WO2002030422A1 - Use of defined substances that bind to the sigma receptor for combating sarcoma and carcinoma - Google Patents
Use of defined substances that bind to the sigma receptor for combating sarcoma and carcinoma Download PDFInfo
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- WO2002030422A1 WO2002030422A1 PCT/EP2001/011710 EP0111710W WO0230422A1 WO 2002030422 A1 WO2002030422 A1 WO 2002030422A1 EP 0111710 W EP0111710 W EP 0111710W WO 0230422 A1 WO0230422 A1 WO 0230422A1
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the invention relates to the use of substances known per se for the treatment of carcinomas and sarcomas.
- the substances whose use is the subject of the invention bind with high affinity to both known sigma receptors ( ⁇ receptors).
- the ⁇ receptors belong to the class of opioid receptors.
- the first evidence of the existence of various opioid receptors came from Martin and co-workers who conducted experiments on dogs (J. Pharma Coll. Exp. Ther. 197: 517 to 532, 1976). Striking differences in the pharmacological behavior of various narcotic analgesics and their inability to replace each other with regard to withdrawal symptoms led Martin and co-workers to postulate the existence of three different types of receptors. These were named after the prototypical pharmaceuticals used ⁇ for morphine, K for ketocyclazocin and ⁇ for SKF 10047 (N-allylnormetazocin). After the discovery of the enkephalins, another group of receptors, the ⁇ receptors, was discovered.
- the ⁇ -opioid receptors which are expressed in the central nervous system like the other opioid receptors, have properties that distinguish them from the other opioid receptors. For example, the effects of these receptors are not offset by naloxone. There is also an overlap between ⁇ binding sites and binding sites for non-opiates such as phencyclidine (angel dust). In the more recent literature, the ⁇ receptors are therefore not included in the opioid receptors.
- ⁇ receptors There are two subtypes of ⁇ receptors, ⁇ i and ⁇ 2 [Quirion et al., Trends Pharmacol. Be. 13, 85, 1992; Walker et al. Aspects of synaptic transmission, editor TW Stone (Taylor and Francis, London) page 91, 1993; Bowen Aspects of synaptic transmission, editor TW Stone (Taylor and Francis, London), page 1 13, 1993].
- ⁇ -receptors can be found in various peripheral tissues such as liver, kidney, gastrointestinal tract and endocrine glands such as ovaries, adrenal glands, testes and pituitary glands, as well as in leukocytes.
- ⁇ -Receptor ligands are known to inhibit the growth of certain cancers, such as small cell lung cancer.
- Various ⁇ -receptor ligands are already known:
- IPAB (2-piperidinylaminoethyl) -4-iodobenzamide
- ⁇ -receptor ligands are all compounds that bind to the ⁇ i-receptor and / or to the ⁇ -receptor with high affinity.
- the affinity is the IC 50 value of the displacement of radioactively labeled SKF-10047 (in the case of the ⁇ i receptor) and of radioactive 1,3-di-o-tolylguanidine (DTG) (in the case of the ⁇ 2 - Receptor).
- Tris-HCl (2-amino-2- (hydroxymethyl) -1, 3-propanediol hydrochloride), pH 7.7 is used as the incubation buffer;
- Tris buffer Tris-HCl buffer, pH 7.7
- Glass-Teflon homogenizer 10 bursts, 800 rpm
- the homogenate is centrifuged for 15 minutes at 2 ° C at 20,000 rpm in a SS-34 rotor;
- the pellet is resuspended in Tris buffer, a concentration of 10 mg of original tissue per ml being set, and frozen in aliquots at - 28 ° C; -
- the suspension is thawed in a water bath at room temperature, washed twice in 50 ml of Tris buffer and then centrifuged at 22,000 g for 10 minutes;
- the ICso value is determined in a volume of 0.5 ml with 0.5 nM 3 H-DTG and 4 mg original tissue per ml at 25 ° C
- the invention further relates to the use of one of the above compounds or the corresponding pharmaceutically acceptable acids, bases or salts for the manufacture of a medicament for the treatment of carcinomas and sarcomas.
- Another object of the invention is the use of one of the above substances for the treatment of small cell lung carcinomas, breast and colon carcinomas and melanomas.
- the compounds used according to the invention are generally more or less basic. They can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation.
- an inert solvent such as ethanol and subsequent evaporation.
- acids that provide physiologically acceptable salts are suitable for this implementation.
- So inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and also organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carbon, sulfone - or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, methanoic acid or isonicotinic acid - thanesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids or laurylsulfuric acid.
- the product obtained is the pharmaceutically acceptable salt of the corresponding base, which was listed above. If compounds to be used according to the invention react acidically in aqueous solution, these can be converted into the corresponding salt by adding basic compounds. If a compound listed above is a salt, the active compound can be released by adding acid or base or, if necessary, by simple hydrolysis. If the compounds are to be used as part of a pharmaceutical composition, care must be taken to ensure that the corresponding partners of the acid-base reaction are pharmaceutically acceptable, that is to say essentially non-toxic to humans in the amounts used.
- the compounds are to be used as ⁇ -receptor ligands in in vitro reactions, compatibility is irrelevant, so that all acids or bases which are inert to the pharmaceuticals, apart from the protolysis reaction, are suitable as partners for the acid-base reaction behavior.
- the substances to be used according to the invention form the active constituent of medicaments and medicaments which are used against cancer, that is to say in particular against carcinomas or sarcomas.
- cancer that is to say in particular against carcinomas or sarcomas.
- carcinomas in particular against carcinomas of the lungs, especially against small cell lung carcinomas and melanomas, is preferred.
- the substances to be used according to the invention are generally administered in the dosage preferably between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit.
- the daily dosage is preferably between about 0.02 and 10 mg per kg of body weight.
- the specific dose for each patient depends on a wide variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight and general health, on sex, on the diet, on the time of administration and on the route of administration, on the rate of elimination , of the drug combination and the severity of the respective disease to which the therapy applies.
- Oral application is preferred.
- rectal application, parenteral application, in particular intravenous, intramuscular, and possibly intraperitoneal application are also possible.
- the patient will be a mammal, with humans included.
- the patient is an animal, including fish and birds. The invention is described in more detail by the following example.
- the affinity of the substances to be used according to the invention on brain homogenate of guinea pigs was determined.
- the affinity value is the IC- 50 value of the displacement of radioactively labeled SKF-10047 (in the case of the ⁇ i receptor) and of DTG (in the case of the ⁇ 2 receptor).
- the affinity for the ⁇ i receptor was determined according to SW Tarn, European Journal of Pharmacology 1985, 109 (1), pages 33-41. Y. Shirayama et al., European Journal Pharmacology, 1993, 237 (1), pages 1 17-126 was used to determine the affinity for the ⁇ 2 receptor. The results are shown below.
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Abstract
Description
Verwendung bestimmter Substanzen, die an den Sigma-Rezeptor binden, zur Behandlung von Sarkomen und Karzinomen Use of certain substances that bind to the sigma receptor for the treatment of sarcomas and carcinomas
Die Erfindung bezieht sich auf die Verwendung von Substanzen, die per se bekannt sind, zur Behandlung von Karzinomen und Sarkomen. Die Substanzen, deren Verwendung Gegenstand der Erfindung ist, binden mit hoher Affinität an beide bekannten Sigma-Rezeptoren (σ-Rezeptoren).The invention relates to the use of substances known per se for the treatment of carcinomas and sarcomas. The substances whose use is the subject of the invention bind with high affinity to both known sigma receptors (σ receptors).
Die σ-Rezeptoren werden historisch zur Klasse der opioiden Rezeptoren gezählt. Die ersten Hinweise auf die Existenz von verschiedenen opioiden Rezeptoren kam von Martin und Mitarbeitern, die Experimente an Hunden durchgeführt haben (J. Pharma Coll. Exp. Ther. 197: 517 bis 532, 1976). Auffällige Unterschiede in dem pharmakologischen Verhalten zu verschiedenen narkotischen Analgetika und ihre Unfähigkeit in bezug auf die Ent- zugssymptome einander zu ersetzen, brachte Martin und Mitarbeiter dazu, die Existenz dreier verschiedener Rezeptortypen zu postulieren. Diese wurden nach den benutzten prototypischen Pharmaka μ für Morphin, K für Ketocyclazocin und σ für SKF 10047 (N-Allylnormetazocin) genannt. Nach Entdeckung der Enkephaline wurde eine weitere Rezeptorgruppe, die δ- Rezeptoren entdeckt. Es zeigte sich aber, daß die σ-opioiden Rezeptoren, die wie die anderen opioiden Rezeptoren im zentralen Nervensystem exprimiert werden, Eigenschaften haben, die sie von den anderen opioiden Rezeptoren unterscheiden. Die Wirkungen dieser Rezeptoren werden zum Beispiel nicht durch Naloxon aufgehoben. Außerdem gibt es eine Ü- berlappung zwischen σ-Bindungsstellen und Bindungsstellen für Nichtopi- ate wie Phencyclidin {angel dust). In der neueren Literatur werden die σ- Rezeptoren daher nicht zu den opioiden Rezeptoren hinzugerechnet.Historically, the σ receptors belong to the class of opioid receptors. The first evidence of the existence of various opioid receptors came from Martin and co-workers who conducted experiments on dogs (J. Pharma Coll. Exp. Ther. 197: 517 to 532, 1976). Striking differences in the pharmacological behavior of various narcotic analgesics and their inability to replace each other with regard to withdrawal symptoms led Martin and co-workers to postulate the existence of three different types of receptors. These were named after the prototypical pharmaceuticals used μ for morphine, K for ketocyclazocin and σ for SKF 10047 (N-allylnormetazocin). After the discovery of the enkephalins, another group of receptors, the δ receptors, was discovered. However, it was found that the σ-opioid receptors, which are expressed in the central nervous system like the other opioid receptors, have properties that distinguish them from the other opioid receptors. For example, the effects of these receptors are not offset by naloxone. There is also an overlap between σ binding sites and binding sites for non-opiates such as phencyclidine (angel dust). In the more recent literature, the σ receptors are therefore not included in the opioid receptors.
Es gibt zwei Subtypen von σ-Rezeptoren, σi und σ2 [Quirion et al., Trends Pharmacol. Sei. 13, 85, 1992; Walker et al. Aspects of synaptic Transmission, Herausgeber T.W. Stone (Taylor and Francis, London) Seite 91 , 1993; Bowen Aspects of synaptic transmission, Herausgeber T.W. Stone (Taylor and Francis, London), Seite 1 13, 1993]. σ-Rezeptoren sind in verschiedenen peripheren Geweben anzutreffen wie Leber, Niere, Gastroin- testinaltrakt und endokrinen Drüsen wie Eierstöcke, Nebenniere, Hoden und Hirnanhangdrüse, daneben auch in Leukozyten. Es ist bekannt, daß σ-Rezeptoren mit zellulären Signaltransduktionswegen, die Protoonko- genprodukte umfassen, interagieren und die Zeilproliferation regulieren (Villner und Bowen, 1993 in.Multiple σ and PCP-Receptor Ligands: Me- chanisms for Neuromodulation and Neuroprotection, Herausgeber J.-M. Kamenka and EF Domino, NPP Books, Ann Arbor, MI, Seite 341 , 1992; Brent et al. (Eur. J. Pharmacol. 278, S. 151 , 1995)There are two subtypes of σ receptors, σi and σ 2 [Quirion et al., Trends Pharmacol. Be. 13, 85, 1992; Walker et al. Aspects of synaptic transmission, editor TW Stone (Taylor and Francis, London) page 91, 1993; Bowen Aspects of synaptic transmission, editor TW Stone (Taylor and Francis, London), page 1 13, 1993]. σ-receptors can be found in various peripheral tissues such as liver, kidney, gastrointestinal tract and endocrine glands such as ovaries, adrenal glands, testes and pituitary glands, as well as in leukocytes. It is known that σ-receptors with cellular signal transduction pathways that include proto-oncogen products interact and regulate cell proliferation (Villner and Bowen, 1993 in. Multiple σ and PCP-Receptor Ligands: Mechanisms for Neuromodulation and Neuroprotection, editor J.-M. Kamenka and EF Domino, NPP Books, Ann Arbor, MI, page 341, 1992; Brent et al. (Eur. J. Pharmacol. 278, p. 151, 1995)
Es ist bekannt, daß σ-Rezeptor-Liganden das Wachstum von bestimmten Karzinomen wie dem kleinzelligen Lungenkarzinom inhibieren. Verschiedene σ-Rezeptor Liganden sind bereits bekannt:Σ-Receptor ligands are known to inhibit the growth of certain cancers, such as small cell lung cancer. Various σ-receptor ligands are already known:
2-IBP (N-(2-(piperidino)ethyl)-2-iodobenzamid)2-IBP (N- (2- (piperidino) ethyl) -2-iodobenzamide)
IfendipinIfendipin
Haloperidolhaloperidol
IPAB (2-Piperidinyl-aminoethyl)-4-iodobenzamidIPAB (2-piperidinylaminoethyl) -4-iodobenzamide
(-ι-)-Pentazocin(-Ι -) - pentazocine
BD10008BD10008
BD1047 (N-[2-(3,4-dichorphenyl)ethyl]-N,N',N'-trimethylethylendiamin) lodosulfonamidBD1047 (N- [2- (3,4-dichorphenyl) ethyl] -N, N ', N'-trimethylethylenediamine) iodosulfonamide
(Moody, Leayton und John Life Sciences Vol. 66, No. 20 (2000), S. 1979- 1986, Elsevier Science Ltd.)(Moody, Leayton and John Life Sciences Vol. 66, No. 20 (2000), pp. 1979-1986, Elsevier Science Ltd.)
1 ,3-Di(2-toiyl)-guanidin reduziertes Haloperidol,1,3-di (2-toiyl) guanidine reduced haloperidol,
(+/-)-N-Allylnormetazocin (SKF 10047)(+/-) - N-Allylnormetazocin (SKF 10047)
(+/-)-Pentazozin(+/-) - pentazocine
Rimcazolrimcazole
(Brent & Pang, European Journal of Pharmacology, 278 (1995), S. 151 160)(Brent & Pang, European Journal of Pharmacology, 278 (1995), p. 151 160)
(+)-3-(3-Hydroxyphenyl)-N-(1 -propyl)-piperidin(+) - 3- (3-Hydroxyphenyl) -N- (1-propyl) piperidine
(+)-Cyclazocin(+) - cyclazocine
Fluphenazinfluphenazine
Perphenazinperphenazine
Trifluoperazintrifluoperazine
Pimozid • Thioridazinpimozide • thioridazine
• (-)-Butactamol• (-) - butactamol
• BD737 ( 1 S.2R-cis-N-[2-(3,4dichlorphenyl)ethyl]-N-methyl-2-(1 - pyrrolidinyl)-cyclohexylamin ) • LRl 72 ( N-[2-(3,4-dichlorphenyl)ethyl]-N-methyl-2-(1 - homopiperidinyl)ethylamin)BD737 (1 S.2R-cis-N- [2- (3,4-dichlorophenyl) ethyl] -N-methyl-2- (1-pyrrolidinyl) cyclohexylamine) • LRl 72 (N- [2- (3,4 -dichlorophenyl) ethyl] -N-methyl-2- (1 - homopiperidinyl) ethylamine)
• SH344 (N-[2-(4-iodphenyl)ethyl]-N-methyl-2-(1 -pyrrolidinyl)ethylamin)SH344 (N- [2- (4-iodophenyl) ethyl] -N-methyl-2- (1-pyrrolidinyl) ethylamine)
• BD1008 (N-[2-(3,4-dichlorphenyl)ethyl]-N-methyl-2-(1 - pyrrolidinyl)ethylamin) • BD1073 (1 -[2-(3,4-dichlorphenyl)ethyl]-4-(n-propyl)piperazin• BD1008 (N- [2- (3,4-dichlorophenyl) ethyl] -N-methyl-2- (1-pyrrolidinyl) ethylamine) • BD1073 (1 - [2- (3,4-dichlorophenyl) ethyl] -4 - (n-propyl) piperazine
• SH322 (1 -[2-(3,4-dichlorphenyl)ethyl]-4-(n-butyl)piperazin• SH322 (1 - [2- (3,4-dichlorophenyl) ethyl] -4- (n-butyl) piperazine
• BD1018 (3S-1 -[2-(3,4-dichlorphenyl)ethyl]-1 ,4- diazabicyclo[4:3:0]nonan)BD1018 (3S-1 - [2- (3,4-dichlorophenyl) ethyl] -1, 4-diazabicyclo [4: 3: 0] nonane)
(Vilner, de Costa & Bowen, The Journal of Neuroscience, 15(1 ) (1995), S. 117-134)(Vilner, de Costa & Bowen, The Journal of Neuroscience, 15 (1) (1995), pp. 117-134)
Es ist Aufgabe der Erfindung, Verbindungen zu benennen, die als σ- Rezeptor Liganden verwendet werden können, und sich zur Bekämpfung von Karzinomen und/oder Sarkomen eignen. Die Aufgabe wird gelöst durch die Verwendung einer Verbindung, ausgewählt ausIt is the object of the invention to name compounds which can be used as σ-receptor ligands and which are suitable for combating carcinomas and / or sarcomas. The task is solved by using a connection selected from
a) 3-[4-(4-Phenyl-1 ,2-3,6-tetrahydro-1 -pyridyl)-butyl]-indol-5-ol, b) 1 -(2-(Bis-(4-fluorphenyl)methoxy)ethyl)-4-(3-phenyl-propyl)piperazin, c) 1 -(4-Hydroxyphenyl)-2-(4-benzyl-1 -piperidinyl)-propanol, d) 3-(4-((3S)-3-Benzyl-1 -piperidyl)-butyl)-indol-5-carbonitril, e) 3-(4-((3R)-3-Benzyl-1 -piperidyl)-butyl)-indol-5-carbonitril, f) 6-(4-(4-(5-Fluor-3-indolyl)-butyl)-1 -piperazinyl)-2H-1 -benzopyran-2- on, g) (5S)-(-)-5-[4-(4-Aminobenzyl)-1 -piperidylmethyl]-3-(4-ethylphenyl)- oxazolidin-2-on, h) 6-{3-[4-(2,4-Difluorbenzyl)-1 -piperidyl]-1 -oxopropyl}-2,3- dihydrobenzoxazol-2-on, i) 3-(4-(3-(4-Fluorphenyl-hydroxymethyl)piperid-1 -yl)butyl)-5- indolcarbonitril, j) 2-(4-[3-(5H-Dibenz[b,f]azepin-5-yl)-propyl]-1 -piperazinyl)-ethanol, k) 1 -[2-(3,4-Dimethoxyphenyl)-ethyl]-4-(3-phenylpropyl)-piperazin, I) (5S)-(-)-5-(4-Benzyl-1 -piperidylmethyl)-3-(4-chlorphenyl)-oxazolidin-2- on, m) 6-{3-[4-(4-Fluorbenzyl)-1 -piperidyl]-2-methylpropionyl}-2,3- dihydrobenzoxazol-2-on, n) (1 R,2S)-(+)-4-(3-(4-Benzyl-piperidin-1 -yl)-1 -hydroxy-2-methyl-propyl)- phenol, o) (E)-4-(3-(4-Benzyl-piperidin-1 -yl)-2-methyl-propenyl)-phenol p) 3-(4-(4-(2,1 ,3-Benzothiadiazol-5-yl)-1 -piperazinyl)-butyl)-indol-5- carbonitril, q) 6-(3-(4-(4-Fluorbenzyl)-1 -piperidyl)-2-propenyl)-2,3- dihydrobenzoxazol-2-on, r) 3-(4-Trifluormethylphenoxymethyl)-pyrrolidin s) 6-{3-[4-(4-Fluorbenzyl)-1 -piperidyl]-propionyl}-3H-benzothiazol-2-on, t) 4-{3-[4-(4-Fluorbenzyl)-piperidin-1 -yl]-propoxy}-phenol u) [2-(4-Methoxy-3-phenethyloxy-phenyl)-ethyl]-dipropyl-amin v) (1 S,5R)-3-(2-(2-Adamantyl)ethyl)-1 ,8,8-trimethyl-3- azabicyclo[3.2.1]octan, w) 6-{3-[4-(2,4-Difluorbenzyl)-piperidin-1 -yl]-propionyl}-3H-benzothiazol- 2-on, x) 1 -{1 -[2-(4-Fluoro-phenyl)-ethyl]-piperidin-4-yl}-indan-1 -ol, y) 1 -[2-(4-Fluor-phenyl)-ethyl]-4-(naphthalin-2-sulfinyl)-piperidin, z) 1 -(lndol-4-yl)-4-[4-(4-fluorphenyl)-butyl]-piperazin, aa) 3-(4-(2-(2-Phenyl-ethyl)-1 -piperidyl, -1 -butyl)-indol, bb) 2-[4-(4-(3-lndolyl)-butyl)-1 -piperazinyl]-benzonitril, cc) (S)-(-)-5-[4-Hydroxy-4-(3,4-methylendioxyphenyl)-pipehdin-1 - ylmethyl]-3-(4-methoxyphenyl)-oxazolidin-2-on, dd) 5-Fluor-3-[4-phenyl-1 -piperidyl)-butyl]-indol, ee) 3-(1 -Phenethyl-1 ,2,3,6-tetrahydro-4-pyridyl)-indol-5-carbonitril, ff) 3-(2-Phenylethyl)-1 ,2,3,4,5, 6-hexahydrobenz[f]isochinolin, gg) 5-Fluor-3-(1 -phenethyl-4-piperidyl)-indol, hh) N-(1 -Benzyl-4-piperidyl)-6-fluor-1 ,2,3,4-tetrahydrocarbazol-3- carboxamid, ii) 3-(4-(4-(4-Cyanophenyl)-1 -piperazinyl)-butyl)-indol-5-carbonitril, jj) 3-(3-(4-(2-Carbamoyl-5-benzofuranyl)-1 -piperazinyl)-propyl)-indol-5- carbonitril, kk) 3-(4-(4-(4-Fluorphenyl)-1 -piperazinyl)-butyl)-indol-5-carbonitril, II) 3-(4-(4-(2-Cyanophenyl)-piperazinyl)-butyl)-indol-5-carbonitril, mm) 5-[3-[4-(-Fluorbenzyl)-1 -piperidyl)-1 -oxopropyl]-6-fluor-2,3-dihydro-1 H- benzimidazol-2-on, nn) 6-(3-[4-(4-Fluorbenzyl)-1 -piperidyl]-1 -oxopropyl)-2,3- dihydrobenzoxazol-2-on, oo) 3-(4-Benzyl-1 -piperidyl)-1 -(4-hydroxyphenyl)-1 -propanon, pp) 3-(4-(4-(4-Fluorphenyl)-1 -piperazinyl)-butyl)indol-5-carbonitril, qq) 6-(3-[4-(4-Fluorbenzyl)-1 -piperidyl]-1 -hydroxypropyl)-2,3- dihydrobenzoxazol-2-on, rr) 1 -(2-Methoxyphenyl)-4-(2-(6,7,8,9-tetrahydro-5H-benzocyclohepten-a) 3- [4- (4-Phenyl-1, 2-3,6-tetrahydro-1-pyridyl) butyl] indole-5-ol, b) 1 - (2- (bis- (4-fluorophenyl ) methoxy) ethyl) -4- (3-phenyl-propyl) piperazine, c) 1 - (4-hydroxyphenyl) -2- (4-benzyl-1-piperidinyl) propanol, d) 3- (4 - (( 3S) -3-benzyl-1-piperidyl) butyl) indole-5-carbonitrile, e) 3- (4 - ((3R) -3-benzyl-1-piperidyl) butyl) indole-5-carbonitrile , f) 6- (4- (4- (5-fluoro-3-indolyl) -butyl) -1 -piperazinyl) -2H-1 -benzopyran-2-one, g) (5S) - (-) - 5 - [4- (4-aminobenzyl) -1 -piperidylmethyl] -3- (4-ethylphenyl) - oxazolidin-2-one, h) 6- {3- [4- (2,4-difluorobenzyl) -1 -piperidyl ] -1-oxopropyl} -2,3- dihydrobenzoxazol-2-one, i) 3- (4- (3- (4-fluorophenyl-hydroxymethyl) piperid-1-yl) butyl) -5-indole carbonitrile, j) 2 - (4- [3- (5H-Dibenz [b, f] azepin-5-yl) propyl] -1-piperazinyl) ethanol, k) 1 - [2- (3,4-dimethoxyphenyl) ethyl] -4- (3-phenylpropyl) piperazine, I) (5S) - (-) - 5- (4-Benzyl-1-piperidylmethyl) -3- (4-chlorophenyl) oxazolidin-2-one, m) 6- {3- [4- (4-fluorobenzyl ) -1-piperidyl] -2-methylpropionyl} -2,3-dihydrobenzoxazol-2-one, n) (1 R, 2S) - (+) - 4- (3- (4-benzyl-piperidin-1-yl ) -1-hydroxy-2-methyl-propyl) -phenol, o) (E) -4- (3- (4-benzyl-piperidin-1-yl) -2-methyl-propenyl) -phenol p) 3- (4- (4- (2,1, 3-Benzothiadiazol-5-yl) -1 -piperazinyl) butyl) indole-5-carbonitrile, q) 6- (3- (4- (4-fluorobenzyl) - 1 -piperidyl) -2-propenyl) -2,3-dihydrobenzoxazol-2-one, r) 3- (4-trifluoromethylphenoxymethyl) pyrrolidine s) 6- {3- [4- (4-fluorobenzyl) -1 -piperidyl ] -propionyl} -3H-benzothiazol-2-one, t) 4- {3- [4- (4-fluorobenzyl) piperidin-1-yl] -propoxy} phenol u) [2- (4-methoxy- 3-phenethyloxyphenyl) ethyl] dipropyl amine v) (1 S, 5R) -3- (2- (2-adamantyl) ethyl) -1, 8,8-trimethyl-3-azabicyclo [3.2.1 ] octane, w) 6- {3- [4- (2,4-difluorobenzyl) piperidin-1-yl] propionyl} -3H-benzothiazol-2-one, x) 1 - {1 - [2- ( 4-fluoro-phenyl) -ethyl] -piperidin-4-yl} -indan-1 -ol, y) 1 - [2- (4-fluorophenyl) -ethyl] -4- (naph thalin-2-sulfinyl) piperidine, z) 1 - (indol-4-yl) -4- [4- (4-fluorophenyl) butyl] piperazine, aa) 3- (4- (2- (2- Phenyl-ethyl) -1-piperidyl, -1-butyl) indole, bb) 2- [4- (4- (3-indolyl) butyl) -1-piperazinyl] benzonitrile, cc) (S) - ( -) - 5- [4-Hydroxy-4- (3,4-methylenedioxyphenyl) -pipehdin-1 - ylmethyl] -3- (4-methoxyphenyl) -oxazolidin-2-one, dd) 5-fluoro-3- [ 4-phenyl-1-piperidyl) butyl] indole, ee) 3- (1-phenethyl-1, 2,3,6-tetrahydro-4-pyridyl) indole-5-carbonitrile, ff) 3- (2nd -Phenylethyl) -1, 2,3,4,5, 6-hexahydrobenz [f] isoquinoline, gg) 5-fluoro-3- (1-phenethyl-4-piperidyl) indole, hh) N- (1-benzyl -4-piperidyl) -6-fluoro-1, 2,3,4-tetrahydrocarbazole-3-carboxamide, ii) 3- (4- (4- (4-cyanophenyl) -1 -piperazinyl) -butyl) -indole- 5-carbonitrile, jj) 3- (3- (4- (2-carbamoyl-5-benzofuranyl) -1 -piperazinyl) propyl) indole-5-carbonitrile, kk) 3- (4- (4- (4 Fluorophenyl) -1-piperazinyl) butyl) indole-5-carbonitrile, II) 3- (4- (4- (2-Cyanophenyl) piperazinyl) butyl) indole-5-carbonitrile, mm) 5- [3- [4 - (- fluorobenzyl) -1 -piperidyl) -1 - oxopropyl] -6-fluoro-2,3-dihydro-1 H -benzimidazol-2-one, nn) 6- (3- [4- (4-fluorobenzyl) -1 -piperidyl] -1 -oxopropyl) -2, 3- dihydrobenzoxazol-2-one, oo) 3- (4-benzyl-1-piperidyl) -1 - (4-hydroxyphenyl) -1-propanone, pp) 3- (4- (4- (4-fluorophenyl) - 1-piperazinyl) butyl) indole-5-carbonitrile, qq) 6- (3- [4- (4-fluorobenzyl) -1 -piperidyl] -1-hydroxypropyl) -2,3-dihydrobenzoxazol-2-one, rr ) 1 - (2-methoxyphenyl) -4- (2- (6,7,8,9-tetrahydro-5H-benzocyclohepten-
6-yliden)-ethyl)-piperazin, ss) 3-(1 -(2-(4-Fluorphenoxy)-ethyl)-4-piperidyl)-4,5-dihydro-2H- benz[g]indazol, rt) (5S)-(-)-5-(4-(4-Fluorbenzyl)-1 -piperidylmethyl)-3-(4-fluorphenyl)- oxazolidin-2-on, uu) 3-(4-((3R)-3-Benzyl-1 -piperidyl)-butyl)-5-fluorindol, w) 3-(4-((3S)-3-Benzyl-1 -piperidyl)-butyl)-5-fluorindol, oder die entsprechenden Säuren, Basen oder Salze als σ-Rezeptor Ligand.6-ylidene) ethyl) piperazine, ss) 3- (1 - (2- (4-fluorophenoxy) ethyl) -4-piperidyl) -4,5-dihydro-2H-benz [g] indazole, rt) (5S) - (-) - 5- (4- (4-fluorobenzyl) -1 -piperidylmethyl) -3- (4-fluorophenyl) - oxazolidin-2-one, uu) 3- (4 - ((3R) - 3-benzyl-1-piperidyl) butyl) -5-fluoroindole, w) 3- (4 - ((3S) -3-benzyl-1-piperidyl) butyl) -5-fluoroindole, or the corresponding acids, bases or salts as a σ receptor ligand.
σ-Rezeptor Liganden sind alle Verbindungen die an den σi-Rezeptor und/oder an den σ≥-Rezeptor mit hoher Affinität binden. Die Affinität ist im Rahmen der Erfindung als IC50-Wert der Verdrängung von radioaktiv markiertem SKF-10047 (im Falle des σi-Rezeptors) und von radioaktivem 1 ,3- di-o-tolylguanidin (DTG) (im Falle des σ2-Rezeptors) definiert.σ-receptor ligands are all compounds that bind to the σi-receptor and / or to the σ≥-receptor with high affinity. In the context of the invention, the affinity is the IC 50 value of the displacement of radioactively labeled SKF-10047 (in the case of the σi receptor) and of radioactive 1,3-di-o-tolylguanidine (DTG) (in the case of the σ 2 - Receptor).
Dabei ist für den σi-Rezeptor das Verfahren nach: S.W. Tarn, European Journal of Pharmacology 1985, 109 (1 ), Seiten 33-41 mit den folgenden Veränderungen:The procedure for the σi receptor according to: S.W. Tarn, European Journal of Pharmacology 1985, 109 (1), pages 33-41 with the following changes:
- als Inkubationspuffer wird 50mM Tris-HCI (2-Amino-2-(hydroxymethyl)- 1 ,3-propandiolhydrochlorid), pH 7,7 benutzt;- 50mM Tris-HCl (2-amino-2- (hydroxymethyl) -1, 3-propanediol hydrochloride), pH 7.7 is used as the incubation buffer;
- die nichtspezifische Bindung wird mit 10 μM Haloperidol bestimmt;- the non-specific binding is determined with 10 μM haloperidol;
- die Inkubation der Meerschweinchen-Ganzhirnmembranen einer Konzentration von 8 mg Frischgewebe pro ml mit 4 nM 3H-SKF10047 wird bei 25°C für 25 Minuten durchgeführt; zugrunde zu legen. Für den σ2-Rezeptor ist das Verfahren nach: Y. Shirayama et al., Europe- an Journal Pharmacoloqy, 1993, 237 (1), Seiten 117-126 mit den folgenden Veränderungen:- The incubation of the guinea pig whole brain membranes with a concentration of 8 mg fresh tissue per ml with 4 nM 3 H-SKF10047 is carried out at 25 ° C for 25 minutes; to be the basis. For the σ 2 receptor, the method according to: Y. Shirayama et al., Europe- an Journal Pharmacoloqy, 1993, 237 (1), pages 117-126 with the following changes:
- Meerschweinchenhirn wird in 20 ml 50 mM Tris-HCI Puffer, pH 7,7 (im folgenden Tris-Puffer) mit einem Glass-Teflon Homogenisator homogenisiert (10 Stöße, 800 rpm);- Guinea pig brain is homogenized in 20 ml 50 mM Tris-HCl buffer, pH 7.7 (hereinafter Tris buffer) with a Glass-Teflon homogenizer (10 bursts, 800 rpm);
- das Homogenat wird 15 Minuten bei 2°C bei 20000 rpm in einem Sor- vall SS-34 Rotor zentrifugiert;- The homogenate is centrifuged for 15 minutes at 2 ° C at 20,000 rpm in a SS-34 rotor;
- der Überstand wird dekantiert; - das Pellet wird in 20 ml Tris-Puffer resuspendiert, homogenisiert und zentrifugiert (dieser Schritt wird dreimal wiederholt);- the supernatant is decanted; - The pellet is resuspended in 20 ml Tris buffer, homogenized and centrifuged (this step is repeated three times);
- das Pellet wird in Tris-Puffer resuspendiert, wobei eine Konzentration von 10 mg Originalgewebe pro ml eingestellt wird, und in Aliquots bei - 28°C eingefroren; - für die Bestimmung des ICso-Wertzes wird die Suspension im Wasserbad bei Raumtemperatur aufgetaut, zweimal in 50ml Tris-Puffer gewaschen und anschließend jeweils bei 22000 g für 10 Minuten zentrifugiert;- The pellet is resuspended in Tris buffer, a concentration of 10 mg of original tissue per ml being set, and frozen in aliquots at - 28 ° C; - For the determination of the IC 50 value, the suspension is thawed in a water bath at room temperature, washed twice in 50 ml of Tris buffer and then centrifuged at 22,000 g for 10 minutes;
- die Bestimmung des ICso-Werts erfolgt in einem Volumen von 0,5 ml mit 0,5 nM 3H-DTG und 4 mg Originalgewebe pro ml bei 25°C nach- The ICso value is determined in a volume of 0.5 ml with 0.5 nM 3 H-DTG and 4 mg original tissue per ml at 25 ° C
40 minütiger Inkubation und anschließender Phasentrennung durch Schnellfiltration mit einer Glasfritte nach vorausgegangener Bestimmung der unspezifischen Bindung in Anwesenheit von 10 μM Haloperidol; zugrunde zu legen.40 minutes incubation and subsequent phase separation by rapid filtration with a glass frit after previous determination of the non-specific binding in the presence of 10 μM haloperidol; to be the basis.
σ-Rezeptor Liganden sind Substanzen, die in bezug auf mindestens einen von beiden σ-Rezeptoren eine Affinität von kleiner 9-10"8 M (= 9E-08 M) (vorzugsweise von kleiner 5-10"8 M oder 1 -10"8 M )aufweisen.σ-receptor ligands are substances that have an affinity of less than 9-10 "8 M (= 9E-08 M) (preferably less than 5-10 " 8 M or 1 -10 " in relation to at least one of the two σ-receptors) 8 M).
Die Verwendung einer Substanz als σ-Rezeptor Ligand beinhaltet die gezielte Ausnützung ihrer Eigenschaft, an den σi -Rezeptor oder den σ2- Rezeptor mit einer Affinität von kleiner 9-10'8 M (= 9E-08 M) (vorzugsweise von kleiner 5-10"8 M oder 1 -10"8 M ) zu binden. Dies schließt die Verwen- düng als Pharmakon ein, umfaßt aber auch zum Beispiel den Einsatz als Radioligand für pharmakologische oder diagnostische Zwecke. Ferner ist Gegenstand der Erfindung die Verwendung einer der vorstehenden Verbindungen oder die entsprechenden pharmazeutisch verträglichen Säuren, Basen oder Salze zur Herstellung eines Medikamentes betreffend die Behandlung von Karzinomen und Sarkomen.The use of a substance as a σ receptor ligand involves the targeted exploitation of its property, on the σi receptor or the σ 2 receptor with an affinity of less than 9-10 '8 M (= 9E-08 M) (preferably less than 5 -10 "8 M or 1 -10 " 8 M). This includes the use as a pharmaceutical, but also includes, for example, the use as a radioligand for pharmacological or diagnostic purposes. The invention further relates to the use of one of the above compounds or the corresponding pharmaceutically acceptable acids, bases or salts for the manufacture of a medicament for the treatment of carcinomas and sarcomas.
Ein weiterer Gegenstand der Erfindung ist die Verwendung einer der vorstehenden Substanzen zur Behandlung von kleinzelligen Lungenkarzinomen, Brust- und Colonkarzinomen sowie von Melanomen.Another object of the invention is the use of one of the above substances for the treatment of small cell lung carcinomas, breast and colon carcinomas and melanomas.
Die erfindungsgemäß verwendeten Verbindungen sind in der Regel mehr oder weniger basisch. Sie können mit einer Säure in das zugehörige Säureadditionssalz überführt werden, beispielsweise durch Umsetzung äquivalenter Mengen der Base und der Säure in einem inerten Lösungsmittel wie Ethanol und anschließendes Eindampfen. Für diese Umsetzung kommen insbesondere Säuren in Frage, die physiologisch unbedenkliche Salze liefern. So können anorganische Säuren verwendet werden, zum Beispiel Schwefelsäure, Salpetersäure, Halogenwasserstoffsäuren wie Chlorwasserstoff säure oder Bromwasserstoffsäure, Phosphorsäuren wie Orthophosphorsäure, Sulfaminsäure, ferner organische Säuren, insbesondere aliphatische, alicyclische, araliphatische, aromatische oder hetero- cyclische ein- oder mehrbasige Carbon-, Sulfon- oder Schwefelsäuren, zum Beispiel Ameisensäure, Essigsäure, Propionsäure, Pivalinsäure, Diethylessigsäure, Malonsäure, Bernsteinsäure, Pimelinsäure, Fumarsäu- re, Maleinsäure, Milchsäure, Weinsäure, Äpfelsäure, Zitronensäure, Glu- consäure, Ascorbinsäure, Nikotinsäure, Isonikotinsäure, Methan- oder E- thansulfonsäure, p-Toluolsulfonsäure, Naphthalin-mono- und disulfonsäu- ren oder Laurylschwefelsäure. Als Produkt erhält man das pharmazeutisch verträgliche Salz der korrespondierenden Base, die vorstehend aufgeführt wurde. Sofern erfindungsgemäß zu verwendende Verbindungen in wässri- ger Lösung sauer reagieren, können diese durch den Zusatz von basischen Verbindungen in das korrespondierende Salz überführt werden. Sollte es sich bei einer vorstehend aufgeführter Verbindung um ein Salz handeln, so läßt sich die aktive Verbindung durch Zusatz von Säure oder Base oder ggf. durch einfache Hydrolyse freisetzen. Falls die Verbindungen als Bestandteil einer pharmazeutischen Zusammensetzung eingesetzt werden sollen, ist darauf zu achten, daß die entsprechenden Partner der Säure-Basereaktion pharmazeutisch verträglich sind, das heißt für den Menschen in den eingesetzten Mengen im wesentlichen untoxisch. Sofern die Verbindungen als σ-Rezeptor Liganden in in vitro Reaktionen eingesetzt werden sollen, spielt die Verträglichkeit keine Rolle, so daß sich als Partner der Säurebasereaktion alle Säuren bzw. Basen eignen, die sich gegenüber den Pharmaka, abgesehen von der Proto- lysereaktion, inert verhalten.The compounds used according to the invention are generally more or less basic. They can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation. In particular, acids that provide physiologically acceptable salts are suitable for this implementation. So inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and also organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carbon, sulfone - or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, methanoic acid or isonicotinic acid - thanesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids or laurylsulfuric acid. The product obtained is the pharmaceutically acceptable salt of the corresponding base, which was listed above. If compounds to be used according to the invention react acidically in aqueous solution, these can be converted into the corresponding salt by adding basic compounds. If a compound listed above is a salt, the active compound can be released by adding acid or base or, if necessary, by simple hydrolysis. If the compounds are to be used as part of a pharmaceutical composition, care must be taken to ensure that the corresponding partners of the acid-base reaction are pharmaceutically acceptable, that is to say essentially non-toxic to humans in the amounts used. If the compounds are to be used as σ-receptor ligands in in vitro reactions, compatibility is irrelevant, so that all acids or bases which are inert to the pharmaceuticals, apart from the protolysis reaction, are suitable as partners for the acid-base reaction behavior.
Die erfindungsgemäß einzusetzenden Substanzen bilden den aktiven Bestandteil von Medikamenten und Arzneimitteln, die gegen Krebs eingesetzt werden, also insbesondere gegen Karzinome oder Sarkome. Der Einsatz gegen Karzinome, insbesondere gegen Karzinome der Lunge, vor allem gegen kleinzellige Lungenkarzinome und Melanome ist bevorzugt.The substances to be used according to the invention form the active constituent of medicaments and medicaments which are used against cancer, that is to say in particular against carcinomas or sarcomas. Use against carcinomas, in particular against carcinomas of the lungs, especially against small cell lung carcinomas and melanomas, is preferred.
Daneben kommt auch ein Einsatz gegen Brust- und Enddarmkrebs in Frage.In addition, an application against breast and rectal cancer is also possible.
Die erfindungsgemäß einzusetzenden Substanzen werden in der Regel in der Dosierung vorzugsweise zwischen etwa 1 und 500 mg, insbesondere zwischen 5 und 100 mg pro Dosierungseinheit verabreicht. Die tägliche Dosierung liegt vorzugsweise zwischen etwa 0,02 und 10 mg pro kg Körpergewicht. Die spezielle Dosis für jeden Patienten hängt jedoch von verschiedensten Faktoren ab, beispielsweise von der Wirksamkeit der einge- setzten speziellen Verbindung, vom Alter, vom Körpergewicht und dem allgemeinen Gesundheitszustand, vom Geschlecht, von der Kost, vom Verabreichungszeitpunkt und vom Verabreichungsweg, von der Ausscheidungsgeschwindigkeit, von der Arzneistoffkombination und der schwere der jeweiligen Erkrankung, welcher die Therapie gilt. Die orale Applikation ist bevorzugt. Daneben kommt aber auch die rektale Applikation, die pa- renterale Applikation insbesondere die intravenöse, intramuskuläre, und gegebenenfalls die intraperitoneale Applikation in Frage.The substances to be used according to the invention are generally administered in the dosage preferably between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit. The daily dosage is preferably between about 0.02 and 10 mg per kg of body weight. However, the specific dose for each patient depends on a wide variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight and general health, on sex, on the diet, on the time of administration and on the route of administration, on the rate of elimination , of the drug combination and the severity of the respective disease to which the therapy applies. Oral application is preferred. In addition, rectal application, parenteral application, in particular intravenous, intramuscular, and possibly intraperitoneal application are also possible.
In der Regel wird der Patient ein Säugetier sein, wobei Menschen einge- schlössen sind. Im weitesten Sinne handelt es bei dem Patienten sich um ein Tier, einschließlich Fische und Vögel. Die Erfindung wird durch das nachfolgende Beispiel näher beschrieben.As a rule, the patient will be a mammal, with humans included. In the broadest sense, the patient is an animal, including fish and birds. The invention is described in more detail by the following example.
Beispielexample
Im Rahmen dieses Beispiels wurde die Affinität der erfindungsgemäß einzusetzenden Substanzen an Hirnhomogenat von Meerschweinchen bestimmt. Es handelt sich bei dem Affinitätswert um den IC-50-Wert der Verdrängung von radioaktiv markiertem SKF-10047 (im Falle des σi- Rezeptors) und von DTG (im Falle des σ2-Rezeptors). Die Affinität an den σi-Rezeptor wurde nach S.W. Tarn, European Journal of Pharmacology 1985, 109 (1 ), Seiten 33-41 bestimmt. Zur Bestimmung der Affinität an dem σ2-Rezeptor wurde Y. Shirayama et al., European Journal Pharmacology, 1993, 237 (1 ), Seiten 1 17-126 herangezogen. Die Ergebnisse sind nachstehend aufgeführt. In the context of this example, the affinity of the substances to be used according to the invention on brain homogenate of guinea pigs was determined. The affinity value is the IC- 50 value of the displacement of radioactively labeled SKF-10047 (in the case of the σi receptor) and of DTG (in the case of the σ 2 receptor). The affinity for the σi receptor was determined according to SW Tarn, European Journal of Pharmacology 1985, 109 (1), pages 33-41. Y. Shirayama et al., European Journal Pharmacology, 1993, 237 (1), pages 1 17-126 was used to determine the affinity for the σ 2 receptor. The results are shown below.
Tabelle 1Table 1
Benzyl-1 - piperidyl)- butyl)-5-
Tabelle 2Table 2
Claims
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2002210527A AU2002210527A1 (en) | 2000-10-11 | 2001-10-11 | Use of defined substances that bind to the sigma receptor for combating sarcoma and carcinoma |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10050236A DE10050236A1 (en) | 2000-10-11 | 2000-10-11 | Use of specified compounds as sigma-receptor ligands, useful for treating carcinomas and sarcomas |
| DE10050236.9 | 2000-10-11 |
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| AR (1) | AR031725A1 (en) |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070197594A1 (en) * | 2004-09-21 | 2007-08-23 | Astellas Pharma Inc. | Cyclic amine derivative or salt thereof |
| WO2009046841A2 (en) | 2007-10-05 | 2009-04-16 | Merck Patent Gmbh | Piperidine and piperazine derivatives for treating tumours |
| EP1945213A4 (en) * | 2005-10-24 | 2009-12-02 | Janssen Pharmaceutica Nv | 3-piperidin-4-yl-indole orl-1 receptor modulators |
| US7786140B2 (en) * | 2003-09-25 | 2010-08-31 | Shionogi & Co., Ltd. | Piperidine derivative having NMDA receptor antagonistic activity |
| WO2010112116A1 (en) * | 2009-04-02 | 2010-10-07 | Merck Patent Gmbh | Heterocyclic compounds as autotaxin inhibitors |
| WO2011044978A1 (en) | 2009-10-13 | 2011-04-21 | Merck Patent Gmbh | Sulfoxide derivatives for treating tumors |
| CN105434438A (en) * | 2015-12-09 | 2016-03-30 | 昆明医科大学 | New application of Vanoxerine dihydrochloride drug |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5232931A (en) * | 1990-05-29 | 1993-08-03 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Oxazolidinones |
| FR2688504A1 (en) * | 1992-03-13 | 1993-09-17 | Synthelabo | 2-(Piperid-1-yl)ethanol derivatives, their preparation and their application in therapeutics |
| FR2717806A1 (en) * | 1994-03-22 | 1995-09-29 | Adir | New amino-alkyl benzo-thiazoline-ones bind to sigma receptors |
| EP0711763A1 (en) * | 1993-07-28 | 1996-05-15 | Santen Pharmaceutical Co., Ltd. | Novel 1,4-di(phenylalkyl)piperazine derivative |
| WO1998057953A1 (en) * | 1997-06-18 | 1998-12-23 | Merck Patent Gmbh | 3-benzylpiperidine |
-
2000
- 2000-10-11 DE DE10050236A patent/DE10050236A1/en not_active Withdrawn
-
2001
- 2001-10-10 AR ARP010104749A patent/AR031725A1/en unknown
- 2001-10-11 AU AU2002210527A patent/AU2002210527A1/en not_active Abandoned
- 2001-10-11 WO PCT/EP2001/011710 patent/WO2002030422A1/en not_active Ceased
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5232931A (en) * | 1990-05-29 | 1993-08-03 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Oxazolidinones |
| FR2688504A1 (en) * | 1992-03-13 | 1993-09-17 | Synthelabo | 2-(Piperid-1-yl)ethanol derivatives, their preparation and their application in therapeutics |
| EP0711763A1 (en) * | 1993-07-28 | 1996-05-15 | Santen Pharmaceutical Co., Ltd. | Novel 1,4-di(phenylalkyl)piperazine derivative |
| FR2717806A1 (en) * | 1994-03-22 | 1995-09-29 | Adir | New amino-alkyl benzo-thiazoline-ones bind to sigma receptors |
| WO1998057953A1 (en) * | 1997-06-18 | 1998-12-23 | Merck Patent Gmbh | 3-benzylpiperidine |
Non-Patent Citations (5)
| Title |
|---|
| BEART P M ET AL: "HETEROCYCLIC AMINO ALCOHOLS RELATED TO IFENPRODIL AS O RECEPTOR LIGANDS: BINDING AND CONFORMATIONAL ANALYSES", EUROPEAN JOURNAL OF PHARMACOLOGY. MOLECULAR PHARMACOLOGY SECTION, ELSEVIER SCIENCE BV, AMSTERDAM, NL, vol. 269, no. 2, 1994, pages 193 - 200, XP000601476, ISSN: 0922-4106 * |
| BRENT P J ET AL: "SIGMA BINDING SITE LIGANDS INHIBIT CELL PROLIFERATION IN MAMMARY AND COLON CARCINOMA CELL LINES AND MELANOMA CELLS IN CULTURE", EUROPEAN JOURNAL OF PHARMACOLOGY, AMSTERDAM, NL, vol. 278, no. 2, 15 May 1995 (1995-05-15), pages 151 - 160, XP000645467, ISSN: 0014-2999 * |
| HUSBANDS STEPHEN M ET AL: "Structure-activity relationships at the monoamine transporters and sigma receptors for a novel series of 9-(3-(cis-3,5-dimethyl-1-pipera zinyl)-propyl)carbazole (rimcazole) analogues.", JOURNAL OF MEDICINAL CHEMISTRY, vol. 42, no. 21, October 1999 (1999-10-01), pages 4446 - 4455, XP001026440, ISSN: 0022-2623 * |
| MAJ, JERZY ET AL: "Some behavioral effects of 1,3-di-O-tolylguanidine, opipramol and sertraline, the sigma site ligands", POL. J. PHARMACOL. (1996), 48(4), 379-395, XP002190536 * |
| PERREGAARD J ET AL: "Sigma ligands with subnanomolar affinity and preference for the sigma 2 binding site. 1. 3-(omega-aminoalkyl)-1H- indoles.", JOURNAL OF MEDICINAL CHEMISTRY, (1995 MAY 26) 38 (11) 1998-2008., XP000941460 * |
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Also Published As
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| DE10050236A1 (en) | 2002-04-25 |
| AU2002210527A1 (en) | 2002-04-22 |
| AR031725A1 (en) | 2003-10-01 |
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