WO1999024022A2 - Isoquinoline derivatives for treating disorders associated with 5ht7 receptors - Google Patents

Isoquinoline derivatives for treating disorders associated with 5ht7 receptors Download PDF

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Publication number
WO1999024022A2
WO1999024022A2 PCT/EP1998/006920 EP9806920W WO9924022A2 WO 1999024022 A2 WO1999024022 A2 WO 1999024022A2 EP 9806920 W EP9806920 W EP 9806920W WO 9924022 A2 WO9924022 A2 WO 9924022A2
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WO
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Prior art keywords
isoquinoline
tetrahydro
ethyl
phenyl
methoxy
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Application number
PCT/EP1998/006920
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French (fr)
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WO1999024022A3 (en
Inventor
Thierry Godel
Walter Hunkeler
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F. Hoffmann-La Roche Ag
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Priority to AU15588/99A priority Critical patent/AU1558899A/en
Publication of WO1999024022A2 publication Critical patent/WO1999024022A2/en
Publication of WO1999024022A3 publication Critical patent/WO1999024022A3/en

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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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine 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
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline

Definitions

  • the invention relates to the use of isoquinoline derivatives of the general- formula
  • R 1 , R 2 and R 3 are hydrogen, halogen, lower alkyl, lower alkoxy or
  • R is CF3, halogen, lower alkoxy, lower alkyl or lower alkyl-halogen,
  • n 0-5 and of their pharmaceutically acceptable salts in the treatment of disorders which are associated with 5HT ⁇ receptors.
  • 5HT ⁇ receptor antagonists are useful in the treatment or prophylaxis of certain CNS and cardiovascular disorders such as hypoperfusion conditions, especially cardiovascular shock, septic shock, hypotension, hypovolemia and renal hypoperfusion, gastrointestinal conditions, especially diarrhoea, irritable bowel syndrome, inflammatory bowel disease and spastic colon and central conditions, especially circadian rhythm disorders (especially jet lag and sleep disorders) stress-related disorders, depression and appetite disorders.
  • the compounds of the present invention are 5HT7 receptor antagonists.
  • lower alkyl denotes a straight or branched- chain alkyl group containing from 1 to 7, preferably from 1 to 4 carbon atoms, for example methyl, ethyl, propyl, i-propyl, n-butyl, 2-butyl, t-butyl and the like.
  • halogen denotes chlorine, fluorine, bromine and iodine.
  • lower alkoxy denotes an alkyl group, as defined earlier which is attached via an oxygen atom, for example methoxy, ethoxy, propoxy and the like.
  • isoquinoline derivatives are known, e.g., from WO 97/23458 where their use as subtype-selective NMDA receptor ligands and for the treatment or prevention of associated dysfunctions are described.
  • isoquinoline compounds of formula I have a surprisingly high capacity to bind to a different receptor type, viz. to serotonin receptors, especially to 5HT ⁇ receptors, allowing the treatment or prevention of corresponding dysfunctions in which these receptors are involved.
  • the invention provides the use of compound of formula I and of their pharmaceutically usable salts for treating a mammal affected with a central or peripheral condition which is ameliorated by blocking serotonin activation of the 5-HT7 receptor, especially in the control or prevention of illnesses of the aforementioned kind and, respectively, for the production of corresponding medicaments, and medicaments, containing these compounds.
  • 5-HT7 Receptor Binding Assays were performed with membranes obtained from CHO cells stably transfected with the human 5-HT7 receptor. Cells were washed with phosphate buffered saline (PBS) by 2 centrifugations for 10 min at 3000 x g. The resulting pellet was resuspended in approximately 20 volumes of ice cold 50 mM Tris-HCl containing 10 mM MgCl2, 0.5 mM EDTA and 0.1 M phenylmethylsulphonyl fluoride (PMSF) using a Polytron homogeniser (15 sec. at maximal speed).
  • PBS phosphate buffered saline
  • This homogenate was incubated for 10 min at 37 °C and subsequently centrifuged at 20000 x g for 20 min. The pellet was resuspended in the same buffer to obtain a concentration corresponding to 4 x 107 cells/ml. One millilitre aliquots of the homogenate were frozen and stored at -80 °C.
  • Displacement curves were constructed using 7 concentrations of the displacing agents (1 data point per log unit of concentration: 10-11 M to 10-5 M). 5-HT7 receptor binding assay were performed at 37 °C for 1 hour. In all cases the reactions were stopped by rapid filtration through Whatmann GF/B filters. The filters were washed with 3 x 2 ml Tris HCl (50 mM, pH 7.4) and the radioactivity retained on the filters was measured by scintillation spectroscopy in 2 ml of scintillation fluid. All experiments were performed in triplicate and repeated 3 times.
  • the Ki value is defined by the following formula:
  • IC 50 values being those concentrations of test compounds in nM by which 50% of the ligands bonded to the receptor are displaced.
  • [L] is the concentration of ligand and the KD value is the dissociation constant of the ligand.
  • the compounds in accordance with the invention have a selective affinity to 5-HT7 receptors with pKi values between 7.00 and 9.00.
  • the compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations.
  • the pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions.
  • the administration can, however, also be effected rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions.
  • the compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations.
  • Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules.
  • Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules.
  • Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like.
  • Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi- liquid or liquid polyols and the like.
  • the pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
  • compounds of formula I as well as their pharmaceutically acceptable salts are useful in the treatment or prevention of certain CNS and cardiovascular disorders, such as hypoperfusion conditions, especially cardiovascular shock, septic shock, hypoptension, hypovolemia and renal hypoperfusion, gastrointestinal conditions, especially diarrhoea, irritable bowel syndrome, inflammatory bowel disease and spastic colon and central conditions, circadian rhythm disorders (especially jet lag and sleep disorders), stress-related disorders, depression and appetite disorders and for the production of corresponding medicaments.
  • hypoperfusion conditions especially cardiovascular shock, septic shock, hypoptension, hypovolemia and renal hypoperfusion
  • gastrointestinal conditions especially diarrhoea, irritable bowel syndrome, inflammatory bowel disease and spastic colon and central conditions
  • circadian rhythm disorders especially jet lag and sleep disorders
  • stress-related disorders especially depression and appetite disorders and for the production of corresponding medicaments.
  • the dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case.
  • the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof.
  • the daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.
  • Tablet Formulation (Wet Granulation)

Abstract

The invention relates to the use of isoquinoline derivatives of general formula (I) wherein R?1, R2 and R3¿ are hydrogen, halogen, lower alkyl, lower alkoxy or R?2 and R3¿ taken together form a methylenedioxy group, Z is (a), (b), (c) or (d); R is CF¿3?, halogen, lower alkoxy, lower alkyl or lower alkyl-halogen; p is 1-3; n is 0-5 and of their pharmaceutically acceptable salts in the treatment of disorders which are associated with 5HT7 receptors.

Description

Isoquinoline derivatives for use against CNS disorders
The invention relates to the use of isoquinoline derivatives of the general- formula
Figure imgf000003_0001
wherein
R1, R2 and R3 are hydrogen, halogen, lower alkyl, lower alkoxy or
R2 and R3 taken together form a methylenedioxy group,
Z is
Figure imgf000003_0002
R is CF3, halogen, lower alkoxy, lower alkyl or lower alkyl-halogen,
P is 1-3 n is 0-5 and of their pharmaceutically acceptable salts in the treatment of disorders which are associated with 5HTγ receptors.
5HTγ receptor antagonists are useful in the treatment or prophylaxis of certain CNS and cardiovascular disorders such as hypoperfusion conditions, especially cardiovascular shock, septic shock, hypotension, hypovolemia and renal hypoperfusion, gastrointestinal conditions, especially diarrhoea, irritable bowel syndrome, inflammatory bowel disease and spastic colon and central conditions, especially circadian rhythm disorders (especially jet lag and sleep disorders) stress-related disorders, depression and appetite disorders. The compounds of the present invention are 5HT7 receptor antagonists.
The following definitions of the general terms used in the specification and claims apply irrespective of whether the terms in question appear alone or in combination.
As used herein, the term "lower alkyl" denotes a straight or branched- chain alkyl group containing from 1 to 7, preferably from 1 to 4 carbon atoms, for example methyl, ethyl, propyl, i-propyl, n-butyl, 2-butyl, t-butyl and the like.
The term "halogen" denotes chlorine, fluorine, bromine and iodine.
The term "lower alkoxy" denotes an alkyl group, as defined earlier which is attached via an oxygen atom, for example methoxy, ethoxy, propoxy and the like.
The compounds of formula I, in which R1 is hydrogen, R2 is hydrogen or chloro and R3 is hydrogen or methoxy and Z is a phenyl group, substituted by methoxy or chloro, n denotes 2-5 and p is 2, are preferred.
Especially preferred compounds are
7-Chloro-2-[2-(2,4,6-trimethoxy-phenyl)-ethyl]-l,2,3,4-tetrahydro- isoquinoline,
8-methoxy-2-[2-(2,4,6-trimethoxy-phenyl)-ethyl]-l,2,3,4-tetrahydro- isoquinoline,
2-(2-pentamethoxyphenyl-ethyl)-l,2,3,4-tetrahydro-isoquinoline, 2-[2-(2,3,4-trimethoxy-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline, 8-methoxy-2-(2-pentamethoxyphenyl-ethyl)-l, 2,3,4- tetrahydro- isoquinoline and 2-[2-(2,6-dichloro-phenyl)-ethyl]-8-methoxy-l,2,3,4-tetrahydro- isoquinoline.
The above mentioned isoquinoline derivatives are known, e.g., from WO 97/23458 where their use as subtype-selective NMDA receptor ligands and for the treatment or prevention of associated dysfunctions are described.
In accordance with the invention it has now been found that isoquinoline compounds of formula I have a surprisingly high capacity to bind to a different receptor type, viz. to serotonin receptors, especially to 5HTγ receptors, allowing the treatment or prevention of corresponding dysfunctions in which these receptors are involved.
The invention provides the use of compound of formula I and of their pharmaceutically usable salts for treating a mammal affected with a central or peripheral condition which is ameliorated by blocking serotonin activation of the 5-HT7 receptor, especially in the control or prevention of illnesses of the aforementioned kind and, respectively, for the production of corresponding medicaments, and medicaments, containing these compounds.
Furthermore, it has been found, that compounds of formula I have a high selectivity to block serotonin activation of the δ-HTγ receptor. In Table 1 it is shown the pKi values of the δHTγ-receptors in comparison with 5HTID, 5HT2C and 5HTβ receptor.
Test description
5-HT7 Receptor Binding Assay 5-HT7 receptor binding assays were performed with membranes obtained from CHO cells stably transfected with the human 5-HT7 receptor. Cells were washed with phosphate buffered saline (PBS) by 2 centrifugations for 10 min at 3000 x g. The resulting pellet was resuspended in approximately 20 volumes of ice cold 50 mM Tris-HCl containing 10 mM MgCl2, 0.5 mM EDTA and 0.1 M phenylmethylsulphonyl fluoride (PMSF) using a Polytron homogeniser (15 sec. at maximal speed). This homogenate was incubated for 10 min at 37 °C and subsequently centrifuged at 20000 x g for 20 min. The pellet was resuspended in the same buffer to obtain a concentration corresponding to 4 x 107 cells/ml. One millilitre aliquots of the homogenate were frozen and stored at -80 °C.
On the day of the experiment, membranes were thawed and resuspended in 10 x the original volume of assay buffer. This assay buffer consisted of Tris-HCl 50 mM, pargyline 10-5 M, MgCl2 5 M and ascorbic acid 0.1 %, pH 7.4. 5-HT7 receptor binding assays consisted of 100 μl of the membrane preparation expressing the 5-HT7 receptor, 50 μl of [3H] -lysergic acid diethylamide ([3HJ-LSD; specific activity 85 Ci / mmole; final concentration 2 nM) and 50 μl of a displacing drug or assay buffer. Nonspecific binding was measured in the presence of 10-5 M 5-HT.
For estimations of the expression levels and the affinity of the radioligand for receptor binding site, saturation experiments were performed using 8 concentrations of [3H]LSD (0.163 - 20 nM).
Displacement curves were constructed using 7 concentrations of the displacing agents (1 data point per log unit of concentration: 10-11 M to 10-5 M). 5-HT7 receptor binding assay were performed at 37 °C for 1 hour. In all cases the reactions were stopped by rapid filtration through Whatmann GF/B filters. The filters were washed with 3 x 2 ml Tris HCl (50 mM, pH 7.4) and the radioactivity retained on the filters was measured by scintillation spectroscopy in 2 ml of scintillation fluid. All experiments were performed in triplicate and repeated 3 times.
The pKi values (pKi = -logioKi) of the test substances have been determined. The Ki value is defined by the following formula:
IC 50
Ki =
1 + [L]
KD
with the IC50 values being those concentrations of test compounds in nM by which 50% of the ligands bonded to the receptor are displaced. [L] is the concentration of ligand and the KD value is the dissociation constant of the ligand.
Table 1
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000010_0001
In this Table the respective compounds are:
A 7-Chloro-2-[2-(2,4,6-trimethoxy-phenyl)-ethyl]-l,2,3,4-tetrahydro- isoquinoline B 8-Methoxy-2-[2-(2,4,6-trimethoxy-phenyl)-ethyl]-l,2,3,4-tetrahydro- isoquinoline C 2-[2-(2,4,6-Trimethoxy-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline D 2-(2-Pentamethoxyphenyl-ethyl)-l,2,3,4-tetrahydro-isoquinolin E 2-[2-(l,3,4-Trimethoxy-phenyl)ethyl]-l,2,3,4-tetrahydro-isoquinoline F 2-[2-(2,3,5,6-Tetramethoxy-phenyl)-ethyl]-l,2,3,4-tetrahydro- isoquinoline G 7-Chloro-2-phenethyl-l,2,3,4-tetrahydro-isoquinoline H 2-[2-(2,6-Dimethoxy-phenyl)-ethyl]-l,2,3.4-tetrahydro-isoquinoline I 2-[2-(2,6-Dichloro-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline J 7-Chloro-2-[2-(3,4-dimethoxy-phenyl)-ethyl]-l,2,3,4-tetrahydro- isoquinoline K 2-[2-(2,3,4,5-Tetramethoxy-phenyl)-ethyl]-l,2,3,4-tetrahydro- isoquinoline L 8-[2-(2,4,6-Trimethoxy-phenyl)ethyl]-6,7,8,9-tetrahydro-[1.3]dioxolo- [4,5-h]isoquinoline
M 2-[2-(3,4,5-Trimethoxy-phenyl-ethyl]-l,2,3,4-tetrahydro-isoquinoline N 2-(2-Naphthalin-l-yl-ethyl)-l,2,3,4-tetrahydro-isoquinoline O 2- [2-(2-Chloro-6-fluoro-phenyl)-ethyl] -1,2, 3 ,4-tetrahydro-isoquinoline P 2-Chloro-2-[2-(2,4,6-trimethoxy-phenyl)-ethyl]-l,2,3,4-tetrahydro- isoquinoline Q 2-[2-(2,4-Dimethoxy-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline
R 2-[2-(2,5-Dimethoxy-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline
S 2-[2-(2-Methoxy-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline
T 2-[2-(2,4,6-Trimethoxy-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline U 2-(2-Biphenyl-4-yl)~l,2,3,4-tetrahydro-isoquinoline
V 2-[2-(2,6-Difluoro-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline W 2-[2-(2,3-Dimethoxy-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline X 2-[2-(2-Chloro-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline
Y 2-[2-(2,4,6-Trimethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline Z 8-Phenethyl-6,7,8,9-tetrahydro-[l,3]dioxolo[4,5-h]isoquinoline
AA 2-[2-(2,4-Dichloro-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline BB 7,8-Dichloro-2-phenethyl-l,2,3,4-tetrahydro-isoquinoline CC 2-[2-(4-tert-Butyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline DD 2-[2-(3,5-Dimethoxy-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline EE 2-(2-Benzo[l,3]dioxol-5-yl-ethyl)-l,2,3,4-tetrahydro-isoquinoline
FF 7-Chloro-2-[2-(4-chloro-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline GG 2-[2-(2-Trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline HH 2- [2-(4-Methoxy-phenyl)-ethyl] - 1 ,2,3 ,4-tetrahydro-isoquinoline II 2-[2-(2-Fluoro-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline JJ 2-[2-(3-Methoxy-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline KK 2-Phenethyl-l,2,3,4-tetrahydro-isoquinoline LL 8-Methoxy-2-(2-pentamethoxyphenyl-ethyl)-l,2,3,4-tetrahydro- isoquinoline MM 2-[2-(2,6-Dichloro-phenyl)-ethyl]-8-methoxy-l,2,3,4-tetrahydro- isoquinoline
NN 8-Methoxy-2-[2-(2,3,4-trimethoxy-phenyl)-ethyl]-l,2,3,4-tetrahydro- isoquinoline OO 2-[2-[3-(2-Chloro-ethyl)-2,4,6-trimethoxy-phenyl]-ethyl]-l,2,3,4- tetrahydro-isoquinoline PP 8-[2-(2,6-Dichloro-phenyl)-ethyl]-6,7,8,9-tetrahydro-[l,3]dioxolo[4,5-h]- isoquinoline QQ 7-Chloro-2-[2-(2,3,4-trimethoxy-phenyl)-ethyl]-l,2,3,4-tetrahydro- isoquinoline RR 7-Chloro-2-[2-(2,6-dichloro-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline SS 2-[2-(3,4-Dimethoxy-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline TT 2-Phenethyl-l,2,3,4-tetrahydro-isoquinolin-8-ol UU 2-Phenethyl-l,2,3,4-tetrahydro-isoquinolin-5-ol W 8-Methoxy-2-phenethyl-l,2,3,4-tetrahydro-isoquinoline WW 5-Methoxy-2-phenethyl-l,2,3,4-tetrahydro-isoquinoline
The compounds in accordance with the invention have a selective affinity to 5-HT7 receptors with pKi values between 7.00 and 9.00.
The compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions.
The compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi- liquid or liquid polyols and the like.
The pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
In accordance with the invention compounds of formula I as well as their pharmaceutically acceptable salts are useful in the treatment or prevention of certain CNS and cardiovascular disorders, such as hypoperfusion conditions, especially cardiovascular shock, septic shock, hypoptension, hypovolemia and renal hypoperfusion, gastrointestinal conditions, especially diarrhoea, irritable bowel syndrome, inflammatory bowel disease and spastic colon and central conditions, circadian rhythm disorders (especially jet lag and sleep disorders), stress-related disorders, depression and appetite disorders and for the production of corresponding medicaments.
The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated. Tablet Formulation (Wet Granulation)
Item Ingredients mg/tablet
5 mg 25 mg 100 mg 500 mg
1. Compound of formula I 5 25 100 500
2. Lactose Anhydrous DTG 125 105 30 150
3. Sta-Rx 1500 6 6 6 30
4. Micro crystalline Cellulose 30 30 30 150
5. Magnesium Stearate 1 1 1 1
Total 167 167 167 831 Manufacturing Procedure
1. Mix items 1, 2, 3 and 4 and granulate with purified water.
2. Dry the granules at 50°C.
3. Pass the granules through suitable milling equipment. 4. Add item 5 and mix for three minutes; compress on a suitable press.
Example 95 Capsule Formulation Item Ingredients mg/capsule
5mg 25 mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500
2. Hydrous Lactose 159 123 148 —
3. Corn Starch 25 35 * 40 70
4. Talc 10 15 10 25
5. Magnesium Stearate 1 2 2 5 Total 200 200 300 600
Manufacturing Procedure
1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.
2. Add items 4 and 5 and mix for 3 minutes.
3. Fill into a suitable capsule.

Claims

Claims
1. The use of a compound of the general formula
Figure imgf000015_0001
wherein
R1, R2 and R3 are hydrogen, halogen, lower alkyl, lower alkoxy or
R2 and R3 taken together form a methylenedioxy group,
Z is
Figure imgf000015_0002
R is CF3, halogen, lower alkoxy, lower alkyl or lower alkyl-halogen, p is 1-3 n is 0-5 as well as pharmaceutically acceptable salts for the manufacture of medicaments for the control or prevention of diseases which represent therapeutic indications associated with 5HT7 receptor antagonist activity, such as hypoperfusion conditions, especially cardiovascular shock, septic shock, hypotension, hypovolemia and renal hypoperfusion, gastrointestinal conditions, especially diarrhoea, irritable bowel syndrome, inflammatory bowel disease, spastic colon and central conditions, circadian rhythm disorders (especially jet lag and sleep disorders), stress-related disorders, depression and appetite disorders.
2. The use of compounds in accordance with claim 1, wherein R1 is hydrogen, R2 is hydrogen or chloro, R3 is hydrogen or methoxy and Z is a phenyl group, substituted by methoxy or chloro, n denotes 2-5 and p is 2.
3. The use of
7-chloro-2-[2-(2,4,6-trimethoxy-phenyl)-ethyl]-l,2,3,4-tetrahydro- isoquinoline,
8-methoxy-2-[2-(2,4,6-trimethoxy-phenyl)-ethyl]-l,2,3,4-tetrahydro- isoquinoline,
2-(2-pentamethoxyphenyl-ethyl)-l,2,3,4-tetrahydro-isoquinoline,
2-[2-(2,3,4-trimethoxy-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline,
8-methoxy-2-(2-pentamethoxyphenyl-ethyl)-l,2,3,4-tetrahydro- isoquinoline and 2-[2-(2,6-dichloro-phenyl)-ethyl]-8-methoxy-l,2,3,4-tetrahydro- isoquinoline according to claim 1.
4. A medicament containing one or more compounds of formula I as defined in claim 1 or pharmaceutically acceptable salts thereof for the treatment of diseases, which represent therapeutic indications, associated with 5HT7 receptor antagonist activity, such as hypoperfusion conditions, especially cardiovascular shock, septic shock, hypotension, hypovolemia and renal hypoperfusion, gastrointestinal conditions, especially diarrhoea, irritable bowel syndrome, inflammatory bowel disease, spastic colon and central conditions, circadian rhythm disorders (especially jet lag and sleep disorders), stress-related disorders, depression and appetite disorders and pharmaceutically inert excipients.
5. The invention as hereinbefore described.
PCT/EP1998/006920 1997-11-10 1998-11-02 Isoquinoline derivatives for treating disorders associated with 5ht7 receptors WO1999024022A2 (en)

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EP97119650 1997-11-10

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US6440988B1 (en) 1999-05-18 2002-08-27 Synaptic Pharmaceutical Corporation Use of agonists or antagonists of the 5-HT7 receptor to treat disorders of the bladder
WO2004014428A1 (en) * 2002-08-09 2004-02-19 Ajinomoto Co.,Inc. Remedy for intestinal diseases and visceral pain
US7101892B2 (en) 2003-05-15 2006-09-05 Merck Sharp & Dohme Ltd. Sulfone derivatives as 5-HT7 receptor ligands
US7211585B2 (en) 2004-08-18 2007-05-01 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor antagonists
US7211584B2 (en) 2004-08-18 2007-05-01 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor ligands
WO2008013556A1 (en) 2006-07-27 2008-01-31 Janssen Pharmaceutical N.V. Combination 5-ht7 receptor antagonist and serotonin reuptake inhibitor therapy
US7345057B2 (en) 2004-12-28 2008-03-18 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor antagonists
US7553965B2 (en) 2002-11-07 2009-06-30 Laboratories Del Dr. Esteve, S.A. 5-HT7 receptor antagonists
EP2149373A1 (en) 2008-08-01 2010-02-03 Laboratorios Del. Dr. Esteve, S.A. 5HT7 receptor ligands and compositions comprising the same
EP2151777A1 (en) 2008-08-01 2010-02-10 Laboratorios Del. Dr. Esteve, S.A. Method for screening of 5HT7 receptor ligands based on a new pharmacophore model and a descriptor's profile filter
US7662862B2 (en) 2004-12-28 2010-02-16 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor antagonists
US7928121B2 (en) 2002-02-19 2011-04-19 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor antagonists
US8148397B2 (en) 2004-08-18 2012-04-03 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor antagonists
US8188115B2 (en) 2004-08-18 2012-05-29 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor antagonists
US8618288B2 (en) 2003-09-17 2013-12-31 Janssen Pharmaceutica Nv Pyrimidine compounds as serotonin receptor modulators
US20140088069A1 (en) * 2011-06-01 2014-03-27 Eric D. Brown Novel antibacterial combination therapy
US8883796B2 (en) 2013-02-08 2014-11-11 Korea Institute Of Science And Technology Biphenyl derivatives, pharmaceutical composition comprising the same, and preparation method thereof
US9663464B2 (en) 2015-02-24 2017-05-30 Korea Institute Of Science And Technology Carbazole derivatives acting on 5-HT7 receptor
WO2018117406A1 (en) 2016-12-22 2018-06-28 한국과학기술연구원 Azepine derivative acting as 5-ht7 receptor modulator
EP3448520A4 (en) * 2016-04-29 2020-07-29 Board Of Regents, The University Of Texas System Sigma receptor binders
US11046670B2 (en) 2015-10-19 2021-06-29 Board Of Regents, The University Of Texas System Piperazinyl norbenzomorphan compounds and methods for using the same

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Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6440988B1 (en) 1999-05-18 2002-08-27 Synaptic Pharmaceutical Corporation Use of agonists or antagonists of the 5-HT7 receptor to treat disorders of the bladder
US7928121B2 (en) 2002-02-19 2011-04-19 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor antagonists
WO2004014428A1 (en) * 2002-08-09 2004-02-19 Ajinomoto Co.,Inc. Remedy for intestinal diseases and visceral pain
US7553965B2 (en) 2002-11-07 2009-06-30 Laboratories Del Dr. Esteve, S.A. 5-HT7 receptor antagonists
US7101892B2 (en) 2003-05-15 2006-09-05 Merck Sharp & Dohme Ltd. Sulfone derivatives as 5-HT7 receptor ligands
US8618288B2 (en) 2003-09-17 2013-12-31 Janssen Pharmaceutica Nv Pyrimidine compounds as serotonin receptor modulators
US7211585B2 (en) 2004-08-18 2007-05-01 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor antagonists
US7211584B2 (en) 2004-08-18 2007-05-01 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor ligands
US8188115B2 (en) 2004-08-18 2012-05-29 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor antagonists
US8148397B2 (en) 2004-08-18 2012-04-03 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor antagonists
US7345057B2 (en) 2004-12-28 2008-03-18 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor antagonists
US7662862B2 (en) 2004-12-28 2010-02-16 Laboratorios Del Dr. Esteve, S.A. 5-HT7 receptor antagonists
US8883808B2 (en) 2005-08-04 2014-11-11 Janssen Pharmaceutica N.V. Combination of 5-HT7 receptor antagonist and serotonin reuptake inhibitor therapy
US7598255B2 (en) 2005-08-04 2009-10-06 Janssen Pharmaceutica Nv Pyrimidine compounds as serotonin receptor modulators
WO2008013556A1 (en) 2006-07-27 2008-01-31 Janssen Pharmaceutical N.V. Combination 5-ht7 receptor antagonist and serotonin reuptake inhibitor therapy
EP2151777A1 (en) 2008-08-01 2010-02-10 Laboratorios Del. Dr. Esteve, S.A. Method for screening of 5HT7 receptor ligands based on a new pharmacophore model and a descriptor's profile filter
EP2149373A1 (en) 2008-08-01 2010-02-03 Laboratorios Del. Dr. Esteve, S.A. 5HT7 receptor ligands and compositions comprising the same
US20140088069A1 (en) * 2011-06-01 2014-03-27 Eric D. Brown Novel antibacterial combination therapy
US8883796B2 (en) 2013-02-08 2014-11-11 Korea Institute Of Science And Technology Biphenyl derivatives, pharmaceutical composition comprising the same, and preparation method thereof
US9663464B2 (en) 2015-02-24 2017-05-30 Korea Institute Of Science And Technology Carbazole derivatives acting on 5-HT7 receptor
US11046670B2 (en) 2015-10-19 2021-06-29 Board Of Regents, The University Of Texas System Piperazinyl norbenzomorphan compounds and methods for using the same
EP3448520A4 (en) * 2016-04-29 2020-07-29 Board Of Regents, The University Of Texas System Sigma receptor binders
US10954217B2 (en) 2016-04-29 2021-03-23 Board Of Regents, The University Of Texas System Sigma receptor binders
WO2018117406A1 (en) 2016-12-22 2018-06-28 한국과학기술연구원 Azepine derivative acting as 5-ht7 receptor modulator
US10435408B2 (en) 2016-12-22 2019-10-08 Korea Institute Of Science And Technology Azepine derivatives as 5-HT7 receptor modulators

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