CN116253642B

CN116253642B - Cannabidiol prodrug, and pharmaceutical composition and application thereof

Info

Publication number: CN116253642B
Application number: CN202310149197.4A
Authority: CN
Inventors: 白信法; 蒋王林; 王文艳; 孙晓琳; 杨会杰; 张睿; 田京伟
Original assignee: Shandong Luye Pharmaceutical Co Ltd
Current assignee: Shandong Luye Pharmaceutical Co Ltd
Priority date: 2021-04-06
Filing date: 2022-04-02
Publication date: 2024-07-09
Anticipated expiration: 2042-04-02

Abstract

The invention relates to a cannabidiol prodrug, a preparation method and a pharmaceutical composition thereof. Also relates to the use of the prodrug compound or the pharmaceutical composition in preparing medicines for treating mammal or human related diseases, such as 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

The application relates to a cannabidiol prodrug with the application number of CN202280002921.4 and the name of cannabidiol prodrug, a pharmaceutical composition thereof and a divisional application of Chinese patent application, wherein the application date is 2022, 4 and 2.

Technical Field

The present invention relates to a class of prodrugs of cannabidiol suitable for mammals; and pharmaceutical compositions comprising cannabidiol prodrugs and their use in the treatment and prevention of diseases and disorders.

Background

Datamonitor Healthcare estimated that in 2018, the us, japan and five large european union markets had 660 ten thousand diagnosed active seizures, and cases in 2038 increased to 710 ten thousand. Domestic epidemiological data show that the 'lifetime prevalence' of epilepsy in China is about 7 per mill, about 900 ten thousand epileptics exist, about 600 ten thousand of which are active epileptics, and about 40 ten thousand of new epileptics exist each year.

From clinical symptoms and electroencephalograms, 2017 ILAE determines the type of epilepsy as four broad categories, including focal, comprehensive combined focal (Combined generalized and focal epilepsy), and unidentified classification of epilepsy. Dravet syndrome and Lennox-Gastaut syndrome belong to the comprehensive combination focal epileptic category and to the refractory epileptic category. The incidence of Dravet syndrome in children aged 3-13 is 11/10, the incidence of Lennox-Gastaut syndrome in children aged 3-13 is 4/10, and the incidence of seizure with tuberous sclerosis syndrome is 8/10.

Refractory seizures refer to seizures that cannot be controlled by drugs, i.e., are not easily controlled or alleviated, also known as controlled or drug resistant seizures. The Door-to-Door study estimated the prevalence of refractory seizures to be 2.7-7.1/1000 in high-income areas and 2.2-22.2/1000 in medium-low-income areas. Currently, drug resistant seizures are difficult to obtain based on the incidence of large sample population surveys. Overall, the incidence of drug resistant seizures in children and adults is 15% and 30%, respectively.

Cannabidiol (cannabidiol, abbreviated as CBD) is white to light yellow resin or crystal, the melting point is 66-67 ℃, and the cannabidiol is almost insoluble in water and soluble in organic solvents such as ethanol, methanol, diethyl ether, benzene, chloroform and the like.Is cannabidiol oral liquid, is approved by FDA in 2018 and is clinically used for treating epileptic seizure related to (1) Dravet syndrome of patients aged one year and older; (2) a Lennox-Gastaut syndrome-associated seizure disorder; approved in 2020 for treatment of seizure related to tuberous sclerosis syndrome (https:// www.accessdata.fda.gov/drugsatfda _ docs/label/2020/210365s005s006s 0070 lbl. Pdf).

The specification of the preparation: 1ml:100mg; the maximum recommended maintenance dose for epileptic seizure patients with Lennox-Gastaut syndrome and Dravet syndrome related to age one and above is 10mg/kg, BID; the maximum recommended maintenance dose for seizure patients associated with the one year old and older tuberous sclerosis syndrome is 12.5mg/kg, BID. Each bottle contains 100ml of absolute ethanol (7.9% w/v), sesame oil, strawberry flavor and sucralose. The inclusion of 7.9% absolute ethanol is a significant problem for infant patients. Meanwhile, cannabidiol has poor water solubility, the bioavailability of oral administration is only 6%, the absorption level of the gastrointestinal tract is unstable, the high-fat diet causes large fluctuation of PK parameters such as AUC _0-∞, C _max and the like (5 times increase relative to fasted state C _max and 4 times increase of AUC), and hepatotoxicity (https:// www.accessdata.fda.gov/drugsatfda _ docs/label/2018/210365lbl. Based on the defects, the prodrug oral preparation for improving the bioavailability, removing absolute ethyl alcohol and sesame oil in the preparation and rapidly converting the absolute ethyl alcohol and the sesame oil into cannabidiol in vivo is a problem to be solved clinically.

Disclosure of Invention

In one aspect, the present invention provides a compound of formula (I), a pharmaceutically acceptable salt or enantiomer thereof,

Wherein,

R ₁、R₂ are the same or different and are each, each independently selected from-OH, -OC (O) -R ₄, or-OC (O) -X- (CH ₂)n-N(Y₁Y₂);

X is NH or O;

y ₁ is independently selected from alkyl of C _2-10; y ₂ is independently selected from hydrogen, alkyl of C _2-10; or Y ₁、Y₂ forms a ring system with the attached N atom, said ring system being an unsubstituted heterocyclyl or heteroaryl group;

R ₃ is C _1-10 alkyl; r ₄ is C _1-10 alkyl; n=2-10;

The conditions are as follows: at least one of R ₁ or R ₂ is-OC (O) -X- (CH ₂)n-N(Y₁Y₂).

In one embodiment of the compounds of formula (I),

X is NH or O;

Y ₁ is independently selected from alkyl of C _2-6; y ₂ is independently selected from hydrogen, alkyl of C _2-6; or Y ₁、Y₂ forms a ring system with the attached N atom, said ring system being an unsubstituted heterocyclyl or heteroaryl group;

R ₃ is C _1-6 alkyl; r ₄ is C _1-6 alkyl;

n=2, 3, 4, 5,6, 7, 8, 9 or 10;

In one embodiment of the compounds of formula (I),

X is NH or O;

Y ₁ is independently selected from C _2-6 straight or branched alkyl;

y ₂ is independently selected from hydrogen, C _2-6 linear or branched alkyl;

Or Y ₁、Y₂ together with the attached N atom form a ring system which is an unsubstituted 3-8 membered heterocyclyl or 3-8 membered heteroaryl.

R ₃ is C _1-6 straight or branched alkyl;

R ₄ is C _1-6 straight or branched alkyl;

n=2, 3, 4, 5,6, 7, 8, 9 or 10;

In one embodiment of the compounds of formula (I),

R ₁、R₂, which are identical or different, are each independently selected from- -OH, OC (O) - -R ₄, or- -OC (O) - -X- - (CH ₂)n-N(Y₁Y₂);

X is NH or O;

Y ₁ is independently selected from ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1-dimethylbutyl, 2-dimethylbutyl, 3-dimethylbutyl, and 2-ethylbutyl;

Y ₂ is 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-dimethylbutyl, 2-dimethylbutyl, 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-dimethylbutyl, 2-dimethylbutyl, 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-dimethylbutyl, 2-dimethylbutyl, 3-dimethylbutyl and 2-ethylbutyl;

n=2, 3, 4, 5,6, 7, 8, 9 or 10;

In one embodiment of the compounds of formula (I),

X is NH or O;

Y ₁、Y₂ forms a ring system with the attached N atom, said ring system being selected from

n=2, 3, 4, 5,6, 7, 8, 9 or 10;

In one embodiment of the compounds of formula (I),

R ₁ is independently selected from

R ₂ is independently selected from the group consisting of-OH,

R ₃ is pentyl.

In one embodiment of the compounds of formula (I),

R ₁ is-OC (O) -X- (CH ₂)n-N(Y₁Y₂);

R ₂ is selected from-OH, -OC (O) -R ₄, or-OC (O) -X- (CH ₂)n-N(Y₁Y₂);

X is NH or O; preferably O;

y ₁、Y₂ forms a ring system with the attached N atom, said ring system being

R ₃ is C _1-6 alkyl; r ₄ is C _1-6 alkyl;

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(Y₁Y₂);

R ₂ is selected from-OH, -OC (O) -R ₄, or-OC (O) -X- (CH ₂)n-N(Y₁Y₂);

X is O; r ₃ is pentyl; r ₄ is methyl, ethyl or propyl; n=2, 3, 4 or 5, preferably n=2.

In one aspect, the present invention provides a compound of formula (II), a pharmaceutically acceptable salt or enantiomer thereof,

Wherein,

X is NH or O;

R ₃ is C _1-10 alkyl; r ₄ is C _1-10 alkyl; n=2-10;

In one embodiment of the compounds of formula (II),

X is NH or O;

Y ₁ is independently selected from alkyl of C _2-6;

y ₂ is independently selected from hydrogen, alkyl of C _2-6;

or Y ₁、Y₂ forms a ring system with the attached N atom, said ring system being an unsubstituted heterocyclyl or heteroaryl group;

R ₃ is C _1-6 alkyl; r ₄ is C _1-6 alkyl;

n=2, 3, 4, 5,6, 7, 8, 9 or 10;

In one embodiment of the compounds of formula (II),

X is NH or O;

Y ₁ is independently selected from C _2-6 straight or branched alkyl;

y ₂ is independently selected from hydrogen, C _2-6 linear or branched alkyl;

R ₃ is C _1-6 straight or branched alkyl;

R ₄ is C _1-6 straight or branched alkyl;

n=2, 3, 4, 5,6, 7, 8, 9 or 10;

In one embodiment of the compounds of formula (II),

X is NH or O;

Y ₁ is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1-dimethylbutyl, 2-dimethylbutyl, 3-dimethylbutyl, and 2-ethylbutyl;

Y ₂ is 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-dimethylbutyl, 2-dimethylbutyl, 3-dimethylbutyl, and 2-ethylbutyl;

n=2, 3, 4, 5,6, 7, 8, 9 or 10;

In one embodiment of the compounds of formula (II),

X is NH or O;

n=2, 3, 4, 5,6, 7, 8, 9 or 10;

In one embodiment of the compounds of formula (II),

R ₁ is independently selected from

R ₂ is independently selected from the group consisting of-OH,

R ₃ is pentyl.

In one embodiment of the compounds of formula (II),

R ₁ is-OC (O) -X- (CH ₂)n-N(Y₁Y₂);

R ₂ is selected from-OH, -OC (O) -R ₄, or-OC (O) -X- (CH ₂)n-N(Y₁Y₂);

X is NH or O; preferably O;

R ₃ is C _1-6 alkyl; r ₄ is C _1-6 alkyl;

n=2, 3,4 or 5.

In one embodiment of the compounds of formula (II),

R ₁ is-OC (O) -X- (CH ₂)n-N(Y₁Y₂);

R ₂ is selected from-OH, -OC (O) -R ₄, or-OC (O) -X- (CH ₂)n-N(Y₁Y₂);

X is O; r ₃ is pentyl; r ₄ is methyl, ethyl or propyl; n=2, 3, 4 or 5; preferably n=2.

In one aspect, the invention provides the following compounds, pharmaceutically acceptable salts or enantiomers thereof:

in one aspect, the invention provides a salt of any one of the compounds described above, or an enantiomer thereof, 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, p-toluenesulfonate, fumarate or hydrochloride salt of compound 25.

In one aspect, the invention provides maleate form I of compound 25 having characteristic diffraction peaks at the following 2θ angles in an X-ray powder diffraction pattern using Cu-ka radiation: 9.016+ -0.2 °,13.765 + -0.2 °,17.411 + -0.2 °,18.411 + -0.2 °,21.575 + -0.2 °,27.798 + -0.2 °.

In one aspect, the compound 25 maleate form I has a characteristic diffraction peak at the following 2θ angles in an X-ray powder diffraction pattern using Cu-ka radiation: 9.016+ -0.2 °,13.765 + -0.2 °,17.411 + -0.2 °,18.411 + -0.2 °,21.575 + -0.2 °,23.289 + -0.2 °,27.798 + -0.2 °.

In one aspect, the compound 25 maleate form I has a characteristic diffraction peak at the following 2 theta angles in an X-ray powder diffraction pattern using Cu-K alpha radiation ：8.676±0.2°,9.016±0.2°,9.580±0.2°,13.765±0.2°,16.154±0.2°,17.411±0.2°,18.411±0.2°,21.575±0.2°,23.289±0.2°,27.798±0.2°.

In one aspect, the compound 25 maleate form I has an X-ray powder diffraction pattern using Cu-ka radiation as shown in fig. 1-1.

In one aspect, the invention provides compound 25 maleate form II having a characteristic diffraction peak at the following 2Θ angles in an X-ray powder diffraction pattern using Cu-ka radiation: 7.868.+ -. 0.2 °, 10.713.+ -. 0.2 °, 12.122.+ -. 0.2 °, 18.535.+ -. 0.2 °.

In one aspect, the compound 25 maleate form II has a characteristic diffraction peak at the following 2θ angles in an X-ray powder diffraction pattern using Cu-ka radiation: 7.868.+ -. 0.2 °, 8.892.+ -. 0.2 °, 9.111.+ -. 0.2 °, 9.760.+ -. 0.2 °, 10.713.+ -. 0.2 °, 12.122.+ -. 0.2 °, 18.061.+ -. 0.2 °, 18.535.+ -. 0.2 °.

In one aspect, the compound 25 maleate form II has an X-ray powder diffraction pattern using Cu-ka radiation as shown in fig. 2-1.

In one aspect, the invention provides compound 25 maleate form III having a characteristic diffraction peak at the following 2Θ angles in an X-ray powder diffraction pattern using Cu-ka radiation: 8.730.+ -. 0.2 °, 10.010.+ -. 0.2 °, 12.578.+ -. 0.2 °, 15.928.+ -. 0.2 °, 17.679.+ -. 0.2 °.

In one aspect, the compound 25 maleate form III has a characteristic diffraction peak at the following 2θ angles in an X-ray powder diffraction pattern using Cu-ka radiation: 6.241.+ -. 0.2 °, 8.730.+ -. 0.2 °, 10.010.+ -. 0.2 °, 12.578.+ -. 0.2 °, 15.928.+ -. 0.2 °, 17.679.+ -. 0.2 °, 19.581.+ -. 0.2 °, 23.836.+ -. 0.2 °.

In one aspect, the compound 25 maleate salt form III has an X-ray powder diffraction pattern using Cu-ka radiation as shown in fig. 3-1.

In one aspect, the invention provides compound 25 maleate form IV having a characteristic diffraction peak at the following 2Θ angles in an X-ray powder diffraction pattern using Cu-ka radiation: 8.004.+ -. 0.2 °, 10.575.+ -. 0.2 °, 12.151.+ -. 0.2 °, 16.137.+ -. 0.2 °, 22.366.+ -. 0.2 °, 24.308.+ -. 0.2 °.

In one aspect, the compound 25 maleate form IV has a characteristic diffraction peak at the following 2 theta angles in an X-ray powder diffraction pattern using Cu-K alpha radiation ：8.004±0.2°,9.600±0.2°,10.575±0.2°,12.151±0.2°,16.137±0.2°,17.008±0.2°,22.366±0.2°,23.296±0.2°,24.308±0.2°.

In one aspect, the compound 25 maleate form IV has an X-ray powder diffraction pattern using Cu-ka radiation as shown in fig. 4-1.

In one aspect, the invention provides a crystalline form of compound 25 fumarate salt having characteristic diffraction peaks at the following 2θ angles in an X-ray powder diffraction pattern using Cu-ka radiation: 7.692.+ -. 0.2 °, 8.305.+ -. 0.2 °, 10.407.+ -. 0.2 °, 18.680.+ -. 0.2 °, 22.187.+ -. 0.2 °.

In one aspect, the compound 25 fumarate salt form has a characteristic diffraction peak at the following 2 theta angles in an X-ray powder diffraction pattern using Cu-K alpha radiation ：7.692±0.2°,8.305±0.2°,10.407±0.2°,15.332±0.2°,17.377±0.2°,18.680±0.2°,20.344±0.2°,22.187±0.2°,23.210±0.2°,23.688±0.2°.

In one aspect, the compound 25 fumarate salt crystalline form has an X-ray powder diffraction pattern using Cu-ka radiation as shown in fig. 5-1.

In one aspect, the invention provides a crystalline form of compound 25 p-toluenesulfonate having characteristic diffraction peaks at the following 2θ angles in an X-ray powder diffraction pattern using Cu-ka radiation: 5.768.+ -. 0.2 °, 8.367.+ -. 0.2 °, 11.406.+ -. 0.2 °, 17.183.+ -. 0.2 °, 23.035.+ -. 0.2 °.

In one aspect, the compound 25 is in the form of p-toluenesulfonate salt, and the X-ray powder diffraction pattern using Cu-ka radiation is shown in fig. 6-1.

In one aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described above, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a crystalline form of any of the compounds described above, and a pharmaceutically acceptable carrier. Such carriers include adjuvant ingredients conventional in the art, such as, for example, fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents, 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, particles, pills, miniature 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 intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular, and intrasternal). The dosage to be administered may be appropriately adjusted according to 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 a specific amount of the active ingredient. For example, the pharmaceutical composition may be provided as 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 can vary widely depending on the condition of the patient and other factors, but can be determined using conventional methods.

In one aspect, the invention provides the use of any of the compounds described above, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for the treatment of a disease or condition. The disease or condition includes: epilepsy (including seizures, epileptic onset with tuberous sclerosis syndrome, dravet syndrome, lennox-Gastaut syndrome, mycoplasma seizures, juvenile mycoplasma seizures, refractory seizures); spasticity (including juvenile spasticity, west syndrome, refractory pediatric spasticity, hemifacial spasticity); encephalopathy (including somnolence, 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 tremors (including essential tremors); insomnia; bell palsy and facial nerve dysfunction; glaucoma; multiple sclerosis; cancers, including brain tumors; post-traumatic stress disorder (PTSD); trigeminal neuralgia; autism/aprepitheliosis; 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; a recess; vomiting; anti-obesity; nausea; alcohol use disorders; dystonia; inflammatory bowel syndrome; neuropathic pain associated with post-herpetic neuralgia; diabetic neuropathy; herpes zoster; burn injury; actinic keratosis; canker sore; actinic keratosis; canker sores and post-craniotomy pain on ulcers; psoriasis; itching contact dermatitis; eczema; bullous dermatitis herpetiformis; exfoliative dermatitis; mycosis; pemphigus; severe erythema multiforme; seborrheic dermatitis; ankylosing spondylitis; psoriatic arthritis; reiter's syndrome; gout; cartilage calcification; pain in the joints; dysmenorrhea; musculoskeletal pain; myositis; bursitis; epicondylitis osteoarthritis; synovitis; pancreatitis; other disease states and conditions will be apparent to those skilled in the art.

Definition and description

The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.

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 salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting neutral forms of such compounds with a sufficient amount of a base in pure solution or in a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of an acid in pure solution or in a suitable inert solvent. Certain specific compounds of the invention contain basic and acidic functionalities that can be converted to either base or acid addition salts.

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.

Unless otherwise indicated, wedge-shaped keys and dashed-line keys are usedRepresenting the absolute configuration of a stereogenic center, usingRepresenting the relative configuration of a stereogenic center. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include E, Z geometric isomers unless specified otherwise. Likewise, all tautomeric forms are included within the scope of the invention.

The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -pairs of enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present invention.

Optically active (R) -and (S) -isomers and 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 chiral auxiliary wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Or when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), forms a diastereomeric salt with an appropriate optically active acid or base, and then undergoes diastereomeric resolution by conventional methods well known in the art, followed by recovery of the pure enantiomer. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amine).

The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium representative that is capable of delivering an effective amount of the active agents of the present invention, does not interfere with the biological activity of the active agents, and has no toxic or side effects to the host or patient.

For a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For the purposes of the present oral dosage form, an "effective amount" of one active agent in a composition refers to that amount which is required to achieve the desired effect when used in combination with another active agent in the composition. 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, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.

The term "active ingredient", "active agent" or "active agent" refers to a chemical entity that is effective in treating a disorder, disease or condition of interest.

Unless otherwise specified, the term "alkyl" is used to denote a straight or branched saturated hydrocarbon group, which may be mono-substituted (e.g., -CH ₂ F) or poly-substituted (e.g., -CF ₃), and may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). The alkyl group is preferably a C _1-10 alkyl group, for example ：C₁、C₂、C₃、C₄、C₅、C₆、C₇、C₈、C₉、C₁₀. 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-dimethylbutyl, 2-dimethylbutyl, 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 contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above-mentioned heterocycles may 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, where R is H or other substituents already defined herein). The heterocycle may be attached to any heteroatom or pendant group of a carbon atom that results in the formation of a stable structure. If the resulting compound is stable, the heterocycles described herein may undergo substitution at the carbon or nitrogen positions. The nitrogen atom in the heterocycle is 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 is not more than 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 aromatic ring comprising a carbon atom 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). Notably, the total number of S and O atoms on the aromatic heterocycle does not exceed 1. Bridged rings are also included in the definition of heterocyclic ring. A bridged ring is formed when one or more atoms (i.e., C, O, N or S) join 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. Notably, one bridge always converts a single ring to a tricyclic ring. In bridged rings, substituents on the ring may also be present on the bridge.

Examples of heterocyclic compounds include, but are not limited to: azetidinyl, acridinyl, azepinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzomercaptophenyl, benzoxazolyl, 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, indolenyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridine, octahydroisoquinolyl, 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, benzoxanthinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, phenazinyl, phenothiazine, benzoxanthinyl, phenoxazinyl, phthalazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, and the like purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyrrolidinyl pyrrolinyl, 2H-pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2, 5-thiadiazinyl, 1,2, 3-thiadiazinyl, 1,2, 4-thiadiazinyl, 1,2, 5-thiadiazinyl, 1,3, 4-thiadiazinyl, thianthrenyl, thiazolyl, isothiazolylthiophene, thienooxazolyl, thienothiazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 5-triazolyl, 1,3, 4-triazolyl and xanthenyl. Also included are fused and spiro compounds.

The term "aryl" means, unless otherwise specified, a polyunsaturated aromatic hydrocarbon substituent, which may be mono-or polysubstituted, and which may be monovalent, divalent or multivalent, and which may be monocyclic 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 group (or ring) containing one to four heteroatoms. In one exemplary embodiment, the heteroatom is selected from B, N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Heteroaryl groups may be attached to the remainder of the molecule through heteroatoms. 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, benzofuranyl, coumarin, 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-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolinyl and 6-quinolinyl. The substituents of any of the above aryl and heteroaryl ring systems are selected from the acceptable substituents described below.

The compounds being prepared by hand or by handSoftware naming, commercial compounds are referred to by vendor catalog names.

Drawings

FIGS. 1-1, 1-2, 1-3, 1-4: XRPD, DSC, TGA, ¹ H NMR spectra of compound 25 maleate form I, respectively

Fig. 2-1, 2-2, 2-3: XRPD, DSC/TGA, ¹ H NMR spectra of compound 25 maleate form II, respectively

Fig. 3-1, 3-2, 3-3: XRPD, DSC/TGA, ¹ H NMR spectra of compound 25 maleate form III, respectively

FIGS. 4-1, 4-2, 4-3: XRPD, DSC/TGA, ¹ H NMR spectra of compound 25 maleate form IV, respectively

FIGS. 5-1, 5-2, 5-3, 5-4: XRPD, DSC, TGA, ¹ H NMR of compound 25 fumarate, respectively

FIGS. 6-1, 6-2, 6-3, 6-4: XRPD, DSC, TGA, ¹ H NMR spectra of compound 25 p-toluenesulfonate, respectively

Fig. 7-1: time profile of compound 24 and 25 hydrochloride in vivo for crude drug in beagle

Fig. 7-2: compound 24 and 25 hydrochloride profiles for drug administration of metabolite CBD in beagle dogs

Fig. 7-3: compound 25 maleate and CBD drug time profile for CBD in high oil diet and fasted model beagle dogs

Fig. 8: time profile of prodrug on administration of the metabolite CBD in rats

Fig. 9-1: hygroscopicity profile of compound 25 maleate form I

Fig. 9-2: XRPD spectra of compound 25 maleate crystal form I before and after hygroscopicity test

Fig. 10-1: XRPD spectrogram of room temperature competitive beating experiment of compound 25 maleate crystal form I and crystal form II

Fig. 10-2: XRPD spectrogram of compound 25 maleate crystal form I and crystal form II high-temperature competitive pulping experiment

Fig. 11: XRPD spectra of compound 25 maleate crystal form I before and after tabletting experiment

Detailed Description

Synthesis method I

The CBD was dissolved in a solvent and a basic catalyst was added and the reaction was stirred at room temperature. Adding phenyl p-nitro chloroformate, and reacting at room temperature. Quenching with water, extracting with ethyl acetate, mixing the organic phases, drying over 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 a solvent, the reagents were added and the reaction was performed at room temperature/heat. Quenched with water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure and separated by high performance liquid chromatography. To obtain the product of formula (II) (namely, the product that one of R ₁ or R ₂ is OH).

Optionally, the product of formula (II) (i.e., the product wherein one of R ₁ or R ₂ is OH) is dissolved in a solvent with an alkaline reagent, and the different reagents are added dropwise and reacted at room temperature after ice bath. Quenched with water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure and separated by high performance liquid chromatography. The product of the formula (II) with different structures of R ₁ and R ₂ is obtained.

Synthesis method II

The CBD was dissolved in the solvent and an alkaline reagent was added and the reaction was stirred at room temperature. Adding p-nitro phenyl chloroformate and reacting at 0 ℃. Quenching with water, extracting with ethyl acetate, mixing the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the organic phase under reduced pressure, and separating by column chromatography to obtain fragment 2.

Fragment 2, the reaction reagent and the alkaline reagent are dissolved in a solvent and heated to reflux for reaction overnight. Quenched with water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure and separated by high performance liquid chromatography. The product of formula (II) (i.e., a product wherein neither R ₁ nor R ₂ is OH) is obtained.

The invention is further illustrated below in conjunction with specific examples and test examples, but is not intended to limit the scope of the invention in any way.

Example 1: synthesis of fragment 1

The synthetic route is as follows:

CBD (2.0 g,6.4mmol,1 eq) was dissolved in 60mL dichloromethane and triethylamine (1.3 g,12.8mmol,2.0 eq) was added and the reaction stirred at room temperature for 0.5h. Phenyl p-nitrochloroformate (1.54 g,7.68mmol,1.2 eq) was added and reacted at room temperature for 2h. Quench with water, then extract with ethyl acetate (50 ml 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure, isolate with column chromatography (petroleum ether: ethyl acetate=5:1) to give fragment 1 (1.1 g, oil), yield: 33%. MS m/z (ESI): 480.4[ M+1].

Example 2: synthesis of Compound 13 trifluoroacetate salt

The synthetic route is as follows:

Fragment 1 (479 mg,0.9mmol,1.0 eq) was dissolved in 10mL of dichloromethane, ethylenediamine (108 mg,1.8mmol,2.0 eq) was added and reacted at room temperature for 3h. Quench with water, then extract with ethyl acetate (50 ml 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure and separate 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 in yield ：40％.MS m/z(ESI)：401.3[M+1]⁺.¹H NMR(400MHz,DMSO-d₆):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

The synthetic route is as follows:

Fragment 1 (479 mg,0.9mmol,1.0 eq) was dissolved in 10mL of dichloromethane, diethylaminoethanol (320 mg,2.7mmol,3.0 eq) was added and reacted at room temperature for 3h. Quench with water, then extract with ethyl acetate (50 ml 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure and separate by high performance liquid chromatography (Waters autopurification HPLC-system C18 50*250mm Wavelength 254nm water (0.1% TFA) -MeCN (0.1% TFA)). Compound 17 trifluoroacetate salt (56.6 mg, white solid) was obtained in yield ：11％.MS m/z(ESI)：458.3[M+1]⁺.¹HNMR(400MHz,DMSO-d₆):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

The synthetic route is as follows:

Fragment 1 (2.0 g,4.0mmol,1 eq) was dissolved in 60mL of dichloromethane, 2-morpholinoethanol (2.6 g,20.0mmol,5.0 eq) was added and the reaction was heated at reflux overnight. Quench with water, then extract with ethyl acetate (50 ml 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure and separate 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 in yield ：9％.MS m/z(ESI)：472.3[M+1]⁺.¹H NMR(400MHz,DMSO-d₆):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

The synthetic route is as follows:

Fragment 1 (450 mg,0.94mmol,1 eq) was dissolved in 10mL of dichloromethane, N-diethyl ethylenediamine (210 mg,1.9mmol,2.0 eq) was added and reacted at room temperature for 2h. Quench with water, then extract with ethyl acetate (50 ml 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure and separate 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 in yield ：44％.MS m/z(ESI)：457.3[M+1]⁺.¹H NMR(400MHz,DMSO-d₆):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

The synthetic route is as follows:

Fragment 1 (450 mg,0.94mmol,1 eq) was dissolved in 10mL of dichloromethane and 2-morpholinoethamine (227 mg,1.9mmol,2.0 eq) was added and reacted at room temperature for 2h. Quench with water, then extract with ethyl acetate (50 ml 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure and separate 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 in yield ：44％.MS m/z(ESI)：471.3[M+1]⁺.¹HNMR(400MHz,DMSO-d₆):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

The synthetic route is as follows:

Compound 18 (320 mg,0.67mmol,1 eq) was dissolved in 5mL of dichloromethane with triethylamine (130 mg,1.3mmol,2 eq), acetyl chloride (130 mg,1.3mmol,2.0 eq) was added dropwise, and the mixture was reacted at room temperature in an ice bath for 3h. Quench with water, then extract with ethyl acetate (50 ml 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure and separate 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 substance) was obtained in yield ：62％.MS m/z(ESI)：514.3[M+1]⁺.¹H NMR(400MHz,DMSO-d₆):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

The synthetic route is as follows:

CBD (2.0 g,6.4mmol,1 eq) was dissolved in 60mL dichloromethane and triethylamine (1.3 g,12.8mmol,2.0 eq) was added and the reaction stirred at room temperature for 0.5h. Phenyl p-nitrochloroformate (5.1 g,25.5mmol,4 eq) was added and reacted at 0℃for 2h. Quench with water, then extract with ethyl acetate (50 ml 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure, isolate with column chromatography (petroleum ether: ethyl acetate=10:1) to give fragment 2 (3.2 g, oil), yield: 78%. MS m/z (ESI): 645.2[ M+1].

Example 9: synthesis of Compound 25 trifluoroacetate salt

The synthetic route is as follows:

fragment 2 (1.0 g,1.6mmol,1.0 eq), 2-morpholinoethanol (2.0 g,16.0mmol,10 eq) and triethylamine (9.39 g,9.30mmol,6 eq) were dissolved in 30mL dichloromethane and reacted overnight under reflux with heating. Quench with water, then extract with ethyl acetate (50 ml 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure and separate 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 substance) was obtained in yield ：62％.MS m/z(ESI)：629.2[M+1]⁺.¹H NMR(400MHz,DMSO-d₆):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

The synthetic route is as follows:

CBD (0.80 g,2.50mmol,1 eq) was dissolved in 8mL tetrahydrofuran and sodium hydride (0.091 g,3.80mmol,1.5 eq) was added and the reaction stirred at 0deg.C for 0.5h. Methyl iodide (0.43 g,3.0mmol,1.2 eq) was added and reacted at 0℃for 2h. Quench with water, then extract with ethyl acetate (50 ml 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure, isolate with column chromatography (petroleum ether: ethyl acetate=10:1) to give fragment 3 (0.13 g, oil), yield: 15%.

Example 11: synthesis of Compound 26 trifluoroacetate salt

The synthetic route is as follows:

3- (4-morpholino) propionic acid (74.5 mg,0.46mmol,1.2 eq), EDCI (113 g,0.59mmol,1.5 eq) and DMAP (60 mg,0.46mmol,1.2 eq) were dissolved in 10mL dichloromethane and reacted at room temperature for 0.5h. Fragment 3 (130 mg,0.39mmol,1.0 eq) was added and the reaction stirred at room temperature for 3h. Quench with water, then extract with ethyl acetate (50 ml 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the organic phase under reduced pressure and separate 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 substance) was obtained in yield ：33％.MS m/z(ESI)：470.3[M+1]⁺.¹H NMR(400MHz,DMSO_d₆):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

The synthetic route is as follows:

compound 24 trifluoroacetate (6278 mg,1mmol,1.0 eq) was dissolved in 10mL of water, saturated sodium bicarbonate solution was added dropwise, ph=9 was adjusted, and stirring was performed at room temperature for 1h. Extracted with ethyl acetate (50 ml x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Compound 24 (488 mg, oil) was obtained in the yield ：95％.MS m/z(ESI)：514.3[M+1]⁺.¹H NMR(600MHz,CDCl₃-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

The synthetic route is as follows:

Compound 24 (514 mg,1mmol,1.0 eq) was dissolved in 10mL ethyl acetate, dioxane solution of hydrochloric acid (4N) was added dropwise, ph=3 was adjusted, and stirring was carried out at room temperature for 2h. The reaction solution was concentrated under reduced pressure. Compound 24 hydrochloride (550 mg, white solid) was obtained in yield: 100%. MS m/z (ESI): 514.3[ M+1] ⁺.

Example 14: synthesis of Compound 25

The synthetic route is as follows:

Compound 25 trifluoroacetate (857 mg,1mmol,1.0 eq) was dissolved in 10mL water, saturated sodium bicarbonate solution was added dropwise, ph=9 was adjusted, and stirring was performed at room temperature for 1h. Extracted with ethyl acetate (50 ml x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Compound 25 (604 mg, white solid) was obtained in yield ：96％.MS m/z(ESI)：629.4[M+1]⁺.¹H NMR(600MHz,CDCl₃-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

The synthetic route is as follows:

Compound 25 (629 mg,1mmol,1.0 eq) was dissolved in 10mL ethyl acetate, dioxane solution of hydrochloric acid (4N) was added dropwise, ph=3 was adjusted, a solid was precipitated, and stirring was carried out at room temperature for 2h. The filter cake was washed with ethyl acetate (5 ml x 3), collected and dried. Compound 25 hydrochloride (491 mg, white solid) was obtained in yield: 70%. MS m/z (ESI): 629.4[ M+1] ⁺.

Example 16: preparation and characterization of Compound 25 maleate Crystal form I

1.1 Preparation of Compound 25 maleate form I

(1) 505.03Mg of Compound 25 was weighed, 5.0mL of acetone (10 vol) was added, and stirred at 20℃for 5min to completely dissolve.

(2) 190.45Mg of maleic acid (2.0 eq) was weighed into 5.0mL of acetone (10 vol) and stirred for 30min to dissolve completely. (3) Dripping the maleic acid solution in the step (2) into the compound 25 solution in the step (1) (after the dripping is completed within 5 min),

Stirring for 24h, no solid precipitated.

(4) 5.0ML of methyl tert-butyl ether (after the completion of the dropwise addition within 10 min) was added, and the mixture was stirred for 24 hours to precipitate, followed by further stirring for 24 hours, filtration and vacuum drying (40 ℃ C.) for 4 days to obtain 339.56mg of compound 25 maleate form I.

1.2 Characterization of Compound 25 maleate salt form I

1.2.1 Powder X-ray diffraction (XRPD)

The X-ray diffraction pattern was obtained from a D2 Phaser type acquisition of a Brookfield instrument, the instrument parameters are shown in Table 1-1. The XRPD patterns are shown in FIGS. 1-1, and the pattern resolution data are shown in tables 1-2.

TABLE 1-1XRPD instrument parameters

Table 1-2 XRPD pattern analysis data for compound 25 maleate form I

1.2.2 Differential scanning calorimetric analysis (DSC)

The method comprises the following steps: DSC curves were obtained from DSC model 3 acquisition of a mertler instrument. The samples were weighed into sample trays, precisely weighed, the weights recorded, and heated 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 test results are shown in FIGS. 1-2, and the results show that the compound 25 maleate form I has an endothermic peak at 115.03 ℃.

1.2.3 Thermogravimetric analysis (TGA)

The TGA profile was obtained from a relaxation-resistant TG209F3 acquisition. The samples were weighed into a sample pan (Al ₂O₃), precisely weighed, and the weights were recorded. The temperature was increased from 40℃to 350℃at a heating rate of 20℃per minute. The nitrogen flow rate was 70mL/min.

The test results are shown in fig. 1-3, and the results show that the loss of weight of the compound 25 maleate form I is 0.2% in the endothermic peak temperature range.

1.2.4 ¹H NMR

Nuclear magnetic results were obtained from a Varian (Varian) 400MHz acquisition using deuterated solvent DMSO.

The test results are shown in fig. 1-4, and the results show that the compound 25 maleate form I has no solvent residue, is an anhydrous form, and has a molar ratio of maleic acid to free base of 2.0:1.0.

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 isopropyl acetate was added at 50℃and 0.8mL acetone was added, and filtered. Transferring the filtrate to-10 ℃ for continuous 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 characterization method was the same as that of example 16.

1.2.2 TGA

The TGA curve is acquired by the TGA550 of the TA instrument. The sample was weighed into a sample pan (Al ₂O₃) and warmed to 300℃at a warming rate of 10℃per minute.

1.2.3 DSC

DSC curves were obtained from DSC model 250 acquisition of TA instruments. The samples were weighed into sample trays, precisely weighed, and the weights were recorded. The temperature was increased from 25℃to 300℃at a heating rate of 10℃per minute.

1.3 Test results

1.3.1 XPRD

XPRD is shown in FIG. 2-1, and the analytical data are shown in Table 2.

Table 2 XRPD pattern analysis data for compound 25 maleate form II

1.3.2 DSC/TGA/¹H NMR

DSC results show that the compound 25 maleate form II has an endothermic peak at 76.47 ℃; TGA results show that compound 25 maleate form II has no weight loss in the melting point range; ¹ H NMR results showed that compound 25 maleate form II was an anhydrous form and the molar ratio of maleic acid to free base was 2.0:1.0.DSC/TGA spectra are shown in FIGS. 2-2 and ¹ H NMR spectra are shown in FIGS. 2-3.

Example 18: preparation and characterization of compound 25 maleate form III

1.1 Preparation method

About 1g of compound 25 maleate form I was weighed, the starting material was dissolved with 4mL of acetonitrile and 40mL of water, and freeze-dried after freezing with dry ice to give compound 25 maleate amorphous form. 30.64mg of compound 25 maleate is weighed into a sample bottle, 0.2mL of isopropanol is added, and the mixture is stirred for 3 days at about 15 ℃ to obtain compound 25 maleate crystal form III.

1.2 Characterization method: the characterization methods of XPRD, TGA/DSC and ¹ HNMR were the same as those of example 17.

1.3 Test results

1.3.1 XPRD

XRPD patterns are shown in fig. 3-1, and pattern resolution data are shown in table 3.

Compound 25 maleate form III, X-ray powder diffraction pattern using Cu-ka radiation is shown in fig. 3-1.

TABLE 3 XRPD pattern resolution data for Compound 25 maleate salt form III

Sequence number	2θ±0.2(°)	Relative intensity (%)	Sequence number	2θ±0.2(°)	Relative intensity (%)
						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/¹H NMR

DSC results show that the compound 25 maleate crystal form III has an endothermic peak at 115.31 ℃ and is the melting point of the crystal form; TGA results show that compound 25 maleate form III has no weight loss in the melting point range, ¹ H NMR results show that compound 25 maleate form III is an anhydrous form, and the molar ratio of maleic acid to free base is 2.0:1.0.DSC/TGA spectra are shown in FIGS. 3-2, and 1H NMR spectra are shown in FIGS. 3-3.

Example 19: preparation and characterization of Compound 25 maleate form IV

1.1 Preparation method

About 1g of compound 25 maleate form I was weighed, the starting material was dissolved with 4mL of acetonitrile and 40mL of water, and freeze-dried after freezing with dry ice to give compound 25 maleate amorphous form. About 30mg of compound 25 maleate salt was weighed into a sample bottle, 0.1mL of acetonitrile-methyl tert-butyl ether (1:8) was added, and stirred at about 15℃for 3 days to obtain compound 25 maleate salt form IV.

1.3 Test results

1.3.1 XPRD

The XRPD patterns are shown in FIG. 4-1, and the pattern resolution data are shown in Table 4.

Table 4 XRPD pattern analysis data for compound 25 maleate form IV

Sequence number	2θ±0.2(°)	Relative intensity (%)	Sequence number	2θ±0.2(°)	Relative intensity (%)
						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/¹H 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 compound 25 maleate form IV has two endothermic peaks visible before 125 ℃; TGA results indicated that compound 25 maleate form IV had 3.2% weight loss before 125 ℃, and converted to amorphous after heating to 100 ℃. DSC/TGA spectrum is shown in 4-2, ¹ H NMR spectrum is shown in 4-3.

Example 20: preparation and characterization of Compound 25 fumarate salt Crystal form

1.1 Preparation method

(1) 504.59Mg of Compound 25 was weighed, 5.0mL of acetonitrile (10 vol) was added, and stirred at 20℃for 5min to completely dissolve.

(2) 187.45Mg of fumaric acid (2.0 eq) was weighed, 5.0mL of acetone (10 vol) was added, and stirred for 30min, and the mixture was completely dissolved.

(3) And (3) dropwise adding the fumaric acid solution into the raw material solution (after the dropwise adding is finished within 5 min), stirring for 24h, and separating out solids.

(4) Stirring was continued for 24h, filtration and vacuum drying (40 ℃ C. For 4 days, 50 ℃ C. For 2 days) to give 560.28mg of compound 25 fumarate as a crystalline form.

1.2 Characterization method: the characterization methods of XPRD, TGA/DSC and ¹ HNMR were the same as those of example 16.

1.3 Test results

1.3.1 XPRD

The XRPD patterns are shown in FIG. 5-1, and the pattern resolution data are shown in Table 5.

Compound 25 fumarate salt form, X-ray powder diffraction pattern using Cu-ka radiation is shown in fig. 5-1.

TABLE 5 XRPD pattern resolution data for Compound 25 fumarate salt form

1.3.2 DSC/TGA/¹H NMR

DSC results show that the compound 25 fumarate salt crystal form has an endothermic peak at 91.76 ℃; TGA results indicate that compound 25 fumarate salt form has no weight loss before 120 ℃; ¹ The H NMR result shows that the compound 25 fumarate salt crystal form has no solvent residue and is an anhydrous crystal form, and the mol ratio of fumaric acid to free base is 2.0:1.0. DSC/TGA/¹ H NMR spectra are shown in FIGS. 5-2, 5-3 and 5-4, respectively.

Example 21: preparation and characterization of the crystalline form of Compound 25 p-toluenesulfonate salt

1.1 Preparation method

(1) 500.80Mg of Compound 25 was weighed, 5.0mL of acetone (10 vol) was added, and stirred at 20℃for 5min to completely dissolve.

(2) 307.70Mg of p-toluenesulfonic acid (2.0 eq) was weighed, 5.0mL of acetone (10 vol) was added, and stirred for 30min, and completely dissolved.

(3) And (3) dripping the p-toluenesulfonic acid solution into the raw material solution (after dripping is completed within 5 min), and stirring for 24h without solid precipitation.

(4) 5.0ML of methyl tert-butyl ether (after the completion of the dropwise addition within 10 min) was added, and the mixture was stirred for 24 hours to precipitate, followed by further stirring for 24 hours, filtration and vacuum drying (40 ℃ C.) for 4 days to obtain 533.47mg of the compound 25 p-toluenesulfonate crystal form.

1.3 Test results

1.3.1 XPRD

The XRPD patterns are shown in FIG. 6-1, and the pattern resolution data are shown in Table 6.

Table 6 XRPD pattern resolution data for compound 25 p-toluenesulfonate crystalline form

Sequence number	2θ±0.2(°)	Relative intensity (%)	Sequence number	2θ±0.2(°)	Relative intensity (%)
						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

1.3.2 DSC/TGA/¹H NMR

DSC results show that the crystal form of the compound 25 p-toluenesulfonate has an endothermic peak at 148.41 ℃; TGA results showed that compound 25 p-toluenesulfonate form had a weight loss of 0.6% before 200 ℃; ¹ H NMR results showed that compound 25 p-toluenesulfonate crystalline form had no solvent residue and the molar ratio of p-toluenesulfonic acid to free base was 2.0:1.0. DSC/TGA/¹ H NMR spectra are shown in FIG. 6-2, FIG. 6-3, and FIG. 6-4, respectively.

Example 22: synthesis of Compound 27 hydrochloride

The synthetic route is as follows:

2-Bromoethanol (10 g,80 mmol) was dissolved in a 500mL flask with ethanol (140 mL), diethylamine (29 g,400 mmol) 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 solution cooled, the mixture was washed with 5% NaHCO ₃ solution (3X 100 mL), water (50 mL), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated to give diethylaminoethanol as a colorless oil, 600mg, yield 9.5%. MS (m/z): 118[ M+H ] ⁺.

Cannabidiol (5 g,16 mmol) was dissolved in 100mL dry dichloromethane, triphosgene (4.76 g,16 mmol) and N, N-diisopropylethylamine (4.12 g,32 mmol) were added sequentially at 0deg.C, the reaction was stirred at 0deg.C for 2h, 2-diethylaminoethanol (3.74 g,32 mmol) and N, N-diisopropylethylamine (4.12 g,32 mmol) were added continuously, the reaction was stirred at 0deg.C for 4h, after completion of the reaction, extracted with dichloromethane/water, the organic phase was concentrated and purified by four normal phase columns (biotin, agela g, dichloromethane/ethyl acetate: 10% -80%) to give 2.4g colorless oil, the colorless oil was dissolved in 40mL dichloromethane, 2mL hydrochloric acid/dioxy (4M) six-ring solution was added dropwise, after stirring at room temperature for two hours, at least a volume of solvent was concentrated, 100mL ethyl acetate was added, stirring was developed as a white solid, and compound 27 hydrochloride (2.1 g, white solid) was obtained after drying under suction 22％.MS(m/z)：602[M+2H]⁺.¹H 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: pharmacokinetic testing of prodrug Compounds in beagle dogs

1. Pharmacokinetic testing of prodrug compounds in fasted model beagle dogs

The beagle dogs weighing about 10 kg were randomly grouped, three animals of each group were fasted for 12 hours before administration, were freely drunk, and were subjected to gastric administration in 32 mu mol/kg of compound 24 hydrochloride aqueous solution, compound 25 hydrochloride aqueous solution, compound 27 hydrochloride aqueous solution and CBD sesame oil aqueous solution (1 mL of solvent contains 79mg of ethanol, 736mg of sesame oil), blood was collected at 0.25, 0.5, 1,2,3, 4, 6, 8, 12 and 24 hours before and after administration, blood was placed in heparinized EP tubes, plasma was centrifuged, and the plasma was pretreated and the concentration of active metabolite CBD and each prodrug in the plasma was measured by LC-MS/MS.

Table 7-1, FIG. 7-1 and FIG. 7-2 are graphs of the drug substitution parameters and time of administration of compound 24 hydrochloride, compound 25 hydrochloride, and/or the post-CBD prodrug form compound and/or CBD orally to beagle dogs. The results show that compound 24 hydrochloride and compound 25 hydrochloride are most metabolized to CBD after passage through the gastrointestinal tract into beagle dogs. The relative bioavailability of the CBD metabolites of compound 24 and compound 25 was 364.7% and 307.5%, respectively, with the CBD dosing group as reference.

TABLE 7-1 Compound 24/Compound 25 and CBD in vivo major drug substitution parameters

* Relative bioavailability compared to CBD

Table 7-2 shows the main pharmacokinetic parameters of compound 27 hydrochloride or the prodrug profile compound and/or CBD following oral administration to beagle dogs. The results show that the prodrug compound 27 hydrochloride is most metabolized to CBD after passage through the gastrointestinal tract into beagle dogs. The relative bioavailability of the compound 27 metabolite CBD was 113.2% with the CBD dosing group as a reference.

Comparing tables 7-1 and 7-2, it is clear that the exposure (AUC) of the CBD metabolites in vivo of compound 24 and compound 25 can be increased by more than 3 times, with reference to the CBD-administered group, while the exposure (AUC) of compound 27 is comparable to that of CBD.

TABLE 7-2 Compound 27 and CBD in vivo major drug substitution parameters

* Relative bioavailability compared to CBD

2. Pharmacokinetic testing of prodrug compounds in high oil diet model beagle dogs

The effect of high fat diet on CBD bioavailability in beagle dogs was examined by simulating high fat diet with sesame oil administered after administration. 16 Beagle dogs weighing about 10kg were randomly divided into 4 groups of 4 dogs each, and the dose was 32 mu mol/kg, fasted 12 hours before dosing, and were free to drink water. Groups 1 and 2 were given by gavage of an aqueous solution of compound 25 maleate at a volume of 3ml/kg, and after administration, group 1 was given by 8ml of water and group 2 was given by 8ml of sesame oil. Group 3 was given by gavage with a CBD sesame oil solution (1 mL vehicle containing 79mg of ethanol, 736mg of sesame oil) at a volume of 0.2mL/kg, and 6mL of sesame oil and 30mL of water were administered after administration. Group 4A CBD sesame oil solution (1 mL of vehicle containing 79mg of ethanol, 736mg of sesame oil) was filled into a quick-release capsule and administered by gavage (about 1mL of sesame oil), and 38mL of water was used for oral administration after administration. Blood was collected before and after administration for 0.25, 0.5, 1,2, 3,4, 6, 8, 12, 24 hours, respectively, and the blood was placed in heparinized EP tubes, and plasma was centrifuged, and the plasma was pretreated and the concentrations of compound 25 and CBD in the plasma were measured by LC-MS/MS method. The test results are shown in FIG. 7-3 and Table 7-3.

The test results show that: compound 25 maleate was most metabolized to CBD in Beagle dogs. In the fasted group, compound 25 maleate (group 1) produced an active metabolite CBD with 2.2 times greater exposure than the CBD group (group 4). In comparison of the fasted and high fat diet groups, compound 25 maleate gave CBD exposures and C _max comparable to the normal group (group 1) following administration of high oil (group 2); while CBD exposure after high oil administration (group 3) and C _max were both 4.8 times higher than in the normal group (group 4). I.e. the effect of a high fat diet on compound 25 maleate exposure and C _max is much less than CBD.

TABLE 7-3 Compound 25 maleate and CBD in vivo major drug substitution parameters

* Relative bioavailability compared to CBD

Test example 2: pharmacokinetic testing of prodrug Compounds in fasted model rats

SD rats weighing about 200 g were randomly grouped, four in each group, administered at 47.7. Mu. Mol/kg, fasted for 12h before administration, and given free water, each group was dosed by gavage separately, test compounds were formulated as 20% aqueous solution of Solutol HS 15 (containing 5% absolute ethanol) and blood was collected at 0.25, 0.5, 1, 2,3, 4, 6, 8,12, 24 hours before and after administration, respectively, and placed in heparinized EP tubes, plasma was centrifuged, and plasma was pre-treated and assayed for the concentration of active metabolite CBD and each prodrug by LC-MS/MS, respectively.

Table 8-1 and FIG. 8 are graphs of the pharmacokinetic parameters and time profiles of the metabolite CBD following intragastric administration of compound 24 hydrochloride and compound 25 hydrochloride in rats. The results show that: compound 24 hydrochloride and compound 25 hydrochloride are metabolized to the active metabolite CBD immediately after entering the rat via the gastrointestinal tract, the concentration of the original compound is low, below the lower limit level of quantification detected, and the prodrug is converted to the active metabolite CBD substantially entirely by oral administration. In contrast, neither prodrug nor CBD was detected after administration of compound 26 trifluoroacetate by intragastric administration.

TABLE 8-1 pharmaceutical parameters of Compound 24 hydrochloride and Compound 25 hydrochloride metabolite CBD

Tables 8-2 and 8-3 are graphs of the drug substitution parameters and time of administration of prodrug form drug and metabolite CBD following intragastric administration of compound 13/compound 19/compound 21 trifluoroacetate in rats. The results indicate that the exposure of the carbamate in vivo metabolite CBD is lower than or equivalent to direct gavage administration of CBD.

Table 8-2 Compound 13 trifluoroacetate and CBD rat in vivo pharmacokinetic parameters

* Relative bioavailability compared to CBD

TABLE 8-3 Compounds 19/21 trifluoroacetate and CBD in vivo parameters of rat drug substitution

* Relative bioavailability compared to CBD

Tables 8-4 are the pharmacokinetic parameters of compound 17/compound 18 trifluoroacetate post-metabolite CBD in rats, and no compound 17 and compound 18 original compounds were detected. The result shows that the in-vivo metabolite CBD of the carbonate compound containing the morpholine ring has higher exposure.

TABLE 8-4 Compound 17/Compound 18 trifluoroacetate and CBD in vivo parameters of the rat

Test example 3: compound 25 different salt stability study

1. Test method

10-15 Mg of compound 25, form I maleate (example 16), form fumarate (example 20), and form p-toluenesulfonate (example 21) were weighed out and placed in stability bins, respectively, and solids were taken for XRPD and HPLC analysis at day 5 and day 10, respectively.

The XRPD procedure is the same as in example 16, with HPLC procedure set forth in Table 9-1.

TABLE 9-1HPLC analysis method

2. Test results

The results show that the maleate form I of the compound 25 has good physical and chemical stability under the test conditions, and the fumarate and p-toluenesulfonate salts have the crystal forms changed under the high-temperature and high-humidity conditions, so that the purity is reduced. See in particular tables 9-2 and 9-3.

TABLE 9-2 results of different salt type day 5 stability test

Table 9-3 results of the different salt type day 10 stability test

Test example 4: compound 25 maleate form I hygroscopicity study

1. Test method

And (3) drying: stable at 40 ℃/0% rh for about 1.5h until dm/dt is less than 0.002%.

The testing process comprises the following steps: after cooling to 25 ℃, dm/dt is less than 0.002%, and measurement is started.

Time mode 25 ℃ sample measurement, 0% -90% -0% RH,10% gradient, each gradient stay for 1h.

2. Test results

The results of the tests are shown in FIGS. 9-1 and 9-2 and show that compound 25 maleate form I has a moisture gain of 0.1251% at 90% RH humidity with little or no hygroscopicity. Compound 25 maleate form I was unchanged in form before and after the moisture induced test (DVS).

Test example 5: competition beating test of compound 25 maleate crystal form

1. Test method

Preparing amorphous saturated solutions of compound 25 maleate in the solvents of table 10 respectively, adding compound 25 maleate crystal form I and crystal form II into each saturated liquid medicine in a mass ratio of 1:1, and stirring at room temperature (about 17 ℃) or 50 ℃ for 3 days to obtain solid which is compound 25 maleate crystal form I, 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.XRPD results are shown in fig. 10-1 and fig. 10-2.

Table 10 competitive beating experimental conditions and results

Numbering device	Solvent(s)	Crystal form I (mg)	Crystal form II (mg)	Temperature (temperature)	Results
						1	N-heptane, 0.5mL	8.63	8.62	Room temperature	Crystal form I
2	Toluene, 0.6mL	6.02	6.05	Room temperature	Crystal form I
						3	Ethyl acetate, 0.6mL	6.14	6.16	Room temperature	Crystal form I
4	Isopropanol, 0.6mL	6.54	6.57	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 crystal form I tabletting test

About 15mg of compound 25 maleate form I was weighed, tabletted at 30MPa, gently ground to a powder, and subjected to XRPD testing, the test results shown in fig. 11. The result shows that the crystal form I of the compound 25 maleate is unchanged after tabletting, and the crystallinity is not obviously reduced.

Claims

1. A compound of formula (I), a pharmaceutically acceptable salt or enantiomer thereof,

Wherein,

R ₁ is-OC (O) -X- (CH ₂)n-N(Y₁Y₂);

R ₂ is selected from the group consisting of-OC (O) -R ₄, or-OC (O) -X- (CH ₂)n-N(Y₁Y₂);

X is O;

R ₃ is C _1-6 alkyl; r ₄ is C _1-6 alkyl;

n=2, 3,4 or 5.

2. A compound of formula (II), a pharmaceutically acceptable salt or enantiomer thereof,

Wherein,

R ₁ is-OC (O) -X- (CH ₂)n-N(Y₁Y₂);

X is O;

R ₃ is C _1-6 alkyl; r ₄ is C _1-6 alkyl;

n=2, 3,4 or 5.

3. The compound, pharmaceutically acceptable salt or enantiomer thereof according to claims 1-2, wherein R ₃ is pentyl; r ₄ is methyl, ethyl or propyl.

4. A compound, a pharmaceutically acceptable salt or enantiomer thereof, selected from the group consisting of:

5. A compound according to any one of claims 1 to 4, a pharmaceutically acceptable salt or enantiomer thereof, said salt being selected from the group consisting of p-toluenesulfonate, fumarate, maleate, oxalate, phosphate, hydrochloride, sulfate, malate, tartrate, citrate or trifluoroacetate salt.

6. A pharmaceutical composition comprising a compound according to any one of claims 1-5, a pharmaceutically acceptable salt or enantiomer thereof, and a pharmaceutically acceptable carrier.

7. Use of a compound according to any one of claims 1-5, a pharmaceutically acceptable salt or enantiomer thereof, or a pharmaceutical composition according to claim 6 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, neuropathic pain, numbness, anxiety, hypertension, autonomic dysfunction, parkinson's disease and tremor, insomnia, belleville paralysis and facial nerve dysfunction, glaucoma, multiple sclerosis, post-traumatic stress disorder, trigeminal neuralgia, autism/apricots, attention deficit disorder and hyperactivity disorder, social isolation, occipital neuralgia, symptoms associated with TMJ dysfunction, cognitive problems, headache, peripheral neuropathy, apnea, smoking cessation, arthritis, depression, emesis, obesity, nausea, alcohol use disorders, dystonia, inflammatory bowel syndrome, neuropathic pain associated with post-herpetic neuralgia, diabetic neuropathy, shingles, burns, actinic keratosis, oral ulcers and post-ulcer craniotomy pain, psoriasis, pruritic contact dermatitis, eczema, bullous dermatitis, exfoliative dermatitis, mycosis, pemphigus, severe polymorphous erythema, seborrheic dermatitis, ankylosing spondylitis, reiter's syndrome, gout, calcification, myopic dermatitis, myositis, pancreatitis, pain.