalline form, with a p-toluenesulfonic acid to free base molar ratio of 2.0. DSC/TGA- 1 The H NMR spectra are shown in FIG. 6-2, FIG. 6-3 and FIG. 6-4, respectively.
Example 22: synthesis of hydrochloride salt of Compound 27
Figure BDA0003824655900000281
The synthetic route is as follows:
Figure BDA0003824655900000282
2-Bromoethanol (10g, 80mmol) was dissolved in a 500mL flask containing ethanol (140 mL), diethylamine (29g, 400mmol) was slowly added dropwise with stirring at room temperature under argon, the reaction was heated and stirred at 60 ℃ for 6h, DCM (300 mL) was added after the reaction was cooled, and the mixture was passed through 5% NaHCO 3 The solution (3X 100 mL), washed with water (50 mL), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to give diethylaminoethanol as a colorless oil, 600mg, 9.5% yield. MS (m/z) 118[ deg. ] M + H] + 。
Dissolving cannabidiol (5g, 169mol) in 100mL dry dichloromethane, adding triphosgene (4.76g, 169mol) and N, N-diisopropylethylamine (4.12g, 32mmol) at 0 deg.C, reacting at 0 deg.C while stirringStirring for 2h, adding 2-diethylaminoethanol (3.74g, 32mmol) and N, N-diisopropylethylamine (4.12g, 32mmol), stirring for 4h at 0 ℃, extracting with dichloromethane/water after the reaction is complete, concentrating the organic phase, purifying by four normal phase columns (biotin, agela 120g, dichloromethane/ethyl acetate: 10% -80%) to obtain 2.4g of colorless oily substance, dissolving the colorless oily substance in 40mL dichloromethane, dropwise adding 2mL hydrochloric acid/dioxygen (4M) hexacyclic solution, stirring for two hours at room temperature, concentrating at least the solvent, adding 100mL ethyl acetate, stirring vigorously to obtain a white solid, and vacuum-filtering and drying to obtain compound 27 hydrochloride (2.1 g, white solid) with a yield of 22%. MS (m/z): 602[ 2 ] M +2H] + 。 1 H NMR(400MHz，Chloroform-d):δ12.88(s，2H)，6.85(s，2H)，5.15(s，1H)，4.78(dd，J＝11.8，6.6Hz，4H)，4.52(s，1H)，4.40(s，1H)，3.55(d，J＝10.4Hz，1H)，3.37(q，J＝4.8Hz，4H)，3.20(q，J＝6.6Hz，8H)，2.66～2.54(m，3H)，2.13(d，J＝13.3Hz，1H)，2.03(s，1H)，1.77(s，1H)，1.66(s，3H)，1.63(s，6H)，1.44(t，J＝7.2Hz，12H)，1.35-1.29(m，4H)，0.89(t，J＝6.6Hz，3H)。
Test example 1: in vivo pharmacokinetic testing of prodrug compound in beagle dogs
1. Pharmacokinetic testing of prodrug compounds in fasted model beagle dogs
Beagle dogs weighing about 10kg were randomly divided into groups, three of which were fasted for 12h before administration, water was freely drunk, compound 24 hydrochloride aqueous solution, compound 25 hydrochloride aqueous solution, compound 27 hydrochloride aqueous solution and CBD sesame oil solution (1 mL solvent containing 79mg ethanol and 736mg sesame oil) were administered by intragastric administration at a dose of 32 μmol/kg, blood was collected at 0.25, 0.5, 1,2,3, 4, 6, 8, 12 and 24 hours before and after administration, respectively, blood was placed in heparinized EP tubes, plasma was separated by centrifugation, and the concentrations of active metabolite CBD and each prodrug in plasma were measured by LC-MS/MS after pretreatment of plasma.
Table 7-1, fig. 7-1, and fig. 7-2 are plots of the pharmacokinetic parameters and the drug timing for oral administration of compound 24 hydrochloride, compound 25 hydrochloride, and the CBD to beagle dogs of the prodrug proto-form and/or the CBD. The results show that compound 24 hydrochloride and compound 25 hydrochloride are mostly metabolized to CBD after gastrointestinal tract entry into beagle dogs. The relative bioavailability of the metabolite CBD of compound 24 and compound 25 was 364.7% and 307.5%, respectively, relative to the CBD-administered group.
TABLE 7-1 Compound 24/Compound 25 and CBD in vivo Primary pharmacokinetic parameters
Figure BDA0003824655900000291
* Relative bioavailability compared to CBD
Tables 7-2 are the main pharmacokinetic parameters for beagle dogs orally administered compound 27 hydrochloride salt or CBD followed by prodrug pro-form compound and/or CBD. The results show that the hydrochloride salt of prodrug compound 27 is metabolized mostly to CBD after gastrointestinal tract entry into beagle dogs. The relative bioavailability of the metabolite CBD of compound 27 was 113.2% relative to CBD administered.
As can be seen from a comparison of tables 7-1 and 7-2, the in vivo exposure (AUC) of metabolites CBD of compounds 24 and 25 was increased by 3-fold or more, while the exposure (AUC) of compound 27 was comparable to that of CBD, with respect to the group to which CBD was administered.
TABLE 7-2 in vivo Primary drug parameters for Compound 27 and CBD dogs
Figure BDA0003824655900000292
* Relative bioavailability compared to CBD
2. Pharmacokinetic testing of prodrug compounds in beagle dogs in a high oil diet model
After administration, sesame oil was infused to simulate a high-fat diet, and the effect of the high-fat diet on the bioavailability of CBD in beagle dogs was examined. 16 Beagle dogs weighing about 10kg were randomly divided into 4 groups of 4 dogs, each administered at a dose of 32 μmol/kg, fasted 12h prior to administration and allowed free access to water. The compound 25-maleate saline solution was administered by intragastric administration in groups 1 and 2 at an administration volume of 3ml/kg, and after administration, group 1 was taken with 8ml of water and group 2 was taken with 8ml of sesame oil. Group 3 CBD sesame oil solution (1 mL vehicle containing 79mg ethanol, 736mg sesame oil) was administered by intragastric administration at a volume of 0.2mL/kg, followed by administration with 6mL sesame oil and 30mL water. Group 4 CBD sesame oil solution (1 mL vehicle containing 79mg ethanol, 736mg sesame oil) was filled into a fast-release capsule and administered by gastric lavage (about 1mL sesame oil), and after administration, the CBD sesame oil solution was taken with 38mL water. Blood was collected at 0.25, 0.5, 1,2,3, 4, 6, 8, 12, and 24 hours before and after administration, respectively, the blood was placed in heparinized EP tubes, plasma was centrifuged, and the plasma was pretreated and then the concentrations of compound 25 and CBD in the plasma were measured by LC-MS/MS. The test results are shown in FIGS. 7-3 and tables 7-3.
The test result shows that: compound 25 maleate is mostly metabolized to CBD in Beagle dogs. In the fasted group, compound 25 maleate (group 1) produced an exposure of the active metabolite CBD that was 2.2 times that of the CBD group (group 4). CBD exposure and C after high oil administration of Compound 25 maleate (group 2) compared to fasted and high fat diet groups max Comparable to normal group (group 1); while exposure and C after CBD given high oil (group 3) max All 4.8 times higher than the normal group (group 4). I.e. high fat diet exposure to Compound 25 maleate and C max The effect of (c) is much less than that of CBD.
TABLE 7-3 Compound 25 maleate and CBD in vivo Primary pharmacokinetic parameters
Figure BDA0003824655900000301
* Relative bioavailability compared to CBD
Test example 2: pharmacokinetic testing of prodrug Compounds in fasting model rats
SD rats weighing about 200 g were randomly grouped into groups of four animals, each group was administered at a dose of 47.7. Mu. Mol/kg, fasted for 12h before administration, and freely drunk water, each group was separately administered by gavage, test compounds were prepared as 20% Solutol HS 15 aqueous solution (containing 5% absolute ethanol), blood was collected at 0.25, 0.5, 1,2,3, 4, 6, 8, 12, and 24h before and after administration, blood was placed in heparinized EP tubes, plasma was separated by centrifugation, and plasma was pretreated and then assayed for the concentrations of active metabolite CBD and each prodrug by LC-MS/MS, respectively.
Table 8-1 and FIG. 8 are plots of the pharmacokinetic parameters and drug timing for the metabolite CBD after intragastric administration of Compound 24 hydrochloride and Compound 25 hydrochloride to rats. The results show that: the hydrochloride salt of compound 24 and the hydrochloride salt of compound 25 are metabolized to the active metabolite CBD immediately after entering the rat body via the gastrointestinal tract, the concentration of the original compound is very low, below the quantitative lower limit level for detection, and the prodrug is substantially completely converted to the active metabolite CBD by oral administration. Neither prodrug nor CBD was detected after gavage of compound 26 trifluoroacetate.
TABLE 8-1 pharmacokinetic parameters for Compound 24 hydrochloride and Compound 25 hydrochloride metabolite CBD
Figure BDA0003824655900000302
Tables 8-2 and 8-3 are graphs of the pharmacokinetic parameters and the time of administration of prodrug proto-drug and metabolite CBD after gavage administration of Compound 13/Compound 19/Compound 21 trifluoroacetate in rats. The results show that the exposure of the metabolite CBD in vivo of the carbamate compound is lower than or equal to that of CBD administered by direct gavage.
TABLE 8-2 Compound 13 trifluoroacetate and CBD in vivo pharmacokinetic parameters in rats
Figure BDA0003824655900000311
* Relative bioavailability compared to CBD
TABLE 8-3 in vivo pharmacokinetic parameters for Compound 19/Compound 21 trifluoroacetate and CBD in rats
Figure BDA0003824655900000312
* Relative bioavailability compared to CBD
Tables 8-4 show the pharmacokinetic parameters for metabolite CBD after intragastric administration of Compound 17/Compound 18 trifluoroacetate in rats, no compound was detected as compound 17 or compound 18. The results show that the in vivo metabolite CBD of the carbonate compound containing the morpholine ring has higher exposure.
TABLE 8-4 in vivo pharmacokinetic parameters in rats for Compound 17/Compound 18 trifluoroacetate and CBD
Figure BDA0003824655900000313
Test example 3: stability study of different salts of Compound 25
1. Test method
10-15 mg of compound 25 in crystalline form I maleate (example 16), crystalline form fumarate (example 20), and crystalline form p-toluenesulfonate (example 21) were weighed out open into a stability box and the solids were taken on day 5 and day 10, respectively, for XRPD and HPLC analysis.
The XRPD method was the same as in example 16, and the HPLC method is shown in Table 9-1.
TABLE 9-1 HPLC analytical methods
Figure BDA0003824655900000321
2. Test results
The results show that the maleate form I of compound 25 has good physical and chemical stability under the test conditions, while the fumarate and p-toluenesulfonate forms change under high temperature and high humidity conditions, and the purity is reduced. See, in particular, tables 9-2 and 9-3.
TABLE 9-2 stability test results on day 5 for different salt forms
Figure BDA0003824655900000322
TABLE 9-3 stability test results on day 10 for different salt forms
Figure BDA0003824655900000323
Test example 4: hygroscopicity study of compound 25 maleate form I
1. Test method
And (3) drying: 40 ℃/0% RH for about 1.5h until dm/dt is less than 0.002%.
And (3) testing process: after cooling to 25 ℃ the measurement was started after dm/dt was less than 0.002%.
Time mode 25 ℃ samples, 0% -90% -0% RH,10% gradients, each gradient resting for 1h.
2. Test results
The results of the experiments are shown in FIGS. 9-1 and 9-2, and show that Compound 25 maleate form I has a 0.1251% increase in moisture at 90% RH humidity, with no or little hygroscopicity. Compound 25 maleate form I did not change form before and after the dewing test (DVS).
Test example 5: competition beating test of compound 25 maleate crystal form
1. Test method
Respectively preparing amorphous saturated solutions of a compound 25 maleate in a solvent shown in the table 10, adding the crystal form I and the crystal form II of the compound 25 maleate into each saturated liquid medicine according to the mass ratio of 1:1, stirring for 3 days at room temperature (about 17 ℃) or 50 ℃, and obtaining a solid which is the crystal form I of the compound 25 maleate, wherein the result shows that the crystal form I is more stable than the crystal form II.
The specific test conditions and results are shown in Table 10. The XRPD results are shown in FIG. 10-1 and FIG. 10-2.
TABLE 10 Competition beating Experimental conditions and results
Numbering Solvent(s) Crystal form I (mg) Crystal form II (mg) Temperature of Results
1 N-heptane, 0.5mL 8.63 8.62 At room temperature Crystal form I
2 Toluene, 0.6mL 6.02 6.05 At room temperature Crystal form I
3 Ethyl acetate, 0.6mL 6.14 6.16 At room temperature Crystal form I
4 Isopropanol, 0.6mL 6.54 6.57 At room temperature Crystal form I
5 N-heptane, 0.5mL 8.63 8.62 50℃ Crystal form I
6 Toluene, 0.6mL 6.02 6.05 50℃ Crystal form I
7 Ethyl acetate, 0.6mL 6.14 6.16 50℃ Crystal form I
8 Isopropanol, 0.6mL 6.54 6.57 50℃ Crystal form I
Test example 6: compound 25 maleate form I tableting test
Approximately 15mg of compound 25 maleate form I was weighed, tableted at 30MPa, lightly ground to a powder and subjected to XRPD testing, the results of which are shown in figure 11. The result shows that after the compound 25 maleate crystal form I is tabletted, the crystal form is not changed, and the crystallinity is not obviously reduced.

Claims (7)

1. Form I of a compound of the formula having characteristic diffraction peaks at the following 2 θ angles in an X-ray powder diffraction pattern using Cu-Kalpha radiation: 9.016 + -0.2 deg., 13.765 + -0.2 deg., 17.411 + -0.2 deg., 18.411 + -0.2 deg., 21.575 + -0.2 deg., 27.798 + -0.2 deg.,
Figure QLYQS_1
。
2. form I according to claim 1, having characteristic diffraction peaks in the X-ray powder diffraction pattern using Cu-ka radiation at the following 2 Θ angles: 9.016 + -0.2 deg., 13.765 + -0.2 deg., 17.411 + -0.2 deg., 18.411 + -0.2 deg., 21.575 + -0.2 deg., 23.289 + -0.2 deg., 27.798 + -0.2 deg..
3. The crystalline form I according to claim 1 having an X-ray powder diffraction pattern using Cu-ka radiation as shown in figures 1-1.
4. A pharmaceutical composition comprising the crystalline form of any one of claims 1-3 and a pharmaceutically acceptable carrier.
5. Use of the crystalline form of any one of claims 1-3 or the pharmaceutical composition of claim 4 in the manufacture of a medicament for the prevention and treatment of a medical condition in a mammal, wherein the medical condition is selected from the group consisting of: epilepsy, spasticity, encephalopathy, neuropathic pain, numbness, anxiety and other mood disorders, hypertension, autonomic dysfunction, parkinson's disease and tremor, insomnia, bell's palsy and facial dysfunction, glaucoma, multiple sclerosis, cancer, post-traumatic stress disorder, trigeminal neuralgia, autism/Asperger's disease, attention deficit disorder and hyperactivity disorder, social isolation, occipital neuralgia, symptoms associated with TMJ dysfunction, headache, peripheral neuropathy, apnea, smoking cessation, arthritis, depression, emesis, obesity, nausea, alcohol use disorders, dystonia, inflammatory bowel syndrome, diabetic neuropathy, shingles, burns, actinic keratosis, canker sores and post-ulcerous craniotomy pain, psoriasis, pruritic contact dermatitis, eczema, bullous dermatitis herpetiformis, exfoliative dermatitis, mycoses, pemphigus, severe erythema multiforme, seborrheic dermatitis, ankylosing spondylitis, reiter's syndrome, gout, cartilage calcification, joint pain, dysmenorrhea, musculoskeletal pain, myositis, bursitis, synovitis, pancreatitis.
6. The use according to claim 5, wherein the epilepsy comprises seizure-accompanied sclerosis syndrome, dravet syndrome, lennox-Gastaut syndrome, mycoplasma seizures or intractable epilepsy.
7. The use of claim 5, wherein the cramp comprises juvenile cramps, west syndrome, pediatric cramps, or hemifacial cramps.
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