US3152180A - Process for the production of nu-tert-alkyl amides and, if desired, nu-tert. alkyl amines - Google Patents

Process for the production of nu-tert-alkyl amides and, if desired, nu-tert. alkyl amines Download PDF

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US3152180A
US3152180A US133061A US13306161A US3152180A US 3152180 A US3152180 A US 3152180A US 133061 A US133061 A US 133061A US 13306161 A US13306161 A US 13306161A US 3152180 A US3152180 A US 3152180A
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Haaf Wolfgang
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Studiengesellschaft Kohle gGmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides

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  • alkyl amides e.g. N-tert. butyl formamide
  • isoparaffins can also be converted into N-tert. alkyl amides.
  • alkyl amine a maximum of 1 mol parafiin is capable of being converted into the N-tert. alkyl amide by 1 mol of olefin or alcohol or alkyl halide. From the olefin charged or the analogous compound, an amide corresponding to this compound is likewise formed invariably. When operating with an excess of isoparafiin, the yield of amide from the parafi'in can be increased. The isoparafiin which is not consumed in the reaction is preferably recycled into the reaction.
  • a preferred catalyst in the process of the invention is concentrated sulfuric acid, especially one having a concentration of 90 to 100%.
  • the process is preferably carried out at a temperature of between 0 and 80 C., especially at 40 C.
  • Particularly good results for the case of using solid reactants are obtained when operating in the presence of inert solvents.
  • Particularly suitable inert solvents are n-parafiins or unbranched cycloparalfins, particularly n-hexane, n-heptane or cyclohexane.
  • Suitable isoparaffins for the process of the invention are acyclic and cyclic saturated hydrocarbons, suitably those having from 4 to 15 carbon atoms, preferably isobutane, isopentane, Z-methyl-pentane, 2,3-dimethylbutane and 3- methylheptane.
  • cyclic isoparafiins include alkyl cyclohexane such as methyl cyclohexane, ethyl cyclohexane or methyl cyclopentane and diand polycyclic compounds such as decahydronaphthalene, adamantane or perhydroacenaphthene, i.e. compounds having from 6 to 15 carbon atoms.
  • the olefins used may be unbranched and branched olefins, particularly those having from 3 to 10 carbon atoms. Butene-l and butene-Z, isobutene or also pentene-l or pentene-Z will preferably be used for a commercial process.
  • Alcohols which are particularly suitable for the process of the invention are alcohols containing up to carbon atoms, particularly tertiary butanol or butanol-2.
  • a particularly suitable alkyl halide is tertiary butyl chloride.
  • other alkyl halides may also be used.
  • N-tertiary alkyl amides produced in accordance with the invention are suitable intermediates in pharmaceutical industry.
  • Example 1 To achieve satisfactory intermixing of sulfuric acid and isoparafiin, the reaction was effected in a 1.5 l. round-bottom flask in which a centrifugal stirrer of stainless steel was arranged almost horizontally, the suction opening of which, when not in operation, covered the total height of the organic phase as well as part of the sulfuric acid. Satisfactory emulsification could be achieved at a speed of 2,000 to 3,000 rpm.
  • Example 2 In the apparatus described in Example 1, 880 gms. of a 96% sulfuric acid and 86 gms. (1 mole) of 2,3-dimethylbutane were emulsified. To this end, 28 gms. (0.5 mol) of isobutene were introduced Within 2 hours at 30 C. During the same time, 27 gms. (1 mol) of liquid hydrocyanic acid were added dropwise. After 3 hours of postreaction, decomposition with ice and saponification, 30 gms.:40 ml. of amine could be obtained.
  • Example 3 360 ml. of 96% sulfuric acid and a solution of 13.6 gms. (0.1 mole) of adamantane in 100 ml. of n-hexane were emulsified in the apparatus described and provided with an inclined centrifugal stirrer. Then a mixture of 46 gms. (1.7 moles) of liquid hydrocyanic acid and 29.6 gms. (0.4 mole) of tertiary butanol was added dropwise within 1.5 hours at about 25 C. After 30 minutes of postreaction, the product was poured on ice. The granular mass which precipitated (N-(adamantyl-1)-formamide) was sucked off and washed with water.
  • Example 4 In the apparatus described in Example 1, 360 ml. of a 96% sulfuric acid and 72 gms. (1 mol) of isopentane were emulsified. A mixture of 74 gms. (1 mol) of tertiary butanol and 82 gms. (2 mols) of acetonitrile were added dropwise within 2% hours at 25 C. After a postreaction time of 10 minutes, the product was decomposed with ice and neutralized with solid sodium carbonate. The weakly alkaline solution was extracted with ether, the ether dried over potassium carbonate and distilled off. The residue was refluxed for 12 hours with a solution of 60 gms. of NaOH in 600 ml. of diethylene glycol.
  • a process for the production of N-tert. alkyl amides which comprises reacting an isoparafiin selected from the group consisting of saturated cyclic and alicyclic hydrocarbons of 4-15 carbon atoms with a member selected from the group consisting of acetonitrile, HCN, and HCN evolving compounds in the presence of a member selected from the group consisting of olefins of 3-10 carbon atoms, tert. butyl chloride and alcohols having up to 5 carbon atoms and in contact with sulfuric acid as catalyst under reaction conditions including thorough mixing of the reactants and recovering the alkyl amide corresponding to the isoparaflin thus produced.
  • said olefin is a member selected from the group consisting of butene-l, butene-2, isobutene, pentene-l and pentene-2.
  • a process according to claim 1 wherein said alcohol is selected from the group consisting of tertiary butanol and butanol-2.
  • a process for the production of N-tert. alkyl amides which comprises reacting 2,3-dimethyl butane with HCN in the presence of isobutene and sulfuric acid as catalyst under reaction conditions including thorough mixing of the reactants and recovering the alkyl amide thus produced.
  • a process for the production of N-tert. alkyl amides which comprises reacting adamantane with HCN in the presence of tert. butanol and sulfuric acid as catalyst under reaction conditions including thorough mixing of the reactants and recovering the alkyl amide thus produced.
  • a process for the production of N-tert. alkyl amides which comprises reacting isopentane with acetonitrile in the presence of tert. butanol and sulfuric acid as catalyst under reaction conditions including thorough mixing of the reactants and recovering the alkyl amide thus produced.

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Description

United States Patent PROCESS FOR THE PRODUCTION OF N-TERT. ALKYL AMIDES AND, [F DESIRED, N-TERT. ALKYL AMINES Wolfgang Haaf, Mulheim (Ruhr), Germany, assignor to Studiengesellsehaft Kohle m.b.H., Mulheim (Ruhr), Germany No Drawing. Filed Aug. 22, 1961, Ser. No. 133,061 Claims priority, application Germany Aug. 25, 1960 7 Ciaims. (Cl. 260561) This invention relates to a process for the production of N-tert. alkyl amides and, if desired, N-tert. alkyl amines.
The addition of nitriles or of HCN to olefins or alcohols in the presence of acid catalysts is known. In this reaction, alkyl amides, e.g. N-tert. butyl formamide, are obtained from isobutene and HCN.
It has now been found very surprisingly that isoparaffins can also be converted into N-tert. alkyl amides.
It is an object of this invention to provide a process for the production of N-tert. alkyl amides and, if desired, of N-tert. alkyl amines with the use of olefins, alkyl halides or aliphatic monoalcohols and nitriles, HCN or HCN evolving compounds in the presence of acid catalysts, which process comprises contacting nitriles, HCN or HCN evolving compounds with olefins, alkyl halides or alcohols in the presence of isoparafiins having at least one tertiary hydrogen atom while thoroughly mixing the reactants and recovering from the reaction product the alkyl amide which corresponds to the isoparaffin and which, if desired, is saponified in conventional manner to form a N-tert. alkyl amine. Theoretically, a maximum of 1 mol parafiin is capable of being converted into the N-tert. alkyl amide by 1 mol of olefin or alcohol or alkyl halide. From the olefin charged or the analogous compound, an amide corresponding to this compound is likewise formed invariably. When operating with an excess of isoparafiin, the yield of amide from the parafi'in can be increased. The isoparafiin which is not consumed in the reaction is preferably recycled into the reaction.
A preferred catalyst in the process of the invention is concentrated sulfuric acid, especially one having a concentration of 90 to 100%. The process is preferably carried out at a temperature of between 0 and 80 C., especially at 40 C. Particularly good results for the case of using solid reactants are obtained when operating in the presence of inert solvents. Particularly suitable inert solvents are n-parafiins or unbranched cycloparalfins, particularly n-hexane, n-heptane or cyclohexane.
Suitable isoparaffins for the process of the invention are acyclic and cyclic saturated hydrocarbons, suitably those having from 4 to 15 carbon atoms, preferably isobutane, isopentane, Z-methyl-pentane, 2,3-dimethylbutane and 3- methylheptane. Examples of suitably cyclic isoparafiins include alkyl cyclohexane such as methyl cyclohexane, ethyl cyclohexane or methyl cyclopentane and diand polycyclic compounds such as decahydronaphthalene, adamantane or perhydroacenaphthene, i.e. compounds having from 6 to 15 carbon atoms.
The olefins used may be unbranched and branched olefins, particularly those having from 3 to 10 carbon atoms. Butene-l and butene-Z, isobutene or also pentene-l or pentene-Z will preferably be used for a commercial process.
Alcohols which are particularly suitable for the process of the invention are alcohols containing up to carbon atoms, particularly tertiary butanol or butanol-2. A particularly suitable alkyl halide is tertiary butyl chloride. However, on principle, other alkyl halides may also be used.
Thorough mixing (emulsification) of the phases which are not miscible with one another (catalyst and isoparaf- 3,152,180 Patented Oct. 6, 1964 fin) is absolutely necessary for the process of the invention, the use of a stirring device permitting smooth emulsification having been found to be particularly advantageous.
In specific cases, e.g. in case of adamantane, it may be desirable to obtain in one reaction stage as high a yield of N-(adamantyl-l)-formamide as is possible. It may be desirable under these conditions to operate with an excess of the relatively inexpensive alcohol, particularly tertiary butanol.
The N-tertiary alkyl amides produced in accordance with the invention are suitable intermediates in pharmaceutical industry.
Example 1 To achieve satisfactory intermixing of sulfuric acid and isoparafiin, the reaction was effected in a 1.5 l. round-bottom flask in which a centrifugal stirrer of stainless steel was arranged almost horizontally, the suction opening of which, when not in operation, covered the total height of the organic phase as well as part of the sulfuric acid. Satisfactory emulsification could be achieved at a speed of 2,000 to 3,000 rpm.
12.2 liters (0.54 mol) of propene were introduced within 3 hours through a frit into an emulsion of 770 gms.:420 ml. of a 96% sulfuric acid and 144 gms. (2 mols) of isopentane at 20 C. At the same time, 27 gms. (1 mol) of liquid hydrocyanic acid were slowly added dropwise from a dropping funnel. After 3 hours of post-reaction, the reaction mixture was decomposed with ice and refluxed overnight. In doing so, the excess isopentane escaped. Then the amine was set free from the sulfuric acid solution by means of a concentrated sodium hydroxide solution, distilled over and dried with solid NaOH. Distillation by means of a spinning band column resulted in 8.5 gms.=27% of the theory of 2- amino-propane (boiling point, 33 C.) and 7.2 gms.=15% of the theory of Z-aminO-Z-methyl-butane (boiling point, 76 C., n =1.4020).
Example 2 In the apparatus described in Example 1, 880 gms. of a 96% sulfuric acid and 86 gms. (1 mole) of 2,3-dimethylbutane were emulsified. To this end, 28 gms. (0.5 mol) of isobutene were introduced Within 2 hours at 30 C. During the same time, 27 gms. (1 mol) of liquid hydrocyanic acid were added dropwise. After 3 hours of postreaction, decomposition with ice and saponification, 30 gms.:40 ml. of amine could be obtained. Precision fractionation resulted in 13 gms.=35% of the theory of tertiary butyl amine (boiling point, 46 C.) and 13 gms.:30% of the theory of 2-amino-2,3-dimethyl-butane (boiling point, 104 C., n =1.4l35).
Example 3 360 ml. of 96% sulfuric acid and a solution of 13.6 gms. (0.1 mole) of adamantane in 100 ml. of n-hexane were emulsified in the apparatus described and provided with an inclined centrifugal stirrer. Then a mixture of 46 gms. (1.7 moles) of liquid hydrocyanic acid and 29.6 gms. (0.4 mole) of tertiary butanol was added dropwise within 1.5 hours at about 25 C. After 30 minutes of postreaction, the product was poured on ice. The granular mass which precipitated (N-(adamantyl-1)-formamide) was sucked off and washed with water. The raw product (37 gms.) was then refluxed for 10 hours with a solution of 60 gms. of NaOH in 600 ml. of diethylene glycol. After cooling, the solution was diluted with 1.5 liters of water and subjected to three extractions with ether. The amine was extracted from the ethereal solution with 2 N HCl and liberated therefrom by the addition of solid NaOH (while cooling). The alkaline solution was extracted with ether and the ethereal solution was dried with solid NaOH. Distillation resulted in 10.6 gins. (=70% of the theory) of l-aminoadamantane which, after sublimation, melted at 180 to 192 C. (seal capillary).
Example 4 In the apparatus described in Example 1, 360 ml. of a 96% sulfuric acid and 72 gms. (1 mol) of isopentane were emulsified. A mixture of 74 gms. (1 mol) of tertiary butanol and 82 gms. (2 mols) of acetonitrile were added dropwise within 2% hours at 25 C. After a postreaction time of 10 minutes, the product was decomposed with ice and neutralized with solid sodium carbonate. The weakly alkaline solution was extracted with ether, the ether dried over potassium carbonate and distilled off. The residue was refluxed for 12 hours with a solution of 60 gms. of NaOH in 600 ml. of diethylene glycol. The amine formed was colected in dilute hydrochloric acid and liberated therefrom with solid NaOH. Precision fractionation resulted in 22 gms. (=30% of the theory) of tertiary butyiamine and 10.5 grns. (=12% of the theory) of 2-amino-2-methyl-butane.
What I claim is:
1. A process for the production of N-tert. alkyl amides, which comprises reacting an isoparafiin selected from the group consisting of saturated cyclic and alicyclic hydrocarbons of 4-15 carbon atoms with a member selected from the group consisting of acetonitrile, HCN, and HCN evolving compounds in the presence of a member selected from the group consisting of olefins of 3-10 carbon atoms, tert. butyl chloride and alcohols having up to 5 carbon atoms and in contact with sulfuric acid as catalyst under reaction conditions including thorough mixing of the reactants and recovering the alkyl amide corresponding to the isoparaflin thus produced.
2. A process according to claim 1 wherein said olefin is a member selected from the group consisting of butene-l, butene-2, isobutene, pentene-l and pentene-2.
3. A process according to claim 1 wherein said alcohol is selected from the group consisting of tertiary butanol and butanol-2.
4. A process for the production of N-tert. alkyl amides,
which comprises reacting isopentane with HCN in the presence of propene and sulfuric acid as catalyst under re action conditions including thorough mixing of the reactants and recovering the alkyl amide thus produced.
5. A process for the production of N-tert. alkyl amides, which comprises reacting 2,3-dimethyl butane with HCN in the presence of isobutene and sulfuric acid as catalyst under reaction conditions including thorough mixing of the reactants and recovering the alkyl amide thus produced.
6. A process for the production of N-tert. alkyl amides, which comprises reacting adamantane with HCN in the presence of tert. butanol and sulfuric acid as catalyst under reaction conditions including thorough mixing of the reactants and recovering the alkyl amide thus produced.
7. A process for the production of N-tert. alkyl amides, which comprises reacting isopentane with acetonitrile in the presence of tert. butanol and sulfuric acid as catalyst under reaction conditions including thorough mixing of the reactants and recovering the alkyl amide thus produced.
References Cited in the file of this patent UNITED STATES PATENTS 2,725,371 Coover et al Nov. 29, 1955 2,762,837 Middleton Sept. 11, 1956 2,914,534 Middleton Nov. 24, 1959 2,916,511 Frazza et a1. Dec. 8, 1959 FOREIGN PATENTS 796,572 Great Britain June 11, 1958 OTHER REFERENCES Morton: The Chemistry of Heterocyclic Compounds, p. VI of the preface; New York, McGraw-Hill, 1946.
American Cyanamid Company: The Chemistry of Acrylonitrile, 2nd ed., pp. 1214, 29-39, New York, American Cyanamid Company, 1959.
Bergmann: The Chemistry of Acetylene and Related Compounds, p. 80, New York, Interscience, 1948.

Claims (1)

1. A PROCESS FOR THE PRODUCTION OF N-TERT, ALKYL AMIDES, WHICH COMPRISES REACTING AN ISOPARAFFIN SELECTED FROM THE GROUP CONSITING OF SATURATED CYCLIC AND ALICYCLIC HYDROCARBONS OF 4-15 CARBON ATOMS WITH A MEMBER SELECTED FROM THE GROUP CONSISTING OF ACETONITRILE, HCN, AND HCN EVOLVING COMPOUNDS IN THE PRESENCE OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF OLEFINS OF 3-10 CARBON ATOMS, TERT, BUTYL CHLORIDE AND ALCOHOLS HAVING UP TO 5 CARBON ATOMS AND IN CONTACT WITH SULFURIC ACID AS CATALYST UNDER REACTION CONDITIONS INCLUDING THOROUGH MIXING OF THE REACTANTS AND RECOVERING THE ALKYL AMIDE CORRESPONDING TO THE ISOPARAFFIN THUS PRODUCED.
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Cited By (16)

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US4272455A (en) * 1979-12-26 1981-06-09 The Dow Chemical Company Production of monoalkyleneglycols, monoalkanolamines and alkylenediamine
FR2572399A1 (en) * 1984-10-31 1986-05-02 Panmedica Sa NOVEL DERIVATIVES OF ADAMANTANAMINE, PROCESSES FOR PREPARING THEM AND MEDICAMENTS CONTAINING SAME
US5576355A (en) * 1993-06-04 1996-11-19 Mobil Oil Corp. Diamondoid derivatives for pharmaceutical use
US5684024A (en) * 1996-01-25 1997-11-04 Viropharma Incorporated Pyrazole dimers compositions and methods for treating influenza
US5821243A (en) * 1996-07-22 1998-10-13 Viropharma Incorporated Compounds compositions and methods for treating influenza
US5880154A (en) * 1994-02-01 1999-03-09 The Board Of Regents Of The University Of Nebraska Polymeric adamantane analogues
WO2003080556A1 (en) 2001-01-19 2003-10-02 Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. Amine derivative with potassium channel regulatory function, its preparation and use
WO2007062272A1 (en) 2005-11-28 2007-05-31 Omega-Biopharma (H.K.) Limited Materials and methods for treating viral infections with a cysteamine compound
EP2243475A1 (en) 2005-04-06 2010-10-27 Adamas Pharmaceuticals, Inc. Combination of memantine and donepezil for treatment of CNS disorders
EP2343057A1 (en) 2004-11-23 2011-07-13 Neuromolecular Pharmaceuticals, Inc Method and composition for administering an NMDA receptor antagonist to a subject
US8329752B2 (en) 2004-11-23 2012-12-11 Adamas Pharmaceuticals, Inc. Composition for administering an NMDA receptor antagonist to a subject
EP2623099A1 (en) 2004-11-24 2013-08-07 Neuromolecular Pharmaceuticals, Inc Composition and method for treating neurological disease
US8741343B2 (en) 2009-12-02 2014-06-03 Adamas Pharmaceuticals, Inc. Method of administering amantadine prior to a sleep period
US10154971B2 (en) 2013-06-17 2018-12-18 Adamas Pharma, Llc Methods of administering amantadine
WO2021209563A1 (en) 2020-04-16 2021-10-21 Som Innovation Biotech, S.A. Compounds for use in the treatment of viral infections by respiratory syndrome-related coronavirus
EP4005565A1 (en) 2020-11-30 2022-06-01 Merz Pharmaceuticals GmbH Novel uses of adamantane derivatives

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Cited By (42)

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US4272455A (en) * 1979-12-26 1981-06-09 The Dow Chemical Company Production of monoalkyleneglycols, monoalkanolamines and alkylenediamine
FR2572399A1 (en) * 1984-10-31 1986-05-02 Panmedica Sa NOVEL DERIVATIVES OF ADAMANTANAMINE, PROCESSES FOR PREPARING THEM AND MEDICAMENTS CONTAINING SAME
EP0187052A1 (en) * 1984-10-31 1986-07-09 S.A. PANMEDICA Société dite: Adamantan amine derivatives, process for their preparation and medicines containing them
US4661512A (en) * 1984-10-31 1987-04-28 S. A. Panmedica Adamantanamine derivatives, processes for their preparation and drugs in which they are present
US5576355A (en) * 1993-06-04 1996-11-19 Mobil Oil Corp. Diamondoid derivatives for pharmaceutical use
US5880154A (en) * 1994-02-01 1999-03-09 The Board Of Regents Of The University Of Nebraska Polymeric adamantane analogues
US5684024A (en) * 1996-01-25 1997-11-04 Viropharma Incorporated Pyrazole dimers compositions and methods for treating influenza
US5935957A (en) * 1996-07-22 1999-08-10 Viropharma Incorporated Compounds, compositions and methods for treating influenza
US6180628B1 (en) 1996-07-22 2001-01-30 Viropharma Incorporated Compounds, compositions and methods for treating influenza
US6271373B1 (en) 1996-07-22 2001-08-07 Viropharma Incorporated Compounds, compositions and methods for treating influenza
US5821243A (en) * 1996-07-22 1998-10-13 Viropharma Incorporated Compounds compositions and methods for treating influenza
US7560473B2 (en) 2001-01-19 2009-07-14 Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences, P.L.A. Amine derivative with potassium channel regulatory function, its preparation and use
WO2003080556A1 (en) 2001-01-19 2003-10-02 Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. Amine derivative with potassium channel regulatory function, its preparation and use
EP1386908A1 (en) * 2001-01-19 2004-02-04 Institute of Pharmacology and Toxicology Academy of Military Medical Sciences P.L.A. Amine derivative with potassium channel regulatory function, its preparation and use
US20040266822A1 (en) * 2001-01-19 2004-12-30 Hai Wang Amine derivative with potassium channel regulatory function, its preparation and use
EP1386908A4 (en) * 2001-01-19 2006-07-12 Inst Pharm & Toxicology Amms Amine derivative with potassium channel regulatory function, its preparation and use
EP2343057A1 (en) 2004-11-23 2011-07-13 Neuromolecular Pharmaceuticals, Inc Method and composition for administering an NMDA receptor antagonist to a subject
US8580858B2 (en) 2004-11-23 2013-11-12 Adamas Pharmaceuticals, Inc. Compositions for the treatment of CNS-related conditions
US8598233B2 (en) 2004-11-23 2013-12-03 Adamas Pharmacueticals, Inc. Method for administering an NMDA receptor antagonist to a subject
US8426472B2 (en) 2004-11-23 2013-04-23 Adamas Pharmaceuticals, Inc. Method and composition for administering an NMDA receptor antagonist to a subject
US8362085B2 (en) 2004-11-23 2013-01-29 Adamas Pharmaceuticals, Inc. Method for administering an NMDA receptor antagonist to a subject
US8338486B2 (en) 2004-11-23 2012-12-25 Adamas Pharmaceuticals, Inc. Methods for the treatment of CNS-related conditions
US8338485B2 (en) 2004-11-23 2012-12-25 Adamas Pharmaceuticals, Inc. Compositions for the treatment of CNS-related conditions
US8329752B2 (en) 2004-11-23 2012-12-11 Adamas Pharmaceuticals, Inc. Composition for administering an NMDA receptor antagonist to a subject
EP2623099A1 (en) 2004-11-24 2013-08-07 Neuromolecular Pharmaceuticals, Inc Composition and method for treating neurological disease
US8293794B2 (en) 2005-04-06 2012-10-23 Adamas Pharmaceuticals, Inc. Methods and compositions for the treatment of CNS-related conditions
US8283379B2 (en) 2005-04-06 2012-10-09 Adamas Pharmaceuticals, Inc. Methods and compositions for the treatment of CNS-related conditions
US20110064804A1 (en) * 2005-04-06 2011-03-17 Adamas Pharmaceuticals, Inc. Methods and Compositions for the Treatment of CNS-Related Conditions
EP2243475A1 (en) 2005-04-06 2010-10-27 Adamas Pharmaceuticals, Inc. Combination of memantine and donepezil for treatment of CNS disorders
US20100311697A1 (en) * 2005-04-06 2010-12-09 Adamas Pharmaceuticals, Inc. Methods and Compositions for the Treatment of CNS-Related Conditions
WO2007062272A1 (en) 2005-11-28 2007-05-31 Omega-Biopharma (H.K.) Limited Materials and methods for treating viral infections with a cysteamine compound
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US10646456B2 (en) 2013-06-17 2020-05-12 Adamas Pharma, Llc Methods of administering amantadine
US11903908B2 (en) 2013-06-17 2024-02-20 Adamas Pharma, Llc Methods of administering amantadine
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