CN105820140A - 3-(morpholine-4-carbonyl)phenyl-based substituted methanesulfonamide new compound, preparation and application - Google Patents
3-(morpholine-4-carbonyl)phenyl-based substituted methanesulfonamide new compound, preparation and application Download PDFInfo
- Publication number
- CN105820140A CN105820140A CN201510001497.3A CN201510001497A CN105820140A CN 105820140 A CN105820140 A CN 105820140A CN 201510001497 A CN201510001497 A CN 201510001497A CN 105820140 A CN105820140 A CN 105820140A
- Authority
- CN
- China
- Prior art keywords
- compound
- reactions steps
- phenyl
- solvent
- morpholine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention provides a new compound. The name of the compound is N-(2,5-diethoxy-4-{3-[4-ethoxy-3-(morpholine-4-carbonyl)-phenyl]-ureidomethyl}-phenyl)-methanesulfonamide; molecular weight of the compound is 564.6; and structure of the compound is as shown in the structural formula (compound 1). Meanwhile, the invention provides a preparation method of the compound 1. The compound provided by the invention has good drug-likeness and can be used in the research field of new drugs, especially in the research field of type-II diabetes innovative drugs.
Description
Technical field
The present invention relates to a kind of N-(2 of offer, 5-diethoxy-4-{3-[4-ethyoxyl-3-(morpholine-4-carbonyl)-phenyl]-ureidomethy }-phenyl)-Methanesulfomide noval chemical compound, preparation method and the purposes in innovation drug research thereof, this compound molecular weight is little, novel structure, stable in properties, simple in construction, it is adaptable to innovation drug research is developed, and belongs to technical field of chemistry.
Background technology
Carbamide compounds (
) when being combined with drug target molecule (macromole such as protein, enzyme) active pocket, owing to the hydrogen atom on nitrogen-atoms in urea groups structure is can critical amino acid residues is combined in drug target molecular activity pocket good hydrogen-bond donor, and carbonyl is the good hydrogen bond receptor that critical amino acid residues is combined in drug target molecular activity pocket in its urea groups, therefore in the compound design of innovation drug research, such group is good dominant group.Compound N-(2,5-diethoxy-4-{3-[4-ethyoxyl-3-(morpholine-4-carbonyl)-phenyl]-ureidomethy }-phenyl)-Methanesulfomide is the carbamide compounds containing urea groups structure, this compound structure is novel, stable in properties, simple in construction, in the docking research of Computer-Aided Drug Design, find that this compound can have preferably combination with the drug target of some type ii diabetes, there is certain innovation drug research DEVELOPMENT PROSPECT.
Summary of the invention
1, a kind of noval chemical compound, it is characterized in that, the entitled N-(2 of this compound, 5-diethoxy-4-{3-[4-ethyoxyl-3-(morpholine-4-carbonyl)-phenyl]-ureidomethy }-phenyl)-Methanesulfomide (compound 1), the molecular weight of this compound is 564.6, and the structural formula of this compound is shown in following formula: compound 1:
2, one prepares noval chemical compound N-(2,5-diethoxy-4-{3-[4-ethyoxyl-3-(morpholine-4-carbonyl)-phenyl]-ureidomethy }-phenyl) method of-Methanesulfomide, it is characterized in that, including reactions steps g6 shown in following reaction scheme 1, reactions steps g7, reactions steps g8, reactions steps g, reactions steps h, following totally 6 reactions steps of reactions steps i, the condition flag that wherein reactions steps g, reactions steps h, this 3 step of reactions steps i are reacted is as follows:
The condition of reactions steps g is: 2,5-diethoxy-4-Nitro-benzyl amine and compound G molar ratio range are 0.8:1 ~ 1.3:1, triethylamine and compound G mol ratio=0.8:1 ~ 5:1), solvent is N, N dimethylformamide or dimethyl sulfoxide or single solvent or the combination of solvent such as acetone or Isosorbide-5-Nitrae dioxane, reaction temperature is 50 ~ 120 degree, response time is 5 ~ 18 hours, and reaction is purified to obtain product compound H, yield spectra 50% ~ 90% through concentrate, extract, crystallization etc. after terminating；The condition of reactions steps h is: Nickel dichloride hexahydrate and compound H molar ratio range are 0.9:1 ~ 2.5:1, sodium borohydride and compound H molar ratio range are 0.9:1 ~ 4:1, solvent is dichloromethane or the single solvent such as oxolane or ether or the combination of solvent, response time is 10 minutes ~ 12 hours, reaction is purified to obtain product compound I, yield spectra 50% ~ 95% through extraction, crystallization etc. after terminating；
The condition of reactions steps i is: alkyl sulfonyl chloride and compound I molar ratio range are 0.8:1 ~ 1.5:1, pyridine and compound I molar ratio range are 0.9:1 ~ 1.5:1, solvent is dichloromethane or oxolane or ether or N, N dimethylformamide or dimethyl sulfoxide or acetone or 1, single solvent or the combinations of solvent such as 4 dioxane, reaction temperature is 0 ~ 80 degree, 3 ~ 18 hours response time, reaction is purified to obtain product compound 1, yield spectra 50% ~ 95% through extraction, crystallization, column chromatography etc. after terminating.
3, the compound that the present invention provides has preferable quasi-medicated property, can be used for new drug research field and especially treats type ii diabetes field of innovative medicine research.
4, a kind of pharmaceutical composition, including the compound described in the claim 1 of therapeutically effective amount or its pharmaceutically acceptable salt.
5, pharmaceutical composition according to claim 4, is characterized in that, this pharmaceutical composition contains one or more pharmaceutically acceptable carrier or excipient further.
6, pharmaceutical composition according to claim 4, is characterized in that, described compound or its pharmaceutically acceptable salt account for gross weight ratio 50% ~ 99.5% as active component.
Below in conjunction with specific embodiment, the present invention is further elaborated, but is not intended to the present invention.
Specific embodiment
Embodiment 1:N-(2,5-diethoxy-4-{3-[4-ethyoxyl-3-(morpholine-4-carbonyl)-phenyl]-ureidomethy }-phenyl) structural formula of-Methanesulfomide (compound 1) is as follows:
Compound N-(2,5-diethoxy-4-{3-[4-ethyoxyl-3-(morpholine-4-carbonyl)-phenyl]-ureidomethy }-phenyl) synthetic route of-Methanesulfomide is as follows:
nullCompound N-(2,5-diethoxy-4-{3-[4-ethyoxyl-3-(morpholine-4-carbonyl)-phenyl]-ureidomethy }-phenyl) the concrete preparation method of-Methanesulfomide is as follows: the preparation of reactions steps g6(compound G1-6): by 2-ethyoxyl-5-nitro-benzoyl chloride (500mg，2.18mmol) add in 100ml eggplant type bottle，Add dichloromethane to be completely dissolved，Add morpholine (185mg，2.18mmol)，Add triethylamine (242mg，2.40mmol)，Room temperature reaction 0.5-2 h，Reaction terminates to wash three times with the hydrochloric acid solution of 10%，It is concentrated under reduced pressure to give crude product，Use column chromatography sharp separation，Use dichloromethane eluent，Obtain sterling (2-ethyoxyl-5-nitro-phenyl)-morpholine-4-base-ketone (500mg，81.9%)；nullThe preparation of reactions steps g7(compound G1-7): by (2-ethyoxyl-5-nitro-phenyl)-morpholine-4-base-ketone (450mg，1.60mmol) add in 100ml eggplant type bottle and add methanol，Add Nickel dichloride hexahydrate (657mg，2.76mmol)，After being completely dissolved，Add sodium borohydride (222mg，5.52mmol)，React 5-10 minute，Reaction carries out concentrating under reduced pressure after terminating，Add the hydrochloric acid solution of 10%，Wash three times by ethyl acetate，Obtain aqueous phase，Add ammonia regulation PH > 11，Wash 3 times by ethyl acetate，Obtain organic facies，Concentrating under reduced pressure i.e. can get crude product，Separate by column chromatography，The methylene chloride/methanol of 100:1 is eluant，Obtain sterling (5-amino-2-ethyoxyl-phenyl)-morpholine-4-base-ketone (330mg，82.5%)；The preparation of reactions steps g8(compound G1-8): by phenyl chloroformate (156.5mg, 1.0 mmol) add in the eggplant type bottle of 100ml, add dichloromethane, add ((5-amino-2-ethyoxyl-phenyl)-morpholine-4-base-ketone (250mg, 1.0mmol) with triethylamine (111mg, 1.1mmol), room temperature reaction 0.5-2 h, reaction is washed 3 times with the hydrochloric acid solution of 10% after terminating, it is concentrated under reduced pressure to give crude product, carry out recrystallization with ethanol and can get sterling [4-ethyoxyl-3-(morpholine-4-carbonyl)-phenyl]-phenyl carbamate (310mg, productivity 83.8%)；The preparation of reactions steps g(compound H): by 2, 5-diethoxy-4-Nitro-benzyl amine (182mg, 0.76mmol), [4-ethyoxyl-3-(morpholine-4-carbonyl)-phenyl]-phenyl carbamate (280mg, 0.76mmol) with triethylamine (0.77g, 7.6mmol) add in the eggplant type bottle of 100ml, add dioxanes, it is heated to 60-80 DEG C, reaction is overnight, reaction is concentrated under reduced pressure to give crude product after terminating, recrystallization is carried out with methanol, obtain sterling 1-(2, 5-diethoxy-4-Nitro-benzyl) and-3-[4-ethyoxyl-3-(morpholine-4-carbonyl)-phenyl]-urea (270mg, productivity 68.9%)；nullThe preparation of reactions steps h(compound I): by 1-(2,5-diethoxy-4-Nitro-benzyl) and-3-[4-ethyoxyl-3-(morpholine-4-carbonyl)-phenyl]-urea (250mg,0.48 mmol) add 100ml eggplant type bottle in，Add methanol，Add Nickel dichloride hexahydrate (196mg，0.82mmol)，After being completely dissolved，Add sodium borohydride (62.5mg，1.65 mmol)，Room temperature reaction 5-10 minute，Reaction carries out concentrating under reduced pressure after terminating，Add the hydrochloric acid solution of 10%，Wash three times by ethyl acetate，Obtain aqueous phase，Add ammonia regulation PH > 11，Wash 3 times by ethyl acetate，Obtain organic facies，Concentrating under reduced pressure i.e. can get crude product，Separate by column chromatography，The methylene chloride/methanol of 100:1 is eluant，Obtain sterling 1-(4-amino-2,5-diethoxy-benzyl) and-3-[4-ethyoxyl-3-(morpholine-4-carbonyl)-phenyl]-urea (150mg，64.4%)；nullThe preparation of reactions steps i(compound 1): by 1-(4-amino-2,5-diethoxy-benzyl) and-3-[4-ethyoxyl-3-(morpholine-4-carbonyl)-phenyl]-urea (130mg，0.27mmol) add in the eggplant type bottle of 100ml，Add dichloromethane，Add pyridine (23.2mg，0.29mmol)，Carry out nitrogen protection，Add methylsufonyl chloride (30.9mg，0.32mmol)，Room temperature reaction is overnight，After reaction terminates，Hydrochloric acid solution with 10% washs three times，Obtain organic facies，Concentrating under reduced pressure i.e. can get crude product，Separate by column chromatography，The methylene chloride/methanol of 100:1 is eluant，Obtain sterling N-(2,5-diethoxy-4-{3-[4-ethyoxyl-3-(morpholine-4-carbonyl)-phenyl]-ureidomethy }-phenyl)-Methanesulfomide (90mg，58.8%).1H NMR (400 MHz, DMSO) δ 8.81 (s, 1H), 8.47 (s,
1H), 7.30–7.24 (m, 2H), 6.93 (d,J
= 7.2 Hz, 2H), 6.87 (s, 1H), 6.32 (t,J = 5.7 Hz, 1H), 4.20 (d,J
= 5.6 Hz, 2H), 3.98 (q,J = 6.8Hz, 6H), 3.65–3.44 (m, 6H), 3.10 (s,
2H), 2.93 (s, 3H), 1.36–1.24 (m, 9H)。
Claims (6)
1. a noval chemical compound, it is characterized in that, the entitled N-(2 of this compound, 5-diethoxy-4-{3-[4-ethyoxyl-3-(morpholine-4-carbonyl)-phenyl]-ureidomethy }-phenyl)-Methanesulfomide (compound 1), the molecular weight of this compound is 564.6, and the structural formula of this compound is shown in following formula: compound 1.
2. prepare noval chemical compound N-(2 for one kind, 5-diethoxy-4-{3-[4-ethyoxyl-3-(morpholine-4-carbonyl)-phenyl]-ureidomethy }-phenyl) method of-Methanesulfomide, it is characterized in that, including reactions steps g6 shown in following reaction scheme 1, reactions steps g7, reactions steps g8, reactions steps g, reactions steps h, following totally 6 reactions steps of reactions steps i, the condition flag that wherein reactions steps g, reactions steps h, this 3 step of reactions steps i are reacted is as follows:
The condition of reactions steps g is: 2,5-diethoxy-4-Nitro-benzyl amine and compound G molar ratio range are 0.8:1 ~ 1.3:1, triethylamine and compound G mol ratio=0.8:1 ~ 5:1), solvent is N, N dimethylformamide or dimethyl sulfoxide or single solvent or the combination of solvent such as acetone or Isosorbide-5-Nitrae dioxane, reaction temperature is 50 ~ 120 degree, response time is 5 ~ 18 hours, and reaction is purified to obtain product compound H, yield spectra 50% ~ 90% through concentrate, extract, crystallization etc. after terminating；The condition of reactions steps h is: Nickel dichloride hexahydrate and compound H molar ratio range are 0.9:1 ~ 2.5:1, sodium borohydride and compound H molar ratio range are 0.9:1 ~ 4:1, solvent is dichloromethane or the single solvent such as oxolane or ether or the combination of solvent, response time is 10 minutes ~ 12 hours, reaction is purified to obtain product compound I, yield spectra 50% ~ 95% through extraction, crystallization etc. after terminating；
The condition of reactions steps i is: alkyl sulfonyl chloride and compound I molar ratio range are 0.8:1 ~ 1.5:1, pyridine and compound I molar ratio range are 0.9:1 ~ 1.5:1, solvent is dichloromethane or oxolane or ether or N, N dimethylformamide or dimethyl sulfoxide or acetone or 1, single solvent or the combinations of solvent such as 4 dioxane, reaction temperature is 0 ~ 80 degree, 3 ~ 18 hours response time, reaction is purified to obtain product compound 1, yield spectra 50% ~ 95% through extraction, crystallization, column chromatography etc. after terminating.
3. the compound that the present invention provides has preferable quasi-medicated property, can be used for new drug research field and especially treats type ii diabetes field of innovative medicine research.
4. a pharmaceutical composition, including the compound described in the claim 1 of therapeutically effective amount or its pharmaceutically acceptable salt.
Pharmaceutical composition the most according to claim 4, is characterized in that, this pharmaceutical composition contains one or more pharmaceutically acceptable carrier or excipient further.
Pharmaceutical composition the most according to claim 4, is characterized in that, described compound or its pharmaceutically acceptable salt account for gross weight ratio 50% ~ 99.5% as active component.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510001497.3A CN105820140A (en) | 2015-01-05 | 2015-01-05 | 3-(morpholine-4-carbonyl)phenyl-based substituted methanesulfonamide new compound, preparation and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510001497.3A CN105820140A (en) | 2015-01-05 | 2015-01-05 | 3-(morpholine-4-carbonyl)phenyl-based substituted methanesulfonamide new compound, preparation and application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105820140A true CN105820140A (en) | 2016-08-03 |
Family
ID=56986777
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510001497.3A Pending CN105820140A (en) | 2015-01-05 | 2015-01-05 | 3-(morpholine-4-carbonyl)phenyl-based substituted methanesulfonamide new compound, preparation and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105820140A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106167456A (en) * | 2015-05-20 | 2016-11-30 | 齐鲁工业大学 | New Type Urea albuminoid tyrosine-phosphatase 1B inhibitor and preparation method thereof, pharmaceutical composition and purposes |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020032195A1 (en) * | 2000-02-16 | 2002-03-14 | Steffen Breitfelder | Compounds useful as anti-inflammatory agents |
| US20040037022A1 (en) * | 2000-09-25 | 2004-02-26 | Minoru Sakurai | Aminoalcohol derivatives |
| CN101142174A (en) * | 2005-03-19 | 2008-03-12 | 株式会社Amorepacific | Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist, and pharmaceutical compositions containing the same |
| CN101163691A (en) * | 2005-01-14 | 2008-04-16 | Cgi药学股份有限公司 | 1,3-diaryl substituted ureas as modulators of kinase activity |
| CN102869261A (en) * | 2010-03-01 | 2013-01-09 | 瑞科西有限公司 | Compounds and therapeutic uses thereof |
-
2015
- 2015-01-05 CN CN201510001497.3A patent/CN105820140A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020032195A1 (en) * | 2000-02-16 | 2002-03-14 | Steffen Breitfelder | Compounds useful as anti-inflammatory agents |
| US20040037022A1 (en) * | 2000-09-25 | 2004-02-26 | Minoru Sakurai | Aminoalcohol derivatives |
| CN101163691A (en) * | 2005-01-14 | 2008-04-16 | Cgi药学股份有限公司 | 1,3-diaryl substituted ureas as modulators of kinase activity |
| CN101142174A (en) * | 2005-03-19 | 2008-03-12 | 株式会社Amorepacific | Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist, and pharmaceutical compositions containing the same |
| CN102869261A (en) * | 2010-03-01 | 2013-01-09 | 瑞科西有限公司 | Compounds and therapeutic uses thereof |
Non-Patent Citations (4)
| Title |
|---|
| BRENT W. MCCLELAND ET AL: "Comparison of N,N’-diarylsquaramides and N,N’-diarylureas as antagonists of the CXCR2 chemokine receptor", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| MARIE REILLE-SEROUSSI ET AL: "Thienopyrimidinedione Formation Versus Ester Hydrolysis from Ureido Carboxylic Acid Methyl Ester", 《SYNTHESIS》 * |
| R.B. 西尔弗曼 主编: "《有机药物化学》", 31 January 2008, 化学工业出版社 * |
| 曹观坤 主编: "《药物化学实验技术》", 29 February 2008, 化学工业出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106167456A (en) * | 2015-05-20 | 2016-11-30 | 齐鲁工业大学 | New Type Urea albuminoid tyrosine-phosphatase 1B inhibitor and preparation method thereof, pharmaceutical composition and purposes |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7374496B2 (en) | N-benzenesulfonylbenzamide compounds, compositions and uses thereof for inhibiting Bcl-2 protein | |
| CN107954906B (en) | Synthetic method of aryl sulfonyl tertiary amine compound | |
| CN111925381A (en) | Synthesis method of baroxavir key intermediate | |
| CN105820094A (en) | 4-methoxy-benzyl-based substituted benzamide new compound, preparation method and application | |
| CN105820093A (en) | N-benzyl-5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethyoxyl benzamide new compound and preparation method and application thereof | |
| CN105820067A (en) | N-{[2,5-diethoxy-4-[(3-phenyl-ureido)-methyl]-phenyl}-methanesulfonamide new compound and preparation method and application thereof | |
| CN105820083A (en) | 5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N-phenyl-benzamide new compound and preparation method and application thereof | |
| CN105820140A (en) | 3-(morpholine-4-carbonyl)phenyl-based substituted methanesulfonamide new compound, preparation and application | |
| CN105820082A (en) | 5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N-isopropyl-benzamide new compound and preparation method and application thereof | |
| CN105820090A (en) | 5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N-(3-methoxy-phenyl)-benzamide new compound and preparation method and application thereof | |
| CN105820087A (en) | 5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N-p-methylphenyl-benzamide new compound and preparation method and application thereof | |
| CN105820139A (en) | 3-(pyrrolidine-1-carbonyl)-phenyl-based substituted methanesulfonamide new compound and preparation and application | |
| CN105820071A (en) | N-{4-[3-(4-bromo-phenyl)-ureidomethyl]-2,5-diethoxy-phenyl}-methanesulfonamide new compound and preparation method and application thereof | |
| CN105820085A (en) | Ethanesulfonic acid{4-[3-(3-bromo-phenyl)-ureidomethyl]-2,5-diethoxy-phenyl}-amide new compound, preparation method and application | |
| CN105820077A (en) | 2-butoxyl-5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-methyl benzoate new compound and preparation method and application thereof | |
| CN105820080A (en) | 5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N-ethyl-benzamide new compound and preparation method and application thereof | |
| CN105820068A (en) | N-{4-[3-(3-bromo-phenyl)-ureidomethyl]-2,5-dipropoxy-phenyl}-methanesulfonamide new compound and preparation method and application thereof | |
| CN105820078A (en) | 2-benzyloxy-5-[3-(2,5-diethoxy-4-methanesulfonyl-benzyl)-ureido]- methyl benzoate new compound and preparation method and application thereof | |
| CN105820081A (en) | 5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxy-N-propyl-benzamide new compound and preparation method and application thereof | |
| CN105820088A (en) | N-(4-bromo-phenyl)-5-[3-(2,5-diethoxy-4-methylsulfonyl-benzyl)-ureido]-2-ethoxylbenzamide new compound and preparation method and application thereof | |
| CN105820066A (en) | 3-methoxy-benzyl-based substituted benzamide new compound, preparation method and application | |
| CN105820069A (en) | N-{4-[3-(3-bromo-phenyl)-ureidomethyl]-2,5-dibutoxy-phenyl}-methanesulfonamide new compound and preparation method and application thereof | |
| CN105820091A (en) | 3,4-dimethoxyphenyl-based substituted benzamide new compound, preparation method and application | |
| CN105820114A (en) | 6-methyl-pyridine-2-yl-based substituted benzamide new compound, preparation and application | |
| CN105820076A (en) | N-[2,5-diethoxy-4-(3-p-tolyl-ureidomethyl)-phenyl]-methanesulfonamide new compound and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160803 |
|
| WD01 | Invention patent application deemed withdrawn after publication |