Abstract

Pharmaceutical compositions of the invention include substituted riluzole prodrugs useful for the treatment of cancers including melanoma, breast cancer, brain cancer, and prostate cancer through the release of riluzole. Prodrugs of riluzole have enhanced stability to hepatic metabolism and are delivered into systemic circulation by oral administration, and then cleaved to release riluzole in the plasma via either an enzymatic or general biophysical release process.

IPC Classes  ?

• C07D 277/82 - Nitrogen atoms
• A61K 31/428 - Thiazoles condensed with carbocyclic rings
• A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• C07D 417/12 - Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The present disclosure is directed to a pharmaceutical formulation intended for oral delivery of synthetic or natural poorly permeable calcitonin gene-related peptide (CGRP) inhibitors or salts/solvates thereof having a therapeutic activity. The pharmaceutical formulation can include a synthetic or natural poorly permeable CGRP inhibitors or salt or solvate thereof in an amount 0.01-10 wt. % of the total weight of the formulation; a lipophilic phase comprising triglycerides of fatty acids in an amount of 50-80 wt. % of the total weight of the formulation; and at least one lipophilic surfactant comprising partial esters of polyol and fatty acids in an amount of about 10-50 wt. % of the total weight of the formulation.

IPC Classes  ?

• A61K 31/496 - Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• A61K 47/14 - Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• C07K 16/18 - Immunoglobulins, e.g. monoclonal or polyclonal antibodies against material from animals or humans
• A61K 47/26 - Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharidesDerivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin

Abstract

Provided is pharmaceutical composition for treating a pain disorder in a subject in need thereof, wherein the pharmaceutical composition includes a therapeutically active ingredient including an intranasally bioavailable CGRP inhibitor. Also provided is a method of treating a pain disorder in a subject in need thereof, wherein the method includes intranasally administering to the subject a composition including a therapeutically active component including an intranasally bioavailable CGRP inhibitor.

IPC Classes  ?

• A61P 25/06 - Antimigraine agents
• A61M 11/00 - Sprayers or atomisers specially adapted for therapeutic purposes
• A61M 13/00 - Insufflators for therapeutic or disinfectant purposes

Abstract

Provided is a pharmaceutical formulation in the form of a softgel dosage form including a calcitonin gene-related peptide (CGRP) inhibitor, a lipophilic phase, and at least one lipophilic surfactant. Also provided is a method for increasing bioavailability of a calcitonin gene-related peptide (CGRP) inhibitor in a subject, including orally administering the pharmaceutical formulation to increase the bioavailability of the CGRP inhibitor in the subject.

IPC Classes  ?

• C07K 14/00 - Peptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof
• A61K 38/00 - Medicinal preparations containing peptides

Abstract

Provided is a pharmaceutical composition including a calcitonin gene-related peptide (CGRP) inhibitor and an absorption increasing amount of a pharmaceutically acceptable substance, such as a carbohydrate surfactant. Also provided is a method for increasing bioavailability of a calcitonin gene-related peptide (CGRP) inhibitor in a subject, including orally administering to increase the bioavailability of the CGRP inhibitor in the subject.

IPC Classes  ?

• A61K 31/416 - 1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
• A61K 31/435 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
• A61K 31/445 - Non-condensed piperidines, e.g. piperocaine
• A61K 31/47 - QuinolinesIsoquinolines
• A61K 31/551 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogens as ring hetero atoms, e.g. clozapine, dilazep
• A61K 47/26 - Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharidesDerivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin

Abstract

Provided is a method for treating COVID-19 in a patient in need of such treatment, wherein the method includes administration to the patient of a therapeutically effective amount of CGRP inhibitor. Also provided is a pharmaceutical composition for treating COVID-19 in a patient in need of such treatment, wherein the pharmaceutical composition includes a therapeutically effective amount of CGRP inhibitor.

IPC Classes  ?

• A61K 38/23 - Calcitonins
• A61P 31/12 - Antivirals
• A61P 31/14 - Antivirals for RNA viruses
• C07K 14/585 - Calcitonins

Abstract

Provided is a fast-dispersing dosage form for oral delivery, wherein the fast-dispersing dosage form includes a rimegepant. Also provided is a method for delivering rimegepant to a subject, wherein the method includes orally administering to the subject a fast-dispersing dosage form including rimegepant.

IPC Classes  ?

• A61K 31/4709 - Non-condensed quinolines containing further heterocyclic rings
• A61K 9/20 - Pills, lozenges or tablets

Abstract

Provided is pharmaceutical composition for intranasal delivery, wherein the pharmaceutical composition includes a therapeutically active ingredient including a CGRP inhibitor. Also provided is a method for delivering a CGRP inhibitor to a subject, wherein the method includes intranasally administering to the subject a composition including a therapeutically active component including a CGRP inhibitor.

IPC Classes  ?

• A61K 9/00 - Medicinal preparations characterised by special physical form
• A61K 31/437 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• A61K 31/444 - Non-condensed pyridinesHydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. amrinone
• A61M 11/00 - Sprayers or atomisers specially adapted for therapeutic purposes
• A61M 13/00 - Insufflators for therapeutic or disinfectant purposes
• A61P 25/06 - Antimigraine agents

Abstract

Pharmaceutical compositions of the invention include substituted riluzole prodrugs useful for the treatment of cancers including melanoma, breast cancer, brain cancer, and prostate cancer through the release of riluzole. Prodrugs of riluzole have enhanced stability to hepatic metabolism and are delivered into systemic circulation by oral administration, and then cleaved to release riluzole in the plasma via either an enzymatic or general biophysical release process.

IPC Classes  ?

• C07D 277/82 - Nitrogen atoms
• A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• C07D 417/12 - Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group containing two hetero rings linked by a chain containing hetero atoms as chain links
• A61K 31/428 - Thiazoles condensed with carbocyclic rings

Abstract

The present disclosure is directed to a pharmaceutical formulation intended for oral delivery of synthetic or natural poorly permeable calcitonin gene-related peptide (CGRP) inhibitors or salts/solvates thereof having a therapeutic activity. The pharmaceutical formulation can include a synthetic or natural poorly permeable CGRP inhibitors or salt or solvate thereof in an amount 0.01-10 wt.% of the total weight of the formulation; a lipophilic phase comprising triglycerides of fatty acids in an amount of 50-80 wt.% of the total weight of the formulation; and at least one lipophilic surfactant comprising partial esters of polyol and fatty acids in an amount of about 10-50 wt.% of the total weight of the formulation.

IPC Classes  ?

• A61K 38/00 - Medicinal preparations containing peptides
• A61K 9/08 - Solutions
• A61K 9/10 - DispersionsEmulsions
• A61K 47/14 - Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• A61K 31/4545 - Non-condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine

Abstract

Disclosed are methods of treating breakthrough migraine in patients using breakthrough CGRP antagonists. Also disclosed are methods for the prophylactic treatment of migraine.

IPC Classes  ?

• A61P 25/06 - Antimigraine agents
• A61K 9/19 - Particulate form, e.g. powders lyophilised
• A61K 9/20 - Pills, lozenges or tablets
• A61K 31/437 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• A61K 31/444 - Non-condensed pyridinesHydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. amrinone
• C07D 401/12 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• C07D 401/14 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• C07K 14/12 - Mumps virusMeasles virus
• C07K 16/28 - Immunoglobulins, e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants

Abstract

Disclosed are prodrugs of CGRP antagonists, methods of treating CGRP related disorders, e.g., migraine, by administering to a patient in need thereof the prodrugs, pharmaceutical compositions comprising prodrugs and kits including the pharmaceutical compositions and instructions for use.

IPC Classes  ?

• A61K 31/438 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring being spiro-condensed with carbocyclic or heterocyclic ring systems
• A61K 31/4545 - Non-condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• A61K 31/496 - Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin

Abstract

Pharmaceutical compositions of the invention include substituted riluzole pro drugs useful for the treatment of amyotrophic lateral sclerosis (ALS) and related disorders through the release of riluzole, especially to avoid patient to patient variability in first pass, hepatic metabolism promoted by Cyp 1∧2. Pro-drugs of riluzole have enhanced stability to hepatic metabolism and are delivered into systemic circulation by oral administration, and then cleaved to release riluzole in the plasma via either an enzymatic or general biophysical release process. The invention further includes pro-drugs of riluzole useful for the treatment of disease states that can be treated with riluzole through the release of riluzole from a pro-drug agent.

IPC Classes  ?

• A61K 31/428 - Thiazoles condensed with carbocyclic rings
• A61K 31/4439 - Non-condensed pyridinesHydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• A61K 31/454 - Non-condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• A61K 31/496 - Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• A61K 31/541 - Non-condensed thiazines containing further heterocyclic rings
• A61K 31/4725 - Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
• A61K 31/5377 - 1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol

Abstract

Disclosed are methods of treating a disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of riluzole, or a pharmaceutically acceptable salt thereof, in the form of an oral solid molded fast-dispersing dosage form. Pharmaceutical compositions and kits are also disclosed.

IPC Classes  ?

• A61K 47/20 - Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• A61K 47/26 - Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharidesDerivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• A61K 31/428 - Thiazoles condensed with carbocyclic rings

Abstract

Disclosed are methods of treating CGRP related disorders, e.g., migraine, by administering to a patient in need thereof rimegepant or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions comprising rimegepant and kits including the pharmaceutical compositions and instructions are also disclosed.

IPC Classes  ?

• A61K 31/437 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• A61K 31/444 - Non-condensed pyridinesHydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. amrinone
• C07D 401/12 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• C07D 401/14 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• C07D 471/04 - Ortho-condensed systems
• A61P 25/06 - Antimigraine agents

Abstract

Disclosed are methods of treating ataxia by administering to a patient in need thereof a riluzole prodrug such as troriluzole. Pharmaceutical compositions and kits including the riluzole prodrugs are also disclosed.

IPC Classes  ?

• A61K 31/427 - Thiazoles not condensed and containing further heterocyclic rings
• A61K 31/428 - Thiazoles condensed with carbocyclic rings
• A61K 31/4985 - Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• A61P 35/00 - Antineoplastic agents
• C07D 277/82 - Nitrogen atoms
• C07D 417/12 - Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

Pharmaceutical compositions of the invention include substituted Lanicemine prodrugs useful for the treatment of conditions associated with dysregulation of NMDA receptor activity such as depression and depressive disordersthrough the release of Lanicemine, Prodrugs of Lanicemine have enhanced stability to hepatic metabolism and are delivered into systemic circulation by oral administration, and then cleaved to release Lanicemine in the plasma via either an enzymatic or general biophysical release process.

IPC Classes  ?

• C07D 401/12 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• A61K 31/4439 - Non-condensed pyridinesHydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole

Abstract

Disclosed are acyl benzo[d]thiazol-2-amines having a structure according to formula (I): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. The compounds may be useful for the treatment of various diseases including, for example, neurological disorders such as amyotrophic lateral sclerosis, bipolar disorder, treatment resistant and major depression, general anxiety disorder, and cancers such as melanoma, breast cancer, brain cancer, and prostate cancer.

IPC Classes  ?

• C07D 417/12 - Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group containing two hetero rings linked by a chain containing hetero atoms as chain links
• C07D 277/42 - Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals

Abstract

Disclosed are methods of treating cancer using a combination of an immunotherapeutic agent, such as, for example, a PD-1, PD-L1 or CTLA-4 checkpoint inhibitor, and a glutamate modulating agent such as riluzole or trigriluzole. Pharmaceutical compositions including the immunotherapeutic agents and glutamate modulating agents are also disclosed.

IPC Classes  ?

• A61K 31/428 - Thiazoles condensed with carbocyclic rings
• C07D 277/82 - Nitrogen atoms

Abstract

Disclosed are methods of treating cancer using a combination of an immunotherapeutic agent, such as, for example, a PD-1, PD-L1 or CTLA-4 checkpoint inhibitor, and a glutamate modulating agent such as riluzole or trigriluzole. Pharmaceutical compositions and kits including the immunotherapeutic agents and glutamate modulating agents are also disclosed.

IPC Classes  ?

• A61K 31/428 - Thiazoles condensed with carbocyclic rings
• C07D 277/82 - Nitrogen atoms

Abstract

Disclose are amine prodrugs and methods of synthesis thereof. In particular, the amine prodrug comprises a drug molecule and at least one or more prodrug appendage moieties and the method for synthesis the amine prodmg comprises a step of coupling the drag molecule and at least one or more prodrug appendage moieties. Also disclosed are exemplary riluzole prodrugs and methods of synthesis thereof.

IPC Classes  ?

• A61K 9/14 - Particulate form, e.g. powders
• A61P 25/16 - Anti-Parkinson drugs

Abstract

Pharmaceutical compositions of the invention include substituted riluzole prodrugs useful for the treatment of cancers including melanoma, breast cancer, brain cancer, and prostate cancer through the release of riluzole. Prodrugs of riluzole have enhanced stability to hepatic metabolism and are delivered into systemic circulation by oral administration, and then cleaved to release riluzole in the plasma via either an enzymatic or general biophysical release process.

IPC Classes  ?

• C07D 277/82 - Nitrogen atoms
• C07D 417/12 - Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group containing two hetero rings linked by a chain containing hetero atoms as chain links
• A61K 31/428 - Thiazoles condensed with carbocyclic rings
• A61K 31/427 - Thiazoles not condensed and containing further heterocyclic rings
• A61P 35/00 - Antineoplastic agents

Abstract

Pharmaceutical compositions of the invention include substituted riluzole prodrugs useful for the treatment of cancers including melanoma, breast cancer, brain cancer, and prostate cancer through the release of riluzole. Prodrugs of riluzole have enhanced stability to hepatic metabolism and are delivered into systemic circulation by oral administration, and then cleaved to release riluzole in the plasma via either an enzymatic or general biophysical release process.

IPC Classes  ?

• C07D 277/82 - Nitrogen atoms
• A61K 31/428 - Thiazoles condensed with carbocyclic rings
• A61P 25/00 - Drugs for disorders of the nervous system
• A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Abstract

Disclosed is sublingual administration of riluzole. In particular, a method for treating a neuropsychiatric disorder or symptom by administering a sublingual formulation of riluzole is provided. In addition, a method of relieving or reducing oral pain using the sublingual formulation of riluzole is disclosed.

IPC Classes  ?

• A61K 9/00 - Medicinal preparations characterised by special physical form
• A61K 9/08 - Solutions
• A61K 9/20 - Pills, lozenges or tablets
• A61K 31/428 - Thiazoles condensed with carbocyclic rings

Abstract

Disclosed is sublingual administration of riluzole. In particular, a method for treating a neuropsychiatric disorder or symptom by administering a sublingual formulation of riluzole is provided. In addition, a method of relieving or reducing oral pain using the sublingual formulation of riluzole is disclosed.

IPC Classes  ?

• A61K 9/00 - Medicinal preparations characterised by special physical form
• A61K 9/08 - Solutions
• A61K 9/20 - Pills, lozenges or tablets
• A61K 31/428 - Thiazoles condensed with carbocyclic rings

Abstract

Pharmaceutical compositions of the invention include substituted riluzole pro drugs useful for the treatment of amyotrophic lateral sclerosis (ALS) and related disorders through the release of riluzole, especially to avoid patient to patient variability in first pass, hepatic metabolism promoted by Cyp 1A2. Pro-drugs of riluzole have enhanced stability to hepatic metabolism and are delivered into systemic circulation by oral administration, and then cleaved to release riluzole in the plasma via either an enzymatic or general biophysical release process. The invention further includes pro-drugs of riluzole useful for the treatment of disease states that can be treated with riluzole through the release of riluzole from a pro-drug agent.

IPC Classes  ?

• A61K 31/541 - Non-condensed thiazines containing further heterocyclic rings
• A61K 31/428 - Thiazoles condensed with carbocyclic rings
• A61K 31/4439 - Non-condensed pyridinesHydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• A61K 31/454 - Non-condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• A61K 31/4725 - Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
• A61K 31/496 - Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• A61K 31/5377 - 1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol

Abstract

Disclosed are methods of treating ataxia by administering to a patient in need thereof a riluzole prodrug such as troriluzole. Pharmaceutical compositions and kits including the riluzole prodrugs are also disclosed.

IPC Classes  ?

• A61K 31/427 - Thiazoles not condensed and containing further heterocyclic rings
• A61K 31/428 - Thiazoles condensed with carbocyclic rings
• A61K 31/4985 - Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• A61P 35/00 - Antineoplastic agents
• C07D 277/82 - Nitrogen atoms
• C07D 417/12 - Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

Disclosed are methods of treating cancer using a combination of an immunotherapeutic agent, such as, for example, a PD-1, PD-L1 or CTLA-4 checkpoint inhibitor, and a glutamate modulating agent such as riluzole or trigriluzole. Pharmaceutical compositions and kits including the immunotherapeutic agents and glutamate modulating agents are also disclosed.

IPC Classes  ?

• A61K 31/428 - Thiazoles condensed with carbocyclic rings
• C07D 277/82 - Nitrogen atoms