The present invention is directed to compounds of Formulas (I, IIa and IIb):

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The invention also relates to pharmaceutical compositions comprising compounds of Formulas (I, IIa and IIb). Methods of making and using the compounds of Formulas (I, IIa and IIb) are also within the scope of the invention.

The present invention relates to methods for treating patients with chronic cough with nalbuphine compositions as well as treating cough, breathlessness, or dyspnea associated with IPF with nalbuphine compositions, wherein the method provides a therapeutic effect in a patient.

The present invention relates to methods for treating patients with chronic cough with nalbuphine compositions as well as treating cough, breathlessness, or dyspnea associated with IPF with nalbuphine compositions, wherein the method provides a therapeutic effect in a patient.

Disclosed are stemospironine salts of Formula 1: wherein HX represents HCl, HBr, L-tartaric acid, D-tartaric acid, sulfuric acid, (+)-(1S)-10-camphorsulfonic acid, ethanesulfonic acid and ethane-1,2-disulfonic acid. This invention also provides crystalline polymorph forms of the compound of Formula 1 wherein HX is HCl, stemospironine hydrochloride. This invention also provides a new crystalline form of the compound of Formula 2, stemospironine free base: Also disclosed are compositions containing one or more compounds of Formula 1, methods for controlling cough comprising administering a therapeutically effective amount of a compound of Formula 1, and methods for preparing compounds of Formula 1. Also disclosed is a method for preparing crystalline stemospironine hydrochloride polymorph Form II from stemospironine hydrochloride polymorph Form I. ##STR00001##

The invention relates to organic chemistry, pharmacology and medicine and is concerned with the treatment of inflammatory and autoimmune diseases, such as psoriasis, atopic dermatitis, prurigo, Crohn's disease, colitis, gastrointestinal diseases such as diarrhoea and irritable bowel syndrome, respiratory diseases such as asthma, COPD, bronchitis, rhinitis, and also cough and a series of other diseases associated with the activity of opioid and tachykinin receptors and of TRPV1 and TRPM8 ion channels using a 2-phenylethylamine N-(p-hydroxyphenylacetyl)phenylalanine compound ##STR00001## The invention, and also pharmaceutically acceptable adducts, hydrates, solvates are agonists of opioid receptors, antagonists of tachykinin receptors and of TRPV1 and TRPM8 ion channels. The invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of the compound according to the invention.

The invention relates to organic chemistry, pharmacology and medicine and is concerned with the treatment of inflammatory and autoimmune diseases, such as psoriasis, atopic dermatitis, prurigo, Crohn's disease, colitis, gastrointestinal diseases such as diarrhoea and irritable bowel syndrome, respiratory diseases such as asthma, COPD, bronchitis, rhinitis, and also cough and a series of other diseases associated with the activity of opioid and tachykinin receptors and of TRPV1 and TRPM8 ion channels using a 2-phenylethylamine N-(p-hydroxyphenylacetyl)phenylalanine compound ##STR00001## The invention, and also pharmaceutically acceptable adducts, hydrates, solvates are agonists of opioid receptors, antagonists of tachykinin receptors and of TRPV1 and TRPM8 ion channels. The invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of the compound according to the invention.

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A method for treating, suppressing or alleviating cough or cough impulse in the field of biomedicine, comprising: administering to a subject in need thereof a therapeutically effective amount of a diaminopyrimidine compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof.

##STR00001##

A method for treating, suppressing or alleviating cough or cough impulse in the field of biomedicine, comprising: administering to a subject in need thereof a therapeutically effective amount of a diaminopyrimidine compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof.

The present discovery pertains generally to the field of therapeutic compounds. More specifically the present discovery pertains to a particular 1-di-alkyl-phosphinoyl-alkane, 1-(Diisopropyl-phosphinoyl)-nonane, referred to herein as “DIPA-1-9”. Surprisingly and unexpectedly, DIPA-1-9, is able to selectively treat (e.g., suppress) sensory discomfort arising from the lumenal epithelial lining of the pharynx and esophagus without side effects. Compared to structurally similar compounds, DIPA-1-9 did not have the problems of painful cold, stinging, or irritancy, or of adverse taste when applied in the oral cavity. To deliver the DIPA-1-9 to the lumenal epithelium of the pharynx and esophagus, an ideal formulation for delivery is a solution of DIPA-1-9 in syrup, at a concentration of 5 to 12 mg/mL and a delivery volume of less than 1 mL. The delivery unit can be a plastic vial with a design such that the syrup is poured onto the base of the tongue, next to the pillars of fauces. The DIPA-1-9 then reaches the nerve endings at the base of the epithelia and transduces signals of coolness and cold. Cooling of the pharyngeal and esophageal lining relieves discomfort and is useful for conditions such as throat irritation, pharyngitis, tonsillitis, cough, chronic cough, heartburn, chest pain, and esophagitis. Moreover, the elicitation of cooling in the pharynx and esophagus can be utilized to treat dysphagia, dyspepsia, and dyspnoea, and to enhance mucus expectoration in inflammatory airway disorders such as cystic fibrosis, asthma, and chronic obstructive pulmonary diseases (which includes bronchitis and bronchiectasis). A particularly preferred embodiment is DIPA-1-9 dissolved in a syrup vehicle in a delivery unit volume of less than 1 mL.

The present discovery pertains generally to the field of therapeutic compounds. More specifically the present discovery pertains to a particular 1-di-alkyl-phosphinoyl-alkane, 1-(Diisopropyl-phosphinoyl)-nonane, referred to herein as “DIPA-1-9”. Surprisingly and unexpectedly, DIPA-1-9, is able to selectively treat (e.g., suppress) sensory discomfort arising from the lumenal epithelial lining of the pharynx and esophagus without side effects. Compared to structurally similar compounds, DIPA-1-9 did not have the problems of painful cold, stinging, or irritancy, or of adverse taste when applied in the oral cavity. To deliver the DIPA-1-9 to the lumenal epithelium of the pharynx and esophagus, an ideal formulation for delivery is a solution of DIPA-1-9 in syrup, at a concentration of 5 to 12 mg/mL and a delivery volume of less than 1 mL. The delivery unit can be a plastic vial with a design such that the syrup is poured onto the base of the tongue, next to the pillars of fauces. The DIPA-1-9 then reaches the nerve endings at the base of the epithelia and transduces signals of coolness and cold. Cooling of the pharyngeal and esophageal lining relieves discomfort and is useful for conditions such as throat irritation, pharyngitis, tonsillitis, cough, chronic cough, heartburn, chest pain, and esophagitis. Moreover, the elicitation of cooling in the pharynx and esophagus can be utilized to treat dysphagia, dyspepsia, and dyspnoea, and to enhance mucus expectoration in inflammatory airway disorders such as cystic fibrosis, asthma, and chronic obstructive pulmonary diseases (which includes bronchitis and bronchiectasis). A particularly preferred embodiment is DIPA-1-9 dissolved in a syrup vehicle in a delivery unit volume of less than 1 mL.