Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/18—Sulfonamides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/12—Antidiarrhoeals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/04—Antipruritics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
  • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P23/00—Anaesthetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/06—Antimigraine agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
  • A61P25/10—Antiepileptics; Anticonvulsants for petit-mal
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
  • A61P25/12—Antiepileptics; Anticonvulsants for grand-mal
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/32—Alcohol-abuse
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/36—Opioid-abuse
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/10—Antioedematous agents; Diuretics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
  • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
  • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
  • C07C211/40—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing only non-condensed rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
  • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
  • C07C211/54—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to two or three six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
  • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
  • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
  • C07C215/14—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic the nitrogen atom of the amino group being further bound to hydrocarbon groups substituted by amino groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
  • C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
  • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
  • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C223/00—Compounds containing amino and —CHO groups bound to the same carbon skeleton
  • C07C223/04—Compounds containing amino and —CHO groups bound to the same carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
  • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
  • C07C229/16—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
  • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
  • C07C233/36—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
  • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
  • C07C233/40—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
  • C07C233/41—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
  • C07C233/62—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
  • C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
  • C07C233/79—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
  • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
  • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
  • C07C235/54—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
  • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
  • C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
  • C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
  • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
  • C07C311/07—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
  • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
  • C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/12—Radicals substituted by oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
  • C07D213/08—Preparation by ring-closure
  • C07D213/09—Preparation by ring-closure involving the use of ammonia, amines, amine salts, or nitriles
  • C07D213/12—Preparation by ring-closure involving the use of ammonia, amines, amine salts, or nitriles from unsaturated compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/81—Amides; Imides
  • C07D213/82—Amides; Imides in position 3
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
  • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
  • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
  • C07D251/40—Nitrogen atoms
  • C07D251/48—Two nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
  • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
  • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
  • C07D251/40—Nitrogen atoms
  • C07D251/54—Three nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
  • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
  • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
  • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
  • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing alicyclic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
  • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

• the invention relates to substituted cyclohexane derivatives that have an affinity to the ⁇ -opioid receptor and the ORL 1-receptor, methods for their production, medications containing these compounds and the use of these compounds for the production of medications.
• Cyclohexane derivatives that have an affinity to the ⁇ -opioid receptor and the ORL 1-receptor are known in the prior art.
• the known compounds occasionally exhibit a certain affinity to the hERG ion channel, the L-type calcium ion channel (phenylalkylamine, benzothiazepine, dihydropyridine binding sites) or to the sodium channel in the BTX assay (batrachotoxin), which can be respectively interpreted as an indication of cardiovascular side-effects.
• many of the known compounds exhibit only a slight solubility in aqueous media, which can adversely affect the bioavailability, inter alia.
• the chemical stability of the known compounds is often merely inadequate.
• the compounds occasionally do not exhibit an adequate pH, UV or oxidation stability, which can adversely affect the storage stability and also the oral bioavailability, inter alia.
• the known compounds have an unfavourable PK/PD (pharmacokinetic/pharmacodynamic) profile in some instances, which can be displayed, for example, in too long a duration of effect.
• the metabolic stability of the known compounds also appears to be in need of improvement.
• An improved metabolic stability can point to an increased bioavailability.
• a weak or absent interaction with transporter molecules that participate in the absorption and excretion of medicinal substances should be considered an indication of an improved bioavailability and possibly low interactions of medications.
• the interactions with the enzymes involved in the breakdown and excretion of medicinal substances should also be as low as possible, since such test results also indicate that low interactions of medications or none at all are possibly to be expected.
• the known compounds at times exhibit only a low selectivity with respect to the kappa-opioid receptor, which is responsible for side-effects such as e.g. dysphoria, sedation, diuresis.
• the known compounds at times exhibit a very high affinity to the ⁇ -opioid receptor, which appears to be associated with other side-effects, in particular respiratory depression, constipation and addiction dependence.
• WO 01/87838 discloses NK-1-receptor antagonists.
• DE 28 39 891 A1 discloses, inter alia, 4-(dimethylamino)-1-methyl-4-p-tolyl cyclohexyl acetate.
• the object forming the basis of the invention is to provide compounds that are suitable for pharmaceutical purposes and have advantages over the compounds of the prior art.
• substituted cyclohexane derivatives can be produced that have an affinity to the ⁇ -opioid receptor and the ORL 1-receptor.
• the invention relates to compounds of the general formula (1),
• Y 1 , Y 1 ′, Y 2 , Y 2 ′, Y 3 , Y 3 ′, Y 4 and Y 4 ′ are respectively selected independently of one another from the group comprising —H, —F, —Cl, —Br, —I, —CN, —NO 2 , —CHO, —R 0 , —C( ⁇ O)R 0 , —C( ⁇ O)H, —C( ⁇ O)—OH, —C( ⁇ O)OR 0 , —C( ⁇ O)NH 2 , —C( ⁇ O)NHR 0 , —C( ⁇ O)N(R 0 ) 2 , —OH, —OR 0 , —OC( ⁇ O)H, —OC( ⁇ O)R 0 , —OC( ⁇ O)OR 0 , —OC( ⁇ O)NHR 0 , —OC( ⁇ O)N(R 0 ) 2
• C 3-8 -cycloaliphatic preferably has 3, 4, 5, 6, 7 or 8 ring-carbon atoms); wherein with respect to “aliphatic” and “cycloaliphatic”, “mono- or polysubstituted” is understood to mean the mono- or polysubstitution, e.g.
• Y 1 , Y 1 ′, Y 2 , Y 2 ′, Y 3 , Y 3 ′, Y 4 and Y 4 ′ and also the combination of residues at substituents thereof such as e.g. —OR 0 , —OC( ⁇ O)R 0 , —OC( ⁇ O)NHR 0 , a substituent, e.g. R 0 , can assume different meanings within a substance for two or more residues, e.g. —OR 0 , —OC( ⁇ O)R 0 , —OC( ⁇ O)NHR 0 .
• the compounds according to the invention exhibit favourable binding to the ORL 1-receptor and the ⁇ -opioid receptor.
• the compounds according to the invention have an affinity ratio of ORL1/ ⁇ of at least 0.1.
• the ORL1/ ⁇ ratio is defined as 1/[K i(ORL1) /K i( ⁇ ) ]. It is particularly preferred if the ORL1/ ⁇ ratio amounts to at least 0.2 or at least 0.5, more preferred at least 1.0 or at least 2.0, further preferred at least 3.0 or at least 4.0, most preferred at least 5.0 or at least 7.5 and in particular at least 10 or at least 15. In a preferred embodiment the ORL1/ ⁇ ratio lies in the range of 0.1 to 30, more preferred 0.1 to 25.
• the compounds according to the invention have an ORL1/ ⁇ affinity ratio of more than 30, more preferred at least 50, further preferred at least 100, most preferred at least 200 and in particular at least 300.
• the compounds according to the invention preferably have a K i value on the ⁇ -opioid receptor of at maximum 500 nM, more preferred at maximum 100 nM, further preferred at maximum 50 nM, most preferred at maximum 10 nM and in particular at maximum 1.0 nM.
• the mixed ORL 1/ ⁇ agonists are thus distinguished by significantly increased safety margins compared to pure ⁇ -opioids. This results in a significantly increased “therapeutic window” in the treatment of pain conditions, preferably chronic pain, more preferred neuropathic pain.
• Y 1 , Y 1 ′, Y 2 , Y 2 ′, Y 3 , Y 3 ′, Y 4 and Y 4 ′ are respectively selected independently of one another from the group comprising —H, —F, —Cl, —Br, —I, —CN, —NH 2 , —NH—C 1-6 -aliphatic, —NH—C 3-8 -cycloaliphatic, —NH—C 1-6 -aliphatic-OH, —N(C 1-6 -aliphatic) 2 , —N(C 3-8 -cycloaliphatic) 2 , —N(C 1-6 -aliphatic-OH) 2 , —NO 2 , —NH—C 1-6 -aliphatic-C 3-8 -cycloaliphatic, —NH—C 1-6 -aliphatic-aryl, —NH—C 1-6 -aliphatic-heteroaryl, —NH-NH-
• Y 1 , Y 1 ′, Y 2 , Y 2 ′, Y 3 , Y 3 ′, Y 4 and Y 4 ′ are respectively selected independently of one another from the group comprising —H, —F, —Cl, —Br, —I, —CN, —NH 2 and —OH.
• one of the residues Y 1 , Y 1 ′, Y 2 , Y 2 ′, Y 3 , Y 3 ′, Y 4 and Y 4 ′ differs from —H and the remaining residues stand for —H.
• Y 1 , Y 1 ′, Y 2 , Y 2 ′, Y 3 , Y 3 ′, Y 4 and Y 4 ′ respectively stand for —H.
• Q preferably stands for —R 0 , —C( ⁇ O)Ro or —C( ⁇ NH)Ro. It is particularly preferred if Q stands for —C 1-8 -aliphatic, -aryl, -heteroaryl, —C 1-8 -aliphatic-aryl, —C 1-8 -aliphatic-deteroaryl, —C( ⁇ O)—C 1-8 -aliphatic, —C( ⁇ O)-aryl, —C( ⁇ O)-heteroaryl, —C( ⁇ O)—C 1-8 -aliphatic-aryl, —C( ⁇ O)—C 1-8 -aliphatic-aryl, —C( ⁇ O)—C 1-8 -aliphatic-heteroaryl, —C( ⁇ NH)—C 1-8 -aliphatic, —C( ⁇ NH)-aryl, —C( ⁇ NH)-heteroaryl, —C( ⁇ NH)—C 1-8
• Q stands for —C 1-8 -aliphatic, -aryl, -heteroaryl, —C 1-8 -aliphatic-aryl, —C( ⁇ O)-heteroaryl or —C( ⁇ NH)-heteroaryl.
• -aryl and -heteroaryl can respectively be unsubstituted or mono- or polysubstituted, preferably with substituents that are selected independently of one another from the group comprising —C 1-8 -aliphatic, —OH, —OC 1-8 -aliphatic, —C 1-8 -aliphatic-O—C 1-8 -aliphatic (e.g. —CH 2 —O—CH 3 ), —CF 3 , —F, —Cl, —Br, —NO 2 , —CN, -heteroaryl, —C 1-8 -aliphatic-aryl and —C 1-8 -aliphatic-heteroaryl.
• substituents that are selected independently of one another from the group comprising —C 1-8 -aliphatic, —OH, —OC 1-8 -aliphatic, —C 1-8 -aliphatic-O—C 1-8 -aliphatic (e.g. —
• Q is selected from the group comprising —C 1-8 -alkyl, -phenyl, -benzyl, -pyrrolyl, -furyl, -thienyl, pyridyl, -indolyl, -benzofuryl and -benzothienyl, wherein these can respectively be unsubstituted or mono- or polysubstituted, preferably with substituents that are selected independently of one another from the group comprising —C 1-8 -aliphatic, —OH, —OC 1-8 -aliphatic, —C 1-8 -aliphatic-O—C 1-8 -aliphatic, —CF 3 , —F, —Cl, —Br, —NO 2 , —CN, -heteroaryl, —C 1-8 -aliphatic-aryl and —C 1-8 -aliphatic-heteroaryl (e.g. -ethyl
• R 0 respectively independently, preferably stands for —C 1-8 -aliphatic, —C 3-12 -cycloaliphatic, -aryl, -heteroaryl, —C 1-8 -aliphatic-C 3-12 -cycloaliphatic, —C 1-8 -aliphatic-aryl or —C 1-8 -aliphatic-heteroaryl.
• —C 1-8 -aliphatic-C 3-12 -cycloaliphatic, —C 1-8 -aliphatic-aryl or —C 1-8 -aliphatic-heteroaryl mean that the residues —C 3-12 -cycloaliphatic, -aryl or -heteroaryl are respectively bonded via a bivalent bridge —C 1-8 -aliphatic-.
• Preferred examples of —C 1-8 -aliphatic-aryl are —CH 2 —C 6 H 5 , —CH 2 CH 2 —C 6 H 5 , and —CH ⁇ CH—C 6 H 5 .
• R 1 and R 2 independently of one another, preferably stand for —H; —C 1-6 -aliphatic; —C 3-8 -cyclo-aliphatic, —C 1-6 -aliphatic-aryl, —C 1-6 -aliphatic-C 3-8 -cycloaliphatic or —C 1-6 -aliphatic-heteroaryl; or the residues R 1 and R 2 together form a ring and represent —CH 2 CH 2 OCH 2 CH 2 —, —CH 2 CH 2 NR 4 CH 2 CH 2 — or —(CH 2 ) 3-6 —, on condition that R 1 and R 2 preferably do not both stand for —H at the same time.
• R 1 and R 2 independently of one another, stand for —H; —C 1-5 -aliphatic; or the residues R 1 and R 2 together form a ring and represent —CH 2 CH 2 OCH 2 CH 2 —, —CH 2 CH 2 NR 4 —CH 2 CH 2 — or —(CH 2 ) 3-6 —, wherein R 4 preferably represents —H or —C 1-5 -aliphatic, on condition that R 1 and R 2 preferably do not both stand for —H at the same time.
• R 1 and R 2 independently of one another, stand for —CH 3 or —H, wherein R 1 and R 2 do not simultaneously represent —H; or R 1 and R 2 form a ring and represent —(CH 2 ) 3-4 —.
• Compounds, in which R 1 and R 2 stand for —CH 3 or in which R 1 stands for —H and R 2 stands for —CH 3 are most particularly preferred.
• R 3 preferably stands for —C 1-8 -aliphatic, —C 3-8 -cycloaliphatic, -aryl, -heteroaryl; or for -aryl, -heteroaryl or —C 3-8 -cycloaliphatic respectively bonded via a —C 1-3 -aliphatic group.
• R 3 stands for -ethyl, -propyl, -butyl, -pentyl, -hexyl, -heptyl, -cyclopentyl, -cyclohexyl, -phenyl, -benzyl, -naphthyl, -anthracenyl, -thiophenyl, -benzothio-phenyl, -furyl, -benzofuranyl, -benzodioxolanyl, -indolyl, -indanyl, -benzodioxanyl, -pyrrolyl, -pyridyl, -pyrimidyl or -pyrazinyl, respectively unsubstituted or mono- or polysubstituted; —C 5-6 -cycloaliphatic, -phenyl, -naphthyl, -anthraceny
• R 3 stands for -propyl, -butyl, -pentyl, -hexyl, -phenyl, -furyl, -thiophenyl, -naphthyl, -benzyl, -benzofuranyl, -indolyl, -indanyl, -benzodioxanyl, -benzodioxolanyl, -pyridyl, -pyrimidyl, -pyrazinyl, -triazolyl or -benzothiophenyl, respectively unsubstituted or mono- or polysubstituted; -phenyl, -furyl or -thiophenyl, respectively unsubstituted or mono- or polysubstituted, bonded via a saturated, unbranched —C 1-3 -aliphatic group.
• R 3 stands for -propyl, -butyl, -pentyl, -hexyl, -phenyl, -phenethyl, -thiophenyl, -pyridyl, -triazolyl, -benzothiophenyl or -benzyl, respectively substituted or unsubstituted, particularly preferred for -propyl, -3-methoxypropyl, -butyl, -pentyl, -hexyl, -phenyl, -3-methylphenyl, -3-fluorophenyl, -benzo[1,3]-dioxolyl, -thienyl, -benzothiophenyl, -4-chlorobenzyl, -benzyl, -3-chlorobenzyl, -4-methylbenzyl, -2-chlorobenzyl, -4-fluorobenzyl, -3-methyl
• R 3 stands for -butyl, -ethyl, -3-methoxypropyl, -benzothiophenyl, -phenyl, -3-methylphenyl, -3-fluorophenyl, -benzo[1,3]-dioxolyl, -benzyl, -1-methyl-1,2,4-triazolyl, -thienyl or -phenethyl.
• R 3 stands for -phenyl, -benzyl or -phenethyl, respectively unsubstituted or mono- or polysubstituted on the ring; —C 1-5 -aliphatic, —C 4-6 -cycloaliphatic, -pyridyl, -thienyl, -thiazolyl, -imidazolyl, -1,2,4 triazolyl or -benzimidazolyl, unsubstituted or mono- or polysubstituted.
• R 3 stands for -phenyl, -benzyl, -phenethyl, -thienyl, -pyridyl, -thiazolyl, -imidazolyl, -1,2,4 triazolyl, -benzimidazolyl or -benzyl, unsubstituted or mono- or polysubstituted with —F, —Cl, —Br, —CN, —CH 3 , —C 2 H 5 , —NH 2 , —NO 2 , —SH, —CF 3 , —OH, —OCH 3 , —OC 2 H 5 or —N(CH 3 ) 2 ; -ethyl, -n-propyl, -2-propyl, -allyl, -n-butyl, -iso-butyl, -sec-butyl, -tert-butyl, -n-pentyl,
• R 3 stands for -phenyl, unsubstituted or mono-substituted with —F, —Cl, —CN, —CH 3 ; -thienyl; -ethyl, -n-propyl or -n-butyl, unsubstituted or mono- or polysubstituted with —OCH 3 , —OH or —OC 2 H 5 , in particular with —OCH 3 .
• R 4 preferably stands for —H, —C 1-5 -aliphatic, —C 3-8 -cycloaliphatic, -aryl, -heteroaryl, —C 1-6 -aliphatic-aryl, —C 1-6 -aliphatic-C 3-8 -cycloaliphatic, —C 1-6 -aliphatic-heteroaryl, —C( ⁇ O)aryl, —C( ⁇ O)heteroaryl, or —C( ⁇ O)C 1-6 -aliphatic, more preferred for —H or —C 1-5 -aliphatic.
• R B preferably stands for —H, —C 1-6 -aliphatic, —C 3-8 -cycloaliphatic, —C 1-6 -aliphatic-C 3-8 -cyclo-aliphatic, —C 1-6 -aliphatic-aryl, —C 1-6 -aliphatic-heteroaryl, -aryl, -heteroaryl, —C( ⁇ O)H, —C( ⁇ O)C 1-6 -aliphatic , —C( ⁇ O)C 3-8 -cycloaliphatic, —C( ⁇ O)C 1-6 -aliphatic-C 3-8 -cycloaliphatic, —C( ⁇ O)C 1-6 -aliphatic-aryl, —C( ⁇ O)C 1-6 -aliphatic-heteroaryl, —C( ⁇ O)—C 3-8 -cycloaliphatic-heteroaryl, —C( ⁇ O)—C 3-8 -cycloali
• R B stands for —H, —C 1-8 -aliphatic, —C 1-8 -aliphatic-aryl, —C 1-8 -aliphatic-heteroaryl, —C( ⁇ O)—C 1-8 -aliphatic, —C( ⁇ O)—C 1-8 -aliphatic-aryl, —C( ⁇ O)—C 1-8 -aliphatic-heteroaryl, —C( ⁇ O)—C 3-8 -cycloaliphatic-aryl, —C( ⁇ O)—C 3-8 -cycloaliphatic-heteroaryl, —C( ⁇ O)NH—C 1-8 -aliphatic, —S( ⁇ O) 1-2 —C 1-8 -aliphatic, —S( ⁇ O) 1-2 -aryl, —S( ⁇ O) 1-2 -heteroaryl, —S( ⁇ O) 1-2 —C 1-8 -aliphatic-aryl,
• X preferably stands for —O— or —NR A —, particularly preferred for —NR A —.
• R B preferably does not stand for —H. If R B stands for —H, then n is preferably 1, 2, 3 or 4. If X stands for —O—, then n preferably stands for 0 or 1 and R B preferably stands for —C 1-8 -aliphatic or —C 1-8 -aliphatic-aryl.
• R A stands for —H, —R 0 , —S( ⁇ O) 0-2 R 0 , —C( ⁇ O)R 0 , —C( ⁇ O)OR 0 , —C( ⁇ O)NH 2 , —C( ⁇ O)NHR 0 or —C( ⁇ O)N(R 0 ) 2 ; preferably for —H or —R 0 (in particular —C 1-8 -aliphatic); particularly preferred for —H or —CH 3 ; or R A jointly with R B forms a ring and stands for —(CH 2 ) 3-4 —.
• R B —X—(CH 2 ) n —” preferably stands for
• R A R B . In another preferred embodiment of the compounds according to the invention R A ⁇ R B .
• n 0 and X stands for —NR A —. This then concerns geminally di-substituted 1,4-diamines of the general formula (1.1)
• hydrocarbon residues are divided into aliphatic hydrocarbon residues and aromatic hydrocarbon residues.
• Cycloaliphatic compounds can be monocyclic or multicyclic.
• Alicyclic hydrocarbon residues (“cycloaliphatic”) comprise both pure aliphatic carbocycles and aliphatic heterocycles, i.e.—unless expressly specified—“cycloaliphatic” comprises pure aliphatic carbocycles (e.g. cyclohexyl), pure aliphatic heterocycles (e.g. piperidyl or piperazyl) and also non-aromatic, multicyclic, possibly mixed, systems (e.g. decalinyl, decahydroquinolinyl).
• the classification of multicyclic, at least partially aromatic systems preferably depends on whether at least one aromatic ring of the multicyclic system has at least one heteroatom (usually N, O or S) in the ring. If at least one such heteroatom is present in this ring, this is preferably a “heteroaryl” (even if a further carbocyclic aromatic or non-aromatic ring with or without heteroatom is possibly present as additionally present cycle of the multicyclic system); if such a heteroatom is not present in any of the possibly several aromatic rings of the multicyclic system, then this is preferably “aryl” (even if a ring heteroatom is present in a possibly additionally present non-aromatic cycle of the multicyclic system).
• C 1-3 -aliphatic covers e.g. —C 1-3 -alkyl, —C 1-3 -alkenyl and —C 1-3 -alkinyl, as well as e.g. —C 1-3 -alkylene-, —C 1-3 -alkenylene- and C 1-3 -alkinylene.
• Aliphatic is preferably respectively a branched or unbranched, saturated or a mono- or polyunsaturated, unsubstituted or mono- or polysubstituted, aliphatic hydrocarbon residue.
• the substituents are selected independently of one another from the group comprising —F, —Cl, —Br, —I, —CN, —NO 2 , —CHO, ⁇ O, —R 0 , —C( ⁇ O)R 0 , —C( ⁇ O)OH, —C( ⁇ O)OR 0 , —C( ⁇ O)NH 2 , —C( ⁇ O)NHR 0 , —C( ⁇ O)N(R 0 ) 2 , —OH, —OR 0 , —OC( ⁇ O)H, —OC( ⁇ O)R 0 , —OC( ⁇ O)OR 0 , —OC( ⁇ O)N
• aliphatic covers acyclic saturated or unsaturated hydrocarbon residues that can be branched or straight-chain, i.e. alkanyls, alkenyls and alkinyls.
• alkenyls have at least one C ⁇ C double bond
• alkinyls have at least one C ⁇ C triple bond.
• Preferred unsubstituted monovalent aliphatics comprise —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CH 2 CH 2 CH 2 —CH 2 CH 3 and —CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ; but also —CH ⁇ CH 2 , —C ⁇ CH, —CH 2 CH ⁇ CH 2 , —CH ⁇ CHCH 3 , —CH 2 C ⁇ CH, —C ⁇ CCH 3 and —CH ⁇ CHCH ⁇ CH 2 .
• Preferred unsubstituted bivalent aliphatics comprise —CH 2 —, —CH 2 CH 2 —, —CH 2 CH(CH 3 )—, —CH(CH 3 )—CH 2 —, —CH 2 CH 2 CH 2 —, —CH(CH 3 )CH 2 CH 2 —, —CH 2 CH(CH 3 )—CH 2 —, —CH 2 CH 2 CH(CH 3 )—, —CH—(CH 2 CH 3 )CH 2 — and —CH 2 CH 2 —CH 2 CH 2 —; but also —CH ⁇ CH—, —C ⁇ C—, —CH 2 CH ⁇ CH—, —CH ⁇ CHCH 2 —, —CH 2 C ⁇ C— and —C ⁇ CCH 2 —.
• Preferred substituted monovalent aliphatics comprise —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CF 2 CF 3 , —CH 2 OH, —CH 2 CH 2 OH, —CH 2 CHOHCH 3 , —CH 2 OCH 3 and —CH 2 CH 2 OCH 3 .
• Preferred substituted bivalent aliphatics comprise —CF 2 —, —CF 2 CF 2 —, —CH 2 CHOH—, —CHOHCH 2 — and —CH 2 CHOHCH 2 —, -Methyl-, -ethyl-, -n-propyl- and -n-butyl-are particularly preferred.
• Cycloaliphatic is preferably respectively a saturated or a mono- or polyunsaturated, unsubstituted or mono- or polysubstituted, aliphatic (i.e. not aromatic), mono- or multicyclic hydrocarbon residue.
• the number of ring-carbon atoms preferably lies in the specified range (i.e. a “C 3-8 -cycloaliphatic” preferably has 3, 4, 5, 6, 7 or 8 ring-carbon atoms).
• C 3-8 -cycloaliphatic is preferably a cyclic hydrocarbon with 3, 4, 5, 6, 7 or 8 ring-carbon atoms, saturated or unsaturated, but not aromatic, wherein possibly one or two carbon atoms are replaced independently of one another by a heteroatom S, N or O.
• cycloalkyl is mono- or polysubstituted
• the substituents are selected independently of one another from the group comprising —F, —Cl, —Br, —I, —CN, —NO 2 , —CHO, ⁇ O, —R 0 , —C( ⁇ O)R 0 , —C( ⁇ O)OH, —C( ⁇ O)OR 0 , —C( ⁇ O)NH 2 , —C( ⁇ O)NHR 0 , —C( ⁇ O)N(R 0 ) 2 , —OH, —OR 0 , —OC( ⁇ O)H, —OC( ⁇ O)R 0 , —OC( ⁇ O)OR 0 , —OC( ⁇ O)NHR 0 , —OC( ⁇ O)—N(R 0 ) 2 , —SH, —SR 0 , —SO 3 H, —S( ⁇ O) 1-2 —R
• C 3-8 -cycloaliphatic is selected from the group comprising cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, but also tetrahydropyranyl, dioxanyl, dioxolanyl, morpholinyl, piperidinyl, piperazinyl, pyrazolinonyl and pyrrolidinyl.
• “mono- or polysubstituted” is preferably understood to mean the mono- or polysubstitution, e.g. the mono-, di-, tri- or 4-substitution, of one or more hydrogen atoms by —F, —Cl, —Br, —I, —OH, —OC 1-6 -alkyl, —OC( ⁇ O)C 1-6 -alkyl, —SH, —NH 2 , —NHC 1-6 -alkyl, —N(C 1-6 -alkyl) 2 , —C( ⁇ O)OC 1-6 -alkyl or —C( ⁇ O)OH.
• aliphatic substituted or “cycloaliphatic substituted” means aliphatic or cycloaliphatic substituted with —F, —Cl, —Br, —I, —CN, —CH 3 , —C 2 H 5 , —NH 2 , —NO 2 , —SH, —CF 3 , —OH, —OCH 3 , —OC 2 H 5 or —N(CH 3 ) 2 , are preferred.
• Particularly preferred substituents are —F, —Cl, —OH, —SH, —NH 2 and —C( ⁇ O)OH.
• Polysubstituted residues are understood to be those residues that are polysubstituted, e.g. twice or three times either at different or at the same atoms, e.g. three times at the same C-atom, as in the case of —CF 3 or —CH 2 CF 3 , or at different sites, as in the case of —CH(OH)—CH ⁇ CH—CHCl 2 .
• the polysubstitution can occur with the same or with different substituents.
• a substituent may also be substituted itself.
• —Oaliphatic also covers —OCH 2 CH 2 O—CH 2 CH 2 OH, amongst others.
• aliphatic or cycloaliphatic is substituted with —F, —Cl, —Br, —I, —CN, —CH 3 , —C 2 H 5 , —NH 2 , —NO 2 , —SH, —CF 3 , —OH, —OCH 3 , —OC 2 H 5 or —N(CH 3 ) 2 . It is most particularly preferred if aliphatic or cycloaliphatic is substituted with —OH, —OCH 3 or —OC 2 H 5 .
• aryl respectively independently stands for a carbocyclic ring system with at least one aromatic ring, but without heteroatoms in this ring, wherein the aryl residues can possibly be condensed with further saturated, (partially) unsaturated or aromatic ring systems and each aryl residue can be present in unsubstituted or mono- or polysubstituted form, wherein the aryl substituents are the same or different and can be in any desired and possible position of the aryl.
• Preferred aryls are phenyl, naphthyl, anthracenyl, phenanthrenyl, fluoroanthenyl, fluoroenyl, indanyl and tetralinyl.
• Phenyl and naphthyl are particularly preferred.
• the aryl substituents can be the same or different and be in any desired and possible position of the aryl, and are selected independently of one another from the group comprising —F, —Cl, —Br, —I, —CN, —NO 2 , —CHO, ⁇ O, —R 0 , —C( ⁇ O)R 0 , —C( ⁇ O)OH, —C( ⁇ O)OR 0 , —C( ⁇ O)NH 2 , —C( ⁇ O)NHR 0 , —C( ⁇ O)N(R 0 ) 2 , —OH, —O(CH 2 ) 1-2 —O—, —OR 0 , —OC( ⁇ O)H, —OC( ⁇ O)R 0 , —OC( ⁇ O)OR 0 , —OC( ⁇ O)NHR 0
• Preferred substituted aryls are 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 2,3-dimethoxy-phenyl, 2,4-dimethoxy-phenyl, 3,4-dimethoxy-phenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 2,3-dimethyl-phenyl, 2,4-dimethyl-phenyl and 3,4-dimethyl-phenyl.
• Heteroaryl preferably stands for a 5-, 6- or 7-membered cyclic aromatic residue that contains 1, 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms, the same or different, are nitrogen, oxygen or sulphur, and the heterocycle can be unsubstituted or mono- or polysubstituted; wherein in the case of the substitution on the heterocycle, the substituents can be the same or different and can be in any desired and possible position of the heteroaryl; and wherein the heterocycle can also be part of a bi- or polycyclic system.
• Heteroaryl is preferably selected from the group comprising pyrrolyl, indolyl, furyl (furanyl), benzofuranyl, thienyl (thiophenyl), benzothienyl, benzothiadiazolyl, benzooxadiazolyl, benzothiazolyl, benzooxazolyl, benzotriazolyl, benzodioxolanyl, benzodioxanyl, phthalazinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazoyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl or
• heteroaryl is mono- or polysubstituted
• the heteroaryl substituents can be the same or different and can be in any desirable and possible position of the heteroaryl, and are selected independently of one another from the group comprising —F, —Cl, —Br, —I, —CN, —NO 2 , —CHO, ⁇ O, —R 0 , —C( ⁇ O)R 0 , —C( ⁇ O)OH, —C( ⁇ O)OR 0 , —C( ⁇ O)—NH 2 , —C( ⁇ O)NHR 0 , —C( ⁇ O)N(R 0 ) 2 , —OH, —O(CH 2 ) 1-2 O—, —OR 0 , —OC( ⁇ O)H, —OC( ⁇ O)R 0 , —OC( ⁇ O)OR 0 , —OC( ⁇ O)NHR 0 , —OC( ⁇ O)N(R
• aryl or “heteroaryl”, “mono- or polysubstituted” are understood to mean the mono- or polysubstitution, e.g. di-, tri-, 4- or 5-substitution, of one or more hydrogen atoms of the ring system.
• substituents or aryl and heteroaryl respectively selected independently of one another from —F, —Cl, —Br, —I, —CN, —CHO, —CO 2 H, —NH 2 , —NO 2 , —NHR 0 , —N(R 0 ) 2 , —N + (R 0 ) 3 , —N + (R 0 ) 2 O ⁇ , —SH, —SR 0 , —OH, —OR 0 , —C( ⁇ O)R 0 , —CO 2 R 0 , —C( ⁇ O)NH 2 , —C( ⁇ O)NHR 0 , —C( ⁇ O)N(R 0 ) 2 , —S( ⁇ O) 1-2 R 0 , —S( ⁇ O) 2 NH 2 , —SO 3 H, ⁇ O or —Ro.
• Preferred substituents are —F, —Cl, —Br, —I, —OH, —OC 1-6 -alkyl, —O—C( ⁇ O)—C 1-6 -alkyl, —SH, —NH 2 , —NHC 1-6 -alkyl, —N(C 1-6 -alkyl) 2 , —C( ⁇ O)OC 1-6 -alkyl or —C( ⁇ O)OH.
• aryl substituted or heteroaryl substituted means aryl or heteroaryl substituted with —F, —Cl, —Br, —I, —CN, —CH 3 , —C 2 H 5 , —NH 2 , —NO 2 , —SH, —CF 3 , —OH, —OCH 3 , —OC 2 H 5 or —N(CH 3 ) 2 , are preferred.
• Particularly preferred substituents are —F, —Cl, —OH, —SH, —NH 2 and —C( ⁇ O)OH.
• the compounds according to the invention can be present in the form of a single stereoisomer or mixture thereof, the free compounds and/or their physiologically compatible salts and/or solvates.
• the compounds according to the invention can be chiral or achiral, depending on the substitution pattern.
• the compounds according to the invention can be isomers, in which the substitution pattern in 1,4 position (1 position: >C(NR 1 R)R 3 ; 4 position: >CQ((CH 2 ) n XR B ) can also be referred to as syn/anti.
• “Syn/anti isomers” are a subgroup of the stereoisomers (configuration isomers).
• the diastereomer excess of the syn-isomer amounts to at least 50% de, more preferred at least 75% de, more preferred at least 90% de, most preferred at least 95% de, and in particular at least 99% de.
• the diastereomer excess of the anti-isomer amounts to at least 50% de, more preferred at least 75% de, more preferred at least 90% de, most preferred at least 95% de, and in particular at least 99% de.
• the compounds according to the invention are chiral, then they are preferably present as racemate or in concentrated form of an enantiomer.
• the enantiomer excess(ee) of the S-enantiomer amounts at least 50% ee, more preferred at least 75% ee, more preferred at least 90% ee, most preferred at least 95% ee, and in particular at least 99% ee.
• the enantiomer excess (ee) of the R-enantiomer amounts to at least 50% ee, more preferred at least 75% ee, more preferred at least 90% ee, most preferred at least 95% ee, and in particular at least 99% ee.
• Suitable methods for separating the enantiomers are known to the person skilled in the art.
• Preparative HPLC on chiral stationary phases and conversion into diastereomeric intermediates can be given as examples.
• the conversion into diastereomeric intermediates can occur, for example, as salt formation by means of chiral, enantiomer-pure acids.
• the salt can then be converted into the free base or another salt again.
• each reference to the compounds according to the invention covers all isomers (e.g. stereoisomers, diastereomers, enantiomers) in any desired mixture ratio.
• each reference to the compounds according to the invention covers the free compounds (i.e. the forms that are not present in the form of salt) and all physiologically compatible salts.
• physiologically compatible salts of the compounds according to the invention are present as salts with anions or acids of the respective compound with inorganic or organic acids, which are physiologically compatible—in particular on application in humans and/or mammals.
• physiologically compatible salts of specific acids are salts of: hydrochloric acid, hydrobromic acid, sulphuric acid, methane sulphonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, saccharinic acid, monomethyl sebacic acid, 5-oxo-proline, hexane-1-sulphonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl benzoic acid, ⁇ -liponic acid, acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic acid.
• the hydrochloride, citrate and hemicitrate are particularly preferred.
• Physiologically compatible salts with cations or bases are salts of the respective compound—as anion with at least one, preferably inorganic, cation, which are physiologically compatible—in particular on application in humans and/or mammals.
• Particularly preferred are the salts of the alkali and earth alkali metals, also ammonium salts, but in particular (mono-) or (di-) sodium, (mono-) or (di-) potassium, magnesium or calcium salts.
• (hetero)aryl stands for hetereoaryl or aryl; preferably phenyl; respectively unsubstituted or mono- or polysubstituted, wherein the substituents are preferably selected independently of one another from the group comprising —F, —Cl, —Br, —I, —CN, —NO 2 , —CHO, —R 0 , —C( ⁇ O)R 0 , —C( ⁇ O)H, —C( ⁇ O)OH, —C( ⁇ O)OR 0 , —C( ⁇ O)NH 2 , —C( ⁇ O)NH—R 0 , —C( ⁇ O)—N(R 0 ) 2 , —OH, —O(CH 2 ) 1-2 O—, —OR 0 , —OC( ⁇ O)H, —OC( ⁇ O)R 0 , —OC( ⁇ O)OR 0 , —OC( ⁇ O)
• Particularly preferred embodiments of the compounds according to the invention of the general formula (2) have the general formula (2.1), (2.2), (2.3), (2.4), (2.5), (2.6), (2.7), (2.8), (2.9), (2.10), (2.11), (2.12), (2.13) or (2.14):
• R C stands for —H, —F, —Cl, —Br, —I, —CN, —NO 2 , —CF 3 , —OH or —OCH 3 ; and, where present, (hetero)aryl stands for heteroaryl or aryl; preferably for -phenyl, -benzyl or -2-indolyl; respectively unsubstituted or mono- or polysubstituted, wherein the substituents are preferably selected independently of one another from the group comprising —F, —Cl, —Br, —I, —CN, —NO 2 , —CHO, —R 0 , —C( ⁇ O)R 0 , —C( ⁇ O)H, —C( ⁇ O)OH, —C( ⁇ O)OR 0 , —C( ⁇ O)NH 2 , —C( ⁇ O)—NH—R 0 ,
• Preferred representatives of the compounds of the general formula (2.14) are e.g. the compounds E-1 to E-12:
• Q′ stands for —(CH 2 ) 0-4 —, —C( ⁇ O)— or —C( ⁇ NH)—; and (hetero-)aryl stands for heteroaryl or aryl; preferably phenyl; respectively unsubstituted or mono- or polysubstituted, wherein the substituents are preferably selected independently of one another from the group comprising —F, —Cl, —Br, —I, —CN, —NO 2 , —CHO, —R 0 , —C( ⁇ O)R 0 , —C( ⁇ O)H, —C( ⁇ O)OH, —C( ⁇ O)OR 0 , —C( ⁇ O)NH 2 , —C( ⁇ O)NH—R 0 , —C( ⁇ O)—N(R 0 ) 2 , —OH, —O(CH 2 ) 1-2 O—, —OR 0 , —OC( ⁇ O)
• Particularly preferred embodiments of the compounds according to the invention of general formula (3) have the general formula (3.1), (3.2), (3.3), (3.4), (3.5), (3.6), (3.7) or (3.8):
• D stands for ⁇ O or ⁇ NH
• W stands for —O—, —S—, —NR 11 —, —CR 12 ⁇ CR 13 —, —CR 12 ⁇ N— or —N ⁇ CR 13 —; preferably for —O—, —S—, or —NR 11 —; particularly preferred for —NR 11 —;
• R 5 , R 6 , R 6 ′, R 11 , R 12 and R 13 respectively independently of one another stand for —H, —F, —Cl, —Br, —I, —CN, —NO 2 , —CHO, —R 0 , —C( ⁇ O)R 0 , —C( ⁇ O)H, —C( ⁇ O)OH, —C( ⁇ O)OR 0 , —C( ⁇ O)NH 2 , —C( ⁇ O)NHR 0 , —C( ⁇ O)—N(R 0 ) 2 , ——C
• R 6 and R 6 ′ together form a six-membered aromatic ring that has no hetero ring atoms, then the following functional groups respectively result:
• the five- or six-membered, saturated, partially unsaturated or aromatic ring possibly formed by R 5 and R 6 or R 6 and R 6 ′ or R 6 ′ and R 12 together can comprise one or two hetero ring atoms, which are selected independently of one another from N, S and O.
• this ring can be unsubstituted or mono- or polysubstituted, wherein the substituents are preferably selected independently of one another from the group comprising F, —Cl, —Br, —I, —CN, —NO 2 , —CHO, —R 0 , —C( ⁇ O)R 0 , —C( ⁇ O)H, —C( ⁇ O)OH, —C( ⁇ O)OR 0 , —C( ⁇ O)NH 2 , —C( ⁇ O)NHR 0 , —C( ⁇ O)—N(R 0 ) 2 , —OH, —O(CH 2 ) 1-2 O—, —OR 0 , —OC( ⁇ O)H, —OC( ⁇ O)R 0 , —OC( ⁇ O)OR 0 , —OC( ⁇ O)NHR 0 , —OC( ⁇ O)N(R 0 ) 2 , —SH
• R 5 preferably stands for —H, —F, —Cl or —R 0 ; more preferred for —H, —F, —C 1-8 -aliphatic, —C 1-8 -aliphatic-aryl, —C 1-8 -aliphatic-heteroaryl or —C 1-8 -aliphatic-O—C 1-8 -aliphatic (e.g. —CH 2 OCH 3 ).
• R 6 and R 6 ′ together form a six-membered, saturated, partially unsaturated or aromatic ring, which can possibly comprise one or two hetero ring atoms that are selected independently of one another from N, S and O.
• This formed ring can be unsubstituted or mono- or polysubstituted, wherein the substituents are preferably selected independently of one another from the group comprising —F, —Cl, —Br, —I, —CN, —NO 2 , —CHO, —R 0 , —C( ⁇ O)R 0 , —C( ⁇ O)H, —C( ⁇ O)OH, —C( ⁇ O)OR 0 , —C( ⁇ O)NH 2 , —C( ⁇ O)NHR 0 , —C( ⁇ O)—N(R 0 ) 2 , —OH, —O(CH 2 ) 1-2 O—, —OR 0 , —OC( ⁇ O
• R 11 , R 12 and R 13 are preferably selected independently of one another from the group comprising —H, —F, —Cl, —CN, —OH, —R 0 and —OR 0 . It is particularly preferred if R 11 , R 12 and R 13 — where present—are respectively —H.
• (hetero)aryl stands for heteroaryl or aryl; preferably phenyl; respectively unsubstituted or mono- or polysubstituted, wherein the substituents are preferably selected independently of one another from the group comprising —F, —Cl, —Br, —I, —CN, —NO 2 , —CHO, —R 0 , —C( ⁇ O)R 0 , —C( ⁇ O)H, —C( ⁇ O)OH, —C( ⁇ O)OR 0 , —C( ⁇ O)NH 2 , —C( ⁇ O)NH—R 0 , —C( ⁇ O)—N(R 0 ) 2 , —OH, —O(CH 2 ) 1-2 O—, —OR 0 , —OC( ⁇ O)H, —OC( ⁇ O)R 0 , —OC( ⁇ O)OR 0 , —OC( ⁇ O)NHR 0
• the substituents of the third generation cannot be substituted again, i.e. there are then no substituents of the fourth generation.
• the substituents of the second generation cannot be substituted again, i.e. there are then already no substituents of the third generation.
• the functional groups for R 0 to Y 4 ′ can possibly be respectively substituted, but the respective substituents cannot then themselves be substituted again.
• the substituents of the first generation cannot be substituted again, i.e. there are then neither substituents of the second generation nor substituents of the third generation.
• the functional groups for R 0 to Y 4 ′ are not respectively substituted.
• Embodiments of the compounds of the general formula (1) that are particularly preferred according to the invention are compounds of the general formula (2.2)
• Q stands for —C 1-8 -aliphatic (preferably —C 1-8 -alkyl), -aryl (preferably -phenyl), —C 1-8 -aliphatic-aryl (preferably —C 1-8 -alkyl-phenyl), -heteroaryl (preferably -indolyl), —C( ⁇ O)-heteroaryl (preferably —C( ⁇ O)-indolyl) or —C( ⁇ NH)-heteroaryl (preferably —C( ⁇ NH)-indolyl);
• R 1 stands for —CH 3 ;
• R 2 stands for —H or —CH 3 ; or R 1 and R 2 jointly form a ring and stand for —(CH 2 ) 3-4 —;
• X stands for —O— or —NR A —;
• R A stands for —H or —C 1-8 -aliphatic (preferably —C 1-8 -alkyl);
• R B
• the compounds according to the invention act, for example, on the relevant ORL 1-receptor in association with different diseases, and therefore they are suitable as pharmaceutical active substance in a medication.
• the invention additionally relates to medications, which contain at least one compound according to the invention, as well as possibly suitable additives and/or adjuvants and/or possibly further active substances.
• the compounds according to the invention have an affinity to the ⁇ -opioid or to the ORL 1-receptor comparable to the compounds disclosed as exemplary compounds in WO 03/008370. However, compared to these compounds they exhibit a higher selectivity with respect to the kappa-opioid receptor, which is responsible for side-effects such as e.g. dysphoria, sedation and diuresis. In addition, with a favourable ORL 1/ ⁇ affinity the compounds according to the invention exhibit a balanced affinity to the ⁇ -opioid receptor that is not too strong. This is an advantage, since the ⁇ -opioid receptor is associated with side-effects, in particular respiratory depression, constipation and addiction dependence. Therefore, they are particularly suitable for drug development.
• the medications according to the invention possibly contain suitable additives and/or adjuvants, hence also support materials, fillers, solvents, dilutants, colouring agents and/or binders, and can be administered as liquid medications in the form of injectable solutions, drops or juices, as semisolid medications in the form of granules, tablets, pellets, patches, capsules, plasters/spray plasters or aerosols.
• suitable additives and/or adjuvants hence also support materials, fillers, solvents, dilutants, colouring agents and/or binders, and can be administered as liquid medications in the form of injectable solutions, drops or juices, as semisolid medications in the form of granules, tablets, pellets, patches, capsules, plasters/spray plasters or aerosols.
• suitable additives and/or adjuvants hence also support materials, fillers, solvents, dilutants, colouring agents and/or binders, and can be administered as liquid medications in the form of injectable
• Preparations in the form of tablets, coated tablets, capsules, granules, drops, juices and syrups are suitable for oral application, solutions, suspensions, readily reconstituted dry preparations as well as sprays are suitable for parenteral, topical and inhalatory application.
• Compounds according to the invention in a depot, in dissolved form or in a plaster, possibly with the addition of skin-penetration promoters, are suitable preparations for percutaneous application. Preparation forms that may be applied orally or percutaneously can release the compounds according to the invention in a delayed manner.
• the compounds according to the invention can also be applied in parenteral long-term depot forms such as e.g. implants or implanted pumps. In principle, other additional active substances known to the skilled person can be added to the medications according to the invention.
• the amount of active substance to be administered to the patient varies depending on the weight of the patient, on the type of application, the indication and the degree of severity of the disease. Usually, 0.00005 to 50 mg/kg, preferably 0.001 to 0.5 mg/kg, of at least one compound according to the invention are applied.
• the medication also contains a further active substance, in particular an opioid, preferably a strong opioid, in particular morphine, or an anaesthetic, preferably hexobarbital or halothane.
• a further active substance in particular an opioid, preferably a strong opioid, in particular morphine, or an anaesthetic, preferably hexobarbital or halothane.
• a contained compound according to the invention is present in the form of pure diastereomer and/or enantiomer.
• ORL 1-receptor was identified in particular in the pain process.
• Compounds according to the invention can be used accordingly for the production of a medication for the treatment of pain, in particular of acute, neuropathic or chronic pain.
• the invention additionally relates to the use of a compound according to the invention for the production of a medication for the treatment of pain, in particular of acute, visceral, neuropathic or chronic pain.
• the invention further relates to the use of a compound according to the invention for the treatment of anxiety conditions, stress and stress-related syndromes, depressive illnesses, epilepsy, Alzheimer's disease, senile dementia, general cognitive dysfunctions, learning and memory disabilities (as nootropic), withdrawal symptoms, alcohol and/or drug and/or medication misuse and/or dependence, sexual dysfunctions, cardiovascular diseases, hypotension, hypertension, tinitus, pruritus, migraine, hearing impairment, deficient intestinal motility, eating disorders, anorexia, bulimia, mobility disorders, diarrhoea, cachexia, urinary incontinence, or as muscle relaxant, anticonvulsive or anaesthetic, or for coadministration in the treatment with an opioid analgesic or with an anaesthetic, for diuresis or anti-natriuresis, anxiolysis, for modulating movement activity, for modulating neurotransmitter release and for treating neuro-degenerative diseases associated therewith, for treating withdrawal symptoms and/or for reducing the addiction potential of opioid
• a used compound is present as a pure diastereomer and/or enantiomer, as a racemate or as non-equimolar or equimolar mixture of the diastereomers and/or enantiomers.
• the invention additionally relates to a method for treating, in particular in one of the aforementioned indications, a non-human mammal or human, which or who requires a treatment for pain, in particular chronic pain, by the administration of a therapeutically effective dose of a compound according to the invention or a medication according to the invention.
• the invention further relates to a method for producing the compounds according to the invention as outlined in the following description and examples.
• Structures of formula A-2 can be produced by the reaction of A-1 ketones with amines and Z-H acid reactants.
• Suitable Z-H reactants are e.g. hydrogen cyanide, 1,2,3-triazole, benzotriazole or pyrazole.
• a particularly preferred path to compounds of structure A-2 is the conversion of ketones with metal cyanides and the corresponding amine in the presence of acid, preferably in an alcohol, at temperatures of ⁇ 40 to 60° C., preferably at room temperature with alkali metal cyanides in methanol.
• a further particularly preferred path to compounds of structure A-2 is the conversion of ketones with 1,2,3-triazole and the corresponding amine in the presence of ? under dehydrating conditions, preferably using a water separator at elevated temperature in an inert solvent or using a molecular sieve or another dehydrating agent.
• structures similar to A-2 can be introduced with benzotriazole or pyrazole groups instead of triazole groups.
• A-3 cyclohexane-1,4-diamines can also be obtained by substituting suitable Z leaving groups in structures of formula A-2.
• suitable leaving groups are preferably cyano groups; 1,2,3-triazol-1-yl groups.
• Further suitable leaving groups are 1H-benzo[d][1,2,3]triazol-1-yl groups and pyrazol-1-yl groups (Katritzky et al., Synthesis 1989, 66-69).
• a particularly preferred path to compounds of structure A-3 is the conversion of A-2 aminonitriles with corresponding organometallic compounds, preferably Grignard compounds, preferably in ethers, preferably at RT.
• the organometallic compounds are either commercially available or can be produced using known methods.
• a further particularly preferred path to compounds of structure A-3 is the conversion of A-2 aminotriazoles with corresponding organometallic compounds, preferably Grignard compounds, preferably in ethers, preferably at RT.
• organometallic compounds are either commercially available or can be produced using methods known in specialist literature.
• Structures of formula A-4 can be produced by reacting A-1 ketones with primary amines and Z-H acid reactants.
• Suitable Z-H reactants are e.g. hydrogen cyanide, 1,2,3-triazole, benzotriazole or pyrazole.
• a particularly preferred path to compounds of structure A-4 is the conversion of ketones with metal cyanides and the corresponding amine in the presence of acid, preferably in an alcohol, at temperatures of ⁇ 40 to 60° C., preferably at room temperature with alkali metal cyanides in methanol.
• a further particularly preferred path to compounds of structure A-4 is the conversion of ketones with 1,2,3-triazole and the corresponding amine in the presence of ? under dehydrating conditions, preferably using a water separator at elevated temperature in an inert solvent or using a molecular sieve or another dehydrating agent.
• structures similar to A-4 can be introduced with benzotriazole or pyrazole groups instead of triazole groups.
• A-5 cyclohexane-1,4-diamines can also be obtained by substituting suitable Z leaving groups in structures of formula A-4.
• suitable leaving groups are preferably cyano groups; 1,2,3-triazol-1-yl groups.
• Further suitable leaving groups are 1H-benzo[d][1,2,3]triazol-1-yl groups and pyrazol-1-yl groups (Katritzky et al., Synthesis 1989, 66-69).
• a particularly preferred path to compounds of structure A-5 is the conversion of A-4 aminonitriles with corresponding organometallic compounds, preferably Grignard compounds, preferably in ethers, preferably at RT.
• the organometallic compounds are either commercially available or can be produced using known methods.
• a further particularly preferred path to compounds of structure A-5 is the conversion of A-4 aminotriazoles with corresponding organometallic compounds, preferably Grignard compounds, preferably in ethers, preferably at RT.
• organometallic compounds are either commercially available or can be produced using methods known in specialist literature.
• Cyclohexane-1,4-diamines of type A-3 can also be synthesised using methods known to the person skilled in the art.
• An introduction of (alkyl) substituents can then occur under conditions of a reductive amination by means of an aldehyde component.
• Such a method known to the skilled person can be the conversion with an aldehyde with the addition of a reducing agent, e.g. sodium boron hydride.
• a hydrolysis under acid conditions then results by splitting imine A-7, X ⁇ O.
• Substituted 4-alkoxycyclohexane-1-amines of type A-10 can be synthesised from the A-1 educt using methods known to the person skilled in the art.
• the conversion of A-9 carbinols to the substituted 4-alkoxycyclohexane-1-amines of type A-10 according to the invention can occur in organic solvents, e.g.
• PdCl 2 sodium, potassium or caesium carbonate or potassium phosphate in the presence of PdCl 2 , Pd(OAc) 2 , PdCl 2 (MeCN) 2 , PdCl 2 (PPh 3 ) 2 or [1,3-bis-(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)palladium(II)-chloride (PEPPSI®), possibly in the presence of additional ligands, e.g. triphenyl-, tri-o-tolyl-, tricyclohexyl or tri-t-butyl phosphine, possibly in the presence of phase transfer catalysts, e.g.
• phase transfer catalysts e.g.
• tetra-n-butyl ammonium chloride tetra-n-butyl ammonium hydroxide or tetra-n-butyl ammonium iodide, and at temperatures between 60° C. and 180° C., also microwave-assisted.
• Substituted 4-aminomethyl-cyclohexyl-1-amines of type A-14 can be synthesised from the known A-1 educts by methods known to the person skilled in the art. Working from ketones such as A-1, the intermediate A-11 alkenes are obtained by a Wittig olefination with phosphorus ylides. Compounds of formula A-12 can then be obtained from the corresponding A-11 precursors in the presence of a cobalt(II)-salen complex by hydrocyanation (Carreira et al. Angew. Chem. Int. Ed., 46, 2006, 4519). A conversion of the nitrile group in A-12 with a reducing agent, e.g.
• a hydride such as sodium or lithium boron hydride, sodium cyanoboron hydride, sodium triacetoxyboron hydride, diisobutyl aluminium hydride, lithium-tri-(sec-butyl)boron hydride (L-Selectride®) or lithium aluminium hydride, possibly in the presence of Lewis acids, e.g. ZnCl 2 , Ni(OAc) 2 or CoCl 2 , gives the A-13 amines.
• Lewis acids e.g. ZnCl 2 , Ni(OAc) 2 or CoCl 2
• Amines of type A-13 can be acylated, sulphonylated or carbamoylated to compounds of A-14 using methods known to the person skilled in the art. Such a method known to the skilled person can be the conversion with an anhydride or an acid chloride with the addition of a base, e.g. triethylamine.
• Amines of type A-13 can be reductively aminated to compounds of A-14 using methods known to the person skilled in the art. Such a method known to the skilled person can be the conversion with an aldehyde with the addition of a reducing agent, e.g. sodium boron hydride.
• a reducing agent e.g. sodium boron hydride.
• Substituted (4-aminocyclohexyl)methanols of type A-18 can be synthesised from the known A-15 educts by methods known to the person skilled in the art.
• a conversion of A-16 can occur with a reducing agent, e.g. a hydride such as sodium or lithium boron hydride, sodium cyanoboron hydride, sodium triacetoxyboron hydride, diisobutyl aluminium hydride, lithium-tri-(sec-butyl)boron hydride (L-Selectride®) or lithium aluminium hydride, possibly in the presence of Lewis acids, e.g. ZnCl 2 , Ni(OAc) 2 or CoCl 2 , and ketone acetal splitting using methods known to the skilled person by deprotection by means of acids.
• a reducing agent e.g. a hydride such as sodium or lithium boron hydride, sodium cyanoboron hydride, sodium triacetoxyboron hydride, diisobutyl aluminium hydride, lithium-tri-(sec-butyl)boron hydride (L-Selectride®) or lithium aluminium
• X is selected from the group alkyl, alkyl/alkylidene/alkylidene substituted with aryl or alkyl (saturated/unsaturated).
• a protection of the hydroxyl group according to methods known to the skilled person, e.g. by conversion with alkyl vinyl ethers, leads to the corresponding A-17 ⁇ -alkyloxy ethyl ethers.
• Structures of formula A-18 can be produced by reaction of A-17 ketones with amines and Z-H acid reactants.
• Suitable Z-H reactants are e.g. hydrogen cyanide, 1,2,3-triazole, benzotriazole or pyrazole.
• a particularly preferred path to such aminonitriles is the conversion of ketones with metal cyanides and the corresponding amine in the presence of acid, preferably in an alcohol, at temperatures of ⁇ 40 to 60° C., preferably at room temperature with alkali metal cyanides in methanol.
• a further particularly preferred path to such aminonitriles is the conversion of ketones with 1,2,3-triazole and the corresponding amine in the presence of ? under dehydrating conditions, preferably using a water separator at elevated temperature in an inert solvent or using a molecular sieve or another dehydrating agent.
• similar structures can be introduced with benzotriazole or pyrazole groups instead of triazole groups.
• the introduction of the residue R 3 can occur by substitution of suitable Z leaving groups such as has already been described for the conversion of A-2 to A-3, for example.
• PG is selected from the group of acetal protective groups for hydroxyl groups known to the skilled person, e.g. an ⁇ -alkyloxy ethyl ether protective group.
• the keto group can be converted into monomethyl aminonitrile using methods known from the specialist literature, in particular applying the literature texts relevant to the synthesis of A-1.
• A-19 aminonitriles can be converted into A-20 alkine derivatives with corresponding organometallic compounds, preferably organo-lithium and Grignard compounds, preferably in ethers, preferably at RT.
• organometallic compounds preferably organo-lithium and Grignard compounds, preferably in ethers, preferably at RT.
• the organometallic compounds are either commercially available or can be produced using known methods.
• A-20 alkine derivatives can be converted into the protected A-21 indole derivatives according to F. Messina et al./Tetrahedron: Asymmetry 11 (2000) 1681-1685.
• A-21 indole derivatives can be converted to A-22 indole derivatives using methods known from specialist literature (cf. Protective Groups in Organic Synthesis by Peter G. M. Wuts, Theodora W. Greene, WileyBlackwell; 4th Edition).
• A-22 indole derivatives can be converted into A-23 amides using methods known to the skilled person.
• Such a method known to the skilled person can be, for example, the conversion of A-22 with a carboxylic acid by adding a coupling reagent, e.g. carbonyl di-imidazole.
• A-22 indole derivatives can be converted into A-23 sulphonamides using methods known to the skilled person.
• Such a method known to the skilled person can be, for example, the conversion of A-22 with a sulphonyl chloride by adding a base, e.g. triethylamine.
• A-22 indole derivatives can be converted into A-23 amines using methods known to the skilled person.
• Such a method known to the skilled person can be, for example, the conversion of A-22 with an aldehyde by adding a reducing reagent, e.g. sodium boron hydride.
• Substituted cyclohexanamines of type A-25 can be synthesised from the A-1 educt by reaction with metallised alkines.
• the conversion of the A-8′ and A-9 carbinols to substituted 4-alkoxycyclohexane-1-amines of type A-10′ can occur in organic solvents, e.g. tetrahydrofuran, dimethylformamide, benzol, toluol, xylols, dimethoxyethane or diethylene glycol dimethyl ether, in the presence of an inorganic base, e.g.
• PdCl 2 sodium, potassium or caesium carbonate or potassium phosphate in the presence of PdCl 2 , Pd(OAc) 2 , PdCl 2 (MeCN) 2 , PdCl 2 (PPh 3 ) 2 or [1,3-bis-(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)palladium(II)-chloride (PEPPSI®), possibly in the presence of additional ligands, e.g. triphenyl-, tri-o-tolyl-, tricyclohexyl or tri-t-butyl phosphine, possibly in the presence of phase transfer catalysts, e.g.
• phase transfer catalysts e.g.
• tetra-n-butyl ammonium chloride tetra-n-butyl ammonium hydroxide or tetra-n-butyl ammonium iodide
• temperatures between 60° C. and 180° C. also microwave-assisted.
• a conversion of A-9′ metallised heterocycles with A-1 educt in organic solvents at temperatures between 24° C. and ⁇ 100° C. can also lead to carbinols of type A-10′.
• the subsequent cyclisation of A-10′ to the A-24 ammonium salt can occur in organic solvents in the presence of fluorinating agents at temperatures between 25° C. and ⁇ 100° C.
• the opening up of the A-24 salt to the substituted cyclohexanamines of type A-25 according to the invention can occur with suitable nucleophiles without or also in the presence of organic solvents at temperatures between 0° C. and 180° C., also microwave-assisted.
• Substituted cyclohexanamines of type A-26 and A-27 can be synthesised from the A-5 educt.
• the remaining leaving groups can be successively replaced by suitable nucleophiles (Nu) and the substituted cyclohexanamines of type A-26 and A-27 according to the invention are obtained.
• ether means diethyl ether, “EE” ethyl acetate and “DCM” dichloromethane.
• equivalents means substance amount equivalents, “mp” melting point or melting range, “decomp.” decomposition, “RT” room temperature, “abs.” absolute (free from water), “rac.” racemic, “conc.” concentrated, “min” minutes, “h” hours, “d” days, “% vol.” percent by volume, “% m” percent by mass and “M” is a concentration detail in mol/l.
• Silica gel 60 (0.040-0.063 mm) from E. Merck, Darmstadt was used as the stationary phase for the column chromatography.
• the thin-film chromatography tests were conducted with silica gel 60 F 254 HPTLC chromatoplates from E. Merck, Darmstadt.
• the mixture ratios of mobile solvents for chromatography tests are always given in volume/volume.
• a mixture of methanol (50 ml) and water (50 ml) was acidified with hydrochloric acid (37%, 0.2 ml) and mixed with an aqueous solution of dimethylamine (40%, 11.5 ml, 91 mmol) with ice cooling and stirring. Then 4-dimethylamino-4-phenylcyclohexanone (2.17 g, 10 mmol) and KCN (1.6 g, 24.6 mmol) were added to the solution. A clear solution was formed after 15 min. The ice cooling was removed and the batch stirred for 2.5 h at RT, and a white solid began to separate out after approx. 1 h. The batch was brought to approx. 0° C.
• N-methyl indole [1.31 g, 10 mmol dissolved in dry THF (10 ml)] was added to a solution of n-butyl lithium (2.5N in n-hexane, 4 ml, 10 mmol) in dry THF (10 ml) with the exclusion of moisture at 0° C.
• the batch was stirred for 60 min while maintaining the cooling, and a solid began to precipitate out after approx. 10 min.
• the addition of the diastereoisomer mixture from the previous step [1.33 g, 5 mmol, dissolved in dry THF (10 ml)] then occurred within 10 min. After the addition had ended the cooling was removed and the batch stirred a further 18 h after RT was reached.
• the more non-polar diastereoisomer (230 mg, 0.61 mmol) was dissolved in propan-2-ol (5 ml) in the boiling heat and mixed with a hot solution of citric acid [382 mg, 2 mmol, in propan-2-ol (4 ml)].
• a precipitate was separated out when the solution cooled to RT. The batch was left for 20 h at 5° C. to complete the precipitation, then the solid was separated by means of a fritted glass filter and dried. The bis-citrate was thus obtained as a vitreous solid with a yield of 310 mg (64%).
• step b) the analogous non-polar compound was also formed as a mixture, this (680 mg) was mixed with 2N HCl (20 ml) and stirred for 18 h at RT. A solid separated out.
• the reaction mixture was basified with 2N NaOH (30 ml) at room temperature.
• the aqueous phase was extracted with ethyl acetate (3 ⁇ 10 ml).
• the combined organic extracts were dried over MgSO 4 and then concentrated to low volume. Attempts to recrystallise the raw product formed (from ethyl acetate and DMSO) did not result in a separation of the impurity.
• step b) The more polar diastereoisomer from Example 1, step b) (248 mg, 0.66 mmol) was dissolved in propan-2-ol (5 ml) in the boiling heat and mixed with a hot solution of citric acid [382 mg, 2 mmol, in hot propan-2-ol (4 ml)]. A precipitate was separated out when the solution cooled to RT. The batch was left for 20 h at 5° C. to complete the precipitation, then the solid was separated by means of a fritted glass filter and dried. The citrate was thus obtained as bis-citrate with a yield of 380 mg (73%, melting point from 80° C.).
• the exemplary compound 1 (250 mg, 0.62 mmol) was mixed with 2N HCl (10 ml) and stirred for 3 h at RT and for 1 h at 50° C. (bath temperature). A precipitate separated out during the reaction time.
• the reaction mixture was firstly neutralised with K 2 CO 3 at room temperature and then strongly basified with 2N NaOH (1 ml). The aqueous phase was extracted with ethyl acetate (3 ⁇ 10 ml). The combined organic extracts were dried over MgSO 4 and then concentrated to low volume.
• the residue obtained (240 mg) was purified by chromatography [silica gel 60 G (10 g); cyclohexane/ethyl acetate 1:1, (100 ml)]. The title compound was thus separated from the starting product still present and obtained with a yield of 120 mg (48%) with a melting point of 165-169° C. (after re-crystallisation from ethanol).
• the exemplary compound 3 (360 mg, 0.9 mmol) was mixed with 2N HCl (10 ml) and stirred for 4 h at 70° C. (bath temperature).
• the reaction mixture was firstly neutralised with K 2 CO 3 at room temperature and then strongly basified with 2N NaOH (1 ml).
• the aqueous solution was extracted with ethyl acetate (3 ⁇ 10 ml).
• the combined organic extracts were dried over MgSO 4 and then concentrated to low volume.
• the residue obtained (240 mg) was purified by chromatography [silica gel 60 G (10 g); cyclohexane/ethyl acetate 1:1, (150 ml), ethyl acetate (50 ml)].
• the title compound was thus isolated with a yield of 234 mg (65%) with a melting point of 109-111° C. (after re-crystallisation from propan-2-ol).
• N-methyl indole [1.31 g, 10 mmol, dissolved in dry THF (10 ml)] was added to a solution of n-butyl lithium (2.5N in n-hexane, 4 ml, 10 mmol) in dry THF (10 ml) with exclusion of moisture at 0° C.
• the batch was stirred for 60 min while maintaining the cooling, and a solid began to separate out after approx. 10 min.
• the diastereoisomer mixture from the previous step [1.49 g, 5 mmol, dissolved in dry THF (20 ml)] was then added within 20 min. After the addition had ended the cooling was removed and the batch stirred a further 18 h after RT was reached.
• Exemplary compound 6, step b) (99 mg, 0.23 mmol) was mixed with 2N HCl (3 ml) and stirred for 18 h at RT. The solution turned orange in colour immediately after the acid was added.
• the reaction mixture was basified with 2N NaOH (5 ml) at room temperature.
• the aqueous phase was extracted with dichloromethane (3 ⁇ 10 ml).
• the combined organic extracts were dried over MgSO 4 and then concentrated to low volume.
• the residue obtained (84 mg) was purified by chromatography [silica gel 60 G (10 g); ethyl acetate (120 ml)]. The title compound was thus isolated with a yield of 68 mg (68%) and a melting point from 134° C.
• Phenyl lithium (8.4 mL, 15 mmol, 1.8 M solution in dibutyl ether) was provided in argon and mixed drop by drop with a solution of the diastereoisomer mixture from the previous step (1.29 g, 5 mmol) in diethyl ether (15 mL) at RT. During this, the temperature of the reaction mixture increased to 35° C. and a solid separated out. The reaction mixture was boiled for 30 min with reflux (bath 50° C.), then hydrolysed in an ice bath (0-10° C.) with 20% NH 4 Cl solution (10 mL) and the organic phase separated. The aqueous phase was extracted with ether (2 ⁇ 30 mL). The combined organic solutions were dried over Na 2 SO 4 and concentrated to low volume in a vacuum.
• step b) A solution of the exemplary compound 9, step b) (223 mg, 0.72 mmol) and formalin (1.0 mL, 37% aqueous solution) in acetonitrile (10 mL) was mixed in portions with sodium cyanoboron hydride (182 mg, 2.9 mmol) and stirred for 45 min at RT. Conc. acetic acid was then added until a neutral reaction occurred and was stirred for 45 min at RT. For work up the solvent was removed in a vacuum, the residue was taken up in 2N NaOH (10 mL) and then extracted with ether (3 ⁇ 10 mL). The organic solution was dried over Na 2 SO 4 and concentrated to low volume in a vacuum. The remaining residue was purified by flash chromatography with CHCl 3 /MeOH (9:1).
• the title compound of the previous step (5.84 g, 20.5 mmol) was dissolved in THF (115 mL) and mixed in drops with benzyl magnesium chloride 2M (36 mL, 71.57 mmol) with ice cooling. The reaction mixture was stirred overnight at room temperature. The reaction mixture was mixed with 20% ammonium chloride solution (15 mL) and water (10 mL) and extracted with diethyl ether (3 ⁇ 50 mL). The combined organic phases were washed with water (50 mL) and saturated NaCl solution (50 mL), dried over Na 2 SO 4 , filtered and concentrated to low volume in vacuum.
• analogous polar diastereomer could also be isolated during the purification of the exemplary compound 12 step b).
• reaction mixture was heated to ⁇ 5° C., mixed drop by drop with a solution of methyl iodide (4.25 g, 30 mmol) in abs. DMSO (25 mL) and stirred for 2 h at 50° C.
• water (30 mL) was added with ice bath cooling and extracted with cyclohexane (4 ⁇ 50 mL).
• the organic phase was washed with 20% ammonium chloride solution, dried over Na 2 SO 4 and concentrated to low volume in a vacuum. The remaining residue was purified by flash chromatography with CHCl 3 /MeOH (20:1).
• the title compound of the previous step (217 mg, 0.55 mmol) was dissolved in hot ethanol (4 mL) and mixed with a solution of citric acid (106 mg, 0.55 mmol) in hot ethanol (2 mL). After standing for 2 h in the refrigerator and adding ether, the solid formed was aspirated and dried in a vacuum.
• reaction mixture was heated to ⁇ 5° C., mixed in drops with a solution of benzyl bromide (1.28 g, 7.5 mmol) in abs. DMSO (10 mL) and stirred 2 h at 50° C.
• water (10 mL) was added with ice bath cooling and extracted with cyclohexane (4 ⁇ 20 mL).
• the organic phase was washed with 20% ammonium chloride solution, dried over Na 2 SO 4 and concentrated to low volume in a vacuum. The remaining residue was purified by flash chromatography with CHCl 3 /MeOH (40:1).
• reaction mixture was heated to ⁇ 5° C., mixed in drops with a solution of ethyl iodide (4.68 g, 30 mmol) in abs. DMSO (30 mL) and stirred for 2 h at 50° C.
• water (30 mL) was added with ice bath cooling and extracted with cyclohexane (4 ⁇ 50 mL).
• the organic phase was washed with 20% ammonium chloride solution, dried over Na 2 SO 4 and concentrated to low volume in a vacuum. The remaining residue was purified by flash chromatography with CHCl 3 /MeOH (20:1).
• N-(2-iodo-phenyl)-acetamide (522 mg, 2.0 mmol), the title compound of the previous step (631 mg, 2.0 mmol) and sodium carbonate (1.06 g, 10.0 mmol) were dissolved in abs. DMF (10 mL) in argon.
• the catalyst (PEPPSI, 272 mg, 0.4 mmol) was then added and the solution stirred for 24 h at 100° C.
• the black reaction solution was concentrated in a vacuum until dry, the residue dissolved in CHCl 3 and washed with water. The organic phase was dried over Na 2 SO 4 and concentrated to low volume in a vacuum. The remaining residue was purified by flash chromatography with CHCl 3 /MeOH (50:1).
• the title compound of the previous step (188 mg, 0.462 mmol) was dissolved in hot ethanol (4 mL) and mixed with a solution of citric acid (89 mg, 0.462 mmol) in hot ethanol (2 mL). After standing for 2 h in the refrigerator and adding ether, the solid formed was aspirated and dried in a vacuum.
• R—R-cobalt(II)-salen complex Jacobsen's ligand, 26.0 mg, 0.04 mmol
• dichloromethane 5 mL
• acetic acid 29 ⁇ L, 0.08 mmol, 2 eq.
• the batch was then concentrated to low volume in a vacuum and the excess acetic acid was azeotropically removed with toluol.
• the cobalt(III) catalyst produced was provided in abs. ethanol (5 mL) in argon.
• the title compound of the previous step (0.120 g, 0.48 mmol) was dissolved in abs. THF (2.5 mL) and mixed with triethylamine (72.0 ⁇ L, 0.53 mmol) and acetyl chloride (42.0 mg, 38.0 ⁇ l, 0.53 mmol). The reaction mixture was stirred for 16 h at room temperature. The batch was concentrated in a vacuum until dry, the residue taken up in ethyl acetate (10 mL) and washed with saturated NaHCO 3 solution (2 ⁇ 10 mL) and with saturated NaCl solution. The organic phase was dried over Na 2 SO 4 , filtered and concentrated to low volume in a vacuum.
• the title compound of the previous step (102 mg, 0.35 mmol) was dissolved in hot ethanol (4 mL).
• Citric acid (67.0 mg, 0.35 mmol) was dissolved in hot ethanol (1.0 mL) and added. The batch was subsequently stirred for 2 h at room temperature. Since no precipitate separated out, the solution was concentrated to low volume in a vacuum. The residue had ether stirred through it, was concentrated once again in a vacuum and then dried in a vacuum. The desired citrate was obtained as a porous solid.
• step c) The title compound from Example 17, step c) (0.160 g, 0.65 mmol) was dissolved in abs. THF (3.4 mL), mixed with triethylamine (97 ⁇ L, 0.714 mmol) and 4-chlorobenzol sulphonic acid chloride (151 mg, 0.71 mmol) and stirred for 1 d at room temperature. The batch was concentrated in a vacuum until dry and the residue purified by flash chromatography: 1st column with ethyl acetate/ethanol (9:1) and 2nd column with ethyl acetate.
• the title compound of the previous step (0.070 g, 0.17 mmol) was dissolved in hot isopropanol (4 mL).
• Citric acid (32.0 mg, 0.17 mmol) was dissolved in hot isopropanol (1.0 mL) and added.
• the batch was stirred for 2 h at room temperature. Since no precipitate separated out, the solution was concentrated to low volume in a vacuum. The residue had ether stirred through it, was concentrated once again in a vacuum and then dried in a vacuum. The desired citrate was obtained as a porous solid.
• the cobalt(III) catalyst (297 mg, 0.456 mmol) was provided in abs. ethanol (100 mL) in argon.
• the title compound of the previous step (11.6 g, 45.3 mmol) dissolved in ethanol (40 mL) was then added and p-toluol sulphonyl cyanide (13.0 g, 68.0 mmol), phenyl silane (5.6 mL, 45.3 mmol) and ethanol (10 mL) were then added.
• the temperature rose to 35° C. and therefore the mixture was cooled with ice water.
• the batch was stirred for 72 h at room temperature and then concentrated in a vacuum until dry.
• the residue was purified by flash chromatography with chloroform/methanol (20:1).
• the pre-purified substance was purified again by MPLC column chromatography with chloroform/methanol (50:1, 20:1).
• step g the polar diastereoisomer was also obtained in pure state during the chromatographic separation.
• step 1 The title compound of step 1 (0.88 g, 2.94 mmol) was dissolved in THF (35 mL) and mixed in drops with 2M phenylmagnesium chloride solution (5.1 mL, 10.2 mmol) with ice cooling. The reaction solution was heated to boiling for 8 h. For work up the solution was mixed with 20% NH 4 Cl solution (0.6 mL) and water (0.4 mL) with ice cooling, extracted with ether (3 ⁇ 25 mL), the ether solution was washed with water, dried (Na 2 SO 4 ) and concentrated to low volume in a vacuum. The residue was purified by column chromatography with EtOH/EE (1:20). 2 fractions were obtained, wherein according to LCMS, inter alia, the more polar fraction (300 mg) contained the desired substance.
• the toluol phase was separated, the aqueous phase extracted with toluol (2 ⁇ 200 mL) and the combined organic phase washed with NaHCO 3 solution (2 ⁇ 200 mL) and water (2 ⁇ 200 mL) and dried with Na 2 SO 4 . The solvent was then removed in a vacuum.
• step 1 The title compound of step 1 (70.8 g, 261 mmol) in a mixture of acetic acid (810 mL) and concentrated hydrochloric acid (354 mL) was heated to boiling for 3.5 h under DC control. The mixture was then cooled to 0 to 5° C., diluted with water (1 L), saturated with NaCl and extracted cold with ethyl acetate (3 ⁇ 300 mL). The ethyl acetate phase was washed with water and concentrated to low volume in a vacuum. The solid residue was dissolved once again in ethyl acetate, washed with NaHCO 3 solution and concentrated until dry.
• step 2 The title compound of step 2 (43.3 g, 217 mmol) and ethylene glycol (27.4 g, 435 mmol) were boiled in toluol (430 mL) with the addition of p-toluol sulphonic acid (1.87 g, 10.9 mmol) at a water separator for 3 h with reflux. After the reaction had ended, the mixture was cooled, washed with NaHCO 3 solution and saturated NaCl solution, dried with Na 2 SO 4 and concentrated to low volume in a vacuum.
• step 4 The title compound of step 4 (5.40 g, 21.8 mmol) was dissolved in acetonitrile (150 mL), and a cloudy solution was formed. Aqueous 37% formalin solution (30.6 mL, 407 mmol) was added. The batch was stirred for 20 min at RT and then mixed with sodium cyanoboron hydride (5.76 g, 91.7 mmol). The reaction was followed by DC in chloroform/methanol (9:1). After 4 h the solution was adjusted to pH 7 with acetic acid and concentrated to low volume in a vacuum. The residue was taken up in chloroform, washed with NaHCO 3 solution and the aqueous phase extracted with ether. The combined organic phases were dried over Na 2 SO 4 and concentrated to low volume in a vacuum. The raw product was purified by flash chromatography with chloroform/methanol (50:1 ⁇ 20:1 ⁇ 9:1).
• step 5 The title compound of step 5 (5.40 g, 19.6 mmol) was dissolved in 5% H 2 SO 4 (300 mL) and stirred for 1 d at RT. The solution was then washed with ether three times and the ether phase discarded. The aqueous phase was made alkaline with 5N NaOH with ice cooling and extracted with dichloromethane three times. The organic phase was washed with a little water, dried over Na 2 SO 4 and concentrated to low volume in a vacuum.
• Phenyl lithium (33 mL, 60 mmol, 1.8 M solution in dibutyl ether) was mixed in drops with a solution of the title compound from step 1 (5.70 g, 20 mmol) in diethyl ether (60 mL) in argon and at room temperature. During this, the temperature of the reaction solution rose to 35° C. and a solid separated out. The reaction mixture was stirred with reflux for 30 min, then hydrolysed in an ice bath with 20% NH 4 Cl solution (40 mL) and the organic phase was separated. The aqueous phase was extracted with ether (3 ⁇ 100 mL). The combined organic phases were dried over Na 2 SO 4 , filtered and concentrated to low volume in a vacuum.
• Lithium aluminium hydride (440 mg, 11.6 mmol) was suspended in abs. THF (50 mL) in argon, mixed in drops with a solution of the title compound of step 3 (1.54 g, 5.53 mmol) in abs. THF (20 mL) and boiled for 4 h with reflux. The batch was then hydrolysed with water (10 mL) at 10° C. and filtered off over diatomaceous earth. The THF was removed in a vacuum, the residue adjusted to pH 11 with 1N NaOH and extracted with ethyl acetate. The combined organic phases were dried over Na 2 SO 4 , concentrated to low volume in a vacuum and the remaining residue was purified by flash chromatography with MeOH+2% NH 3 .
• step 1 The title compound from step 1 (290 mg, 0.702 mmol) was dissolved in abs. THF (15 mL) and mixed with LiAlH 4 (52 mg, 1.40 mmol) in argon. The batch was boiled for 7 h with reflux and then cooled to room temperature. The batch was filtered over a fritted glass filter with diatomaceous earth and subsequently rinsed with dichloromethane (50 mL). The combined filtrates were concentrated to low volume in vacuum.
• step 1 The title compound from step 1 (130 mg, 0.3 mmol) was dissolved in anisole (0.5 mL) and trifluoroacetic acid (2.5 mL) and stirred for 20 h at RT. The mixture was then concentrated until dry in a vacuum, 1N NaOH stirred through the solid residue, the solid filtered, washed with water and dried in a vacuum.
• step 1 The title compound from step 1 (6.80 g, 23 mmol) was dissolved in ether (100 mL), mixed with 5% H 2 SO 4 (100 mL) and the solution vigorously stirred for 2 d at RT. The phases were separated and the ether phase discarded. The aqueous phase was made alkaline with 5N NaOH with ice cooling and extracted three times with ether, the combined organic phases were then washed with water, dried over Na 2 SO 4 and concentrated to low volume in a vacuum.
• Phenyl lithium (12.9 mL, 23.3 mmol, 1.8 M solution in dibutyl ether) was provided in argon and mixed in drops with a solution of the title compound from step 3 (2.23 g, 7.76 mmol) in abs. diethyl ether (30 mL) at RT. During this, the reaction solution heated to 35° C. and a solid separated out. The reaction mixture was stirred for 1 h with reflux (bath 50° C.), then hydrolysed in the ice bath (0-10° C.) with 20% NH 4 Cl solution (20 mL) and the organic phase was separated. The aqueous phase was extracted with ether (3 ⁇ 50 mL).
• the polar diastereomer could also be isolated during the synthesis of the title compound from Example 68 as part of step 4.
• Lithium aluminium hydride (1.82 g, 48.0 mmol) was suspended in abs. THF (200 mL) in argon, mixed in drops with a solution of the title compound from step 3 (6.25 g, 24.0 mmol) in abs. THF (20 mL) and boiled for 4 h with reflux. The batch was then hydrolysed with water (20 mL) at 10° C. and filtered off over diatomaceous earth. The THF was removed in a vacuum, the residue adjusted to pH 11 with 1N NaOH and extracted with ethyl acetate. The combined organic phases were dried over Na 2 SO 4 , concentrated to low volume in a vacuum and the remaining residue separated by flash chromatography with MeOH+1% NH 3 .
• the aqueous phase was adjusted to pH 11 with 5N NaOH and extracted three times with ethyl acetate.
• the combined organic phases were dried over Na 2 SO 4 , concentrated to low volume in a vacuum and the remaining residue purified by flash chromatography with ethyl acetate/MeOH 1:1+1% NH 3 .
• the aqueous phase was adjusted to pH 11 with 5N NaOH and extracted three times with ethyl acetate.
• the combined organic phases were dried over Na 2 SO 4 , concentrated to low volume in a vacuum and the remaining residue purified by flash chromatography with ethyl acetate/MeOH (1:1+1% NH 3 ).
• the hydroxymethyl compound (240 mg, 0.57 mmol) was dissolved in 1N NaOH (2 mL) and THF (2 mL) and boiled for 2 h with reflux. The mixture was then extracted with ether (2 ⁇ 20 mL). The organic solution was dried over Na 2 SO 4 and concentrated to low volume in a vacuum. The remaining residue was purified by flash chromatography with EE/MeOH (1:1+1% NH 3 ).
• the hydroxymethyl compound was formed as intermediate product as part of the synthesis of Example 79.
• Example 103 The title compound of Example 103 (200 mg, 0.31 mmol) was dissolved in a 33% methylamine solution in ethanol (2 mL) and stirred in the microwave for 30 min at 100° C. and 60 min at 120° C. The precipitated precipitate was aspirated and dried in a vacuum.
• n-butyl lithium (8.39 mmol, 3.35 ml, 2.5M in hexane) was slowly added to a solution of skatole (1.00 g, 7.62 mmol) in absolute tetrahydrofuran (25 ml) in an argon atmosphere at ⁇ 78° C. A colourless precipitate was formed. After 10 min the solution was heated to room temperature. Carbon dioxide was then introduced into the reaction mixture for approx. 3 min. A colourless solution was formed. After 5 min the volatile constituents were completely removed in a vacuum at room temperature (water bath temperature ⁇ 30° C.). The colourless solid residue was again dissolved in absolute tetrahydrofuran (20 ml). The light yellow reaction mixture was cooled to ⁇ 78° C.
• the mother liquor was separated by chromatography [silica gel 60 (150 g); trichloromethane/ethanol 50:1 (500 ml), 19:1 (500 ml), 9:1 (300 ml), 5:1 (300 ml), 1:1 (300 ml), 0.5% triethylamine in each case, better begin with trichloromethane/ethanol 100:1].
• the obtained fractions of the two diastereoisomers had to be recrystallised from methanol.
• step 1 The alcohol from step 1 (both diastereoisomers, 2.20 g, 6.00 mmol) was suspended in absolute dichloromethane (50 ml) at ⁇ 78° C. Triethylamine (3.65 g, 36.02 mmol, 4.99, 0.73 g/ml), DMAP (16 mg, 0.12 mmol) and DAST (2.90 g, 18.01 mmol, 2.36 ml, 1.23 g/ml) were added one after the other. The solution was stirred for 1 h at ⁇ 78° C. The reaction mixture was then heated to room temperature within 10 h (overnight). Saturated sodium hydrogencarbonate solution (50 ml) was then added and stirred for 15 min (until the gas development was finished). Sodium hydroxide solution (5N, 20 ml) was then added and stirred for 10 min. The phases were separated.
• step 2 The title compound from step 2 (500 mg, 1.36 mmol) was suspended in acetonitrile/methanol (1:1.20 ml). Dimethylamine (2M in tetrahydrofuran, 14 ml, 27.15 mmol) was then added and stirred for 2 d at room temperature. The solution was stirred for 6 h at 80° C. (oil bath temperature), then applied to coarse silica gel and separated by flash chromatography [silica gel 60 (150 g); trichloromethane/ethanol 50:1 (1000 ml), 19:1 (500 ml), 9:1 (1000 ml), 0.5% triethylamine in each case]. The more non-polar diastereoisomer was firstly isolated.
• the non-polar diastereomer was also formed during the synthesis of the title compound of Example 94, step 3. 152 mg (0.39 mmol, 29%) (mp 126-132° C.) were isolated.
• E Cinnamic acid chloride
• polar diastereomer 98
• the raw product was mixed with water (10 mL) and extracted with dichloromethane (3 ⁇ 20 mL), the organic phase was then dried over Na 2 SO 4 and concentrated to low volume in a vacuum. The residue was purified by flash chromatography with ethyl acetate/methanol (9:1 ⁇ 4:1).
• step 1 The title compound from step 1 (57 mg, 0.12 mmol) was dissolved in a 2M dimethylamine solution in THF (2.0 mL, 4 mmol) and stirred in the microwave for 2 h at 120° C.
• the reaction solution was concentrated to low volume in a vacuum, the remaining residue taken up in ethyl acetate (10 mL) and washed with saturated NaHCO 3 solution (2 ⁇ 5 mL) and saturated NaCl solution (5 mL).
• the organic phase was dried over Na 2 SO 4 and concentrated to low volume in a vacuum.
• the raw product was purified by flash chromatography with ethyl acetate/MeOH (20:1).
• Example 131 The title compound from Example 131 (100 mg, 0.244 mmol) was provided in abs. dichloromethane (5 mL), mixed with trifluoroacetic anhydride (135 ⁇ L, 0.976 mmol) and stirred for 10 min. Tert-butyl alcohol (2 mL) was added to the batch and subsequently stirred for 30 min. The batch was then mixed with 10% NaOH and the phases separated. The organic phase was washed with H 2 O (1 ⁇ 10 mL), dried over Na 2 SO 4 and concentrated to low volume in a vacuum.
• step 1 The title compound of step 1 (166 mg, 0.39 mmol), 4-methoxyphenol (56 mg, 0.45 mmol) and sodium hydride (18 mg, 0.45 mmol, 60% dispersion in mineral oil) were stirred in abs. dioxan (10 mL) for 4 h at RT. The solvent was then removed in a vacuum, the remaining residue dissolved in ethyl acetate, washed with saturated NaHCO 3 solution and saturated NaCl solution, dried over Na 2 SO 4 and purified by flash chromatography with ethyl acetate/MeOH (4:1).
• Phenyl acetonitrile (11.7 g, 100 mmol) and methylacrylate (47 mL, 500 mmol) were provided in tert-butyl alcohol (60 mL) and heated to boiling. The heat source was then removed.
• Triton B benzyl trimethyl ammonium hydroxide, 40% in methanol, 15.2 mL
• tert-butyl alcohol 23 mL was firstly added slowly in drops and then quickly. After the addition in drops, the batch was heated to boiling for 4 h. The reaction mixture was cooled to room temperature overnight.
• the batch was mixed with toluol (100 mL) and water (70 mL), the organic phase separated and washed with water (70 mL) and saturated NaCl solution (50 mL). After drying with Na 2 SO 4 the solvent was distilled. Purification occurred by bulb tube distillation at a temperature of approx. 235° C. The product could be isolated as a colourless, viscous substance.
• step 3 The title compound from step 3 (8.91 g, 44.73 mmol) was taken up in toluol (300 mL) and mixed with ethylene glycol (6 mL, 106.8 mmol). After adding p-toluol sulphonic acid (0.128 g, 0.745 mmol), the batch was heated to boiling in the water separator for 3.5 h. The course of the reaction was followed by DC. After the reaction batch cooled, the toluol solution was extracted with water (5 ⁇ 60 mL) and saturated NaCl solution (3 ⁇ 40 mL) and dried over Na 2 SO 4 . After removal of the solvent in a vacuum, the ketone acetal was obtained as yellow solid.
• step 5 The title compound from step 5 (8.00 g, 30.48 mmol) was dissolved in dichloromethane (240 mL) and mixed with 1,3-diisopropyl carbodiimide (4.44 g, 5.44 mL, 35.52 mmol) and 1-hydroxy-1H-benzotriazole hydrate (5.44 g, 35.5 mmol) at 0° C. The reaction mixture was stirred for 5 min with ice cooling and then N-benzyl methylamine (3.87 g, 4.12 mL, 32.0 mmol) was added. The reaction mixture was stirred for 3 d at room temperature. For work up the batch was concentrated until dry in a vacuum. The residue was purified by flash chromatography with cyclohexane/ethyl acetate (1:1).
• step 6 The title compound from step 6 (1.20 g, 3.28 mmol) was dissolved in abs. tetrahydrofuran (160 mL), LiAlH 4 (0.25 g, 6.59 mmol) added in argon and stirred for 5 h with reflux. The batch was then cooled to room temperature and stirred overnight. The batch was hydrolysed with THF (20 mL) and H 2 O (20 mL) with ice cooling and subsequently stirred for 30 min. The batch was filtered via a fritted glass filter with diatomaceous earth, subsequently washed with THF and dichloromethane (50 mL) and concentrated to low volume in a vacuum. The residue was purified by means of flash chromatography and cyclohexane/ethyl acetate (1:1).
• step 7 The title compound from step 7 (3.40 g, 9.67 mmol) was mixed with 5% sulphuric acid (300 mL) and stirred for 48 h at room temperature.
• 5% sulphuric acid 300 mL
• the reaction mixture was mixed with ether (100 mL), the phases separated and the aqueous phase extracted with ether (2 ⁇ 100 mL).
• the aqueous phase was then basified with 5N NaOH and extracted with dichloromethane (3 ⁇ 100 mL).
• the organic phase was dried over Na 2 SO 4 , filtered and concentrated until dry in a vacuum.
• Phenyl lithium (12.9 mL, 23.2 mmol, 1.8 M in dibutyl ether) was provided in argon, mixed in drops with the title compound from step 9 (2.69 g, 7.74 mmol) in THF (15 mL), and the reaction solution was stirred for 1 h with reflux.
• the reaction mixture was hydrolysed with saturated NH 4 Cl solution (27 mL) with ice bath cooling and the phases separated.
• the aqueous phase was extracted with ether (3 ⁇ 50 mL).
• the combined organic phases were dried over Na 2 SO 4 , filtered and concentrated until dry in a vacuum.
• the residue was separated by Chromatotron and dichloromethane dichloromethane/methanol (9:1) methanol. 1.20 g of ketone were isolated.
• the desired product was obtained as diastereomer mixture and as such was further converted.
• step 1 The title compound from step 1 (3.50 g, 10.6 mmol) was dissolved in abs. tetrahydrofuran (400 mL), LiAlH 4 (0.66 g, 17.5 mmol) added in argon and stirred for 5 h with reflux. The batch was then cooled to room temperature and stirred overnight. The batch was hydrolysed with THF (20 mL) and H 2 O (20 mL) with ice cooling and subsequently stirred for 30 min. The batch was filtered via a fritted glass filter with diatomaceous earth, rewashed with THF and dichloromethane (50 mL) and concentrated to low volume in a vacuum. The residue was purified by flash chromatography and cyclohexane/ethyl acetate (9:1% 1:1).
• step 2 The title compound from step 2 (2.50 g, 7.8 mmol) was mixed with 5% sulphuric acid (300 mL) and stirred for 48 h at room temperature.
• 5% sulphuric acid 300 mL
• the reaction mixture was mixed with ether (100 mL), the phases separated and the aqueous phase extracted with ether (2 ⁇ 100 mL).
• the aqueous phase was basified with 5N NaOH and extracted with dichloromethane (3 ⁇ 10 mL).
• the organic phase was dried over Na 2 SO 4 , filtered and concentrated until dry in a vacuum.
• Phenyl lithium (9.33 mL, 16.8 mmol, 1.8 M in dibutyl ether) was provided in argon, mixed in drops with the title compound from step 4 (1.76 g, 5.61 mmol) in ether (15 mL) and the reaction solution stirred for 1 h at 50° C.
• the reaction mixture was hydrolysed with saturated NH 4 Cl solution (100 mL) with ice bath cooling and the phases separated.
• the aqueous phase was extracted with ether (3 ⁇ 50 mL).
• the combined organic phases were dried over Na 2 SO 4 , filtered and concentrated until dry in a vacuum. The residue was separated by Chromatotron and dichloromethane.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Pharmacology & Pharmacy (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Biomedical Technology (AREA)
• Epidemiology (AREA)
• Pain & Pain Management (AREA)
• Psychiatry (AREA)
• Addiction (AREA)
• Reproductive Health (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Endocrinology (AREA)
• Gynecology & Obstetrics (AREA)
• Hematology (AREA)
• Diabetes (AREA)
• Urology & Nephrology (AREA)
• Pregnancy & Childbirth (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Anesthesiology (AREA)
• Rheumatology (AREA)
• Hospice & Palliative Care (AREA)
• Dermatology (AREA)
• Obesity (AREA)
• Physical Education & Sports Medicine (AREA)
• Nutrition Science (AREA)
• Child & Adolescent Psychology (AREA)

Priority Applications (3)

Applications Claiming Priority (2)

Related Child Applications (1)

Publications (1)

Family

ID=39628983

Family Applications (4)

Family Applications After (3)

Country Status (22)

Cited By (27)

Families Citing this family (9)

Citations (13)

Family Cites Families (65)

• 2009
  • 2009-03-25 NZ NZ600207A patent/NZ600207A/xx not_active IP Right Cessation
  • 2009-03-25 PE PE2012000621A patent/PE20121313A1/es not_active Application Discontinuation
  • 2009-03-25 EP EP12003857.5A patent/EP2518052B1/de not_active Not-in-force
  • 2009-03-25 CN CN2013100686774A patent/CN103214376A/zh active Pending
  • 2009-03-25 CN CN2013100685875A patent/CN103183630A/zh active Pending
  • 2009-03-25 KR KR1020107023865A patent/KR20100136521A/ko not_active Application Discontinuation
  • 2009-03-25 PL PL09725217T patent/PL2260021T3/pl unknown
  • 2009-03-25 NZ NZ600210A patent/NZ600210A/xx not_active IP Right Cessation
  • 2009-03-25 JP JP2011501140A patent/JP5674635B2/ja not_active Expired - Fee Related
  • 2009-03-25 CA CA2719735A patent/CA2719735A1/en not_active Abandoned
  • 2009-03-25 US US12/410,801 patent/US20090247530A1/en not_active Abandoned
  • 2009-03-25 NZ NZ588779A patent/NZ588779A/en not_active IP Right Cessation
  • 2009-03-25 AU AU2009228642A patent/AU2009228642B2/en not_active Ceased
  • 2009-03-25 AR ARP090101054A patent/AR074615A1/es unknown
  • 2009-03-25 PE PE2012000622A patent/PE20121314A1/es not_active Application Discontinuation
  • 2009-03-25 BR BR122013017387-0A patent/BR122013017387A2/pt not_active IP Right Cessation
  • 2009-03-25 BR BR122013017393-5A patent/BR122013017393A2/pt not_active IP Right Cessation
  • 2009-03-25 RU RU2012120387/04A patent/RU2532545C2/ru not_active IP Right Cessation
  • 2009-03-25 KR KR1020127016148A patent/KR20120075499A/ko not_active Application Discontinuation
  • 2009-03-25 KR KR1020127016152A patent/KR20120075500A/ko not_active Application Discontinuation
  • 2009-03-25 RU RU2010143438/04A patent/RU2503660C2/ru not_active IP Right Cessation
  • 2009-03-25 CN CN200980119483.4A patent/CN102046595B/zh not_active Expired - Fee Related
  • 2009-03-25 ES ES12003857.5T patent/ES2663398T3/es active Active
  • 2009-03-25 ES ES09725217.5T patent/ES2464102T3/es active Active
  • 2009-03-25 RU RU2012120389/04A patent/RU2525236C2/ru not_active IP Right Cessation
  • 2009-03-25 CL CL2009000734A patent/CL2009000734A1/es unknown
  • 2009-03-25 PE PE2009000445A patent/PE20091689A1/es not_active Application Discontinuation
  • 2009-03-25 BR BRPI0909527A patent/BRPI0909527A2/pt not_active IP Right Cessation
  • 2009-03-25 ES ES12003856.7T patent/ES2694103T3/es active Active
  • 2009-03-25 EP EP09725217.5A patent/EP2260021B1/de not_active Not-in-force
  • 2009-03-25 WO PCT/EP2009/002179 patent/WO2009118168A1/de active Application Filing
  • 2009-03-25 EP EP12003856.7A patent/EP2502907B1/de not_active Not-in-force
  • 2009-03-25 MX MX2010010407A patent/MX2010010407A/es active IP Right Grant
• 2010
  • 2010-09-21 IL IL208282A patent/IL208282A0/en unknown
  • 2010-09-24 CO CO10118549A patent/CO6251240A2/es active IP Right Grant
  • 2010-10-08 EC EC2010010533A patent/ECSP10010533A/es unknown
  • 2010-10-26 ZA ZA2010/07647A patent/ZA201007647B/en unknown
• 2011
  • 2011-04-01 HK HK11103313.1A patent/HK1149257A1/xx not_active IP Right Cessation
• 2012
  • 2012-04-24 US US13/454,256 patent/US8835689B2/en not_active Expired - Fee Related
  • 2012-05-02 IL IL219529A patent/IL219529A/en not_active IP Right Cessation
  • 2012-05-02 IL IL219530A patent/IL219530A/en not_active IP Right Cessation
  • 2012-06-29 JP JP2012146520A patent/JP5674722B2/ja not_active Expired - Fee Related
  • 2012-06-29 JP JP2012146521A patent/JP5674723B2/ja not_active Expired - Fee Related
• 2013
  • 2013-03-14 US US13/803,295 patent/US9403767B2/en not_active Expired - Fee Related
• 2014
  • 2014-08-14 US US14/459,540 patent/US9580386B2/en not_active Expired - Fee Related

Patent Citations (14)

Also Published As

Similar Documents

Legal Events