WO2009124755A1 - Composés à nouvelles utilisations médicales et procédés d'identification de ces composés - Google Patents

Composés à nouvelles utilisations médicales et procédés d'identification de ces composés Download PDF

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WO2009124755A1
WO2009124755A1 PCT/EP2009/002620 EP2009002620W WO2009124755A1 WO 2009124755 A1 WO2009124755 A1 WO 2009124755A1 EP 2009002620 W EP2009002620 W EP 2009002620W WO 2009124755 A1 WO2009124755 A1 WO 2009124755A1
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group
optionally substituted
cycloalkyl
hydrogen
heterocycloalkyl
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Michael Kuhn
Monica Campillos
Peer Bork
Lars Juhl Jensen
Anne-Claude Gavin
Evangelia Petsalaki
Eduardo Garcia Urdales
Rob Russel
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European Molecular Biology Laboratory (Embl)
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    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin

Definitions

  • the present invention relates to a method for identifying a novel medical indication of a pharmaceutically active compound.
  • the invention further provides novel medical indications for several pharmaceutically active compounds.
  • compounds are provided for the prevention and treatment of a disease or disorder treatable with a serotonin-norepinephrine reuptake inhibitor (SNRI), a serotonin receptor antagonist, an estazolam, a dopamine receptor antagonist, a dopamine receptor agonist, an L-type calcium channel blocker, a selective estrogen receptor modulator (SERM), an antihistamine.
  • SNRI serotonin-norepinephrine reuptake inhibitor
  • SERM selective estrogen receptor modulator
  • an antihistamine also provided is a pharmaceutically active compound for the prevention or treatment of tachycardia.
  • NRIs Norepinephrine reuptake inhibitors
  • NARIs noradrenaline reuptake inhibitors
  • ADHD attention-deficit hyperactivity disorder
  • depression is useful sedatives, anxiolytics, sympathomimetics, and anticholinergics.
  • NRIs can further be used to treat chronic fatigue syndrome, chronic pain and migraine's.
  • Serotonin-norepinephrine reuptake inhibitors are a class of antidepressants used in the treatment of clinical depression and other affective disorders. They are also sometimes used to treat anxiety disorders, obsessive-compulsive disorder, attention deficit hyperactivity disorder (ADHD) and chronic neuropathic pain. They act upon two neurotransmitters in the brain that are known to play an important part in mood, namely, serotonin and norepinephrine. This can be contrasted with the more widely-used selective serotonin reuptake inhibitors (SSRIs), which act only on serotonin.
  • SSRIs selective serotonin reuptake inhibitors
  • Serotonin (5-hydroxytryptamine, or 5-HT) is a monoamine neurotransmitter synthesized in serotonergic neurons in the central nervous system (CNS) and enterochromaffin cells in the gastrointestinal tract of animals including humans. Serotonin is also found in many mushrooms and plants, including fruits and vegetables. Serotonin receptor antagonists are important antiemetic agents. They are particularly important in treating the nausea and vomiting that occur during anticancer chemotherapy using cytotoxic drugs. Another application is in treatment of post-operative nausea and vomiting. Applications to the treatment of depression and other mental and psychological conditions have also been investigated with some positive results. Serotonin receptor antagonists can also be used to treat intestinal pathologies or a psychosis.
  • Estazolam (marketed under the brand names ProSom, Eurodin) is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. Estazolam is an intermediate-acting benzodiazepine. It is commonly prescribed for short-term treatment of insomnia.
  • a dopamine antagonist is a drug which blocks dopamine receptors by receptor antagonism.
  • dopamine receptors There are five types of dopamine receptors in the human body; they are found in the brain, peripheral nervous system, blood vessels, and the kidney).
  • Dopamine receptor antagonist preferably a D2-like dopamine receptor antagonist find applications in the treatment of diseases such as psychosis, nausea, depression, Parkinson's Disease (depending on the patient's background) and migraine.
  • Dopamine receptor agonist can be used to treat, for example, Parkinson's disease, pars intermedia hyperplasia or Equine Cushing's Syndrome (ECS).
  • ECS Equine Cushing's Syndrome
  • L-type calcium channel blockers can be used to treat hypertension, angina pectoris, cardiac arrhythmia and a headache.
  • Calcium channel blockers work by blocking L-type voltage- gated calcium channels (VGCCs) in muscle cells of the heart and blood vessels. This prevents calcium levels from increasing as much in the cells when stimulated, leading to less muscle contraction.
  • VGCCs voltage- gated calcium channels
  • a decrease in calcium available for each beat results in a decrease in cardiac contractility.
  • vasodilation In blood vessels, a decrease in calcium results in less contraction of the vascular smooth muscle and therefore an increase in blood vessel diameter, a phenomenon called vasodilation.
  • Vasodilation decreases total peripheral resistance, while a decrease in cardiac contractility decreases cardiac output. Since blood pressure is in part determined by cardiac output and peripheral resistance, blood pressure drops.
  • SERMs Selective Estrogen Receptor Modulators
  • Their mode of action may be different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues.
  • SERMs can be used to treat, for example, breast cancer, prostate cancer and for the treatment of serious side effects of androgen deprivation therapy.
  • a histamine antagonist is an agent which serves to inhibit the release or action of histamine.
  • Antihistamine can be used to describe any histamine antagonist, but it is usually reserved for the classical antihistamines that act upon the Hl histamine receptor.
  • Histamine antagonist can be used to treat, for example, allergy such as hay fever, angioedema, and urticaria.
  • Tachycardia refers to rapid beating of the heart. By convention it defined as a heart rate greater than 100 beats per minute in adults. Treatment of tachycardia is usually directed at chemical conversion using antiarrythmics.
  • An antidepressant is a psychiatric medication or other substance (nutrient or herb) used for alleviating depression or dysthymia ('milder' depression).
  • MAOIs Drug groups known as MAOIs, tricyclics and SSRIs are particularly associated with the term. These medications are now amongst the drugs most commonly prescribed by medical psychologists, psychiatrists and general practitioners, and their effectiveness and adverse effects are the subject of many studies. Most antidepressants have a delayed onset of action and are usually taken over the course of weeks, months or years. They are generally considered distinct from stimulants, and drugs used for an immediate euphoric effect only are not generally considered antidepressants.
  • agents which act as serotonin-norepinephrine reuptake inhibitor (SNRI), a serotonin receptor antagonist, a dopamine receptor antagonist, a dopamine receptor agonist, an L-type calcium channel blocker, a selective estrogen receptor modulator (SERM), an antihistamine or which act like the pharmaceutically active compound estazolam can be administered for the prophylaxis and treatment of above mentioned diseases.
  • SNRI serotonin-norepinephrine reuptake inhibitor
  • SERM selective estrogen receptor modulator
  • the present invention provides as a first aspect the use of a compound having a structure according to formula I:
  • X is O or S
  • Z is in each instance CR 4 R 5 ; ni is an integer from 1 to 5; n 2 is an integer from 1 to 5; m is an integer from 0 to 4;
  • R 1 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 3 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; and if two R 3 substituents are on adjacent carbon atoms, they may together form a cycloalkyl, heterocycloalkyl or alicyclic system; optionally substituted;
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 6 R 7 ; optionally substituted;
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted; or pharmaceutically acceptable salts thereof, for the prevention or treatment of a disease or disorder treatable with a Serotonin-norepinephrine reuptake inhibitor (SNRI).
  • SNRI Serotonin-norepinephrine reuptake inhibitor
  • the invention further provides the use of a compound having a structure according to formula III:
  • Y is selected from the group consisting of hydrogen, halogen, -NO 2 , -CN, -OR 6 , -NR 6 R 7 , -COOR 6 , -CONR 6 R 7 , -NR 4 COR 5 , -NR 4 COR 5 , -NR 4 CONR 6 R 7 , -NR 5 SO 2 A, -COR 6 - SO 2 NR 6 R 7 , -00CR 4 and -CR 4 R 5 OH; R 1 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted; R 2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 3 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; and if two R 3 substituents are on adjacent carbon atoms, they may together form a cycloalkyl, heterocycloalkyl or alicyclic system; optionally substituted;
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 6 R 7 ; optionally substituted;
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted;
  • R 6 ' and R 7 ' is each independently selected from the group consisting of hydrogen, alkyl, alkenyl or together form a heterocycloalkyl; optionally substituted; or pharmaceutically acceptable salts thereof, for the prevention or treatment of a disease or disorder treatable with a Serotonin-norepinephrine reuptake inhibitor (SNRI).
  • SNRI Serotonin-norepinephrine reuptake inhibitor
  • W is alkyl, -OR 6 ', -CR 4 R 5 OH, or -NR 6 'R 7 '; Z is in each instance CR 4 R 5 ;
  • xv ⁇ is an integer from 1 to 5;
  • R 1 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 6 R 7 ; optionally substituted;
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted;
  • R 6 ' and R 7 ' is each independently selected from the group consisting of hydrogen, alkyl, alkenyl or together form a heterocycloalkyl; optionally substituted;
  • R 8 is each individually selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; or pharmaceutically acceptable salts thereof, for the prevention or treatment of a disease or disorder treatable with a norepinephrine reuptake inhibitors (NRIs).
  • NRIs norepinephrine reuptake inhibitors
  • the invention further provides the use of a compound having a structure according to formula VII:
  • X is in each instance O or S; X' is in each instance O or S; Y is in each instance selected from the group consisting of hydrogen, halogen, -NO 2 , -CN,
  • R 2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 3 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; and if two R 3 substituents are on adjacent carbon atoms, they may together form a cycloalkyl, heterocycloalkyl or alicyclic system; optionally substituted;
  • R 3 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; and if two R 3 substituents are on adjacent carbon atoms, they may together form a cycloalkyl, heterocycloalkyl or alicyclic system; optionally substituted;
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 6 R 7 ; optionally substituted; R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted; R 8 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; or pharmaceutically acceptable salts thereof, for the prevention or treatment of a psychosis and/or a disease or disorder treatable with an antihistamine.
  • the invention further provides the use of a compound having a structure according to formula IX:
  • A is in each instance S, O or NR ';
  • X is O or S;
  • Z is in each instance CR 4 R 5 ;
  • m is an integer from 0 to 4;
  • ni is an integer from 1 to 5;
  • n 2 is an integer from 1 to 5;
  • R is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R- is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted;
  • R > * 4' and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl and heteroaryl; optionally substituted;
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted;
  • R 6 ' is selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl; optionally substituted;
  • R 9 is in each instance independently selected from the group consisting of hydrogen,
  • -OOCR 4 and -CR 4 R 5 OH;- R 10 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted; or pharmaceutically acceptable salts thereof, for the prevention or treatment of disease or disorder treatable with a serotonin receptor antagonist, preferably a 5-HT2 type serotonin receptor antagonist.
  • the invention further provides the use of a compound having a structure according to formula XI:
  • B is C or N
  • E is C or N
  • X is O or S; if A is S then X is O; ml is an integer from O to 6; m2 is an integer from O to 3; m3 is an integer from O to 3; n 3 is an integer from 1 to 3;
  • 1I 4 is an integer from 1 to 3;
  • Y is selected from the group consisting of hydrogen, halogen, -NO 2 , -CN, -OR 6 ,
  • Y' is selected from the group consisting of hydrogen, halogen, -NO 2 , -CN, -OR 6 ,
  • Y is selected from the group consisting of hydrogen, halogen, -NO 2 , -CN, -OR 6 , -NR 6 R 7 , -COOR 6 , -CONR 6 R 7 ,
  • Z is in each instance CR 4 R 5 ;
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 6 R 7 ; optionally substituted;
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted;
  • R 6 ' is selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl; optionally substituted;
  • R 8 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; and wherein the bond indicated by the dashed line may be present
  • the invention further provides the use of a compound having a structure according to formula XIII:
  • B is C or N; G is C or S; X is in each instance O or S; Z is in each instance CR 4 R 5 ; m is an integer from 0 to 3; n] is an integer from 1 to 5; n 2 is an integer from 1 to 5; R 1 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 3 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; and if two R 3 substituents are on adjacent carbon atoms, they may together form a cycloalkyl, heterocycloalkyl or alicyclic system; optionally substituted;
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 6 R 7 ; optionally substituted;
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted;
  • R 8 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; or pharmaceutically acceptable salts thereof, for the prevention or treatment of a disease or disorder treatable with a dopamine receptor antagonist, preferably a type D2-like dopamine receptor antagonist.
  • the invention further provides the use of a compound having a structure according to formula XV:
  • A is S, O or NR 6 ';
  • X is O or S;
  • Y is in each instance selected from the group consisting of hydrogen, halogen, -NO 2 , -CN,
  • R 1 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 6 R 7 ; optionally substituted;
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted;
  • A is each independently selected from S, O or NR 6 ' ; Z is in each instance CR 4 R 5 ; ml is an integer from 0 to 3; m2 is an integer from O to 3; n is an integer from 1 to 5; R 1 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted; R 3 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; and if two R 3 substituents are on adjacent carbon atoms, they may together form a cycloalkyl, heterocycloalkyl or alicyclic system; optionally substituted;
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 6 R 7 ; optionally substituted;
  • R and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted;
  • R 6 ' is selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl; optionally substituted;
  • R 8 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; and wherein the bond indicated by the dashed line may be present or not; or pharmaceutically acceptable salts thereof, for the prevention or treatment of a disease or disorder treatable with a dopamine receptor agonist.
  • the invention further provides the use of a compound having a structure according to formula XIX:
  • R 3 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted;
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 6 R 7 ; optionally substituted;
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted;
  • R 6 ' is selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl; optionally substituted;
  • R 8 is in each instance selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; and wherein each of the bonds indicated by the dashed line may be present or not; or pharmaceutically acceptable salts thereof, for the prevention or treatment of a disease or disorder treatable with an L-type calcium channel blocker.
  • the invention further provides the use of a compound having a structure according to formula XXI:
  • X is O or S; Z is in each instance CR 4 R 5 ; n is an integer from 1 to 5;
  • R 1 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 3 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted;
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 6 R 7 ; optionally substituted;
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted;
  • R 6 ' and R 7 ' is each independently selected from the group consisting of hydrogen, alkyl, alkenyl or together form a heterocycloalkyl; optionally substituted; and R 8 is in each instance selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; or pharmaceutically acceptable salts thereof, for the prevention or treatment of cancer and/or a disease or disorder treatable with a selective estrogen receptor modulator (SERM).
  • SERM selective estrogen receptor modulator
  • the invention further provides the use of a compound having a structure according to formula XXIII:
  • XXIII wherein X is O or S; n is an integer from 1 to 5;
  • R 3 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; and if two R 3 substituents are on adjacent carbon atoms, they may together form a cycloalkyl, heterocycloalkyl or alicyclic system; optionally substituted;
  • R 3 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; or pharmaceutically acceptable salts thereof, for the prevention or treatment of a disease or disorder treatable with an antihistamine.
  • the invention further provides the use of a compound having a structure according to formula XXV:
  • XXV wherein ml is an integer from O to 5; m2 is an integer from 0 to 4; X is O or S; Y is in each instance selected from the group consisting of hydrogen, halogen, -NO 2 , -CN,
  • Y' is in each instance selected from the group consisting of hydrogen, halogen, -NO 2 , -CN,
  • R 2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 3 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted;
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 6 R 7 ; optionally substituted;
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted;
  • R 8 is in each instance selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; and wherein the bond indicated by the dashed line may be present or not; or pharmaceutically acceptable salts thereof, for the prevention or treatment of a disease or disorder treatable with an antihistamine.
  • the invention further provides the use of a compound having a structure according to formula XXVII:
  • m is an integer from O to 3; B is C or N; X is O or S; Y is selected from the group consisting of hydrogen, halogen, -NO 2 , -CN, -OR 6 ,
  • R 3 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted;
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 6 R 7 ; optionally substituted;
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted;
  • R 6 ' and R 7 ' is each independently selected from the group consisting of hydrogen, alkyl, alkenyl or together form a heterocycloalkyl; optionally substituted; or pharmaceutically acceptable salts thereof, for the prevention or treatment of tachycardia or a disease or disorder treatable with an antihistamine, for example an allergy such as hay fever, angioedema or urticaria.
  • the invention further provides the use of a compound having a structure according to formula XXIX:
  • X is O or S
  • R 1 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R x is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; or pharmaceutically acceptable salts thereof, for the prevention or treatment of a disease or disorder treatable with an antihistamine.
  • the invention further provides the use of a compound having a structure according to formula XXXI:
  • XXXI wherein ml is an integer from 0 to 2; m2 is an integer from 1 to 2; m3 is an integer from 0 to 4; Y is in each instance selected from the group consisting of hydrogen, halogen, -NO 2 , -CN, -OR 6 ,
  • Y' is in each instance selected from the group consisting of hydrogen, halogen, -NO 2 , -CN,
  • Y' ' is in each instance selected from the group consisting of hydrogen, halogen, -NO 2 , -CN,
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 6 R 7 ; optionally substituted;
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted;
  • R 8 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted;
  • R 11 is selected from the group consisting of hydrogen, -COR 12 , -CR 4 R 5 OH, alkyl, alkynyl and cycloalkyl; optionally substituted;
  • R 12 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl; optionally substituted; or pharmaceutically acceptable salts thereof, for the prevention or treatment of a depression and/or a disease or disorder treatable with an antihistamine.
  • the invention further provides the use of a compound having a structure according to formula XXXIII:
  • m is an integer between 0 and 2; B is in each instance C or N; X is O or S; Y is selected from the group consisting of hydrogen, halogen, -NO 2 , -CN, -OR 6 ,
  • R 1 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 6 R 7 ; optionally substituted;
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted;
  • R 11 is selected from the group consisting of hydrogen, -COR 12 , -CR 4 R 5 OH, alkyl, alkynyl and cycloalkyl; optionally substituted;
  • R 12 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl; optionally substituted; or pharmaceutically acceptable salts thereof, for the prevention or treatment of a depression and/or a disease or disorder treatable with an antihistamine.
  • the invention further provides a method for identifying a novel medical indication of a pharmaceutically active compound comprising the steps:
  • the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", Leuenberger, H.G.W, Nagel, B. and Klbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).
  • alkyl "heteroalkyl”, “cycloalkyl”, “heterocycloalkyl”, “alicyclic system”, “aryl”, “aralkyl”, “heteroaryl”, “heteroaralkyl”, "alkenyl”, “cycloalkenyl”, “alkynyl” and “optionally substituted” are provided.
  • alkyl refers to a saturated straight or branched carbon chain.
  • the chain comprises from 1 to 10 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 e.g. methyl, ethyl methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl, heptyl, or octyl.
  • Alkyl groups are optionally substituted.
  • heteroalkyl refers to a saturated straight or branched carbon chain.
  • the chain comprises from 1 to 9 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 e.g. methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, sec-butyl, tert-butyl, pentyl or hexyl, heptyl, octyl, which is interrupted one or more times, e.g. 1, 2, 3, 4, 5, with the same or different heteroatoms.
  • the heteroatoms are selected from O, S, and N, e.g.
  • Heteroalkyl groups are optionally substituted.
  • cycloalkyl and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively, with preferably 3, 4, 5, 6, 7, 8, 9 or 10 atoms forming a ring, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc.
  • cycloalkyl and “heterocycloalkyl” are also meant to include bicyclic, tricyclic and polycyclic versions thereof.
  • heterocycloalkyl preferably refers to a saturated ring having five members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N; a saturated ring having six members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N or two additional N atoms; or a saturated bicyclic ring having nine or ten members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms.
  • Cycloalkyl and “heterocycloalkyl” groups are optionally substituted. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • Preferred examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl, bicyclo[4.
  • heterocycloalkyl examples include l-(l,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3- piperidinyl, 4-morpholinyl, 3-morpholinyl, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro- [5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro[5,4] decyl, 3,7 diaza-
  • alicyclic system refers to mono, bicyclic, tricyclic or polycyclic version of a cycloalkyl or heterocycloalkyl comprising at least one double and/or triple bond.
  • an alicyclic system is not aromatic or heteroaromatic, i.e. does not have a system of conjugated double bonds/free electron pairs.
  • the number of double and/or triple bonds maximally allowed in an alicyclic system is determined by the number of ring atoms, e.g. in a ring system with up to 5 ring atoms an alicyclic system comprises up to one double bond, in a ring system with 6 ring atoms the alicyclic system comprises up to two double bonds.
  • the "cycloalkenyl" as defined below is a preferred embodiment of an alicyclic ring system.
  • Alicyclic systems are optionally substituted.
  • aryl preferably refers to an aromatic monocyclic ring containing 6 carbon atoms, an aromatic bicyclic ring system containing 10 carbon atoms or an aromatic tricyclic ring system containing 14 carbon atoms. Examples are phenyl, naphtyl or anthracenyl. The aryl group is optionally substituted.
  • aralkyl refers to an alkyl moiety, which is substituted by aryl, wherein alkyl and aryl have the meaning as outlined above. An example is the benzyl radical.
  • the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g.
  • aralkyl group is optionally substituted at the alkyl and/or aryl part of the group.
  • heteroaryl preferably refers to a five or six-membered aromatic monocyclic ring wherein at least one of the carbon atoms are replaced by 1, 2, 3, or 4 (for the five membered ring) or 1, 2, 3, 4, or 5 (for the six membered ring) of the same or different heteroatoms, preferably selected from O, N and S; an aromatic bicyclic ring system wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 8, 9, 10, 11 or 12 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S; or an aromatic tricyclic ring system wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 13, 14, 15, or 16 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S.
  • Examples are oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3- triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzisoxazoyl, benzothiazolyl, 1,2-benzisothiazolyl,
  • heteroarylkyl refers to an alkyl moiety, which is substituted by heteroaryl, wherein alkyl and heteroaryl have the meaning as outlined above.
  • An example is the 2- alklypyridinyl, 3-alkylpyridinyl, or 2-methylpyridinyl.
  • the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g.
  • heteroaralkyl group is optionally substituted at the alkyl and/or heteroaryl part of the group.
  • alkenyl and cycloalkenyl refer to olefinic unsaturated carbon atoms containing chains or rings with one or more double bonds. Examples are propenyl and cyclohexenyl.
  • the alkenyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g.
  • cycloalkenyl ring comprises from 3 to 14 carbon atoms, i.e. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, e.g.
  • alkynyl refers to unsaturated carbon atoms containing chains or rings with one or more triple bonds.
  • An example is the propargyl radical.
  • the alkynyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g. ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, hexynyl, pentynyl, octynyl.
  • substituents e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituents which are in each instance independently selected from the group consisting of halogen, in particular F, Cl, Br or I; -R', -NO 2 , -CN, -OR 1 , -NR'R", -COOR', -CONR'R", -NR"'COR"' ⁇ -NR'"COR”", -NR'"CONR'R", -NR"SO 2 A, -COR'”; -SO 2 NR 5 R", -OOCR'", -CR'"R”"OH, R'"OH, and -E;
  • R' and R" is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, or heterocycloalkyl;
  • R'" and R"" is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR'R";
  • E is selected from the group consisting of alkyl, alkenyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • the term "a compound according to the invention” refers to a compound according to any of formulas I through XXXTV including all preferred respective embodiment
  • drug and pharmaceutically active compound(s) are used interchangeably.
  • unexpected activities derived from off-targets are usually unwanted and harmful, they can sometimes be beneficial. As will be explained herein, they can, for example, lead to new therapeutic indications for existing, marketed drugs.
  • the inventors of the present invention have established a computer implemented method to explore the vast amount of human phenomenological data generated from the use of marketed drugs, namely side effects, to infer molecular activities of drugs that are not implicit by their chemical similarity or the sequence similarity of their known targets. Simply making an "educated guess" that two compounds which have closely related side-effects will also share a common therapeutic target is prone to result in too many false predictions. Therefore, the present inventors have invested in refining and optimizing a complex computer implemented method which considers a plurality of data dependencies and which integrates the data by elaborous filtering and weighing steps as will be described herein. Unexpectedly, the optimized computer
  • program was capable of identifying several hundred pairs of compounds which (a) merely have low chemical similarity and are, thus, structurally different, which (b) the prior art has classified in different therapeutic categories, which (c) were previously not known to share the same therapeutical target and which (d) are not related by the amino acid sequence similarity of their respective therapeutic target proteins. Importantly, for several of these identified compounds it was shown in "wet-lab” experiments that the respective drug pairs indeed share the same therapeutic target. In the following, novel medical indications will be provided for known compounds.
  • the disorder or disease treatable with the respective compound according to the invention is frequently defined herein as a disorder or disease which is currently treated with a different pharmaceutical compound or any different pharmaceutical compound that belongs to a generic class of medicaments.
  • the invention provides the use of a compound having a structure according to formula I:
  • X is O or S; preferably X is O Z is in each instance CR 4 R 5 ; ni is an integer from 1 to 5; i.e. an integer selected from 1, 2, 3, 4 or 5; preferably nl is 2; n 2 is an integer from 1 to 5; i.e. an integer selected from 1, 2, 3, 4 or 5; preferably n2 is 1 ; m is an integer from 0 to 4; i.e.
  • R 1 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted
  • R 2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 3 is selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I), alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; and if two R 3 substituents are on adjacent carbon atoms, they may together form a cycloalkyl, heterocycloalkyl or alicyclic system; optionally substituted;
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 6 R 7 ; optionally substituted;
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted; or pharmaceutically acceptable salts thereof, for the prevention or treatment of a disease or disorder treatable with a Serotonin-norepinephrine reuptake inhibitor (SNRI).
  • SNRI Serotonin-norepinephrine reuptake inhibitor
  • SNRI Serotonin-norepinephrine reuptake inhibitor
  • At least one of the respective substituents of the compound according to formula I is defined as follows:
  • R 1 is preferably aryl (in particular phenyl, naphthalenyl or anthracenyl), or heteroaryl (in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl,
  • 1,2,5-thiadiazolyl pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2- benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl,
  • R 2 is preferably aryl (in particular phenyl, naphthalenyl or anthracenyl), or heteroaryl (in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2- benzothienyl, lH-indazolyl, benzimidazoly
  • R 4 and R 5 is preferably each independently selected from the group consisting of hydrogen, alkyl (in particular Ci-C ⁇ alkyl, e.g. C 1 , C 2 , C 3 , C 4 , C 5 , or Ce alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl), alkenyl and alkynyl; optionally substituted.
  • alkyl in particular Ci-C ⁇ alkyl, e.g. C 1 , C 2 , C 3 , C 4 , C 5 , or Ce alkyl, preferably methyl, ethyl, propyl, wo-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl
  • alkenyl and alkynyl optionally substituted.
  • nl is 2, n2 is 1,
  • the compound according to structure I has a structure according to formula II (cetirizine):
  • the invention further provides the use of a compound having a structure according to formula III:
  • n is an integer from 0 to 9; i.e. an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9; preferably m is 0;
  • X is O or S; preferably X is O;
  • Y is selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I),
  • R 1 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 3 is selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I), alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; and if two R substituents are on adjacent carbon atoms, they may together form a cycloalkyl, heterocycloalkyl or alicyclic system; optionally substituted;
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen,
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted;
  • R 6 ' and R 7 ' is each independently selected from the group consisting of hydrogen, alkyl, alkenyl or together form a heterocycloalkyl; optionally substituted; or pharmaceutically acceptable salts thereof, for the prevention or treatment of a disease or disorder treatable with a Serotonin-norepinephrine reuptake inhibitor (SNRI).
  • SNRI Serotonin-norepinephrine reuptake inhibitor
  • At least one of the respective substituents of the compound according to formula III is defined as follows:
  • Y is preferably selected from the group consisting of hydrogen, -OR 6 , -NR 6 R 7 and -COOR 6 ;
  • R 1 is preferably aryl (in particular phenyl, naphthalenyl or anthracenyl), or heteroaryl (in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl,
  • 1,2,5-thiadiazolyl pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2- benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl,
  • R is preferably aryl (in particular phenyl, naphthalenyl or anthracenyl), or heteroaryl (in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl,
  • 1,2,5-thiadiazolyl pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2- benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl,
  • R 6 and R 7 is preferably each independently selected from the group consisting of hydrogen, alkyl
  • Ci-C ⁇ alkyl e.g. C 1 , C 2 , C 3 , C 4 , C 5 , or Ce alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyl
  • alkenyl alkynyl, cycloalkyl, heterocycloalkyl (C 3 -C 14 -heterocycloalkyl, e.g.
  • 2,1-benzisoxazolyl benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl), and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted; and most preferably R 6 and/or R 7 is hydrogen; and
  • R 6 ' and R 7 ' is preferably alkyl (in particular Ci-C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, /s ⁇ -propyl, butyl, /so-butyl, tert-butyl, pentyl or hexy ⁇ ); optionally substituted.
  • X is O
  • R 6 ' and R 7 ' is methyl and m is zero and preferably Y is -OH.
  • the compound according to structure III has a structure according to formula IV (tiotropium):
  • the invention further provides the use of a compound having a structure according to formula V:
  • W is alkyl, -OR 6 ', -CR 4 R 5 OH, or -NR 6 'R 7 '; Z is in each instance CR 4 R 5 ;
  • n! is an integer from 1 to 5; i.e. an integer selected from 1, 2, 3, 4 or 5; preferably n ⁇ is 2;
  • R is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 6 R 7 ; optionally substituted; R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted; R 6 ' and R 7 ' is each independently selected from the group consisting of hydrogen, alkyl, alkenyl or together form a heterocycloalkyl; optionally substituted; R 8 is each individually selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; or pharmaceutically acceptable salts thereof
  • At least one of the respective substituents of the compound according to formula V is defined as follows: W is preferably -NR 6 'R 7 ';
  • R 1 is preferably aryl (in particular phenyl, naphthalenyl or anthracenyl), or heteroaryl (in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2- benzothienyl, lH-indazolyl, benzimidazoly
  • R 2 is preferably aryl (in particular phenyl, naphthalenyl or anthracenyl), or heteroaryl (in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2- benzothienyl, lH-indazolyl, benzimidazoly
  • R 6 ' and R 7 ' is preferably each independently selected from the group consisting of hydrogen and alkyl (in particular Ci-C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted; and
  • R 8 is preferably hydrogen or alkyl (in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted.
  • nl is 2
  • W is -NH 2
  • R 8 is isopropyl.
  • the compound according to structure V has a structure according to formula VI (disopyramide):
  • a compound according to formula V or VI can be used for the prevention or treatment of a disease or disorder treatable with an antihistamine.
  • a compound according to any of formulas I - VI can be used for the prevention or treatment of a depression and/or an anxiety disorder.
  • the invention further provides the use of a compound having a structure according to formula VII:
  • X is in each instance O or S; preferably X is O; X' is in each instance O or S; preferably X' is O; Y is in each instance selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I), -NO 2 , -CN, -OR 6 , -NR 6 R 7 , -COOR 6 , -CONR 6 R 7 , -NR 4 COR 5 , -NR 4 COR 5 , -NR 4 CONR 6 R 7 , -NR 5 SO 2 A, -COR 6 , -SO 2 NR 6 R 7 , -OOCR 4 and -CR 4 R 5 OH;
  • halogen preferably F, Cl, Br or I
  • Z is in each instance CR 4 R 5 ; n is an integer from 1 to 5; i.e. an integer selected from 1, 2, 3, 4 or 5; preferably n is 1; In 1 is an integer between O and 3; i.e. an integer selected from O, 1, 2 or 3; preferably mi is O; m 2 is an integer between O and 3; i.e.
  • R 2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted
  • R 3 is selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I), alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; and if two R 3 substituents are on adjacent carbon atoms, they may together form a cycloalkyl, heterocycloalkyl or alicyclic system; optionally substituted;
  • R 3 is selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I), alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; and if two R 3 substituents are on adjacent carbon atoms, they may together form a cycloalkyl, heterocycloalkyl or alicyclic system; optionally substituted;
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 6 R 7 ; optionally substituted;
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted;
  • R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; or pharmaceutically acceptable salts thereof, for the prevention or treatment of a psychosis and/or a disease or disorder treatable with an antihistamine such as, for example, an allergy.
  • At least one of the respective substituents of the compound according to formula VII is defined as follows:
  • Y is preferably in each instance selected from the group consisting of -OR 6 , -NR 6 R 7 and -COOR 6 ; and is most preferably -OH;
  • R 2 is preferably cycloalkyl or heterocycloalkyl (C 3 -C 14 -heterocycloalkyl, e.g. C 3 , C 4 , C5, C 6 ,
  • R 4 and R 5 is preferably each independently selected from hydrogen or alkyl (in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted;
  • alkyl in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl
  • R 6 and R 7 is preferably each independently selected from hydrogen or alkyl (in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted; and R 8 is preferably alkyl (in particular C1-C6 alkyl, e.g.
  • C2, C3, C4, C5, or C6 alkyl preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted.
  • the compound according to structure VII has a structure according to formula VIII (doxorubicin):
  • the invention further provides the use of a compound having a structure according to formula IX:
  • A is in each instance S, O or NR 6 '; preferably A is O; X is O or S; preferably X is O; Z is in each instance CR 4 R 5 ; m is an integer from O to 4; i.e. an integer selected from 0, 1 , 2, 3 or 4; preferably m is 0; ni is an integer from 1 to 5; i.e. an integer selected from 1, 2, 3, 4 or 5; preferably n t is 1; n 2 is an integer from 1 to 5; i.e. an integer selected from 1, 2, 3, 4 or 5; preferably n 2 is 1; R is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 3 is selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I), alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted;
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl and heteroaryl; optionally substituted;
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted;
  • R 6 ' is selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl; optionally substituted;
  • R 9 is in each instance independently selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I), -NO 2 , -CN, -OR 6 , -NR 6 R 7 , -COOR 6 , -CONR 6 R 7 ,
  • R 10 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted; or pharmaceutically acceptable salts thereof, for the prevention or treatment of disease or disorder treatable with a serotonin receptor antagonist, preferably a 5-HT2 type serotonin receptor antagonist and most preferably a 5-HT2C type serotonin receptor antagonist.
  • a serotonin receptor antagonist preferably a 5-HT2 type serotonin receptor antagonist and most preferably a 5-HT2C type serotonin receptor antagonist.
  • At least one of the respective substituents of the compound according to formula IX is defined as follows:
  • R 1 is preferably cycloalkyl or heterocycloalkyl (C 3 -C 14 -heterocycloalkyl, e.g. C 3 , C 4 , C 5 , C 6 ,
  • C 7 , C 8 , C 9 , C 10 , Cn, Ci 2 , Cu or C ⁇ -heterocycloalkyl in particular piperidinyl, morpholinyl, 1 ,3-diazacyclohexanyl, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl,
  • R 2 is preferably aryl (in particular phenyl, naphthalenyl or anthracenyl), or heteroaryl (in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2- benzothienyl, lH-indazolyl, benzimidazoly
  • R 3 is preferably hydrogen or alkyl (in particular Ci-C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyt); optionally substituted;
  • Ci-C 6 alkyl e.g. Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyt
  • R 4 and R 5 is preferably each independently selected from hydrogen or alkyl (in particular Ci-C 6 alkyl, e.g. Ci, C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, preferably methyl, ethyl, propyl, /so-propyl, butyl, wo-butyl, tert-butyl, pentyl or hexyt); optionally substituted; and
  • R 10 is preferably aryl (in particular phenyl, naphthalenyl or anthracenyl), or heteroaryl (in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2- benzothienyl, lH-indazolyl, benzimidazoly
  • the compound according to structure IX has a structure according to formula X (ketoconazole):
  • a compound according to formula IX or X is used for the prevention or treatment of a psychosis and/or nausea.
  • the invention further provides the use of a compound having a structure according to formula XI:
  • A is S, O or NR 6' ; preferably A is O; B is C or N; preferably B is N; E is C or N; preferably E is C; X is O or S; if A is S then X is O; preferably X is O; ml is an integer from O to 6; i.e. an integer selected from O, 1, 2, 3, 4, 5 or 6; preferably ml is O; m2 is.an integer from 0 to 3; i.e. an integer selected from 0, 1, 2 or 3; preferably m2 is 1; m3 is an integer from 0 to 3; i.e.
  • n 3 is an integer from 1 to 3; i.e. an integer selected from 1, 2 or 3; preferably n 3 is 2;
  • Xi 4 is an integer from 1 to 3; i.e. an integer selected from 1, 2 or 3; preferably 11 4 is 2;
  • Y is selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I),
  • Y' is selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I),
  • Y is selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I),
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 6 R 7 ; optionally substituted;
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted;
  • R 6 ' is selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl; optionally substituted;
  • R 8 is selected from the group consisting of hydrogen, alkyl (preferably C1-C6 alkyl, e.g.
  • Y' is preferably selected from the group consisting of hydrogen, halogen (preferably F, Cl,
  • R 4 and R 5 is preferably hydrogen or alkyl (in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted; and
  • R 8 is preferably selected from the group consisting of alkyl (in particular Cl -C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso- butyl, tert-butyl, pentyl or hexyl), alkenyl and alkynyl; optionally substituted.
  • alkyl in particular Cl -C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso- butyl, tert-butyl, pentyl or hexyl
  • alkenyl and alkynyl optionally substituted.
  • A is O
  • X is O
  • B is N
  • E is C
  • m 2 l
  • In 3 O
  • n 3 2
  • Hi 1 O
  • 11 4 2 and the bond indicated by the dashed line is present.
  • the compound according to structure XI has a structure according to formula XII (loratadine):
  • a compound according to formula XI or XII is used for the prevention or treatment of a disease or disorder selected from the group consisting of anxiety disorder, insomnia, agitation, a seizure, a muscle spasm and substance abuse-related disorder.
  • the invention further provides the use of a compound having a structure according to formula XIII:
  • B is C or N; preferably B is N; G is C or S; preferably G is S; X is in each instance O or S; preferably X is O; Z is in each instance CR 4 R 5 ;
  • m is an integer from 0 to 3; i.e. an integer selected from 0, 1, 2 or 3; preferably m is 1;
  • n ! is an integer from 1 to 5; i.e. an integer selected from 1, 2, 3, 4 or 5; preferably n t is 3; n 2 is an integer from 1 to 5; i.e.
  • R 1 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 3 is selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I), alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; and if two R 3 substituents are on adjacent carbon atoms, they may together form a cycloalkyl, heterocycloalkyl or alicyclic system; optionally substituted;
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR R ; optionally substituted;
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted;
  • R 8 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; or pharmaceutically acceptable salts thereof, for the prevention or treatment of a disease or disorder treatable with a dopamine receptor antagonist, preferably a type D2-like dopamine receptor antagonist.
  • At least one of the respective substituents of the compound according to formula XIII is defined as follows:
  • R 1 is preferably aryl (in particular phenyl, naphthalenyl or anthracenyl), or heteroaryl (in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1 -benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2- benzothienyl, lH-indazolyl, benzimid
  • R 3 is preferably alkyl; optionally substituted
  • R 4 and R 5 is preferably each independently selected from hydrogen or alkyl (in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted; and R 8 is preferably selected from the group consisting alkyl (in particular C 1 -C6 alkyl, e.g.
  • C 1 , C2, C3, C4, C5, or C6 alkyl preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl), alkenyl and alkynyl; optionally substituted.
  • the compound according to structure XIII has a structure according to formula XIV (rabeprazole):
  • a compound according to formula XIII or XIV is used for the prevention or treatment of a disease or disorder selected from the group consisting of psychosis, nausea, depression, Parkinson's disease and migraine.
  • the invention further provides the use of a compound having a structure according to formula XV:
  • m is an integer from 1 to 4; i.e. an integer selected from 1, 2, 3 or 4; preferably m is 1;
  • A is S, O or NR 6 ' ; preferably A is S;
  • X is O or S; preferably X is O;
  • Y is in each instance selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I), -NO 2 , -CN, -OR 6 , -NR 6 R 7 , -COOR 6 , -CONR 6 R 7 , -NR 4 COR 5 , -NR 4 COR 5 ,
  • R is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 6 R 7 ; optionally substituted;
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted;
  • R 6 ' is selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl; optionally substituted; or pharmaceutically acceptable salts thereof, for the prevention or treatment of a disease or disorder treatable with Tegaserod (2-((5-Methoxy-lH-indol-3-yl)methylene)-N- penty lhydrazinecarboximidamide) .
  • At least one of the respective substituents of the compound according to formula XV is defined as follows: Y is preferably in each instance selected from the group consisting of -OR 6 , -NR 6 R 7 and
  • R 1 is preferably aryl (in particular phenyl, naphthalenyl or anthracenyl), or heteroaryl (in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl,
  • 1,2,5-thiadiazolyl pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2- benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl,
  • R 2 is preferably aryl (in particular phenyl, naphthalenyl or anthracenyl), or heteroaryl (in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl,
  • 1,2,5-thiadiazolyl pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2- benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl,
  • R 6 and R 7 is preferably each independently selected from the group consisting of hydrogen or alkyl (in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted.
  • alkyl in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl
  • X is O
  • A is S
  • the compound according to structure XV has a structure according to formula XVI (raloxifene):
  • a compound according to formula XV or XVI is used for the prevention or treatment of an intestinal pathology, for example gastric stasis or irritable bowel syndrome;
  • the invention further provides the use of a compound having a structure according to formula XVII:
  • A is each independently selected from S, O or NR 6 '; preferably A is S; Z is in each instance CR 4 R 5 ;
  • In 1 is an integer from 0 to 3; i.e. an integer selected from 0, 1, 2 or 3; preferably In 1 is 1; m 2 is an integer from 0 to 3; i.e. an integer selected from 0, 1, 2 or 3; preferably m 2 is 1; n is an integer from 1 to 5; i.e. an integer selected from 1, 2, 3, 4 or 5; preferably n is 2;
  • R 1 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 3 is selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I), alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; and if two R 3 substituents are on adjacent carbon atoms, they may together form a cycloalkyl, heterocycloalkyl or alicyclic system; optionally substituted;
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 6 R 7 ; optionally substituted;
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted;
  • R 6 ' is selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl; optionally substituted;
  • R 8 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; and wherein the bond indicated by the dashed line may be present or not; preferably the bond is present; or pharmaceutically acceptable salts thereof, for the prevention or treatment of a disease or disorder treatable with a dopamine receptor agonist.
  • R 1 is selected from the group consisting of cycloalkyl, heterocycloalkyl (C 3 -C 14 - heterocycloalkyl, e.g.
  • R 3 is selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I), and alkyl (in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted; R 4 and R 5 is each independently selected from the group consisting of hydrogen and alkyl (in particular C1-C6 alkyl, e.g.
  • C2, C3, C4, C5, or C6 alkyl preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted; and
  • R' 8 is hydrogen or alkyl (in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted.
  • C1-C6 alkyl e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl
  • the compound according to structure XVII has a structure according to formula XVIII (tiagabine):
  • a compound according to formula XVII or XVIII is used for the prevention or treatment of a disease or disorder selected from the group consisting of Parkinson's disease, pars intermedia hyperplasia and Equine Cushing's Syndrome (ECS).
  • a disease or disorder selected from the group consisting of Parkinson's disease, pars intermedia hyperplasia and Equine Cushing's Syndrome (ECS).
  • the invention further provides the use of a compound having a structure according to formula XIX:
  • n is an integer from 2 to 6; i.e. an integer selected from 2, 3, 4, 5 or 6; preferably n is 3; o is an integer from 0 to 4; i.e. an integer selected from 0, 1, 2, 3 or 4; preferably o is 0; X is in each instance O or S; preferably X is O;
  • Y is selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I), -NO 2 , -CN, -OR 6 ,
  • R 3 is selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I), alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted;
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 6 R 7 ; optionally substituted;
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted;
  • R 6 ' is selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl; optionally substituted;
  • R 8 is in each instance selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; and wherein each of the bonds indicated by the dashed line may be present or not; preferably the bond is present; or pharmaceutically acceptable salts thereof, for the prevention or treatment of a disease or disorder treatable with an L-type calcium channel blocker.
  • At least one of the respective substituents of the compound according to formula XIX is defined as follows:
  • R 3 is preferably hydrogen, halogen (preferably F, Cl, Br or I) or alkyl (in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted;
  • halogen preferably F, Cl, Br or I
  • alkyl in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl
  • R 6 ' is preferably hydrogen or alkyl (in particular C 1 -C6 alkyl, e.g. C 1 , C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted; and R 8 is preferably hydrogen or alkyl (in particular C1-C6 alkyl, e.g.
  • C2, C3, C4, C5, or C6 alkyl preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted.
  • n 3
  • R 6 is methyl
  • the compound according to structure XIX has a structure according to formula XX (vitamin Kl):
  • a compound according to formula XIX or XX is used for the prevention or treatment of a disease or disorder selected from the group consisting of hypertension, angina pectoris, cardiac arrhythmia and a headache.
  • the invention further provides the use of a compound having a structure according to formula XXI:
  • X is O or S; preferably X is O; Z is in each instance CR 4 R 5 ; n is an integer from 1 to 5; i.e. an integer selected from 1, 2, 3, 4 or 5; preferably n is 1; R 1 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted; R 2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted; R 3 is selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I), alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl,
  • At least one of the respective substituents of the compound according to formula XXI is defined as follows:
  • R 1 is preferably aryl (in particular phenyl, naphthalenyl or anthracenyl), or heteroaryl (in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1 ,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2- benzothienyl, lH-indazolyl, benzimid
  • R 2 is preferably aryl (in particular phenyl, naphthalenyl or anthracenyl), or heteroaryl (in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2- benzothienyl, lH-indazolyl, benzimidazoly
  • C2, C3, C4, C5, or C6 alkyl preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted;
  • R 4 and R 5 is preferably each independently selected from hydrogen and alkyl (in particular Cl- C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso- propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted;
  • alkyl in particular Cl- C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso- propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl
  • R 6 and R 7 is preferably each independently selected from the group consisting of hydrogen and alkyl (in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted;
  • alkyl in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl
  • alkyl in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl
  • R 6 ' and R 7 ' is preferably each independently selected from the group consisting of hydrogen and alkyl (in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted; and R 8 is preferably alkyl (in particular C1-C6 alkyl, e.g.
  • C2, C3, C4, C5, or C6 alkyl preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted.
  • n l
  • R 6 and R 7 is methyl and X is O.
  • the compound according to structure XXI has a structure according to formula XXII (Methadone):
  • a compound according to formula XXI or XXII is used for the prevention or treatment of a disease or disorder selected from the group consisting of breast cancer, prostate cancer and for the treatment of serious side effects of androgen deprivation therapy.
  • a disease or disorder selected from the group consisting of breast cancer, prostate cancer and for the treatment of serious side effects of androgen deprivation therapy.
  • the disease is any form of cancer.
  • the invention further provides the use of a compound having a structure according to formula XXIII:
  • X is O or S; preferably X is O; n is an integer from 1 to 5; i.e. an integer selected from 1, 2, 3, 4 or 5; preferably nis 2;
  • R 3 is selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I), alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; and if two R 3 substituents are on adjacent carbon atoms, they may together form a cycloalkyl, heterocycloalkyl or alicyclic system; optionally substituted;
  • R ,3 J ' is selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I), alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted;
  • R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; or pharmaceutically acceptable salts thereof, for the prevention or treatment of a disease or disorder treatable with treatable with an antihistamine.
  • At least one of the respective substituents of the compound according to formula XXIII is defined as follows:
  • R 3 is preferably selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I), and alkyl (in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted; R 3' is preferably alkyl (in particular C1-C6 alkyl, e.g.
  • C2, C3, C4, C5, or C6 alkyl preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted; and
  • R 8 is preferably alkyl (in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted.
  • alkyl in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl
  • n 2 and X is O.
  • the compound according to structure XXIII has a structure according to formula XXIV (acitretin):
  • the invention further provides the use of a compound having a structure according to formula XXV:
  • ml is an integer from O to 5; i.e. an integer selected from O, 1, 2, 3, 4 or 5; preferably ml is O; m2 is an integer from 0 to 4; i.e. an integer selected from 0, 1, 2, 3 or 4; preferably m2 is 0;
  • X is O or S; preferably X is O; Y is in each instance selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I), -NO 2 , -CN, -OR 6 , -NR 6 R 7 , -COOR 6 , -CONR 6 R 7 ,
  • Y' is in each instance selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I), -NO 2 , -CN, -OR 6 ,
  • R 2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 3 is selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I), alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted;
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 6 R 7 ; optionally substituted;
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted;
  • R 8 is in each instance selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted and preferably substituted with -NR 6 R 7 ; and wherein the bond indicated by the dashed line may be present or not; preferably the bond is present; or pharmaceutically acceptable salts thereof, for the prevention or treatment of a disease or disorder treatable with an antihistamine.
  • At least one of the respective substituents of the compound according to formula XXV is defined as follows:
  • R 2 is preferably aryl (in particular phenyl, naphthalenyl or anthracenyl), or heteroaryl (in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl,
  • 1,2,5-thiadiazolyl pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2- benzothienyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1- benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 2,3-benzodiazinyl, quinoxalinyl, quinazolinyl, 1,2,3-benzotriazinyl, or 1 ,2,4-benzotriazinyl); optionally substituted;
  • R 3 is preferably halogen (preferably F, Cl, Br or I).
  • R 8 is preferably alkyl (in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted.
  • alkyl in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl
  • the compound according to structure XXV has a structure according to formula XXVI (clomiphene):
  • the compound according to formula XXV or XXVI is comprised in a composition, which further comprises citrate.
  • a compound according to formula XXV or XXVI is used for the prevention or treatment of an allergy such as hay fever, angioedema or urticaria.
  • the invention further provides the use of a compound having a structure according to formula XXVII:
  • m is an integer from O to 3; i.e. an integer selected from 0, 1 , 2 or 3; preferably m is 0; B is C or N; preferably B is N; X is O or S; preferably X is S; Y is selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I),
  • R 3 is selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I), alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted;
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 6 R 7 ; optionally substituted;
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted;
  • R 6 ' and R 7 ' is each independently selected from the group consisting of hydrogen, alkyl, alkenyl or together form a
  • At least one of the respective substituents of the compound according to formula XXVII is defined as follows:
  • R 3 is preferably halogen (preferably F, Cl, Br or I) or alkyl (in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso- butyl, tert-butyl, pentyl or hexyl); optionally substituted; and
  • R 6 ' and R 7 ' is preferably hydrogen or alkyl (in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted.
  • alkyl in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl
  • the compound according to structure XXVII has a structure according to formula XXVIII (ethionamide):
  • the invention further provides the use of a compound having a structure according to formula XXIX:
  • X is O or S; preferably X is O;
  • R 1 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 8 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted; or pharmaceutically acceptable salts thereof, for the prevention or treatment of a disease or disorder treatable with an antihistamine.
  • R 1 is preferably cycloalkyl or heterocycloalkyl (C 3 -C ]4 -heterocycloalkyl, e.g.
  • Ci 2 , Ci 3 or C ⁇ -heterocycloalkyl in particular piperidinyl, morpholinyl, 1,3-diazacyclohexanyl, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza-spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro-[5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spir
  • R 2 is preferably aryl (in particular phenyl, naphthalenyl or anthracenyl), or heteroaryl (in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, benzothienyl, 2- benzothienyl, lH-indazolyl, benzimidazoly
  • R 8 is hydrogen, X is O and R 1 is optionally substituted with alkyl.
  • the compound according to structure XXIX has a according to formula XXX (nateglinide):
  • a compound according to formula XXIX or XXX is used for the prevention or treatment of an allergy such as hay fever, angioedema or urticaria.
  • the invention further provides the use of a compound having a structure according to formula XXXI:
  • ml is an integer from O to 2; i.e. an integer selected from 0, 1 or 2; preferably ml is 0; m2 is an integer from 1 to 2; i.e. an integer selected from 1 or 2; preferably m2 is 1 ; m3 is an integer from 0 to 4; i.e. an integer selected from 0, 1, 2, 3 or 4; preferably m3 is 0; Y is in each instance selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I), -NO 2 , -CN, -OR 6 ,
  • Y' is in each instance selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I), -NO 2 , -CN, -OR 6 ,
  • Y is in each instance selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I), -NO 2 , -CN, -OR 6 ,
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 6 R 7 ; optionally substituted;
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted;
  • R 8 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl and cycloalkyl; optionally substituted;
  • R 11 is selected from the group consisting of hydrogen, -COR 12 , -CR 4 R 5 OH, alkyl, alkynyl and cycloalkyl; optionally substituted
  • At least one of the respective substituents of the compound according to formula XXXI is defined as follows: Y' is preferably -NO 2 or -CN; R 8 is preferably hydrogen or alkyl (in particular C1-C6 alkyl, e.g. Cl, C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted; and
  • R 1 ' is preferably -COR 12 ; wherein R 12 is preferably alkyl (in particular C 1 -C6 alkyl, e.g. C 1 , C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl); optionally substituted.
  • alkyl in particular C 1 -C6 alkyl, e.g. C 1 , C2, C3, C4, C5, or C6 alkyl, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl or hexyl
  • R 12 is preferably alkyl (in particular C 1 -C6 alkyl, e.g. C 1 , C2, C3, C4, C5, or C6 al
  • the compound according to structure XXXI has a according to formula XXXII (zaleplon):
  • a compound according to formula XXXI or XXXII is used for the prevention or treatment of an allergy such as hay fever, angioedema or urticaria.
  • the invention further provides the use of a compound having a structure according to formula XXXIII:
  • m is an integer between 0 and 2; i.e. an integer selected from 0, 1 or 2; preferably m is 0; B is in each instance C or N; preferably B is N; X is O or S; preferably X is O;
  • Y is selected from the group consisting of hydrogen, halogen (preferably F, Cl, Br or I), -NO 2 , -CN, -OR 6 ,
  • R 1 is selected from the group consisting of cycloalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted;
  • R 4 and R 5 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR 6 R 7 ; optionally substituted;
  • R 6 and R 7 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl or together form a heteroaryl, and heterocycloalkyl; optionally substituted;
  • R 11 is selected from the group consisting of hydrogen, -COR I2 ; -CR 4 R 5 OH, alkyl, alkynyl and cycloalkyl; optionally substituted;
  • R 12 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl; optionally substituted; or pharmaceutically acceptable salts thereof, for the prevention or treatment of a depression and/or a disease or disorder treatable with an antihistamine.
  • R 1 is preferably aryl (in particular phenyl, naphthalenyl or anthracenyl), or heteroaryl (in particular furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1-benzofuranyl, 2-benzofuranyl, indolyl, isoindolyl, be
  • Ci 2 , Ci 3 or Ci 4 - heterocycloalkyl in particular piperidinyl, morpholinyl, 1,3-diazacyclohexanyl, 1,8 diaza-spiro-[4,5] decyl, 1,7 diaza-spiro-[4,5] decyl, 1,6 diaza-spiro-[4,5] decyl, 2,8 diaza- spiro[4,5] decyl, 2,7 diaza-spiro[4,5] decyl, 2,6 diaza-spiro[4,5] decyl, 1,8 diaza-spiro- [5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 diaza-spiro-[5,4] decyl, 2,7 diaza-spiro[5,4] decyl, 3,8 diaza-spiro- [5,4] decyl, 1,7 diaza-spiro-[5,4] decyl, 2,8 di
  • R 11 is , wherein the asterisk indicates where the substitutent is attached to the O atom of formula (XXXIII) and wherein n is an integer between 0 and 2; i.e. an integer selected from 0, 1 or 2; preferably n is 0; and Y and has the above outlined meaning.
  • the compound according to structure XXXIII has a structure according to formula XXXIV (zopiclone):
  • a compound according to formula XXXIII or XXXIV is used for the prevention or treatment of an allergy such as hay fever, angioedema or urticaria.
  • a compound of the invention is used for for the prevention or treatment of a depression, then it is preferred that the depression is selected from the group consisting of clinical depression, melancholic depression, atypical depression, psychotic depression and postnatal depression. If a compound of the invention is used for for the prevention or treatment of an anxiety disorder, then it is preferred that the anxiety disorder is selected from the group consisting of panic disorder, agoraphobia, social anxiety disorder, obsessive-compulsive disorder, posttraumatic stress disorder and separation anxiety.
  • a compound of the invention is used for for the prevention or treatment of a psychosis, then it is preferred that the psychosis is selected from the group consisting of schizophrenia, bipolar disorder, mania and delusional disorder.
  • Several compounds described herein are useful to treat an allergy. These compounds are preferably used to treat an allergy selected from the group consisting of: allergic rhinitis, asthma, atopic eczema, anaphylaxis, an insect venom-induced allergy, a drug induced allergy, a food- induced allergy and a multiple allergy disorder.
  • table 3 lists pairs of pharmaceuticals which share the same therapeutic target.
  • a pharmaceutical listed in column “Drug 1 (PugChem ID)” can also be used for the therapy of a disease or disorder that is generally treatable which a respective compound listed in the column “Drug 2 (PugChem ID)” of table 3.
  • a pharmaceutical listed in column “Drug 2 (PugChem ID)” can be used for the therapy of a disease or disorder that is generally treatable which a respective compound listed in the column “Drug 1 (PugChem ID)”.
  • a compound listed in table 3 under "Drug 1 (PugChem ID)" for the prevention or treatment of a medical indication as indicated under “T. Cat Drug2” and encoded by table 2.
  • a compound listed in table 3 under “Drug 1 (PugChem ID)” can be used for the treatment of a disease or disorder treatable with a drug of the therapeutic class indicated under "T. Cat Drug2” and encoded by table 2.
  • Clobetasol may be used for the treatment of a disease treatable with an antiinflamatory agent (therapeutic category "SOlB") or with a corticosteroid for systemic use (therapeutic category "H02").
  • Spironolactone may be used for the treatment of a disease treatable with an androgen (therapeutic category "G03B").
  • a compound according to the invention can be administered by various well known routes, including oral, rectal, intragastrical, intracranial and parenteral administration, e.g. intravenous, intramuscular, intranasal, intradermal, subcutaneous, and similar administration routes.
  • parenteral administration and particular intravenous administration preferably by depot injection, is preferred.
  • different pharmaceutical formulations are required and some of those may require that protective coatings are applied to the drug formulation to prevent degradation of a compound of the invention in, for example, the digestive tract.
  • a compound of the invention is formulated as a syrup, an infusion or injection solution, a tablet, a capsule, a capslet, lozenge, a liposome, a suppository, a plaster, a band-aid, a retard capsule, a powder, or a slow release formulation.
  • the diluent is water, a buffer, a buffered salt solution or a salt solution and the carrier preferably is selected from the group consisting of cocoa butter and vitebesole.
  • Particular preferred pharmaceutical forms for the administration of a compound of the invention are forms suitable for i ⁇ jectionable use and include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases the final solution or dispersion form must be sterile and fluid.
  • such a solution or dispersion will include a solvent or dispersion medium, containing, for example, water-buffered aqueous solutions, e.g. biocompatible buffers, ethanol, polyol, such as glycerol, propylene glycol, polyethylene glycol, suitable mixtures thereof, surfactants or vegetable oils.
  • a compound of the invention can also be formulated into liposomes, in particular for parenteral administration. Liposomes provide the advantage of increased half life in the circulation, if compared to the free drug and a prolonged more even release of the enclosed drug.
  • Sterilization of infusion or injection solutions can be accomplished by any number of art recognized techniques including but not limited to addition of preservatives like anti-bacterial or anti-fungal agents, e.g. parabene, chlorobutanol, phenol, sorbic acid or thimersal. Further, isotonic agents, such as sugars or salts, in particular sodium chloride may be incorporated in infusion or injection solutions.
  • preservatives like anti-bacterial or anti-fungal agents, e.g. parabene, chlorobutanol, phenol, sorbic acid or thimersal.
  • isotonic agents such as sugars or salts, in particular sodium chloride may be incorporated in infusion or injection solutions.
  • sterile injectable solutions containing one or several of the compounds of the invention is accomplished by incorporating the respective compound in the required amount in the appropriate solvent with various ingredients enumerated above as required followed by sterilization. To obtain a sterile powder the above solutions are vacuum-dried or freeze-dried as necessary.
  • Preferred diluents of the present invention are water, physiological acceptable buffers, physiological acceptable buffer salt solutions or salt solutions.
  • Preferred carriers are cocoa butter and vitebesole.
  • Excipients which can be used with the various pharmaceutical forms of a compound of the invention can be chosen from the following non-limiting list: a) binders such as lactose, mannitol, crystalline sorbitol, dibasic phosphates, calcium phosphates, sugars, microcrystalline cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, polyvinyl pyrrolidone and the like; b) lubricants such as magnesium stearate, talc, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, leucine, glycerids and sodium stearyl fumarates, c) disintegrants such as starches, croscaramellose, sodium methyl cellulose, agar, bentonite, alginic acid, carboxymethyl cellulose, polyvinyl pyrrolidone and the like.
  • binders such as lactose, mannitol, crystalline sorb
  • the dosage of a compound of the invention in the therapeutic or prophylactic use of the invention should be in the range of about 0.1 mg to about 1 g serum per kg body weight.
  • a compound of the invention is administered to a subject in need thereof in an amount ranging from 1.0 to 500 mg/kg body weight, preferably ranging from 10 to 200 mg/kg body weight, preferably ranging from 50 to 150 mg/kg body weight, preferably ranging from 90 to 100 mg/kg body weight.
  • the duration of therapy with a compound of the invention will vary, depending on the severity of the disease being treated and the condition and idiosyncratic response of each individual patient.
  • the pharmaceutically effective amount of a given composition will also depend on the administration route. In general the required amount will be higher, if the administration is through the gastrointestinal tract; e.g.
  • a compound of the invention will be administered in ranges of 50 mg to 1 g/kg body weight, preferably 100 mg to 500 mg/kg body weight, if rectal or intragastric administration is used and in ranges of 10 to 100 mg/kg body weight, if parenteral administration is used.
  • a prophylactic administration of the biologically active blood serum or the pharmaceutical composition according to the invention may be possible.
  • the respective compound of the invention is preferably administered in above outlined preferred and particular preferred doses on a daily basis. Preferably, between 0.1 mg to 1 g/kg body weight once a day, preferably 10 to 200 mg/kg body weight. This administration can be continued until the risk of developing the respective disorder has lessened. In most instances, however, a compound of the invention will be administered once a disease/disorder has been diagnosed. In these cases it is preferred that a first dose of a compound of the invention is administered one, two, three or four times daily. Preferably the administration is discontinued for one day, one week or one month and then repeated until the symptoms of the respective disease are no longer worsening or improving.
  • the present invention provides in one aspect a method for identifying a novel medical indication of a pharmaceutically active compound comprising the steps: (a) extracting side-effects of a first pharmaceutically active compound from at least one database;
  • the method of the invention further comprises the step
  • step (d) determining a chemical similarity score which is the degree of structural similarity between the first and the second pharmaceutically active compound. It is further preferred that the method according to the invention further comprises the step (e) determining the probability that the second pharmaceutically active compound binds to the same therapeutic target protein as the first pharmaceutically active compound; wherein the probability is a function of the side-effect similarity score from step (c) and/or of the chemical similarity score from step (d).
  • the method according to the invention further comprises the step (f) repeating steps (a) through (e) for a multiplicity of non-redundant pairs of pharmaceutically active compounds; wherein each pair comprises a respective first and second pharmaceutically active compound. It is further preferred that the method according to the invention further comprises the step
  • step (g) if the probability determined in step (e) is greater than 20% preferably greater than 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35%, 40%, 45%, or 50% and most preferably greater than 25%, then: selecting the medical indication of the first pharmaceutically active compound as a novel medical indication for the second pharmaceutically active compound; and/or selecting the medical indication of the second pharmaceutically active compound as a novel medical indication for the first pharmaceutically active compound; Further preferred is the method of the invention, wherein in step (a) and/or (b), extracted side- effects that are synonymous and/or fall into a common classification class such as defined e.g. by the Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART) or the International Classification of Primary Care (ICPC), are grouped and treated as one side-effect throughout the method.
  • COSTART Coding Symbols for a Thesaurus of Adverse Reaction Terms
  • ICPC International Classification of Primary Care
  • the method of the invention wherein at least one parent side-effect from at least one ontology, for example from one described above, is assigned to each side-effect of the first and/or second pharmaceutical compound to provide an "is-a" relation which is preferably used to determine similarities between closely related side effects.
  • the extracted side effects are expanded with concepts related to them by a "is-a" relation from an ontology such as COSTART, i.e. parents terms from the ontology are assigned to capture similarities between closely related side effects.
  • an ontology such as COSTART
  • parents terms from the ontology are assigned to capture similarities between closely related side effects.
  • macrocytic anaemia is a parent term of megaloblastic anaemia and is, thus, automatically assigned to all drugs that have this side effect.
  • step (c) is a similarity measure and preferably is a distance measure.
  • the similarity measure used in the method according to the invention is the sum of all side-effects shared between the first and second pharmaceutically active compound.
  • An example for the aforementioned preferred embodiment is provided in example 1 and figure IE.
  • the similarity measure may also be selected from the group consisting of: a Cosine coefficient, a Dice coefficient, an Euclid coefficient, a Forbes coefficient, a Hamman coefficient, a Jaccard coefficient, a Kulczynski coefficient, a Manhattan coefficient, a Matching coefficient, a Pearson correlation, a Rogers-tanimoto coefficient, a Russell-rao coefficient, a Simpson coefficient, a Tanimoto coefficient and a Yule coefficient.
  • each shared side-effect is weighted according to the frequency of its occurrence and/or according to the frequency with which the side-effect correlates with other side-effects.
  • An example for this is given in figure 1C and ID and in the respective examples.
  • the method of the invention wherein the weight used to account for the frequency of correlation is determined using a tree weighting algorithm, for example the Gerstein-Sonnhammer-Chothia algorithm (see for example also the examples and fig. 1C).
  • the weight of the side-effect frequency is the negative logarithm of the side-effect's frequency of occurrence (see for example also the examples and fig. ID).
  • the side-effect similarity score is normalized by determining what fraction of a multiplicity of pairs of pharmaceutically active compounds, each of which has randomized side effects, has a side-effect similarity score which is equal or greater than the side-effect similarity score of the first and the second pharmaceutically active compound. Further preferred is the method of the invention, wherein
  • each pair of said multiplicity of pairs of pharmaceutically active compounds has the same respective number of side-effects than the first and the second pharmaceutically active compound;
  • step (iii) random side effects are selected for each pharmaceutically active compound by replacing each original side effect with one side-effect that is randomly selected from a set of side effects with similar frequency of occurrence.
  • the chemical similarity score in step (d) is a Tanimoto 2D chemical similarity score, a Tanimoto 3D chemical similarity score, or a Tversky index.
  • the probability in step (e) is determined using a continuous or discontinuous probability function that has been derived from a reference dataset comprising pharmaceutically active compounds, their respective side-effects as well as their respective one or more therapeutic target proteins.
  • a reference dataset comprising pharmaceutically active compounds, their respective side-effects as well as their respective one or more therapeutic target proteins.
  • derived preferably refers to selecting a mathematical function, i.e. said probability function which preferably statistically correlates data comprised in said reference dataset of one pharmaceutically active compound to the data comprised in said reference dataset of a further pharmaceutically active compound.
  • the probability function correlates the side-effect similarity score determined according to step (c) and/or the chemical similarity score determined according to step (d) of a pair of pharmaceutically active compounds in the reference set with the probability that said pair shares the same therapeutic target protein.
  • the probability function is a sigmoid function.
  • x is the side-effect similarity score
  • y is the chemical similarity score
  • H is a real number between 0.7 and 0.9, preferably 0.83;
  • A is a real number between 0.01 and 0.03, preferably 0.0167;
  • B is a real number between 50 and 60, preferably 55.507;
  • C is a real number between -600 and -1000, preferably -810.16;
  • D is a real number between -50 and -200, preferably -129.6;
  • E is a real number between 400 and 600, preferably 455.6;
  • F is a real number between 500 and 700, preferably 617.3;
  • G is a real number between 0.1 and 0.8, preferably 0.415.
  • the probability function is a discontinuous function derived from the fraction of drug pairs that share a target within intervals of side-effect similarity scores and chemical similarity scores.
  • the side-effect similarity score in step (c) is the weighted sum of all side-effects shared between the first and second pharmaceutically active compound; wherein the chemical similarity score in step (d) is a Tanimoto 2D chemical similarity score and wherein the probability function is a sigmoid function.
  • the invention also provides a computer program product stored on a computer readable storage medium comprising a computer-readable program code for causing a computer to carry out the method according to the invention.
  • an apparatus for carrying out the method according to the invention is also comprised.
  • a data processing system e.g. a personal computer, comprising a memory device, an operating system and the computer program product according to the invention which is loaded into the memory device of said data processing system and wherein the data processing system is capable of carrying out the method according to the invention.
  • the invention provides the use of a pharmaceutically active compound for which a novel medical indication has been identified according to the method of of the invention for the prevention or treatment of the respective novel medical indication that has been identified according to the method of the invention.
  • Fig. 1 Flowchart of the method.
  • A) Terms for side effects are extracted from the package inserts, B) subjected to ontological annotation in the UMLS ontology and then weighted for C) cross-correlation and D) frequency.
  • macrocytic anaemia (E) is a parent term of megaloblastic anaemia (A) and is thus automatically assigned to all drugs that have this side effect.
  • A) a raw side-effect similarity score is derived and F) normalized.
  • Fig. 2 Breakdown of drug pairs predicted to share a target.
  • A) The predicted 2903 drug pairs were subjected to consecutive filtering for a number of properties, leaving 754 pairs that imply unexpected drug-target relations.
  • B) The subset of pairs and implied predictions that are predominantly based on side-effect similarity (requiring an additional stringent p-value ⁇ 0.1) was used for network analysis (Fig. 3).
  • Fig. 3 Drug network based on likelihoods for having common protein targets.
  • a drug subnetwork around the anti-ulcer drug Rabeprazole and other 15 experimentally confirmed predictions are shown around the network.
  • Fig. 4 Novel drug— target relationships.
  • the line delimits the area used to construct the network in Fig. 3 with shared target probability >25% and side-effect p-value ⁇ 0.1.
  • Drug pairs that have been experimentally confirmed to share a target are denoted by black and grey dots according to Ki value.
  • Fig. 5 Drug-protein interactions of reference set.
  • Our reference set was derived from the MATADOR database (Manually Annotated Targets and Drugs Online Resource,(i)), DrugBank (2) and the PDSP Ki database (3). Metabolizing enzymes and proteins with unspecific drug binding were excluded from the reference set. From the PDSP Ki database, we only included interactions with an inhibition constant below lO ⁇ M. The number of drugs with annotated targets in MATADOR, DrugBank and the PDSP Ki database are 381, 462 and 148, respectively. The contributions of drug-protein interactions of the three databases to our reference are shown in a Venn diagram. The different databases treat interactions with protein groups such as complexes and families of proteins differently.
  • Fig. 6 Benchmarking of target prediction methods. Three probabilistic methods that evaluate the probability of two drugs to share a target were compared. A) The first method is based on the comparison of side effects information of drugs (SE). The dotted line represents 50% probability of sharing targets at which the side-effect similarity p-value is 0.0045. B) The second method uses the information provided by the chemical similarity between drugs (2D) and the third method combines both individual predictors (SE_2D). Both individual methods show a clear correlation between similarity and the probability of sharing a common target. In our reference set, a Tanimoto 2D similarity score of 0.85 implies a 74% chance of sharing a target.
  • Fig. 7 The number of drug pairs falsely predicted to share targets depends on the number of side effects of the drugs involved.
  • the number of drugs that do not share targets but are predicted to share a target with the given drug with at least 25% probability is calculated and averaged over a sliding window of 11 drugs.
  • Drug pairs involving at least one drug with less than 7 side effects produce relatively many false positives and are thus discarded for prediction purposes.
  • Our model employs small contributions of many side effects towards overall side effect similarity. Thus, very low numbers of side effects do not provide sufficient information for a reliable prediction.
  • Fig. 8 Breakdown of drug pairs predicted to share targets in different probability intervals. Drug pairs with less than 25% probability of sharing targets (A) are contrasted with those in various probability intervals between 25% and 100% (B). C) Subset of (B) with the additional requirement of a side-effect similarity pvalue lower than 0.1. The type of drug pair (see boxed inset) is indicated. In the bar graph the type of drug pair is ordered from top to bottom as indicated in the boxed inset.
  • Similarity of protein targets correlates with probability of binding the same ligand.
  • Fig. 10 Extension of Fig. 4 in main manuscript with details of experimental validation of 20 predicted drug pairs in the network.
  • Predicted targets for drugs from the 20 drug pairs candidates in the network were tested in in vitro binding assays at 50 ⁇ M.
  • Ki inhibition constant
  • Prob. is the probability of sharing a target and nh refers to the Hill coefficient of the concentration-curves.
  • Drug pairs sharing targets in the reference set were grouped in intervals by their probability of sharing targets as predicted by the combination of both side effect similarity and chemical similarity (A), side effect similarity alone (B) or chemical similarity alone (C).
  • A side effect similarity and chemical similarity
  • B side effect similarity alone
  • C chemical similarity alone
  • the average number of targets that are not shared (as indicated) and the average numbers of targets , that are shared (as indicated) were calculated within the intervals. Linear regression reveals that the probability of sharing a target correlates negatively with the number of targets that is not shared by the drug pair. This correlation is not observed when the number of targets shared for the drug pair is compared.
  • ⁇ The square of the Pearson product-moment correlation coefficient is shown ( ⁇ ) along with the statistical significance of the correlation as assessed by 1000 randomizations of the drug pairs. The error bars indicate the standard deviation of the data.
  • Fig. 12 Two-dimensional histogram representing the probabilities that two drugs share the same target as a function of side effect similarity p-value and chemical similarity.
  • Table 1 FDA-approved drugs analyzed in this work. ID is the drug PubChem identifier. (Stereoisomers were merged into one compound.) Table 2 List of therapeutic categories.
  • Table 3 Excerpt of the list of the 1018 drugs pairs with a probability (Prob) of sharing a target higher than 25% and side effect similarity p-value (SE) below 0.1.
  • the Tanimoto coefficient of the drugs of the pairs (2D) is also given.
  • Drug pairs are classified into five groups (1-5) according to the main text ( Figure 2 and Figure 3) whereby the respective groups are subtracted from the total 1018 prediction in the following order to arrive at the unexpected findings (group 5). From the total 1018 drug pairs, we first subtracted those drug pairs that are known to share targets (group 1); in this group 57 drug pairs with high chemical similarity can be found, as the chemical similarity filter was not applied to them.
  • Classification System ATC (comprised in table 2), additional indications which are not covered included in table 2 can be found.
  • the compounds ethionamide, zaleplon, zopiclone and doxorubicin can be used as antihistamines.
  • these compounds can be used to inhibit the release or action of histamine.
  • Histamine can be quantified using, for example, an ELISA assay and anti-histamine specific antibodies.
  • Drugs that are part of the reference set and that imply a known human target are marked with an asterisk.
  • the majority of the drugs that are not part of the reference set are drugs directed against non-human proteins (for example, antibiotics), but there is also a small number of drugs with as yet unknown target.
  • drugs directed against human were retrievable from the resources used, and some drugs directed against human were not annotated in the reference sets (for example, endogenous compounds).
  • the list contains a few drug pairs that are labelled as predictions (groups 2-5) although they are known to share a target (which underlines the predictive power of the approach).
  • Example 1 Quantification and normalization of side-effect similarities
  • UMLS Unified Medical Language System
  • Fig. 3 we focused on those areas in the network that contain drugs with human targets, which belong to different therapeutic categories.
  • Rabeprazole a proton pump inhibitor.
  • five drug pairs are predicted to share targets with a probability in the range of 30-75%; four of them involve Rabeprazole.
  • Fig. 4 We validated all our predictions in this subnetwork both with in vitro and cell assays (Fig. 4). It appears that Rabeprazol binds both the dopamine receptor DRD3 with an antagonist activity and, with lower affinity, the serotonin receptor HTRlD. We could not detect binding to the serotonin transporter SLC6A4 (Fig. 3B).
  • the nervous system drugs Pergolide, Paroxetine and Fluoxetine are known to share two of the three targets above (Fig. 3B), while Zolmitriptan only seems to bind to its primary target serotonin receptor HTRlD that it shares with Rabeprazol (Fig. 3B).
  • Donepezil's primary targets are cholinesterases. We show here that it also binds to serotonin transporter SLC6A4 in vitro and inhibits it in cell assays; this might explain Donepezil's strong side-effect similarity with Venlafaxin (Fig. 3B).
  • the sharing of side effects of the proton pump inhibitor Rabeprazole revealed two nervous system off-targets with affinities (Fig.
  • the reference set is composed of 502 drugs approved by the FDA (Food and Drug Administration) with 4857 associated drug-protein interactions.
  • the drug- protein interactions were extracted from the MATADOR database (1), DrugBank (2) and the PDSP Ki database (3) (K. binding affinity lower than 10 ⁇ M).
  • the different contributions of drug-target interactions of the databases are shown in a Venn diagram (Fig. 5).
  • a target as a protein that binds physically to the drug and might be responsible of the drug mechanism of action.
  • metabolizing enzymes and unspecific protein binders like albumin also bind drugs, they cannot generally be associated with the mechanism of action and they were therefore excluded from our reference set.
  • the side effect and indication area sections of drug labels were extracted and searched for known terms of side effects. 1443 concepts from UMLS ontology were found by text mining. In order to avoid spurious hits resulting from the description of the drug's purpose within the side effect section, concepts found in the indication area section were masked and discarded from the concepts extracted from the side effect section.
  • Drug labels were assigned to chemical compounds by matching of drug synonyms. Labels for combinations of drugs were discarded during the name mapping and by manual inspection of labels that contain the names of other drugs in the side-effect section. In some cases, groups of closely related drugs, such as Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), are listed together on one label. These labels require manual intervention, as our the text-mining approach assigns all mentioned side effects to all drugs of the label although some of the side effect might only be relevant for some of the drugs. Therefore, these labels were manually annotated to assign the listed side effects to the specific drugs.
  • NSAIDs Nonsteroidal Anti-Inflammatory Drugs
  • the weighting scheme consists of two parts, a rareness weight and a correlation weight.
  • the rareness weight for a side effect, ⁇ is defined as the negative logarithm of the side-effect frequency fi. (This frequency refers to the fraction of drug labels that feature a certain side effect, not the relative occurrence of the side effect in patients).
  • the correlation of side effects was determined by clustering all side effects according to their assigned drugs using a Tanimoto/Jacquard score to compute a distance matrix: The distance between two drugs was calculated by dividing the number of drugs that feature both side effects by the number of drugs that have either side effect associated.
  • the Gerstein-Sonnhammer- Chothia algorithm (7) was used to compute weights based on a hierarchal clustering with the aforementioned distance matrix (S).
  • a raw score for the side-effect similarity of a drug-drug pair was calculated by summing the product of the weights over all shared concepts. This raw score was converted into a p-value by generating 10,000 drug pairs in which each side effect has been replaced by a randomly chosen side effect of similar frequency. For each side effect, a set of neighbours was assembled from the 100 side effects that are closest in frequency. This set was then extended to include all side effects of equal rareness.
  • the open-source Chemistry Development Kit (P) was used to calculate chemical fingerprints and the commonly used Tanimoto 2D chemical similarity scores (10, 11).
  • Example 11 Combining 2D and side effect similarity for target prediction.
  • Drug pairs were scored by their probability of sharing targets based on a function of side- effect similarity and 2D similarity. To this end, we distributed drug pairs from the reference set in a two-dimensional histogram (Figure 12). In the first dimension, drug pairs were distributed using logarithmic percentiles of their ranked side effect similarity p-values, and in the second dimension, they were distributed using percentiles or their ranked chemical similarity. Equal similarity values were assigned to the same percentile.
  • the fraction of drug pairs that share a target is computed as a function of the natural logarithm of the average side effect similarity p-value (JC in the following equations) and average chemical similarity (2D Tanimoto coefficient, y) within the cell.
  • JC average side effect similarity
  • 2D Tanimoto coefficient, y average chemical similarity
  • PSE,2D represents the probability of sharing the same target for a drug pair with a given side effect similarity p-value and chemical similarity.
  • P2D is the probability of sharing the same target as a function of chemical similarity of drug pairs only.
  • the function used to model the probability of sharing the same target as predicted using only side effect similarity information is the following:
  • PSE is the probability of sharing the same target for a drug pair predicted using only side effect similarity information.
  • Example 12 Quantifying the impact of target similarity.
  • Ki values less or equal to 10 ⁇ M were considered as binding, whereas higher Ki values were considered as non-binding.
  • Normalized bitscores of 0 in Fig. 9A were caused by low-similarity alignments that are not reported. Protein- protein pairs were sorted by normalized bitscores and binned (14).
  • the company Cerep performed the enzymatic assay for the prostaglandinendoperoxide synthase 2 (COX2, 777-2hr) and binding assays to the dopamine receptor type 3 (D3h, 803-3h), the serotonin transporter (5-HT transporter, 808-Uh), the serotonin receptor ID (5-HTID, 808- ldc), the alpha-2 adrenergic receptor (alpha2A, 802- IbAh), the alpha- 1 adrenergic receptor (alphal, non-selective, 802-la), the beta-1 adrenergic receptor (betal, 802-2ah), the peripheral- type benzodiazepine receptor (BZD, 852), the calcium-activated potassium channel (SKCa, 863- 3), the dopamine receptor type 1 (Dl, 803-lh), the dopamine receptor 2 (D2S,803-2h), the GABA receptor (GABA, non-selective,
  • L concentration of radioligand in the assay
  • KD affinity of the radioligand for the receptor.
  • the specificity of the in vitro binding assay was controlled by using negative controls at 50 ⁇ M. For assays where our own tested candidates did not give negative results (Fig. 10), we ordered tests against compounds we did not expect to bind to verify the specificity. Those compounds are Mafenide on the 808-Uh (5-HT transporter) and 808- ldc (5-HTID) assays and Aspirin on the 805-Ih (Hl) assay.
  • Example 14 Cell assays. The agonist and antagonist responses of all drugs that showed binding activity (inhibitory activity of the reference compound binding activity) above 40% were tested by Cerep at 50 ⁇ M using the following assays: Donepezil: serotonin uptake assay (710); Ketoconazole: serotonin receptor 2C (agonist effect: 722-13a, antagonist effect: 722-13b); Fluoxetine, Rabeprazole and Paroxetine: dopamine receptor 3 (agonist effect: 758-19a, antagonist effect: 758-19b); Zaleplon, Disopyramide, Clomiphene and Acitretin: histamine Hl receptor (agonist effect: 721 -7a, antagonist effect: 721 -7b).

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Abstract

La présente invention concerne un procédé d'identification d'une nouvelle indication médicale d'un composé pharmaceutiquement actif. L'invention propose en outre de nouvelles indications médicales pour plusieurs composés pharmaceutiquement actifs. En particulier, elle propose des composés pour la prévention et le traitement d'une maladie ou d'un trouble qui peuvent être traités avec un inhibiteur de la réabsorption de la sérotonine-norépinéphrine (SNRI), un antagoniste des récepteurs de la sérotonine, un estazolam, un antagoniste des récepteurs de la dopamine, un agoniste des récepteurs de la dopamine, un agent de blocage des canaux de calcium de type L, un modulateur sélectif des récepteurs d'oestrogène (SERM) et un antihistaminique. L'invention propose également un composé pharmaceutiquement actif pour la prévention ou le traitement de la tachycardie.
PCT/EP2009/002620 2008-04-08 2009-04-08 Composés à nouvelles utilisations médicales et procédés d'identification de ces composés WO2009124755A1 (fr)

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