PATENT CLAIM ANALYSIS

Application Number: 15768960
Application Type: Utility
Filing Date: 2018-04
Publication Date: 2018-11
Patent Classification: ["514", "220000"]

Abstract:
The present invention relates to a benzodiazepine derivative of Formula I as a short-acting anesthetic, a pharmaceutical composition comprising the same, a kit comprising the same, a preparation method thereof, an method of anesthesia using the same and use thereof in the manufacture of an anesthetic medicament.

Claim (Index 10):
A method for preparing the compound of  claim 1 , wherein when J is N, the method is carried out according to Scheme I, wherein R 1 -R 5 , n, m, W, X, and Y are as defined in  claim 1 ; and the bond between X and Y is a single bond or a double bond; the method comprising the following steps: a. allowing compound A to react with N,O-dimethylhydroxylamine hydrochloride, preferably in the presence of a base such as DIPEA, N-methylmorpholine or TEA and in the presence of a condensing agent such as HATU, DCC, EDCI, PyBOP, BOP-Cl or T3P, preferably in a solvent such as THF, DMF or DCM, to obtain amide intermediate B; b. allowing the amide intermediate B to react with a lithium reagent such as n-butyllithium and a bromo-substituted aryl or heteroaryl compound such as bromobenzene, 1-bromo-2-fluorobenzene or 2-bromopyridine, preferably in a suitable solvent such as THF or diethyl ether, to obtain ketone intermediate C; c. carrying out a condensation reaction between the ketone intermediate C and an N-protected chiral amino acid or a derivative thereof such as 5-methyl L-glutamate or 5-ethyl L-glutamate, preferably in a ice-water bath or at room temperature, preferably in the presence of a base such as DIPEA, N-methylmorpholine or TEA and in the presence of a condensing agent such as HATU, DCC, EDCI, PyBOP, BOP-Cl or T3P, preferably in a suitable solvent such as THF, DMF or DCM, to obtain intermediate D; d. deprotecting the intermediate D, preferably under acidic conditions of e.g. trifluoroacetic acid or hydrochloric acid, to obtain benzodiazepine intermediate E; f. allowing the benzodiazepine intermediate E to react with dimorpholino phosphinic chloride, preferably in the presence of a strong base such as sodium hydride or t-BuOK, preferably in a suitable solvent such as THF or diethyl ether, to obtain reactive intermediate F; g. carrying out a substitution reaction between the reactive intermediate F and an amino alcohol such as 2-amino-1-cyclopropylethanol, 1-amino-3-methoxypropan-2-ol, 2-amino-1-cyclopropylpropan-1-ol, 2-amino-2-cyclopropylethanol or 1-amino-2,3,3,3-tetradeuteropropan-2-ol, to obtain intermediate G; and. h. oxidizing the intermediate G with an oxidizing agent such as PCC, PDC, TEMPO or Dess-Martin periodinane or through Swern oxidation, preferably in a suitable solvent such as CH 3 CN, DMF or DCM, to achieve ring closure and obtain the target product I-1; or h\u2032. carrying out a substitution reaction between the reactive intermediate F and a hydrazide such as cyclopropane carbohydrazide, 2-methylpropionyl hydrazide, propionyl hydrazide, 2-methoxyacethydrazide or acethydrazide-D 3 , followed by cyclization via condensation, to obtain the target product I-2; or when K is CR 4  and J is N, the method is carried out according to Scheme II: wherein R 1 -R 4 , W, X, and Y are as defined in  claim 1 ; the bond between X and Y is a single bond or a double bond; m and n are each 1; and R 5  is C 1-6  alkyl optionally substituted with one or more (e.g., 1, 2, 3 or 4) substituents independently selected from the group consisting of deuterium, halogen, hydroxy, cyano, C 1-6  alkyl, R 6 R 7 N\u2014, C 1-6  alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-14 membered aryl and 5-14 membered heteroaryl, preferably, R 5  is selected from the group consisting of methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, N,N-diethylaminomethyl, and deuteromethyl; Hal is a halogen, such as chlorine or bromine; the method comprising the following steps: a. allowing intermediate A\u2032 to react with a halogen-substituted acetyl halide such as chloroacetyl chloride or bromoacetyl bromide to obtain intermediate B\u2032; b. cyclizing the intermediate B\u2032, preferably in an alcohol (e.g. methanol, ethanol or isopropanol) or ether (e.g. tetrahydrofuran or dioxane) solution of excess ammonia, preferably under heating conditions such as at a temperature of 30\u00b0 C. to 80\u00b0 C., to obtain lactam intermediate C; c. carrying out a sulfur-oxygen exchange reaction on the lactam intermediate C\u2032, preferably under heating conditions such as at a temperature of 80\u00b0 C. to 150\u00b0 C., in the presence of a thiating agent such as phosphorus pentasulfide or Lawesson's reagent, to obtain thiolactam intermediate D\u2032; d. carrying out a substitution reaction between the thiolactam intermediate D\u2032 and an amino-containing alkyne such as prop-2-yn-1-amine, but-2-yn-1-amine, 4-methoxybut-2-yn-1-amine, N,N-dimethylpent-2-yn-1,5-diamine or 3-cyclopropylprop-2-yn-1-amine, and then carrying out a cyclization reaction, preferably in the presence of a catalyst such as Hg(OAc) 2  or HgSO 4 , to obtain intermediate F\u2032; and e. carrying out a Michael addition reaction between the intermediate F\u2032 and an enoate ester such as methyl acrylate, ethyl methylbut-2-enoate or methyl methacrylate or an alkynoate ester such as methyl propiolate or methyl methylbut-2-ynoate, preferably in the presence of a base such as sodium hydride, LDA or t-BuOK, preferably in a suitable solvent such as THF or 2-methyltetrahydrofuran, to obtain racemic target molecule I-1\u2032, and further carrying out a chiral separation to obtain enantiomerically pure target molecule I-1; or when K is N and J is CR 4 , the method is carried out according to Scheme III: wherein R 1 -R 5 , W, X, and Y are as defined in  claim 1 ; the bond between X and Y is a single bond or a double bond; and m and n are each 1; the method comprising the following steps: a. allowing intermediate A\u2033 to react with substituted ethyl imidate such as ethyl acetimidate, propionimidic acid ethyl ester, 2-methoxy-acetimidic acid ethyl ester or cyclopropanecarboximidic acid ethyl ester to obtain intermediate B\u2033; b. carrying out a condensation reaction between the intermediate B\u2033 and 2-bromomalonaldehyde, preferably under heating conditions such as at a temperature of 50\u00b0 C. to 150\u00b0 C., to obtain intermediate C\u2033; c. carrying out a two-step reaction to convert the intermediate C\u2033 to intermediate D\u2033, wherein the first step converts the aldehyde group in the intermediate C\u2033 to aminomethyl using reductive amination, and the second step protects the amino group in the aminomethyl with Boc 2 O to obtain a tert-butyl carbamate; d. allowing the amide intermediate D\u2033 to react with a lithium reagent such as n-butyllithium and a bromo-substituted aryl or heteroaryl compound such as bromobenzene, 1-bromo-2-fluorobenzene or 2-bromopyridine, preferably in a suitable solvent such as THF or diethyl ether, to obtain ketone intermediate E\u2033; e. deprotecting the intermediate E\u2033, preferably under acidic conditions of e.g. trifluoroacetic acid or hydrochloric acid, followed by cyclization under the same conditions, to obtain intermediate F\u2033; and f. carrying out a Michael addition reaction between the intermediate F\u2033 and an enoate ester such as methyl acrylate, ethyl methylbut-2-enoate or methyl methacrylate or an alkynoate ester such as methyl propiolate or methyl methylbut-2-ynoate, preferably in the presence of a base such as sodium hydride, LDA or t-BuOK, preferably in a suitable solvent such as THF or 2-methyltetrahydrofuran, to obtain racemic target molecule I-3\u2033, and further carrying out a chiral separation to obtain enantiomerically pure target molecule I-3.

Metadata:
- Claim Count in Document: 29.0
- Percentile: 91.0
- Lexical Diversity: 1.57576
- Patent Class: 514.0
- Transitional Phrase Type: open
- Component Type: 1
- Foreign Priority: True
- Related Applications: ['12598882', '14858159', '14448160', '09927324', '15150038']

Analysis Scores:
- 35 USC 101 Eligibility (BERT): 0.796381791618479
- 35 USC 102 Novelty (BERT): 0.5333532101393038
- Combined Prediction Score: 0.7700789334705614
- Mean Citation Score: 356.00754
- Max Citation Score: 373.12048
- Similarity Product: 282.3385025569916

Labels:
- Claim Label 101: 1
- Claim Label 102: 1
- Claim Label 103: 1
- Claim Label 112: 1
- Combined Label: 1
- Label 101 Adjusted: 1

Dataset: test