CA1334075C - Therapeutic use of serotonin antagonists - Google Patents
Therapeutic use of serotonin antagonistsInfo
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- CA1334075C CA1334075C CA000616654A CA616654A CA1334075C CA 1334075 C CA1334075 C CA 1334075C CA 000616654 A CA000616654 A CA 000616654A CA 616654 A CA616654 A CA 616654A CA 1334075 C CA1334075 C CA 1334075C
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Abstract
Use of a compound of formula A-B-C-D
wherein either A is a monocyclic, bicyclic or heterocyclic residue, B is -CO- or -SO2-, C is -O- or -NH or a bond, and D is a heterocyclic residue, or A-B-C-forms a carbazolyl residue, and D is an imidazolyl residue, in the manufacture of a medicament suitable for the treatment of rhinitis or serotonin-induced disorders and/or coadministration with another active agent to increase the bioavailability thereof, or for nasal administration.
wherein either A is a monocyclic, bicyclic or heterocyclic residue, B is -CO- or -SO2-, C is -O- or -NH or a bond, and D is a heterocyclic residue, or A-B-C-forms a carbazolyl residue, and D is an imidazolyl residue, in the manufacture of a medicament suitable for the treatment of rhinitis or serotonin-induced disorders and/or coadministration with another active agent to increase the bioavailability thereof, or for nasal administration.
Description
` -13 3 ~ 0 7 5 CASE 100-6939/II
THERAPEUTIC USE OF SEROTONIN ANTAGONISTS
This invention relates to new uses and modes of ~clmini~tration of specific mono- or bicyclic carboxylic, or heterocyclic carboxylic, acid esters, and amides of formula I and imidazolylmethylcarbazols of formula Ia as defined hereinafter. It is a divisional of application Serial No. 543,271, filed July 29, 1987.
The compounds may be used in any pharmaceutically acceptable form, including the free base and at least for the esters and amides, in acid additionand quaternary ammonium salt forms.
These compounds are referred to hereinafter as compounds of the invention.
The above mentioned esters, and amides and imidazolylmethylcarbazols have in general 5-HT3 antagonist activity which may have not been previously recognized. These esters, amides and carbazols are in general known for example frorn Belgian patents 897117, 900425 and 901274. The compounds of these patents are described as being 5-HT3 receptor antagonists or serotonin M
receptor antagonists (serotonin M receptors have been reclassified as 5-HT3 receptors).
,1' ~
THERAPEUTIC USE OF SEROTONIN ANTAGONISTS
This invention relates to new uses and modes of ~clmini~tration of specific mono- or bicyclic carboxylic, or heterocyclic carboxylic, acid esters, and amides of formula I and imidazolylmethylcarbazols of formula Ia as defined hereinafter. It is a divisional of application Serial No. 543,271, filed July 29, 1987.
The compounds may be used in any pharmaceutically acceptable form, including the free base and at least for the esters and amides, in acid additionand quaternary ammonium salt forms.
These compounds are referred to hereinafter as compounds of the invention.
The above mentioned esters, and amides and imidazolylmethylcarbazols have in general 5-HT3 antagonist activity which may have not been previously recognized. These esters, amides and carbazols are in general known for example frorn Belgian patents 897117, 900425 and 901274. The compounds of these patents are described as being 5-HT3 receptor antagonists or serotonin M
receptor antagonists (serotonin M receptors have been reclassified as 5-HT3 receptors).
,1' ~
133407a The compounds are indicated for use as anti-migraine agents, anti-arrhythmics, and for treatment of serotonin-induced gastro-intestinal disorders including emesis, e.g. induced by anti-cancer agents.
Other classes of the compounds of the invention are known from e.g.
European patent publications 13138A, 250444A, and 214772A and British Patent publication 2153821A.
We have now discovered that these compounds have interesting new uses and modes of administration which have been hitherto unrecognized.
The present invention relates to the uses of specific 5-HT3 antagonists for the treatment of rhinitis or serotonin-induced nasal disorders or for increasing vigilance, or co-administration with another active agent to increase the bioavailability thereof, or for nasal administration.
The invention provides the use of a compound of formula I
A-8-C-O (~) wherein A iS a group of for~ula R7~ z~R2 ~2~ 2 ( I ~ ) ( ~ I a) ( ~ ~b ) ( ~ ~C ) ยข~ C~3 3~3 (Ird~ (IIe) - 4 - 1( R6~ ~ R4 1 (I~I) (IY) ,~
~ N~ ( ) wherein the free valence is attached to either fused rin~
in formula II,IIa,IIb,IIe or IV, X-Y is -CH=CH-, -O-CH2- or -N=CH-, s C 2 ' 3 ' S , Rl and R2 are independently hytrogen, halogen, (Cl 4)alkyl, (Cl 4)alkoxy, hydroxy, amino, (Cl 4)alkylamino, di(Cl 4)alkylamino, mercapto or (Cl_4)alkylthio, R3 is hydrogen, (Cl 4)alkyl, (Cl 4)alkylcarbonyl, - ~C3 5)alkenyl, phenyl or phenyl(Cl 3)alkyl, and R4 to R7 are, independently, hydrogen, amino, nitro, (Cl 4)alkylamino, di(Cl 4)alkylamino, halogen, (Cl~4)alkoxy~ (C1-4)alkyl~ (Cl 4)alkano pyrrolyl, sulfamoyl, or car~amoyl, 3 is -CO- or -S02-~
C is -O- or -NH- or a bond~
D is a group of formula 13 3 4 0 7 S case 100-6939/II
~((a~2)n~"N R8 --~"N-R8 (VI) (VII) wherein n is 2, 3 or 4 orR-~
(VIII) (IX) wherein R~ is hydrogen, (C, 7)alkyl, (C3 5)alkenyl or phenyl(CI 3)alkyl, and in formula VIII the bond is in position 3 or 4, when B is CO, additionally D may be a group of formula ~N
(X) 2 2 8 (XI) (J
~N-R (XII) - 6 - Case 100-6939/II
- 133~75 ~ 2) 3 ~ (XIII) wherein t is 1 or 2, and R8 is as defined above, ~N (XIV) (xv) N
(*)~>
[*]
wherein the bond is in the position 3 (*) or 4 [*], /~
~CH2)1~N-R8 (XVI) wherein 1 is 2 or 3, ~ R8 (XvII) wherein Z is (Cl 1)alkoxy, - 13 310 7 5 Case 100-6939/II
Rg R1 o \/
(CH2)m C
-(CH2)p ~ \ N-R8 (XVIII) (CH2)n (C)O
/\
Rll R12 wherein Rg to R,2 are independently hydrogen or (Cl 4)alkyl m is 0, 1 or 2 and n, o, p independently are O or 1, ~(cH2)q --N
R14 (XIX) wherein q is 2 or 3, Rl3 and Rl4 independently are (Cl 4)alkyl, ~; (xx) wherein the bond is in position 3 or 4, H " (XXI ) / 3~
C~ H-R8 (XXII ) \H3C C~
/H3C~ /\
H3C2 / N-~3 (XXIII) C~H~ /
~N(C~ N-R8 (XXIVa) ~ \
~N ( CH2 ) 3 N-R8 \/ / (XXIVb) Z~ (XXY) 1334~75 and R8 is as defined above, in free base form, acid additiGn salt form or quaternary ammonium salt form, or a compound of formula Ia o R17~ ~R18 N ~f N Ia wherein Rl5 is hydrogen, (C1_1O)alkyl, (C3_9)cycloalkyl, (C3_6)alkenyl, phenyl or phenyl(Cl_3)alkyl and one of the groups R16, R17 and R18 is hydrogen, (C1_6)alkyl, (C3_7 )cycloalkyl, (C2_6)alkenyl or phenyl(Cl_3)alkyl and the others independently are hydrogen or (C1_4)alkyl, for the treatment of rhinitis or serotonin-induced nasal disorders.
In a sub-group the compound is of formula I wherein A chosen from formula II, III, IV and V, R3 is other than acyl, C is -O- or -NH- and D is chosen from formula VI to XVIII, with the proviso that, when A is formula III, B is CO and C is NH, D
is not a group of formula VI, in free form, in acid addition salt form or in quaternary ammonium salt form.
-- lo - 13 3 ~ 0 7 ~ Case 100-6939/II
In a further group of compounds of formula I' A is a group of formula II' ~/
~d~ x ~
wherein the free bond may be .cit~l~te~l in any of the rings, X' is -CH2-, -NR 3-, -O-, -S-, R' and R2', independently of one another, are hydrogen, halogen, Cl 4)alkyl, (C~ 4)alkoxy, hydroxy, amino, (Cl 4)alkylamino, di(CI4)alkylamino, mercapto or (C, 4)alkylthio, and R3' is hydrogen, (Cl 4)alkyl, (C3 5)alkenyl, phenyl or phenyl(C, 3)alkyl, or a group of formula m `R ' I I I
whereln R4 to R7, independently of one another, are hydrogen, amino, nitro, (Cl 4)alkylamino, di(CI 4)alkylamino, halogen, (Cl 4)alkoxy, (Cl 4)alkyl, (Cl 4)alkanoylamino or pyrrolyl, C signifies -O- or -NH-, D signifies a group of formula IV/, ,~,~N-R8 IV
wherein 11 - Case 100-6939/II
133407~
n is 2, 3 or4 and R8' is hydrogen, (C, ~)alkyl, ~C3 5)alkenyl or phenyl(C, 3)alkyl, or a group of formula V', ~> V~
with the proviso that when A is a group of formula m and C is -NH-, then D signifies a group of formula V'.
A further group comprises formula I wherein A is a group of formula II or III wherein B
= -CO-, C = -O- or -NH- and D is a group of formula VII, IX, X, XI or one of XIII to XXV or A is a group of formula IIa, IIb, IIc, IId, IIe, IV or V and B, C and D are as defined above.
Another group of compounds of formula I comprises compounds wherein A is formula II
or III, wherein R4 to R7 are other than sulfamoyl or carbamoyl, D is VI or vm with the proviso when A is III and C is -NH- then D is vm.
Preferred compounds include:
Indole-3-yl-carboxylic acid endo-8-methyl-8-aza-bicyclo[3,2,1]oct-3-yl ester, (hereinafter compound E) benzo[b]thiophen-3-ylcarboxylic acid endo-9-methyl-9-aza-bicyclo[3,3,1]-non-3-yl ester, 5-fluoro-l-methyl-indol-3-yl carboxylic acid endo-9-methyl-9-aza-bicyclo[3,3,1]-non-3-yl ester, 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-lH-imi~1~701-1-yl)methyl-4H-carbazol-4-one (hereinafter compound H) and 1-methyl-indazol-3-yl carboxylic acid 9-methyl-9-aza-bicyclo[3,3,1]-non-3a-yl-amide.
In one group of compounds the compounds of formula I is a group of formula II, in particular Z is NR3, 0 or S.
In another group the compound of formula I has a group of formula III.
In a sub-group D is VI. In a 2nd sub-group D is VII. In a 3rd sub-group D is VIII. In a 4th sub-group D is IX. In a 5th sub-group D
is X. In a 6th sub-group D is XI. In a 7th sub-group D is XII. In a 8th sub-group D is XIII. In a 9th sub-group D is XIV. In a 10th sub-group D is XV. In a 11th sub-group D is XVI. In a 12th sub-group D
is XVII. In a 13th sub-group D is XVIII.
Preferably D is VI or VIII.
A preferred group of compounds comprises a compound wherein A is a group of formula II wherein R1 and R2 are independently hydrogen, halogen, (Cl_4)alkyl or alkoxy; R1 is in position 4 or 5;
R3 is hydrogen, acetyl or (C1_4)alkyl and the corresponding bond is in position 3,4 or 5.
The antagonistic action against 5-HT3 receptors of the preferred compound ICS 205-930 (indol-3-yl carboxylic acid endo-8-methyl-8-aza-bicyclot3,2,1~oct-3-yl ester) on the rabbit vagus, rabbit heart and guinea pig ileum has been described (P.Donatsch et al., Br,J. Pharmacol.
1984, 81, 348), and also its topical application to humans as the first S-HT3 antagonist.
In the Belgian Patent No. 897,117 it was also stated that the compounds disclosed therein are indicated as anti-psychotics.
133~075 '~e have now found that the co~pounds of the inven-tion may he administered nasally and have an especially interesting resorption profileO
Furthermore the compounds of the invention increase the nasal resorption or bioavailability of other active agents such as peptides particularly when administered by the nasal route, The compounds of the invention mareover are useful in the treatment of rhinitis and serotonin-intuced nasal disorders as indicated by an inhibition of nasal secretions on admi-nistration of the compounds of the invention The testing may be effected as follo~s:-The ~ioavailability and pharmacokinetic profile of thecompounds of the invention may be determined in conven-tional manner, e,g. in mammals including rhesus monkeys and humans. The concentrations of the compounds of the in-vention in the blood plasma after administration of from about OoOl to about 10 mg/kg to each nostril, e.g. 7,5 mg in the case of compound E, locally to the nasal mucous membrane, e.g. as a spray, may be determined in conventional manner by e.g. ratioimmunoassay or HPLC methodsO The com-pounds of the invention are rapitly absorbed, e.g. over about 10 minutes, ~ven after ca. 5 to 10 minutes follo~ing nasal administra-tion, 200 ng of the compound indol-3-yl-carboxylic acid-endo-8-methyl-8-aza-bicyclot3,2,1]oct-3-yl ester may be detected in 1 ml of plasma. Upon oral administration, this concentration of active ingredient in the plasma is reached only after ca. 30 to 40 minutes. The general bioavailability - lS - 100 133~07~
of the compounds of the invention over a period of 6 hours is the same for nasal administration as for oral administration.
Nasal secretions are also inhibited. Additionally, the compounds of the invention when administered, e.g. at a dose of from 0.01 to 10 mg/kg with a therapeutically effective dosage of another compound, e.g. a peptide, such as salmon calcitonin increases the absorption thereof.
For example, in the case of compound E (15 mg) and salmon calcitonin (100 IU) half of which is applied to each nostril, the bioavailability of salmon calcitonin (AUC up to 2 hours) is increased from 0.08 IU/ml/hr plasma to 1.632 IU/ml/hr/plasma in the rhesus monkey.
For the rhinitis and nasal serotonin-induced disorder indications, the appropriate dosage will, of course, vary depending upon, for example, the compound of invention employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results are indicated to be obtained at daily dosages from about 0.01 mg/kg to about 10 mg/kg animal body weight. In humans, an indicated daily dosage for oral administration is in the range from about 5 mg to about 300 mg of a compound of formula I conveniently administered, for example, in divided doses up to four times a day, e.g. in the range of about 40 mg p.o. in the case of compound E.
In another aspect the present invention provides a pharmaceutical composition comprising (i) a 5-HT3 antagonist of formula I as defined above and (ii) a pharmaceutically acceptable peptide.
1334~75 ~hen a compound of sne invention is co-administered ~ith ~nother active agent, the Appropriate dosage will, of course, vary depending upon, for example, t6e active agent of the compound of the invention and other active agent employed, the host, the mode of administration and the nature and severity of the condition being treated. How-ever, in general, satisfactory results are indicated to be obtained at daily dosages from about one half to one tenth the usual dose of the other active agent. The com-pound of the invention is indicated to be administered at about one half to one tenth the usual dose.
The compounds of the invention may be administered for t6e rhinitis and nasal serotonin-induced disorders and for co-administration with another active agent, e.g. a peptide, by any conventional route, in particular enterally, preferably orally, eOg., in the form of tablets or cap-sules, or parenterally, e.g., in the form of injectable solutions or suspensions. The local apptication by the nasal route is preferred.
For the nasal administration route, the appropriate dosage will, of course, vary depending upon, for example, the com-pound of the invention employed, the host, and the nature and severity of the condition 6eing treated, However, in general, satisfactory results in animals are indicated to be obtained at daily dosages from about 0.001 mg/kg to about 10 mg/kg animal body weight. In humans, an indicated dosage per actuation is in the range from about 0.01 mg to a~out 1 mg of a compound ofthe invention conveniently ad-ministered, for example, in toses up to four times a day.
1 n~-6939 /I I
Thus for sastrOintestinal disorders or for migraine prophy-laxis a compound according to the inventlon is indicated to be administered to the body nasally in a dosa~e of ~.13 to 0,4 mg k~ ~ody weight, i,e. ca. 10 to 30 mg or 1 to 3 pu,~ps of the nasal spray per patient, and in order to con-trol arrhythmia, it should be given in a dosage which is caO 10 times higher, i~e, from 1,3 to 4 mg per kg body weight or 100 to 300 mg, or resp. 10 to 30 pumps of the nasal spray per patient.
The compound E is the preferred compound for the rhinitis and nasal route administration. It is indicated that the compound of example may be administered at daily dosages of about 0~1 mg nasally to humans.
The compounds of the invention may be administered nasally in any pharmacologically active form, e.g. in free base form, in acid addition salt form or in quaternary ammonium salt formO
The nasal mode of administration creates a simple method of administration ~hich rapidly gives results and can be easily carried out by the patient himself, e.g,by admini-stering a liquid form for nasal administration, for example a nasal spray or drop solution using a nasal ap~tcator, or by inserting a gelatinous sponge or lyophi-lisate soaked in the active substance, or by blowing the galenic form in powder form into t~e nostrils.
The compounds of the invention may be present in the liquid form for nasal administration in a proportion of 1 to 30%, prefera~ly 5 to 20~, especially 10 to 15Y
(weight/volume), - 18 - 10( The present invention accordingly relates also to a liquid form for nasal administration, containing 1) a compound of the invention 2) a preservative, especially benzalkonium chloride, and 3) a liquid diluent or a carrier, suitable for application to the nasal mucous membrane.
In another aspect the invention provides a liquid nasal pharmaceutical composition containing a compound of formula I as defined above wherein A is of formula II' a preservative, and a liquid diluent or carrier suitable for application to the nasal mucous membrane.
The proportion of benzalkonium chloride in the compositions according to the invention is preferably ca. 0.002 to ca,. 0.02, especially ca.
0.01% (weight/volume) of the total composition.
In accordance with the invention, the above-mentioned forms of administration may be administered to the nasal mucous membrane, e.g.
as drops or as a spray. As described hereinafter, however, they are preferably administered as a spray, i.e. as finely dispersed droplets.
One further possible way of bringing the above-mentioned liquid form for nasal administration into contact with the nasal mucous membrane is to soak a gelatinous sponge (SPONGOSTAN - Registered Trade Mark) or lyophilisate with the substance and then to insert the sponge into the nostrils.
The liquid diluent or carrier employed is conveniently water (pharmaceutical grade). An aqueous salt solution is preferred in particular. The liquid forms for nasal administration according to the invention are formulated such that they allow administration to be effected nasally. With this in mind, they can e.g. also contain minimal amounts of further desired components or excipients, e.g.
additional preservatives, or e.g. ciliary stimulants such as caffeine.
- I9- 133~075 rhe liquid forms for nasal administration ~ccording t~
the invention preferably have a pH value of ; S to 6, The liquid forms for nasal administration should also nave an appropriate isotonicity and viscosity . They prefera~ly have an osmotic pressure of ca, 260 to ca. 38 mOsm/litreO The desired viscosity of the compositions according to the invention depends on the relevant form of administration, eOg, whether nasal drops or a nasal spray are administered. For nasal drops, a viscosity of ca. 2 to ca, 40 x 10 3 Pa,S is suitable, For nasal sprays, a viscosity of less than 2 x 10 3 Pa,S is suitable.
~f desired, the liquid forms for nasal administration may also contain further components, especialty conventional pharmaceutically available surface-active agents, In this connection and as a further aspect of the present inven-tion, it was found that the use of surface-active compounds in the nasal a~ministration of the compounds of the inven-tion increases their resorption through the nasal mucous membrane and improves the initial bio-availability. In this case, preference is given to non-ionic surface-active agents, for example polyoxyalkylene ethers of higher alco-hols, e.g. of the general formula, R0 ~(cH2)n~ ~ H
wherein R0 signifies t~e radical of a higher alkanol, especialty a higher alkanol such as lauryl or cetyl alcohol, or of an alkylephenol, or a sterol, especially lanosterol, dihydrocholesterol or cholesterol, as well as mixtures of two or several such ethers, Preferred polyoxy-alkylene ethers which can be used for the present inven-~ - 20 - 1 3 3 4 0 7 ~ Case 100-6939m tion are polyoxyethylene- and polyoxypropylene-ethers (i.e. wherein n in the above-mentioned formula is 2 or 3), especially lauryl-, cetyl- and cholesterylpolyoxyethylene-and -polyoxypropylene-ethers, as well as mixtures of two or several such ethers.
Especially suitable polyethers for use according to the invention are those in which the average value of the recurring units in the polyoxyalkylene component (x in the above formula) lies between 4 and 75, especially between 8 and 30 and particularly between 16 and 26. The polyethers may be obtained in accordance with known methods. A largechoice of such products is available commercially and is sold e.g. by Amerchol under the trane name Solulan by KAO Soap, ICI and Atlas under the trade names Emalex, Brij and Laureth, and by Croda under the trade name Cetomacrogol.
SOLULAN, EMALEX AND LAURETH as used herein are Registered Trade Marks.
Examples of polyoxyalkylene ethers which are suitable for use according to the invention, (e.g. POE = polyoxyethylene ethers: POP = polyoxypropylene ether; x = average value of the recurring units in the POE/POP component) are listed in the following:-- 21 - 133 107~ Case 100-6939m 1. Cholesterylethers:
1.1 Solulan (R) C-24 - POE, x = 24 2. Ethers of lanolin alcohols:
2.1 Solulan (R) 16 - POE, x = 16 2.2 Solulan (R) 26 - ROE, x = 25 2.3 Solulan (R) 75 - POE, x = 75 2.4 Solulan (R) PB-10 - PPE, x = 10 2.5 Solulan (R) 98 - POE, x = 10 - partly acetylated 2.6 Solulan (R) 97 - POE, x = 9 - wholly acetylated 3. Laurylethers:
3.1 Emalex (R) 709 / Laureth (R) 9 - POE,x = 9 3.2 Laureth (R) 4 / Brij (R) 30 - POE, x = 4 3.3 Laureth (R) 23 / Brij (R) 35 - POE, x = 23 4. Cetylethers:
4. I Cetomacrogol (R) - POE, x = 20 to 24 Lanolin alcohols are also known as wool fat alcohols and are a rnixture of cholesterol, dihydrocholesterol and lanosterol.
Preferred polyethers for use according to the invention are cholesteryl polyoxyethylene ethers, e.g. polyethers of the above formula wherein n = 2 and RO is a cholesteryl radical, in particular polyethers wherein the number of recurring units in the polyoxy-- - 22 - 133~075 ethylene companent is 16 to 26, especlally about 24.
These polyethers are preferably free from impurities, and especially from other polyoxyalkylene ethers. They prefera~Ly contain at least 75~, most particularly at least 8S% and especlally at lea~t 90~ (weight) of the pure cholesteryl ?oly-oxyethylene ether.
If a surface-active agent, e.g. a polyoxyalkylene ether, Ls used, the amount present ln the composltlon~ accordlng to the invention wlll depend on the surface-actlve agent u~ed in partlcular, the form of admlnistratlon (e.g. dropq or spray) and the deslred effect.
In general, the amount of surface-active agent employed is between ca. 2.0 and ca. 200 (preferably up to ca. 100, especially up to ca. 20), especlally between ca. 5 and ca. 30 (preferably up to ca. 15) and ln particular ca. 10 mg/ml.
For nasal ~tn1~tration~ the liquid fon~ for nasal administratlo~
are preferably placed ln an applicator, which is equipped with a device that enable~ the compo~ition to be applied to the nasal mucous m~mhrane, e.g. a na~al spray applicator.
Such appllcator~ ar- known per se and lnclude those which are suitable for the admini~tratlon of llquld preparatlon~ a~ drops or a~ a spray to the nasal mucou~ membrane. Slnce the doslng of the compound~ of the invention should ~e a~ exact as po~sible, the u~- of ~pray appllcator~ ln which an exact controL
over the quantlty ~tnt~tered 1~ po~glble 1~ generally preferrec Suitaole appliance for administration are e g. atomizers such dS pump dispensers or aerosot cans. ~n the latter case, the applicator contains a composition according to the invention as well as a propellant which is suitable for use in a nasal spray applicator. The atomizer appli-ance is provided with an appropriate spray device which enables the composition to be applied to the nasal mucous membraneO Such devices are known in general.
The container, e~g. a nasal spray applicator, may contain a quantity of the composition ~hic~ is sufficient for a single nasal dose or for administration several doses, e.g.
over a periGd of several days or weeks. The amounts of the individual doses will preferably correspond to the above-mentioned doses.
Applicators as defined above are preferably spray a~licators for nasal usage. They preferably ena61e t~e composition con-tained t~erein to be administered in single doses of ca~
a . os to ca. 0015 ml, e.g. ca. 0.1 mlO
Suitable compositions, as well as the individual components 1,2 and 3 for use in an applicator, are those which have been previously described. The dosages which are suitable for use similarly correspond to the dosages given previously.
Furthermore, the invention relates to a process for the pro-duction of a liquid form for nasal administration, con-taining 1) compounds according to the invention 2) a preservative, especially 6enzalkonium chloride,and 3) a liquid diluent or a carrier,which are suitable for administering to the nasal mucous membrane, as well as optionally a surface-active agent which is suitable for administering to the nasal mucous membrane/
- 133~075 characterised in that the components are intimately mixed together, and if desired, the composition obtained i5 placed in ~n applicator which is provided with a spray device which enables the co~position thus obtained ta ~e administered to the nasal mucous membrane. Furthermore, a sponge (SPONG~-STAN) may be soaked with the composition obtained and the soaked sponge can be inserted into the nostrils.
The stability of the composition according to the invention can be determined in the usual way.
The co~positions according to the invention containing benz-alkonium chloride are stable to~ards contamination by germs, e,g as in standard tests such as those described by S Urban et al.in Z61OBakt,Hyg.I Abt,Orig.8 1972,478-484 (lg81) and S~Ur~an,Acta Pharm,Technol.22, 247-253 (1976).
For example, the cell count of the standard bacteria, namely Elcoli ATCC 8739, Pseud.aeruginosa ATCC 9027, Staph.aureus ATCC 6538, Strept. pyogenes ATCC 8668 and standard fungi CandOalbicans ATCC 10231, Sacch.cerevisae ATCC 9763, Aspergillus niger ATCC 16404 and Pen.steckil ATCC 10499, is reduced to O.lX or less ~ithin 24 hours after injecting them withthe composition, as can be sho~n in standard tests.
In a stability test, the nasal spray composition of the follo~ing example 1 was kept for 3 months at 30C under a nitrogen atmosphere in a glass container. Pseud,aeruginosa ATCC 9027, Staph.aureus ATCC 6538, Strept. pyogenes ATCC
8668 and the fungi cand,albicans ATCC 10231, Sacch.cerevi-sae ATCC 9763, Aspergillus niger ATCC 16404 ant Pen.stechii ATCC 10499 ~ere addet until a cell count of ca. 2 x 10 organisms ~as reached in the in~ected liquid. Within 2 hours, the germ count had reduced to less than O.lX, Withi-n 4 weeks, the germs could no longer be detected.
E~uall~ favourable results are obtained if the compounds of tne invention are administered in a galenic form, which is in the form of a powder and is introduced by blowing into the nostrils.
Toxicity and Tolerability:
Toxicity and Tolerability studies may be effected in con-ventional manner with the compounds of the invention to determine the upper dosage.
Toxicity studies may be effected for example in the rat and the dog over for example 26 weeks.
For compound E over 26 weeks the no toxic effect bowel in the dog was 5-20 mglkg/daily p.o,. For the rat it was 16 to 45 mg/kg per day p.o.. Other compounds of the invention may have the same order of tolerabilityO ~n healthy human volunteers single doses up to 150 mg were well tolerated - without relevant side effects.
- 26 - 100-53~9 /I I
133~075 Tne fallcwing examples illustrate the invention.
.X~FLE l: TaDlets for oral administration _ _ _ _ _ _ _ _ _ _ _ _ _ _ Tablets containing the constituents as specified below were produced lnconventional manner and are used in the indications specified above.
Compound E in form of hydrochloride 16.9 mg (corresponding to 15 mg free base) Hydroxy-propyl-cellulose 1.2 mg Corn Starch 12.0 mg Lactose 92.8 mg Silica 0.6 mg Magnesium stearate l.S m5 ~ablet weight 125.0 mg EXAMP!E 2: Capsules for oral administration _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Capsules containing the constituents as specified below are produced inconventional manner and are used in the indications specified above.
l-methyl-N (-endo-9-methyl-9-aza-bicyclo-t3,3,1] indol-3-yl) carboxylic acid amide in form of the hydrochloride ( corresponding to 15 mg base) 16.9 mg bactose 28.7 mg Silica 1.5 mg Magnesium stearate 3 ~9 Capsule Content weight of S0.1 mg `- 13 3 ~ 0 7 5 EXAMPLF 3: Injection solution for i.v. administration _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ A composltion for injection is made up in conventional manner and is ~seo at a dose of 10 mg a day.
A B C
Compound E in form of hydrochloride 1 131) 2.2562)11.2823) Acetic acid (99 to lOOZ)~ 1.2 0.6 0.6 Sodium acetate 3. H20~ 1.8 3.18 3.18 Sodium chloride 8 7.5 6.5 Water for injection to 1,0 ml 1) = 1 mg free base, 2) - 2 mg free base, 3) = 10 mg free base pH value 4.3;*8uffer used 1/30 molar EXAMPLE 4: Capsules for oral administration _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 5 mg and 15 mg capsules (A and B respectively) containing the constitu-ents as specified below were produced in conventional manner and are used in the indications specified above 2 - 4 times a day in the case of A and once a day in the case of B.
A mg B mg Compound E in form of hydrochloride 5.641 16.92 Lactose 200 mesh 84.929 79.29 ~actose 100 mesh 84.43 79.29 Corn starch 120.00 120.00 Silica 1.5 1,5 Magnesium stearate 3.0 3.0 300 mg 300 mg Capsules containing other weights can be formulated in conventional manner.
EXAMP'E 5 ~asal liquid_Composi~ion-Quantity of Comoonents components indol-3-yl-carboxylic acid-endo-8-methyl-8-aza-bicycloC3,2,1Joct-3-yl-ester. HCl 100 mg benzalkonium chloride 0.1 mg NaCl (0.970 aqueous solution) 0.6 ml distilled water 0.4 ml rhe solution obtained is filtered (e.g. through a 0.2 ~m filter) and filled into a nasal canister, or a gelatinous foam (SPONGOSTAN) is soaked with the solution. It is administered e.g. for the treatment of rhinitis, lung embolism or to improve the absorption of other active agents.
EXAMPLE 6: Nasal liquid Composition _ _ _ _ _ _ _ _ _ _ _ Quantity of Components components l-methyl-N-endo-9-methyl-9-azabicyclo-L3 . 3, 1~ i ndol-3-yl-carboxylic acid amide 50 mg benzalkonium chloride 0.1 mg NaCl (0.970 aqueous solution) 0.83 ml distilled water 0.17 ml The solution obtained is filtered (e.g. through a 0.2 ~m filter) and filled into a nasal spray canister, or a gelatinous foam (SPONGOSTAN) i soaked with the solution. It is administered in analogous manner to tha disclosed in example S.
The active agents in ~xamples 1 to 6 may be replaced by the following compounds of formula I wherein: n(YI) A=II B= -C0- D =
No. Rl 2 C0-Position C Conf. VIII (pcs-) ~j3 1 H H NH 3 NH endo 3 (VI) CH3 2 5-F H NCH3 3 0 endo 3 (VI) H
3 H Z-Cl NH 3 0 endo 2 ( vr ) CH3 4 H 2-OCH3 NH 3 0 endo 2 (VI) CH3 H 3-J NH 4 0 endo 2 (VI) CH3 6 H H NH 4 0 endo 2 (VI) CH3 7 H H NH 4 0 endo 3 tVI) CH3 8 5-CI H NH 3 0 endo 2 (VI) CH3 9 4-OCH3 H NH 3 0 endo 2 (VI) CH3 5-OCH3 H NH 3 0 endo 2 (VI) CH3 11 H H NCH3 3 0 endo 2 (VI) CH3 12 H H NH 3 0 exo 2 (VI) CH3 13 5-F H NH 3 NH endo 2 (VI) CH3 14 H H NCH3 3 NH endo 2 (VI) CH3 lS H 2-CH3 NH 3 NH endo 2 (VI) C 3 16 H H NH 3 NH exo 2 (VI) CH3 17 H H NH 3 NH endo 2 (VI) CH3 18 5-Cl H NH 3 H endo 2 (VI) CH3 19 H H NH 3 0 endo 3 (VI) Bz H H NCH3 3 0 endo 3 (VI) Bz 21 5-F H NH 3 0 endo 3 (VI) Bz 22 H H S 3 0 endo 3 tVI) CH3 23 H H S 3 NH endo 3 (VI) CH3 24 H H 0 3 NH endo 3 (VI) CH3 H H 0 3 0 endo 3 (VI) CH3 26 H H CH2 3 NH endo 3 (VI) CH3 n(VI ) A=lI, B= -CO- Carboxyl- O =
No. Rl 2 Position C Conf. VIII(pos.l R8 27 H H NH 3 NH exo 4 (VI) CH3 28 H H NH 3 0 exo 4 (VI) CH3 29 H H NH 3 O endo 3 (VI) CH3 30 H H NH 3 0 endo 2 (VI) n-c3H7 31 H H NH 3 0 exo 2 (VI) Bz 32 H H NH 3 0 endo 2 (VI) Bz 33 H H NH 3 0 endo 2 (VI) H
34 5-F H NH 3 0 endo 3 (VI) H
35 H H NCH3 3 0 endo 3 (VI) H
36 H H NH 3 0 endo 3 (VI) H
37 s-CH3 H NH 3 0 endo 3 (VI) CH3 38 H 2-CH3 NH 3 0 endo 3 (VI) CH3 39 5-F H NCH3 3 0 endo 3 (VI) CH3 5-F H NH 3 0 endo 3 ~VI) CH3 41 5-F H NCH3 3 0 endo 3 (VI) Bz 42 H H NCH3 3 0 endo 3 (VI) CH3 43 5-CH3 H NH 3 NH endo 3 (VI) CH3 44 H H NH 5 0 endo 2 (VI) CH3 45 H H NH 5 0 endo 3 (VI) CH3 46 H 3-J NH 5 0 endo 3 (VI) CH3 47 H H NH 4 NH exo 2 (VI) CH3 48 H H NH 4 NH endo 2 (YI) CH3 49 H H NH 5 H endo 2 (VI) CH3 50 H H NH 3 0 - VIII (3) _ 31 1334075 lCO-693g /II
n(!V) A=II r, 8= -CO- O =
~o R4 R5 R6 R7 C Conf. VlII(pos.) R8 51 OCH3 H NHCH3 Cl o VI'I (3) --52 OCH3 H NH2 Cl o - 2 (VI) Bz 3 2 Cl o exo 2 (VI) H
54 OCH3 H NHCH3 Cl O endo 2 (VI) CH3 55 OCH3 H N(CH3)2 H O exo 2 (VI) Bz 56 OCH3 H NH2 Cl O endo 2 (YI) CH3 3 2 Cl O endo 2 (VI) H
58 OCH3 H NH2 H O endo 2 (VI) H
59 OCH3 H NH2 H O exo 2 (VI) H
60 OCH3 H NH2 H O endo 2 (VI) CH3 61 OCH3 H N(CH3)2 H O endo 2 (VI) 3 62 Cl H NH2 H O endo 2 (VI) CH3 63 OCH3 I NH2 H O endo 2 (VI) CH3 64 OCH3 I NHCH3 H O endo 3 (VI) CH3 65 OCH3 H NHCH3 H O endo 3 (VI) CH3 66 Cl H N02 H O endo 2 (VI) 3 67 OCH H Br H O endo 2 (VI) CH3 3 Cl O endo 3 (VI) CH3 69 OCH3 H l-Pyrrolyl Cl o endo 2 (VI) CH3 70 OCH3 H l-Pyrrolyl H O endo 2 (VI) CH3 71 OCH3 H NHCH3 Cl NH -- VIII (3) --72 H Cl H Cl Cl -- VIII (3) --73 OCH3 H NH2 C1 NH -- VIII (3) --- 32 - lOC-6939 /II
~o. Formul d II, B= -CO- cdr3oxyl- C Conf. D = Group 28 Rl 2 Position 74 H H NH 3 0 exo (X) --H H NH 3 0 endo (XVII) CH3 (Z=OCH3)*
76 H H NH 3 0 (endo) (XYI) (r=3) CH3 77 H H NH 3 0 endo (XI) CH3 78 H H NH 3 0 (endo) (XVI) (r=2) CH3 79 H H NH 3 0 (exo) (XVI) (r=3) CH3 H H NH 3 0 endo (X) --81 H H NH 3 0 exo (XIII)(t=l) CH3 82 ~-) H H NH 3 0 endo (XI) CH3 83 (~) H H NH 3 0 endo (XI) CH3 84 H H NH 3 0 endo (XII) CH3 85 H H NH 5 0 endo (XVII) CH3 (Z=OCH3)*
( ) = Ring is in Chairform * = (ls*, 3r~, 5R*, 6R~) Bz in R8 = Benzyl A=III, B= -CO- n(VI) No R4 R5 R6 R7 C Conf. D - R8 86 OCH3 H NHCH3 Cl NH exo (X) 87 OCH3 H NHCH3 Cl NH endo (X) C -- -- o -- o o o o o o o o o _ _ _ _ _ _ _ E ~ ~ -- o ~ _ _ ~ _ _ IS===_~S
S
CC I = S = S = ~ = = =
-O ~
-- = = = = S S ~ = S
-E~a = = S = = = ~ = = =
o CO = S = = = S
= ~ S
o C~ Y ~: ~ lY ~ ~ C~
I
OOOOOOOOZZ
o ~ ._ o U-O
C~
Z Z S Z Z ZS ZS Z S Z
, -~1 0 _ .) ~
E l C~ = S = I S = = S
ll O
O CO 1~ 0 -- ~J ~ G n ~D r~
133~07S
o C o E -- o N
C~ = =
Y
O
T
X
-E c~
o CO =
=
C V~
O =: =
~ Z Z
o I~
N ~J
~ = =
C~ Z Z
-1~
E ~ = =
o I_ O O
o :~
Z
-- 35 - 133~07~
C~= T = = = = = _ I I ~ I I
_ * * * _ ~ ~ C V Y CC
o c ~, y ~ y ~
~ 5 ~ Y Y
o V-o o o o-- -- ~
L~ -------------- -- ----_ __ X
Co -------------- -- ___ __ o -_ ~
V~ ------____ _ CO ----_____ _ O O O O O O O O O O O ~ 'J
~ O O
r~J ZZIIIIZ Z ~
~-- T C~l 11 1 = I I I ~O = =
X I I ZI ~J O I I ~ ~ ~ = T
z y = = =~ = = = T ~ = = O = ~
=
-- C
~ = = == = = = = ~ = = = O T
S
O
~ _ _ _ _ _ _ _ _ _ _ _ _ il _ _ ~_ ~ ~ _ _ _ _ _ _ _ _ _ _~ _ _ _ _ _ _ _ _ _ O -- ---- ---- _ _ _ _ _ _ _ _ CO ~ O --O O O O O OO O O O O -- -- --Z _ _ _ _ __ _ _ _ _ _ _ ~J ^ CJ
G O ~ u'~ ~ O
O l~
. _ . ~ O ~ O CO ~ o O ~ O
C = = = T = = T T T
~) T = = = = = = T = T
o o X X X X X X X X X X
X X X X X X X X X X
2 = = = = = ~ S =
Z Z Z Z Z O Z Z Z Z
O
X _ n~ O
C
= = = = = = = ~
Z Z Z Z Z Z Z Z Z Z
S S = S S = S S S S
~ C U ~ ~ ~ O --O _ Z
,. ~ .
~ ~ t C~ C
~, .. .
_ ~ o ~
o ~ C ~, o ~ ,~ ~, _ o o ~ ~ ~ o o E -- -- ---- E ~ ~ --o = I CL ~ ~
X X X
X X X
ll C~
o ", _-- o C ' l ~ O o O o , C
>, ,_ o O
~: S 2 ~ 1~ Z z a~ 2~
= ~ ~ ~ _ y S
1~ "
~ C~ = S S ~ S S
o ~ _ Z _ _ Z
~ o _, '' ; - ~, .. .
_ O ~, ~ ~ O er . z ~
C
U o ~ o Ct~, ~ ~ -- -- C~ ~ C
~ , = = _ Il _ ~ _ C _ ~ ~ ~ ~
" _ _ " _ , 1 C ~ ~
Z ~ o o Z
o X ._ o ~
o CL
T
r~l Z Z
O O
O (~
ll ll y T ~ CD ~ C5 -- --U
~ 11 11 I l ~ ~ O C T ~ -a~ o O ~ ~ ~ ~ ~q Z _ _ _ _ _ - 39 - 1334075 100-6939/~
~ " _ . _ _ o o --O ~ O ~ O G' '~
-- ~ L ~ ~
~G' _ ~ S c --E ~
CS~ = = S
Y
Cl ~ ~ r~
o ~ , S
O
ll 'I ~ I CD S
Il Y I ~: =
~ ~ er Z _ _ _ 1~4075 o U .
~;
., ~ o 3 r~ ~ __ _ E ---- ~c ~ U
o~ o ~ ~ =
_ _ E ~--X X
X X
Cl _ _ -X
C U ~ X
O ~ C- ~_ O
~ O O O~
_ C ~ Z
>, O
X _ o ~o _ V~
O r~
O ~Z
O
C~
Y
~ CC = = --Il 11 =
= = ~ ~O
O ~ '~7 0 Z _ _ Z
_ 4~ _ 133~075 100-6939 /II
L ~ , U _ _ O-- O C~ OC~ O C O C~ O
t~ _~ e ~ ~ -- _ ~ OC~ o a~ UO COO U ~ ~
~ ~ _ e.~J t_ ~ ~ e.~~
~ ~ O :~ ~ ~ 3 ~ e.~J
G =crl S CO S 1~ = I-- S
= = S S S
-- _ Il _ _ _ _ 11 X 11 X
X X
O O O O O O
C t~
O 1~1 L.. l I~J L-~ Z l.LJ
~_~ e ~ S
O O O I O O
~ O
O ~
O
S S S S
1~ 2 Z Z Z Z Z
O O
o Il ~ S S = 2 a~ S C:~ 2 -- _ S o 2 S ~ S ~ 2 o -- ~ ~
O ~ ~ ~ ~ er q' Z _ _ _ _ _ _ - 42 - 13340~5 l00-6939/II
o.
, _ , , o _ ~ _ o o C~
E ----/~
T
C _ ~ ~ C
~ --Il _11 X 11 X 11 C -- C -- C ~ i ~ , O O
O I Z L~J
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~ 11 Z
C~
~ _ -e e o ~ ~ ~
Z
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o ~-- o ~, .5 ~ I ~
C C~ ~ cr, _ 3 ~
O ~ C ~ _ C) ~J G ~ 3 E ~ ~5 V~ C
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X ~ .
X ~ O
C X
o ~
Gl --, ' C
._ G ~
~1 ~ ~ 3 C
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._ C~ C C
. C
~ Z ~ ~ ~ . _ _ C O _ X ~_ T
'-- I _ _ ~ ~ ~ t ~ O ~ E ~
~ C ~
,.
5 ~
r~ _ C ~
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C~ ~ Z '~ ~D ,c ~ X
~ _ G
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o _ E ~ ~ ,~ O
133~07~ 100-6939 /II
Reference example for the preparatton of the compound ~o 147 l-Acetyl-lH-indol-3-Carboxylic acid 8-methyl-8-azabicycloE3.2.1~oct-~-yl-es ter 2.84 9 lH-indol-3-carboxylic acid 8-methyl-8-azabicyclot3.2.1]oct-3a-yl-ester are dissolved at 30 in 30 ml tetrahydrofuran. The solution is cooled to 0 and treated at this temperature dropwise with 5.9 ml butyl-lithium within 15 minutes. A slightly exothermic reaction takes place.
The mixture is stirred at 0 for 1 hour, then cooled to -10 and treated dropwise with a solution of 0.~5 ml acetyl chloride in 4 ml tetrahydrofu-ran. The mixture is stirred overnight at room temperature and then parti-tioned between 2 N aqueous sodium carbonate solution and CH2 C12. The organic phase is evaporated to give the title compound, which crtstalli~es 2 C12 / C2H50H, m.p. 170 - 1710 Reference example for the preparation of the compound No. 113 N-~2-(N,N-Diethylamino)ethyl~indol-2-carboxamide To a suspension of 4.83 9 indol-2-carboxylic acid and 3.8 9 N-hydroxy-succinimide in 60 ml abs. acetonitrile is adted at room temperature a solution of 6.8 9 dicyctohexyl-carbodiimide in 30 ml abs. diethyl ether, whereby the temperature arises rapidly to 33. The suspension goes into solution and urea precipitates. The mixture is stirred at room tempera-ture for 3 hours, filtered and the filtrate washed with acetonitrile.
The filtrate is treated dropwise with 8.5 ml (60 mM) diethyl-aminoethyl amine, whereby the temperature rises from 20 to 28.
The mixture is left overnight and then is partitioned be-tween 1 N aqueous sodium carbonate solution and CH2 C12. The organicphase is evaporated to give the title compound, recrystallised from CH2 C12 / hexane m.p. 133 - 134.
Reference example for the preparation of the compound No. 141 ~ndol-3-carbonyl-8-methyl-8-azabicyclo~3.2.1ioct-3~yl-ane a) 3-Chloro-8-methyl-8-azabicyclot3.2.1~octane ______________________ - 133~075 c ~ solution of 95 9 pseudotropine in 420 ml abs. CHC13 are added dropwise at 0 195 ml thionyl chloride within 20 minutes. The reaction mixture is refluxed for 4 hours, then left overnight at room temperature and then heated to 60 - 65 for 3 hours. The mixture is then diluted with CH2C12 to a volume of ca. 100 to 150 ml and poured on ice-water. A
35 % aqueous NaOH solution is added to a pH 11 and then dry ice to a pH
Other classes of the compounds of the invention are known from e.g.
European patent publications 13138A, 250444A, and 214772A and British Patent publication 2153821A.
We have now discovered that these compounds have interesting new uses and modes of administration which have been hitherto unrecognized.
The present invention relates to the uses of specific 5-HT3 antagonists for the treatment of rhinitis or serotonin-induced nasal disorders or for increasing vigilance, or co-administration with another active agent to increase the bioavailability thereof, or for nasal administration.
The invention provides the use of a compound of formula I
A-8-C-O (~) wherein A iS a group of for~ula R7~ z~R2 ~2~ 2 ( I ~ ) ( ~ I a) ( ~ ~b ) ( ~ ~C ) ยข~ C~3 3~3 (Ird~ (IIe) - 4 - 1( R6~ ~ R4 1 (I~I) (IY) ,~
~ N~ ( ) wherein the free valence is attached to either fused rin~
in formula II,IIa,IIb,IIe or IV, X-Y is -CH=CH-, -O-CH2- or -N=CH-, s C 2 ' 3 ' S , Rl and R2 are independently hytrogen, halogen, (Cl 4)alkyl, (Cl 4)alkoxy, hydroxy, amino, (Cl 4)alkylamino, di(Cl 4)alkylamino, mercapto or (Cl_4)alkylthio, R3 is hydrogen, (Cl 4)alkyl, (Cl 4)alkylcarbonyl, - ~C3 5)alkenyl, phenyl or phenyl(Cl 3)alkyl, and R4 to R7 are, independently, hydrogen, amino, nitro, (Cl 4)alkylamino, di(Cl 4)alkylamino, halogen, (Cl~4)alkoxy~ (C1-4)alkyl~ (Cl 4)alkano pyrrolyl, sulfamoyl, or car~amoyl, 3 is -CO- or -S02-~
C is -O- or -NH- or a bond~
D is a group of formula 13 3 4 0 7 S case 100-6939/II
~((a~2)n~"N R8 --~"N-R8 (VI) (VII) wherein n is 2, 3 or 4 orR-~
(VIII) (IX) wherein R~ is hydrogen, (C, 7)alkyl, (C3 5)alkenyl or phenyl(CI 3)alkyl, and in formula VIII the bond is in position 3 or 4, when B is CO, additionally D may be a group of formula ~N
(X) 2 2 8 (XI) (J
~N-R (XII) - 6 - Case 100-6939/II
- 133~75 ~ 2) 3 ~ (XIII) wherein t is 1 or 2, and R8 is as defined above, ~N (XIV) (xv) N
(*)~>
[*]
wherein the bond is in the position 3 (*) or 4 [*], /~
~CH2)1~N-R8 (XVI) wherein 1 is 2 or 3, ~ R8 (XvII) wherein Z is (Cl 1)alkoxy, - 13 310 7 5 Case 100-6939/II
Rg R1 o \/
(CH2)m C
-(CH2)p ~ \ N-R8 (XVIII) (CH2)n (C)O
/\
Rll R12 wherein Rg to R,2 are independently hydrogen or (Cl 4)alkyl m is 0, 1 or 2 and n, o, p independently are O or 1, ~(cH2)q --N
R14 (XIX) wherein q is 2 or 3, Rl3 and Rl4 independently are (Cl 4)alkyl, ~; (xx) wherein the bond is in position 3 or 4, H " (XXI ) / 3~
C~ H-R8 (XXII ) \H3C C~
/H3C~ /\
H3C2 / N-~3 (XXIII) C~H~ /
~N(C~ N-R8 (XXIVa) ~ \
~N ( CH2 ) 3 N-R8 \/ / (XXIVb) Z~ (XXY) 1334~75 and R8 is as defined above, in free base form, acid additiGn salt form or quaternary ammonium salt form, or a compound of formula Ia o R17~ ~R18 N ~f N Ia wherein Rl5 is hydrogen, (C1_1O)alkyl, (C3_9)cycloalkyl, (C3_6)alkenyl, phenyl or phenyl(Cl_3)alkyl and one of the groups R16, R17 and R18 is hydrogen, (C1_6)alkyl, (C3_7 )cycloalkyl, (C2_6)alkenyl or phenyl(Cl_3)alkyl and the others independently are hydrogen or (C1_4)alkyl, for the treatment of rhinitis or serotonin-induced nasal disorders.
In a sub-group the compound is of formula I wherein A chosen from formula II, III, IV and V, R3 is other than acyl, C is -O- or -NH- and D is chosen from formula VI to XVIII, with the proviso that, when A is formula III, B is CO and C is NH, D
is not a group of formula VI, in free form, in acid addition salt form or in quaternary ammonium salt form.
-- lo - 13 3 ~ 0 7 ~ Case 100-6939/II
In a further group of compounds of formula I' A is a group of formula II' ~/
~d~ x ~
wherein the free bond may be .cit~l~te~l in any of the rings, X' is -CH2-, -NR 3-, -O-, -S-, R' and R2', independently of one another, are hydrogen, halogen, Cl 4)alkyl, (C~ 4)alkoxy, hydroxy, amino, (Cl 4)alkylamino, di(CI4)alkylamino, mercapto or (C, 4)alkylthio, and R3' is hydrogen, (Cl 4)alkyl, (C3 5)alkenyl, phenyl or phenyl(C, 3)alkyl, or a group of formula m `R ' I I I
whereln R4 to R7, independently of one another, are hydrogen, amino, nitro, (Cl 4)alkylamino, di(CI 4)alkylamino, halogen, (Cl 4)alkoxy, (Cl 4)alkyl, (Cl 4)alkanoylamino or pyrrolyl, C signifies -O- or -NH-, D signifies a group of formula IV/, ,~,~N-R8 IV
wherein 11 - Case 100-6939/II
133407~
n is 2, 3 or4 and R8' is hydrogen, (C, ~)alkyl, ~C3 5)alkenyl or phenyl(C, 3)alkyl, or a group of formula V', ~> V~
with the proviso that when A is a group of formula m and C is -NH-, then D signifies a group of formula V'.
A further group comprises formula I wherein A is a group of formula II or III wherein B
= -CO-, C = -O- or -NH- and D is a group of formula VII, IX, X, XI or one of XIII to XXV or A is a group of formula IIa, IIb, IIc, IId, IIe, IV or V and B, C and D are as defined above.
Another group of compounds of formula I comprises compounds wherein A is formula II
or III, wherein R4 to R7 are other than sulfamoyl or carbamoyl, D is VI or vm with the proviso when A is III and C is -NH- then D is vm.
Preferred compounds include:
Indole-3-yl-carboxylic acid endo-8-methyl-8-aza-bicyclo[3,2,1]oct-3-yl ester, (hereinafter compound E) benzo[b]thiophen-3-ylcarboxylic acid endo-9-methyl-9-aza-bicyclo[3,3,1]-non-3-yl ester, 5-fluoro-l-methyl-indol-3-yl carboxylic acid endo-9-methyl-9-aza-bicyclo[3,3,1]-non-3-yl ester, 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-lH-imi~1~701-1-yl)methyl-4H-carbazol-4-one (hereinafter compound H) and 1-methyl-indazol-3-yl carboxylic acid 9-methyl-9-aza-bicyclo[3,3,1]-non-3a-yl-amide.
In one group of compounds the compounds of formula I is a group of formula II, in particular Z is NR3, 0 or S.
In another group the compound of formula I has a group of formula III.
In a sub-group D is VI. In a 2nd sub-group D is VII. In a 3rd sub-group D is VIII. In a 4th sub-group D is IX. In a 5th sub-group D
is X. In a 6th sub-group D is XI. In a 7th sub-group D is XII. In a 8th sub-group D is XIII. In a 9th sub-group D is XIV. In a 10th sub-group D is XV. In a 11th sub-group D is XVI. In a 12th sub-group D
is XVII. In a 13th sub-group D is XVIII.
Preferably D is VI or VIII.
A preferred group of compounds comprises a compound wherein A is a group of formula II wherein R1 and R2 are independently hydrogen, halogen, (Cl_4)alkyl or alkoxy; R1 is in position 4 or 5;
R3 is hydrogen, acetyl or (C1_4)alkyl and the corresponding bond is in position 3,4 or 5.
The antagonistic action against 5-HT3 receptors of the preferred compound ICS 205-930 (indol-3-yl carboxylic acid endo-8-methyl-8-aza-bicyclot3,2,1~oct-3-yl ester) on the rabbit vagus, rabbit heart and guinea pig ileum has been described (P.Donatsch et al., Br,J. Pharmacol.
1984, 81, 348), and also its topical application to humans as the first S-HT3 antagonist.
In the Belgian Patent No. 897,117 it was also stated that the compounds disclosed therein are indicated as anti-psychotics.
133~075 '~e have now found that the co~pounds of the inven-tion may he administered nasally and have an especially interesting resorption profileO
Furthermore the compounds of the invention increase the nasal resorption or bioavailability of other active agents such as peptides particularly when administered by the nasal route, The compounds of the invention mareover are useful in the treatment of rhinitis and serotonin-intuced nasal disorders as indicated by an inhibition of nasal secretions on admi-nistration of the compounds of the invention The testing may be effected as follo~s:-The ~ioavailability and pharmacokinetic profile of thecompounds of the invention may be determined in conven-tional manner, e,g. in mammals including rhesus monkeys and humans. The concentrations of the compounds of the in-vention in the blood plasma after administration of from about OoOl to about 10 mg/kg to each nostril, e.g. 7,5 mg in the case of compound E, locally to the nasal mucous membrane, e.g. as a spray, may be determined in conventional manner by e.g. ratioimmunoassay or HPLC methodsO The com-pounds of the invention are rapitly absorbed, e.g. over about 10 minutes, ~ven after ca. 5 to 10 minutes follo~ing nasal administra-tion, 200 ng of the compound indol-3-yl-carboxylic acid-endo-8-methyl-8-aza-bicyclot3,2,1]oct-3-yl ester may be detected in 1 ml of plasma. Upon oral administration, this concentration of active ingredient in the plasma is reached only after ca. 30 to 40 minutes. The general bioavailability - lS - 100 133~07~
of the compounds of the invention over a period of 6 hours is the same for nasal administration as for oral administration.
Nasal secretions are also inhibited. Additionally, the compounds of the invention when administered, e.g. at a dose of from 0.01 to 10 mg/kg with a therapeutically effective dosage of another compound, e.g. a peptide, such as salmon calcitonin increases the absorption thereof.
For example, in the case of compound E (15 mg) and salmon calcitonin (100 IU) half of which is applied to each nostril, the bioavailability of salmon calcitonin (AUC up to 2 hours) is increased from 0.08 IU/ml/hr plasma to 1.632 IU/ml/hr/plasma in the rhesus monkey.
For the rhinitis and nasal serotonin-induced disorder indications, the appropriate dosage will, of course, vary depending upon, for example, the compound of invention employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results are indicated to be obtained at daily dosages from about 0.01 mg/kg to about 10 mg/kg animal body weight. In humans, an indicated daily dosage for oral administration is in the range from about 5 mg to about 300 mg of a compound of formula I conveniently administered, for example, in divided doses up to four times a day, e.g. in the range of about 40 mg p.o. in the case of compound E.
In another aspect the present invention provides a pharmaceutical composition comprising (i) a 5-HT3 antagonist of formula I as defined above and (ii) a pharmaceutically acceptable peptide.
1334~75 ~hen a compound of sne invention is co-administered ~ith ~nother active agent, the Appropriate dosage will, of course, vary depending upon, for example, t6e active agent of the compound of the invention and other active agent employed, the host, the mode of administration and the nature and severity of the condition being treated. How-ever, in general, satisfactory results are indicated to be obtained at daily dosages from about one half to one tenth the usual dose of the other active agent. The com-pound of the invention is indicated to be administered at about one half to one tenth the usual dose.
The compounds of the invention may be administered for t6e rhinitis and nasal serotonin-induced disorders and for co-administration with another active agent, e.g. a peptide, by any conventional route, in particular enterally, preferably orally, eOg., in the form of tablets or cap-sules, or parenterally, e.g., in the form of injectable solutions or suspensions. The local apptication by the nasal route is preferred.
For the nasal administration route, the appropriate dosage will, of course, vary depending upon, for example, the com-pound of the invention employed, the host, and the nature and severity of the condition 6eing treated, However, in general, satisfactory results in animals are indicated to be obtained at daily dosages from about 0.001 mg/kg to about 10 mg/kg animal body weight. In humans, an indicated dosage per actuation is in the range from about 0.01 mg to a~out 1 mg of a compound ofthe invention conveniently ad-ministered, for example, in toses up to four times a day.
1 n~-6939 /I I
Thus for sastrOintestinal disorders or for migraine prophy-laxis a compound according to the inventlon is indicated to be administered to the body nasally in a dosa~e of ~.13 to 0,4 mg k~ ~ody weight, i,e. ca. 10 to 30 mg or 1 to 3 pu,~ps of the nasal spray per patient, and in order to con-trol arrhythmia, it should be given in a dosage which is caO 10 times higher, i~e, from 1,3 to 4 mg per kg body weight or 100 to 300 mg, or resp. 10 to 30 pumps of the nasal spray per patient.
The compound E is the preferred compound for the rhinitis and nasal route administration. It is indicated that the compound of example may be administered at daily dosages of about 0~1 mg nasally to humans.
The compounds of the invention may be administered nasally in any pharmacologically active form, e.g. in free base form, in acid addition salt form or in quaternary ammonium salt formO
The nasal mode of administration creates a simple method of administration ~hich rapidly gives results and can be easily carried out by the patient himself, e.g,by admini-stering a liquid form for nasal administration, for example a nasal spray or drop solution using a nasal ap~tcator, or by inserting a gelatinous sponge or lyophi-lisate soaked in the active substance, or by blowing the galenic form in powder form into t~e nostrils.
The compounds of the invention may be present in the liquid form for nasal administration in a proportion of 1 to 30%, prefera~ly 5 to 20~, especially 10 to 15Y
(weight/volume), - 18 - 10( The present invention accordingly relates also to a liquid form for nasal administration, containing 1) a compound of the invention 2) a preservative, especially benzalkonium chloride, and 3) a liquid diluent or a carrier, suitable for application to the nasal mucous membrane.
In another aspect the invention provides a liquid nasal pharmaceutical composition containing a compound of formula I as defined above wherein A is of formula II' a preservative, and a liquid diluent or carrier suitable for application to the nasal mucous membrane.
The proportion of benzalkonium chloride in the compositions according to the invention is preferably ca. 0.002 to ca,. 0.02, especially ca.
0.01% (weight/volume) of the total composition.
In accordance with the invention, the above-mentioned forms of administration may be administered to the nasal mucous membrane, e.g.
as drops or as a spray. As described hereinafter, however, they are preferably administered as a spray, i.e. as finely dispersed droplets.
One further possible way of bringing the above-mentioned liquid form for nasal administration into contact with the nasal mucous membrane is to soak a gelatinous sponge (SPONGOSTAN - Registered Trade Mark) or lyophilisate with the substance and then to insert the sponge into the nostrils.
The liquid diluent or carrier employed is conveniently water (pharmaceutical grade). An aqueous salt solution is preferred in particular. The liquid forms for nasal administration according to the invention are formulated such that they allow administration to be effected nasally. With this in mind, they can e.g. also contain minimal amounts of further desired components or excipients, e.g.
additional preservatives, or e.g. ciliary stimulants such as caffeine.
- I9- 133~075 rhe liquid forms for nasal administration ~ccording t~
the invention preferably have a pH value of ; S to 6, The liquid forms for nasal administration should also nave an appropriate isotonicity and viscosity . They prefera~ly have an osmotic pressure of ca, 260 to ca. 38 mOsm/litreO The desired viscosity of the compositions according to the invention depends on the relevant form of administration, eOg, whether nasal drops or a nasal spray are administered. For nasal drops, a viscosity of ca. 2 to ca, 40 x 10 3 Pa,S is suitable, For nasal sprays, a viscosity of less than 2 x 10 3 Pa,S is suitable.
~f desired, the liquid forms for nasal administration may also contain further components, especialty conventional pharmaceutically available surface-active agents, In this connection and as a further aspect of the present inven-tion, it was found that the use of surface-active compounds in the nasal a~ministration of the compounds of the inven-tion increases their resorption through the nasal mucous membrane and improves the initial bio-availability. In this case, preference is given to non-ionic surface-active agents, for example polyoxyalkylene ethers of higher alco-hols, e.g. of the general formula, R0 ~(cH2)n~ ~ H
wherein R0 signifies t~e radical of a higher alkanol, especialty a higher alkanol such as lauryl or cetyl alcohol, or of an alkylephenol, or a sterol, especially lanosterol, dihydrocholesterol or cholesterol, as well as mixtures of two or several such ethers, Preferred polyoxy-alkylene ethers which can be used for the present inven-~ - 20 - 1 3 3 4 0 7 ~ Case 100-6939m tion are polyoxyethylene- and polyoxypropylene-ethers (i.e. wherein n in the above-mentioned formula is 2 or 3), especially lauryl-, cetyl- and cholesterylpolyoxyethylene-and -polyoxypropylene-ethers, as well as mixtures of two or several such ethers.
Especially suitable polyethers for use according to the invention are those in which the average value of the recurring units in the polyoxyalkylene component (x in the above formula) lies between 4 and 75, especially between 8 and 30 and particularly between 16 and 26. The polyethers may be obtained in accordance with known methods. A largechoice of such products is available commercially and is sold e.g. by Amerchol under the trane name Solulan by KAO Soap, ICI and Atlas under the trade names Emalex, Brij and Laureth, and by Croda under the trade name Cetomacrogol.
SOLULAN, EMALEX AND LAURETH as used herein are Registered Trade Marks.
Examples of polyoxyalkylene ethers which are suitable for use according to the invention, (e.g. POE = polyoxyethylene ethers: POP = polyoxypropylene ether; x = average value of the recurring units in the POE/POP component) are listed in the following:-- 21 - 133 107~ Case 100-6939m 1. Cholesterylethers:
1.1 Solulan (R) C-24 - POE, x = 24 2. Ethers of lanolin alcohols:
2.1 Solulan (R) 16 - POE, x = 16 2.2 Solulan (R) 26 - ROE, x = 25 2.3 Solulan (R) 75 - POE, x = 75 2.4 Solulan (R) PB-10 - PPE, x = 10 2.5 Solulan (R) 98 - POE, x = 10 - partly acetylated 2.6 Solulan (R) 97 - POE, x = 9 - wholly acetylated 3. Laurylethers:
3.1 Emalex (R) 709 / Laureth (R) 9 - POE,x = 9 3.2 Laureth (R) 4 / Brij (R) 30 - POE, x = 4 3.3 Laureth (R) 23 / Brij (R) 35 - POE, x = 23 4. Cetylethers:
4. I Cetomacrogol (R) - POE, x = 20 to 24 Lanolin alcohols are also known as wool fat alcohols and are a rnixture of cholesterol, dihydrocholesterol and lanosterol.
Preferred polyethers for use according to the invention are cholesteryl polyoxyethylene ethers, e.g. polyethers of the above formula wherein n = 2 and RO is a cholesteryl radical, in particular polyethers wherein the number of recurring units in the polyoxy-- - 22 - 133~075 ethylene companent is 16 to 26, especlally about 24.
These polyethers are preferably free from impurities, and especially from other polyoxyalkylene ethers. They prefera~Ly contain at least 75~, most particularly at least 8S% and especlally at lea~t 90~ (weight) of the pure cholesteryl ?oly-oxyethylene ether.
If a surface-active agent, e.g. a polyoxyalkylene ether, Ls used, the amount present ln the composltlon~ accordlng to the invention wlll depend on the surface-actlve agent u~ed in partlcular, the form of admlnistratlon (e.g. dropq or spray) and the deslred effect.
In general, the amount of surface-active agent employed is between ca. 2.0 and ca. 200 (preferably up to ca. 100, especially up to ca. 20), especlally between ca. 5 and ca. 30 (preferably up to ca. 15) and ln particular ca. 10 mg/ml.
For nasal ~tn1~tration~ the liquid fon~ for nasal administratlo~
are preferably placed ln an applicator, which is equipped with a device that enable~ the compo~ition to be applied to the nasal mucous m~mhrane, e.g. a na~al spray applicator.
Such appllcator~ ar- known per se and lnclude those which are suitable for the admini~tratlon of llquld preparatlon~ a~ drops or a~ a spray to the nasal mucou~ membrane. Slnce the doslng of the compound~ of the invention should ~e a~ exact as po~sible, the u~- of ~pray appllcator~ ln which an exact controL
over the quantlty ~tnt~tered 1~ po~glble 1~ generally preferrec Suitaole appliance for administration are e g. atomizers such dS pump dispensers or aerosot cans. ~n the latter case, the applicator contains a composition according to the invention as well as a propellant which is suitable for use in a nasal spray applicator. The atomizer appli-ance is provided with an appropriate spray device which enables the composition to be applied to the nasal mucous membraneO Such devices are known in general.
The container, e~g. a nasal spray applicator, may contain a quantity of the composition ~hic~ is sufficient for a single nasal dose or for administration several doses, e.g.
over a periGd of several days or weeks. The amounts of the individual doses will preferably correspond to the above-mentioned doses.
Applicators as defined above are preferably spray a~licators for nasal usage. They preferably ena61e t~e composition con-tained t~erein to be administered in single doses of ca~
a . os to ca. 0015 ml, e.g. ca. 0.1 mlO
Suitable compositions, as well as the individual components 1,2 and 3 for use in an applicator, are those which have been previously described. The dosages which are suitable for use similarly correspond to the dosages given previously.
Furthermore, the invention relates to a process for the pro-duction of a liquid form for nasal administration, con-taining 1) compounds according to the invention 2) a preservative, especially 6enzalkonium chloride,and 3) a liquid diluent or a carrier,which are suitable for administering to the nasal mucous membrane, as well as optionally a surface-active agent which is suitable for administering to the nasal mucous membrane/
- 133~075 characterised in that the components are intimately mixed together, and if desired, the composition obtained i5 placed in ~n applicator which is provided with a spray device which enables the co~position thus obtained ta ~e administered to the nasal mucous membrane. Furthermore, a sponge (SPONG~-STAN) may be soaked with the composition obtained and the soaked sponge can be inserted into the nostrils.
The stability of the composition according to the invention can be determined in the usual way.
The co~positions according to the invention containing benz-alkonium chloride are stable to~ards contamination by germs, e,g as in standard tests such as those described by S Urban et al.in Z61OBakt,Hyg.I Abt,Orig.8 1972,478-484 (lg81) and S~Ur~an,Acta Pharm,Technol.22, 247-253 (1976).
For example, the cell count of the standard bacteria, namely Elcoli ATCC 8739, Pseud.aeruginosa ATCC 9027, Staph.aureus ATCC 6538, Strept. pyogenes ATCC 8668 and standard fungi CandOalbicans ATCC 10231, Sacch.cerevisae ATCC 9763, Aspergillus niger ATCC 16404 and Pen.steckil ATCC 10499, is reduced to O.lX or less ~ithin 24 hours after injecting them withthe composition, as can be sho~n in standard tests.
In a stability test, the nasal spray composition of the follo~ing example 1 was kept for 3 months at 30C under a nitrogen atmosphere in a glass container. Pseud,aeruginosa ATCC 9027, Staph.aureus ATCC 6538, Strept. pyogenes ATCC
8668 and the fungi cand,albicans ATCC 10231, Sacch.cerevi-sae ATCC 9763, Aspergillus niger ATCC 16404 ant Pen.stechii ATCC 10499 ~ere addet until a cell count of ca. 2 x 10 organisms ~as reached in the in~ected liquid. Within 2 hours, the germ count had reduced to less than O.lX, Withi-n 4 weeks, the germs could no longer be detected.
E~uall~ favourable results are obtained if the compounds of tne invention are administered in a galenic form, which is in the form of a powder and is introduced by blowing into the nostrils.
Toxicity and Tolerability:
Toxicity and Tolerability studies may be effected in con-ventional manner with the compounds of the invention to determine the upper dosage.
Toxicity studies may be effected for example in the rat and the dog over for example 26 weeks.
For compound E over 26 weeks the no toxic effect bowel in the dog was 5-20 mglkg/daily p.o,. For the rat it was 16 to 45 mg/kg per day p.o.. Other compounds of the invention may have the same order of tolerabilityO ~n healthy human volunteers single doses up to 150 mg were well tolerated - without relevant side effects.
- 26 - 100-53~9 /I I
133~075 Tne fallcwing examples illustrate the invention.
.X~FLE l: TaDlets for oral administration _ _ _ _ _ _ _ _ _ _ _ _ _ _ Tablets containing the constituents as specified below were produced lnconventional manner and are used in the indications specified above.
Compound E in form of hydrochloride 16.9 mg (corresponding to 15 mg free base) Hydroxy-propyl-cellulose 1.2 mg Corn Starch 12.0 mg Lactose 92.8 mg Silica 0.6 mg Magnesium stearate l.S m5 ~ablet weight 125.0 mg EXAMP!E 2: Capsules for oral administration _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Capsules containing the constituents as specified below are produced inconventional manner and are used in the indications specified above.
l-methyl-N (-endo-9-methyl-9-aza-bicyclo-t3,3,1] indol-3-yl) carboxylic acid amide in form of the hydrochloride ( corresponding to 15 mg base) 16.9 mg bactose 28.7 mg Silica 1.5 mg Magnesium stearate 3 ~9 Capsule Content weight of S0.1 mg `- 13 3 ~ 0 7 5 EXAMPLF 3: Injection solution for i.v. administration _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ A composltion for injection is made up in conventional manner and is ~seo at a dose of 10 mg a day.
A B C
Compound E in form of hydrochloride 1 131) 2.2562)11.2823) Acetic acid (99 to lOOZ)~ 1.2 0.6 0.6 Sodium acetate 3. H20~ 1.8 3.18 3.18 Sodium chloride 8 7.5 6.5 Water for injection to 1,0 ml 1) = 1 mg free base, 2) - 2 mg free base, 3) = 10 mg free base pH value 4.3;*8uffer used 1/30 molar EXAMPLE 4: Capsules for oral administration _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 5 mg and 15 mg capsules (A and B respectively) containing the constitu-ents as specified below were produced in conventional manner and are used in the indications specified above 2 - 4 times a day in the case of A and once a day in the case of B.
A mg B mg Compound E in form of hydrochloride 5.641 16.92 Lactose 200 mesh 84.929 79.29 ~actose 100 mesh 84.43 79.29 Corn starch 120.00 120.00 Silica 1.5 1,5 Magnesium stearate 3.0 3.0 300 mg 300 mg Capsules containing other weights can be formulated in conventional manner.
EXAMP'E 5 ~asal liquid_Composi~ion-Quantity of Comoonents components indol-3-yl-carboxylic acid-endo-8-methyl-8-aza-bicycloC3,2,1Joct-3-yl-ester. HCl 100 mg benzalkonium chloride 0.1 mg NaCl (0.970 aqueous solution) 0.6 ml distilled water 0.4 ml rhe solution obtained is filtered (e.g. through a 0.2 ~m filter) and filled into a nasal canister, or a gelatinous foam (SPONGOSTAN) is soaked with the solution. It is administered e.g. for the treatment of rhinitis, lung embolism or to improve the absorption of other active agents.
EXAMPLE 6: Nasal liquid Composition _ _ _ _ _ _ _ _ _ _ _ Quantity of Components components l-methyl-N-endo-9-methyl-9-azabicyclo-L3 . 3, 1~ i ndol-3-yl-carboxylic acid amide 50 mg benzalkonium chloride 0.1 mg NaCl (0.970 aqueous solution) 0.83 ml distilled water 0.17 ml The solution obtained is filtered (e.g. through a 0.2 ~m filter) and filled into a nasal spray canister, or a gelatinous foam (SPONGOSTAN) i soaked with the solution. It is administered in analogous manner to tha disclosed in example S.
The active agents in ~xamples 1 to 6 may be replaced by the following compounds of formula I wherein: n(YI) A=II B= -C0- D =
No. Rl 2 C0-Position C Conf. VIII (pcs-) ~j3 1 H H NH 3 NH endo 3 (VI) CH3 2 5-F H NCH3 3 0 endo 3 (VI) H
3 H Z-Cl NH 3 0 endo 2 ( vr ) CH3 4 H 2-OCH3 NH 3 0 endo 2 (VI) CH3 H 3-J NH 4 0 endo 2 (VI) CH3 6 H H NH 4 0 endo 2 (VI) CH3 7 H H NH 4 0 endo 3 tVI) CH3 8 5-CI H NH 3 0 endo 2 (VI) CH3 9 4-OCH3 H NH 3 0 endo 2 (VI) CH3 5-OCH3 H NH 3 0 endo 2 (VI) CH3 11 H H NCH3 3 0 endo 2 (VI) CH3 12 H H NH 3 0 exo 2 (VI) CH3 13 5-F H NH 3 NH endo 2 (VI) CH3 14 H H NCH3 3 NH endo 2 (VI) CH3 lS H 2-CH3 NH 3 NH endo 2 (VI) C 3 16 H H NH 3 NH exo 2 (VI) CH3 17 H H NH 3 NH endo 2 (VI) CH3 18 5-Cl H NH 3 H endo 2 (VI) CH3 19 H H NH 3 0 endo 3 (VI) Bz H H NCH3 3 0 endo 3 (VI) Bz 21 5-F H NH 3 0 endo 3 (VI) Bz 22 H H S 3 0 endo 3 tVI) CH3 23 H H S 3 NH endo 3 (VI) CH3 24 H H 0 3 NH endo 3 (VI) CH3 H H 0 3 0 endo 3 (VI) CH3 26 H H CH2 3 NH endo 3 (VI) CH3 n(VI ) A=lI, B= -CO- Carboxyl- O =
No. Rl 2 Position C Conf. VIII(pos.l R8 27 H H NH 3 NH exo 4 (VI) CH3 28 H H NH 3 0 exo 4 (VI) CH3 29 H H NH 3 O endo 3 (VI) CH3 30 H H NH 3 0 endo 2 (VI) n-c3H7 31 H H NH 3 0 exo 2 (VI) Bz 32 H H NH 3 0 endo 2 (VI) Bz 33 H H NH 3 0 endo 2 (VI) H
34 5-F H NH 3 0 endo 3 (VI) H
35 H H NCH3 3 0 endo 3 (VI) H
36 H H NH 3 0 endo 3 (VI) H
37 s-CH3 H NH 3 0 endo 3 (VI) CH3 38 H 2-CH3 NH 3 0 endo 3 (VI) CH3 39 5-F H NCH3 3 0 endo 3 (VI) CH3 5-F H NH 3 0 endo 3 ~VI) CH3 41 5-F H NCH3 3 0 endo 3 (VI) Bz 42 H H NCH3 3 0 endo 3 (VI) CH3 43 5-CH3 H NH 3 NH endo 3 (VI) CH3 44 H H NH 5 0 endo 2 (VI) CH3 45 H H NH 5 0 endo 3 (VI) CH3 46 H 3-J NH 5 0 endo 3 (VI) CH3 47 H H NH 4 NH exo 2 (VI) CH3 48 H H NH 4 NH endo 2 (YI) CH3 49 H H NH 5 H endo 2 (VI) CH3 50 H H NH 3 0 - VIII (3) _ 31 1334075 lCO-693g /II
n(!V) A=II r, 8= -CO- O =
~o R4 R5 R6 R7 C Conf. VlII(pos.) R8 51 OCH3 H NHCH3 Cl o VI'I (3) --52 OCH3 H NH2 Cl o - 2 (VI) Bz 3 2 Cl o exo 2 (VI) H
54 OCH3 H NHCH3 Cl O endo 2 (VI) CH3 55 OCH3 H N(CH3)2 H O exo 2 (VI) Bz 56 OCH3 H NH2 Cl O endo 2 (YI) CH3 3 2 Cl O endo 2 (VI) H
58 OCH3 H NH2 H O endo 2 (VI) H
59 OCH3 H NH2 H O exo 2 (VI) H
60 OCH3 H NH2 H O endo 2 (VI) CH3 61 OCH3 H N(CH3)2 H O endo 2 (VI) 3 62 Cl H NH2 H O endo 2 (VI) CH3 63 OCH3 I NH2 H O endo 2 (VI) CH3 64 OCH3 I NHCH3 H O endo 3 (VI) CH3 65 OCH3 H NHCH3 H O endo 3 (VI) CH3 66 Cl H N02 H O endo 2 (VI) 3 67 OCH H Br H O endo 2 (VI) CH3 3 Cl O endo 3 (VI) CH3 69 OCH3 H l-Pyrrolyl Cl o endo 2 (VI) CH3 70 OCH3 H l-Pyrrolyl H O endo 2 (VI) CH3 71 OCH3 H NHCH3 Cl NH -- VIII (3) --72 H Cl H Cl Cl -- VIII (3) --73 OCH3 H NH2 C1 NH -- VIII (3) --- 32 - lOC-6939 /II
~o. Formul d II, B= -CO- cdr3oxyl- C Conf. D = Group 28 Rl 2 Position 74 H H NH 3 0 exo (X) --H H NH 3 0 endo (XVII) CH3 (Z=OCH3)*
76 H H NH 3 0 (endo) (XYI) (r=3) CH3 77 H H NH 3 0 endo (XI) CH3 78 H H NH 3 0 (endo) (XVI) (r=2) CH3 79 H H NH 3 0 (exo) (XVI) (r=3) CH3 H H NH 3 0 endo (X) --81 H H NH 3 0 exo (XIII)(t=l) CH3 82 ~-) H H NH 3 0 endo (XI) CH3 83 (~) H H NH 3 0 endo (XI) CH3 84 H H NH 3 0 endo (XII) CH3 85 H H NH 5 0 endo (XVII) CH3 (Z=OCH3)*
( ) = Ring is in Chairform * = (ls*, 3r~, 5R*, 6R~) Bz in R8 = Benzyl A=III, B= -CO- n(VI) No R4 R5 R6 R7 C Conf. D - R8 86 OCH3 H NHCH3 Cl NH exo (X) 87 OCH3 H NHCH3 Cl NH endo (X) C -- -- o -- o o o o o o o o o _ _ _ _ _ _ _ E ~ ~ -- o ~ _ _ ~ _ _ IS===_~S
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Reference example for the preparatton of the compound ~o 147 l-Acetyl-lH-indol-3-Carboxylic acid 8-methyl-8-azabicycloE3.2.1~oct-~-yl-es ter 2.84 9 lH-indol-3-carboxylic acid 8-methyl-8-azabicyclot3.2.1]oct-3a-yl-ester are dissolved at 30 in 30 ml tetrahydrofuran. The solution is cooled to 0 and treated at this temperature dropwise with 5.9 ml butyl-lithium within 15 minutes. A slightly exothermic reaction takes place.
The mixture is stirred at 0 for 1 hour, then cooled to -10 and treated dropwise with a solution of 0.~5 ml acetyl chloride in 4 ml tetrahydrofu-ran. The mixture is stirred overnight at room temperature and then parti-tioned between 2 N aqueous sodium carbonate solution and CH2 C12. The organic phase is evaporated to give the title compound, which crtstalli~es 2 C12 / C2H50H, m.p. 170 - 1710 Reference example for the preparation of the compound No. 113 N-~2-(N,N-Diethylamino)ethyl~indol-2-carboxamide To a suspension of 4.83 9 indol-2-carboxylic acid and 3.8 9 N-hydroxy-succinimide in 60 ml abs. acetonitrile is adted at room temperature a solution of 6.8 9 dicyctohexyl-carbodiimide in 30 ml abs. diethyl ether, whereby the temperature arises rapidly to 33. The suspension goes into solution and urea precipitates. The mixture is stirred at room tempera-ture for 3 hours, filtered and the filtrate washed with acetonitrile.
The filtrate is treated dropwise with 8.5 ml (60 mM) diethyl-aminoethyl amine, whereby the temperature rises from 20 to 28.
The mixture is left overnight and then is partitioned be-tween 1 N aqueous sodium carbonate solution and CH2 C12. The organicphase is evaporated to give the title compound, recrystallised from CH2 C12 / hexane m.p. 133 - 134.
Reference example for the preparation of the compound No. 141 ~ndol-3-carbonyl-8-methyl-8-azabicyclo~3.2.1ioct-3~yl-ane a) 3-Chloro-8-methyl-8-azabicyclot3.2.1~octane ______________________ - 133~075 c ~ solution of 95 9 pseudotropine in 420 ml abs. CHC13 are added dropwise at 0 195 ml thionyl chloride within 20 minutes. The reaction mixture is refluxed for 4 hours, then left overnight at room temperature and then heated to 60 - 65 for 3 hours. The mixture is then diluted with CH2C12 to a volume of ca. 100 to 150 ml and poured on ice-water. A
35 % aqueous NaOH solution is added to a pH 11 and then dry ice to a pH
10. After extraction with CH2C12 and distillation of the extracts (second fraction ^~ 97 - 985) the title compound is obtained.
b) 3-Cyano-8-methyl-8-azabicyclo~3.2.1~octane To a solution of 18.16 9 KCN in 28 ml H20 is added a solution of 42 g of the step a) compound in 90 ml ethanol and the mixture heated to 80.
Thereafter the mixture is refluxed for 22 hours. The mixture is evapor~-ted to about 1/4 of its volume in a rotatory evaporator, then rendered alkaline with potassium carbonate and extracted with ether. Distillation of the residue yields at about 0.4 mm Hg and 85 the title compund.
c) 3-Methoxycarbonyl-8-methyl-8-azabicycloC3 2.1~octane _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ To 30 9 of the step b) compound in 300 ml methanol and 3.7 ml water is introduced within 1 hour gaseous HCl, whereby the temperature rises to 60 (cooling). The mixture is left at room temperature for 18 hours. The resulting white suspension is filtered, the filtrate is concentrated, rendered alkaline with potassium carbonate to a pH 10 and extracted with ether (3 times). The ether phase is washed with water and evapora-ted to give the title compound, as an oil, b.p. 72 - 74 / 0.13 - 0.15 mm Hg.
d) 3-Carboxy-8-methyl-8-azabicyclo~3.2.1~octane _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ A solution of 25.2 9 of the step c) compound in 20 ml methanol is treated portionwise with 70 ml 2N aqueous NaOH solution within 30 minutes (~H dt the end 13.2). The mixture is left at room temperature f~r 3 hours and then treated with the same amount of 2N HCl to a pH 5.8.
,he reaction mixture is chromatographed on about 300 ml amberlite TR 120 (H+form) using lOX ~H3 as eluant to give the title compound (recrystallised from ethanol/hexane), m.p. 222-224 (decomp.).
e) 3-Chloro-carbonyl-8-methyl-8-azabicyclo~3.2.1~octane _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ To a solution of 4.22 9. of the step d) compound in 50 ml CH2C12 are added dropwise at about 15' 2.8 ml oxalyl chloride diluted with 5 ~1 CH2 C12.
The resulting white suspension is stirred 30 minutes at room temperature, diluted with 50 ml hexane, filtered and washed with CH2C12 / hexane (1:2), to yield the hydrochloride of the title compound, decomp. from 205'.
f) Indol -3-carbonyl-8-methyl-8-azabicyclot3.2.1~oct-3B~yl-ane _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ To a Grignard reagent prepared from 1.44 9 magnesium, 3.75 ml methyliodide and 55 ml abs. ether is added dropwise at boiling temperature a solution of 3.519 indole in 20 ml abs. ether. The resulting silvergrey mixture is refluxed for 1 hour, then cooled to 0 and treated portion-wise with 6.72 9 of the hydrochloride of the step e) compound, under slight exothermic reaction. A resin precipitates. The mixture is allowed to come to room temperature, whereby the resin solidifies. After leaving overnight water and CH2C12 are added. Stirring is effected un-til a white suspension results, which is extracted with CH2C12 (3 times). The aqueous phase is extracted with CH2C12 and 10 to 15~
C2H50H (5 times). The evaporated extracts (about 5 9) are dissolved in CH2C12 ~ 10% CH30H and filtered (residue about 2 9). The solution is chromatographed on 250 9 silicagel KG 004 using CH2C12 + lOX C2H50H as an eluant whereby the title compound is obtained (800 9). The residue and 800 mg of the compound obtained by chromatography are together re-crystali~ed from H20/C2H50H to give the hydrochloride of the title compound, m.~. 278 - 280 (decomp.).
_ ~ 47 _ 133~075 Reference example for the preparation of the compound No. 148 3-(6-Hydroxyindolyl)-8-azabicyclo~3.2.1~-3~-methyl-ketone a) 8-Benzyl-8-azabicyclo~3.2.1]octane-3~-acetic acid ethyl ester _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ To 14 9 3-carbethoxy-methylen-8-benzyl-8-azabicyclo~3.2.1]octane in 300 ml aqueous NH3 and 100 ml toluene at -40 are added 2.5 9 sodium. The resulting blue mixture is decomposed after 5 minutes with solid NH4Cl and the NH3 is distilled off. Aft.er addition of water the mixture is extracted with CH2C12 and chromatographed on silicium dioxide with ethyl acetate/hexane (1:8) to yield the title compound as a colourless oil.
b) 8-AzabicycloL3.2.1~octane-3~-acetic acid ethyl ester _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ To a solution of 8.4 9 of the step a) compound in 350 ml C2H50H are added 1 9 Pd/C and the mixture ls hydrogenated 4 hours. The mixture is filtered and evaporacted to give the title compound as a colourless oil.
c) 8-Benzyloxycarbonyl-8-azabicycloC3.2.1~-3p-acetic acid ethyl ester _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 5.7 9 of the step b) compound, 100 ml toluene and 7.5 ml triethylamine are treated with 12.3 ml chloroformic acid benzyl ester. The mixture is heated 3 hours to 50, then poured into 200 ml 0.1 N HCl and extracted 3 times with CH2C12. The organic phase is dried (Na2S04) and evaFora~ed to give the title compound as a colourless oil.
d) 8-Benzyloxycarbonyl-8-azabicycloC3.2.1~-3~-acetic acid _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 9.1 9 of the step c) compound are dissolved in 60 ml ethanol, treated with 60 ml 2 N aqueous NaOH solution and refluxed 1 hour. After remo-val of ethanol by distillation, the remaining aqueous phase is acidi-fied by addition `- 133407~
of 10~ tartaric acid and extracted with CH2C12. ~he combined organic phases are dried and evaporated to give the title compound as a yello~ish foam.
e) 8-Benzyloxycar~onyl-8-azabicycloL3.2.1~-3~-acetic acid chloride _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ A solution of 7.3 9 of the step d) compound in 60 ml CHC13 is tre~te~
with 4.4 ml thionyl chloride and refluxed 2 hours. rhe solution is then treated several times with toluene and evaporated to give the title com-pound.
f) 3-(6-Methoxyindolyl)-8-benzyloxycarbonyl-8-azabicyclor3.2.1~-3~-_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ methyl ketone _ _ _ _ _ _ _ Methyl magnesium iodide, prepared from 1.6 ml methyl iodide and 630 mg magnesium in 80 ml ether, is treated at room temperature with 1.5 9 6-methoxyindole in 70 ml ether. The mixture is heated 2 hours under reflux, then cooled to 0 and treated with 3.2 9 of the step e) compound in 50 ml toluene. The reaction mixture is stirred 2 hours, poured into 2 N hydrochloric acid and extracted 3 times with CH2C12. The CH2C12-phases are washed with aqueous sodiuM bicarbonate solution and chroma-tographed on silicium dioxide eluting with ethyl acetete / hexane (1:10 ~1:1) to give the title compound as a colourless foam.
9) 3-(6-Hydroxyindolyl)-8-azabicyclor3.2.1~-3B-methyl-ketone _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 300 mg of the step f) compound in 30 ml CH2C12 are treated at -78 with a solution of 0.8 ml boron tribromide in 10 ml CH2C12. After stirring 1 hour at -78 and 2~ hours at 0 aqueous sodiu~ bicarbonate solution is added and the mixture extracted with n-butanol (3 ti~es). The organic phases are.evaporated and the residue is chromatographed on silica gel with CH2 C12 / CH3 0~ ~ aq, `~H3 (95:5:1> 85:15:1) to yield the compoun~
as colour~ess crystalls, m.p.~ 280.
b) 3-Cyano-8-methyl-8-azabicyclo~3.2.1~octane To a solution of 18.16 9 KCN in 28 ml H20 is added a solution of 42 g of the step a) compound in 90 ml ethanol and the mixture heated to 80.
Thereafter the mixture is refluxed for 22 hours. The mixture is evapor~-ted to about 1/4 of its volume in a rotatory evaporator, then rendered alkaline with potassium carbonate and extracted with ether. Distillation of the residue yields at about 0.4 mm Hg and 85 the title compund.
c) 3-Methoxycarbonyl-8-methyl-8-azabicycloC3 2.1~octane _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ To 30 9 of the step b) compound in 300 ml methanol and 3.7 ml water is introduced within 1 hour gaseous HCl, whereby the temperature rises to 60 (cooling). The mixture is left at room temperature for 18 hours. The resulting white suspension is filtered, the filtrate is concentrated, rendered alkaline with potassium carbonate to a pH 10 and extracted with ether (3 times). The ether phase is washed with water and evapora-ted to give the title compound, as an oil, b.p. 72 - 74 / 0.13 - 0.15 mm Hg.
d) 3-Carboxy-8-methyl-8-azabicyclo~3.2.1~octane _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ A solution of 25.2 9 of the step c) compound in 20 ml methanol is treated portionwise with 70 ml 2N aqueous NaOH solution within 30 minutes (~H dt the end 13.2). The mixture is left at room temperature f~r 3 hours and then treated with the same amount of 2N HCl to a pH 5.8.
,he reaction mixture is chromatographed on about 300 ml amberlite TR 120 (H+form) using lOX ~H3 as eluant to give the title compound (recrystallised from ethanol/hexane), m.p. 222-224 (decomp.).
e) 3-Chloro-carbonyl-8-methyl-8-azabicyclo~3.2.1~octane _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ To a solution of 4.22 9. of the step d) compound in 50 ml CH2C12 are added dropwise at about 15' 2.8 ml oxalyl chloride diluted with 5 ~1 CH2 C12.
The resulting white suspension is stirred 30 minutes at room temperature, diluted with 50 ml hexane, filtered and washed with CH2C12 / hexane (1:2), to yield the hydrochloride of the title compound, decomp. from 205'.
f) Indol -3-carbonyl-8-methyl-8-azabicyclot3.2.1~oct-3B~yl-ane _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ To a Grignard reagent prepared from 1.44 9 magnesium, 3.75 ml methyliodide and 55 ml abs. ether is added dropwise at boiling temperature a solution of 3.519 indole in 20 ml abs. ether. The resulting silvergrey mixture is refluxed for 1 hour, then cooled to 0 and treated portion-wise with 6.72 9 of the hydrochloride of the step e) compound, under slight exothermic reaction. A resin precipitates. The mixture is allowed to come to room temperature, whereby the resin solidifies. After leaving overnight water and CH2C12 are added. Stirring is effected un-til a white suspension results, which is extracted with CH2C12 (3 times). The aqueous phase is extracted with CH2C12 and 10 to 15~
C2H50H (5 times). The evaporated extracts (about 5 9) are dissolved in CH2C12 ~ 10% CH30H and filtered (residue about 2 9). The solution is chromatographed on 250 9 silicagel KG 004 using CH2C12 + lOX C2H50H as an eluant whereby the title compound is obtained (800 9). The residue and 800 mg of the compound obtained by chromatography are together re-crystali~ed from H20/C2H50H to give the hydrochloride of the title compound, m.~. 278 - 280 (decomp.).
_ ~ 47 _ 133~075 Reference example for the preparation of the compound No. 148 3-(6-Hydroxyindolyl)-8-azabicyclo~3.2.1~-3~-methyl-ketone a) 8-Benzyl-8-azabicyclo~3.2.1]octane-3~-acetic acid ethyl ester _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ To 14 9 3-carbethoxy-methylen-8-benzyl-8-azabicyclo~3.2.1]octane in 300 ml aqueous NH3 and 100 ml toluene at -40 are added 2.5 9 sodium. The resulting blue mixture is decomposed after 5 minutes with solid NH4Cl and the NH3 is distilled off. Aft.er addition of water the mixture is extracted with CH2C12 and chromatographed on silicium dioxide with ethyl acetate/hexane (1:8) to yield the title compound as a colourless oil.
b) 8-AzabicycloL3.2.1~octane-3~-acetic acid ethyl ester _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ To a solution of 8.4 9 of the step a) compound in 350 ml C2H50H are added 1 9 Pd/C and the mixture ls hydrogenated 4 hours. The mixture is filtered and evaporacted to give the title compound as a colourless oil.
c) 8-Benzyloxycarbonyl-8-azabicycloC3.2.1~-3p-acetic acid ethyl ester _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 5.7 9 of the step b) compound, 100 ml toluene and 7.5 ml triethylamine are treated with 12.3 ml chloroformic acid benzyl ester. The mixture is heated 3 hours to 50, then poured into 200 ml 0.1 N HCl and extracted 3 times with CH2C12. The organic phase is dried (Na2S04) and evaFora~ed to give the title compound as a colourless oil.
d) 8-Benzyloxycarbonyl-8-azabicycloC3.2.1~-3~-acetic acid _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 9.1 9 of the step c) compound are dissolved in 60 ml ethanol, treated with 60 ml 2 N aqueous NaOH solution and refluxed 1 hour. After remo-val of ethanol by distillation, the remaining aqueous phase is acidi-fied by addition `- 133407~
of 10~ tartaric acid and extracted with CH2C12. ~he combined organic phases are dried and evaporated to give the title compound as a yello~ish foam.
e) 8-Benzyloxycar~onyl-8-azabicycloL3.2.1~-3~-acetic acid chloride _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ A solution of 7.3 9 of the step d) compound in 60 ml CHC13 is tre~te~
with 4.4 ml thionyl chloride and refluxed 2 hours. rhe solution is then treated several times with toluene and evaporated to give the title com-pound.
f) 3-(6-Methoxyindolyl)-8-benzyloxycarbonyl-8-azabicyclor3.2.1~-3~-_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ methyl ketone _ _ _ _ _ _ _ Methyl magnesium iodide, prepared from 1.6 ml methyl iodide and 630 mg magnesium in 80 ml ether, is treated at room temperature with 1.5 9 6-methoxyindole in 70 ml ether. The mixture is heated 2 hours under reflux, then cooled to 0 and treated with 3.2 9 of the step e) compound in 50 ml toluene. The reaction mixture is stirred 2 hours, poured into 2 N hydrochloric acid and extracted 3 times with CH2C12. The CH2C12-phases are washed with aqueous sodiuM bicarbonate solution and chroma-tographed on silicium dioxide eluting with ethyl acetete / hexane (1:10 ~1:1) to give the title compound as a colourless foam.
9) 3-(6-Hydroxyindolyl)-8-azabicyclor3.2.1~-3B-methyl-ketone _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 300 mg of the step f) compound in 30 ml CH2C12 are treated at -78 with a solution of 0.8 ml boron tribromide in 10 ml CH2C12. After stirring 1 hour at -78 and 2~ hours at 0 aqueous sodiu~ bicarbonate solution is added and the mixture extracted with n-butanol (3 ti~es). The organic phases are.evaporated and the residue is chromatographed on silica gel with CH2 C12 / CH3 0~ ~ aq, `~H3 (95:5:1> 85:15:1) to yield the compoun~
as colour~ess crystalls, m.p.~ 280.
Claims (11)
1 . Use of a compound of formula I
A-B-C-D (I) wherein A is a group of formula (II) (IIa) (IIb) (IIc) (IId) (IIe) (III) (IV) (V) wherein the free valence is attached to either fused ring in formula II,IIa, IIb,IIe or IV
X-Y is -CH=CH-, -O=CH2- or -N=CH-, Z is -CH?, -NR3-, -O- or -S-, R1 and R2 are independently hydrogen, halogen, (C1-4)alkyl, (C1-4)alkoxy, hydroxy, amino, (C1-4)alkylamino, di(C1-4)alkylamino, mercapto or (C1-4)alkylthio, R3 is hydrogen, (C1-4)alkyl, (C1-4)alkylcarbonyl, (C3-5) alkenyl, phenyl or phenyl(C1-3)alkyl, and R4 to R7 are,independently,hydrogen,amino,nitro, (C1-4)alkylamino,di(C1-4)alkylamino,halogen,(C1-4)-alkoxy, (C1-4)alkyl, (C1-4)alkanoylamino, pyrrolyl, sulfamoyl, or carbamoyl B is -CO- or -SO2-, C is -O- or -NH- or a bond D is a group of formula (VI) (VII) wherein n is 2, 3 or 4 or (VIII) (IX) wherein R8 is hydrogen, (C1-7)alkyl, (C3-5)alkenyl or phenyl(C1-3)alkyl, and in formula VIII the bond is in position 3 or 4, when B is CO, additionally D may be a group of formula (X) (XI) (XII) (XIII) wherein t is 1 or 2, and R8 is as defined above, (XIV) (XV) wherein the bond is in the position 3 (*) or 4 [*], (XVI) wherein 1 is 2 or 3, (XVII) wherein Z is (C1-4)alkoxy, (XVIII) wherein R9 to R12 are independently hydrogen or (C1-4)alkyl m is 0, 1 or 2 and n, o, p independently are 0 or 1, (XIX) wherein q is 2 or 3, R13 and R14 independently are (C1-4)alkyl, (XX) wherein the bond is in position 3 or 4, (XXI) (XXII) (XXIII) (XXIVa) (XXIVb) (XXV) and R8 is as defined above in free base form, acid addition salt form or quaternary ammonium salt form, or a compound of formula Ia Ia wherein R15 is hydrogen, (C1-10)alkyl, (C3-9)cycloalkyl, (C3-6)-alkenyl, phenyl or phenyl(C1-3)alkyl and one of the groups R16, R17 and R18 is hydrogen, (C1-6)alkyl, (C3-7)cycloalkyl, (C2-6k)alkenyl or phenyl(C1-3)alkyl, and the others independently are hydrogen or (C1-4)alkyl, for treating rhinitis or other serotonin-induced nasal disorders.
A-B-C-D (I) wherein A is a group of formula (II) (IIa) (IIb) (IIc) (IId) (IIe) (III) (IV) (V) wherein the free valence is attached to either fused ring in formula II,IIa, IIb,IIe or IV
X-Y is -CH=CH-, -O=CH2- or -N=CH-, Z is -CH?, -NR3-, -O- or -S-, R1 and R2 are independently hydrogen, halogen, (C1-4)alkyl, (C1-4)alkoxy, hydroxy, amino, (C1-4)alkylamino, di(C1-4)alkylamino, mercapto or (C1-4)alkylthio, R3 is hydrogen, (C1-4)alkyl, (C1-4)alkylcarbonyl, (C3-5) alkenyl, phenyl or phenyl(C1-3)alkyl, and R4 to R7 are,independently,hydrogen,amino,nitro, (C1-4)alkylamino,di(C1-4)alkylamino,halogen,(C1-4)-alkoxy, (C1-4)alkyl, (C1-4)alkanoylamino, pyrrolyl, sulfamoyl, or carbamoyl B is -CO- or -SO2-, C is -O- or -NH- or a bond D is a group of formula (VI) (VII) wherein n is 2, 3 or 4 or (VIII) (IX) wherein R8 is hydrogen, (C1-7)alkyl, (C3-5)alkenyl or phenyl(C1-3)alkyl, and in formula VIII the bond is in position 3 or 4, when B is CO, additionally D may be a group of formula (X) (XI) (XII) (XIII) wherein t is 1 or 2, and R8 is as defined above, (XIV) (XV) wherein the bond is in the position 3 (*) or 4 [*], (XVI) wherein 1 is 2 or 3, (XVII) wherein Z is (C1-4)alkoxy, (XVIII) wherein R9 to R12 are independently hydrogen or (C1-4)alkyl m is 0, 1 or 2 and n, o, p independently are 0 or 1, (XIX) wherein q is 2 or 3, R13 and R14 independently are (C1-4)alkyl, (XX) wherein the bond is in position 3 or 4, (XXI) (XXII) (XXIII) (XXIVa) (XXIVb) (XXV) and R8 is as defined above in free base form, acid addition salt form or quaternary ammonium salt form, or a compound of formula Ia Ia wherein R15 is hydrogen, (C1-10)alkyl, (C3-9)cycloalkyl, (C3-6)-alkenyl, phenyl or phenyl(C1-3)alkyl and one of the groups R16, R17 and R18 is hydrogen, (C1-6)alkyl, (C3-7)cycloalkyl, (C2-6k)alkenyl or phenyl(C1-3)alkyl, and the others independently are hydrogen or (C1-4)alkyl, for treating rhinitis or other serotonin-induced nasal disorders.
2. Use of claim 1 wherein A is of formula II':- II' wherein the free bond may be situated in any of the rings, X' is -CH2-, -NR3'-, -O-, -S-, R1' and R2', independently of one another are hydrogen, halogen, (C1-4)alkyl, (C1-4)alkoxy, hydroxy, amino, (C1-4)alkylamino, di(C1-4)alkylamino, mercapto or (C1-4)alkylthio, and R3' is hydrogen, (C1-4)alkyl, (C3-5)alkenyl, phenyl or phenyl(C1-3)alkyl, or a group of formula III' III' wherein R4' to R7' independently of one another are hydrogen, amino, nitro, (C1-4)alkylamino, di(C1-4)alkylamino, halogen, (C1-4)alkoxy, (C1-4)alkyl, (C1-4)alkanoylamino or pyrrolyl, C signifies -O- or -NH-, D signifies a group of formula IV', IV' wherein n is 2, 3 or 4 and R8' is hydrogen, (C1-7)alkyl, (C3-5)alkenyl or phenyl(C1-3)alkyl, or a group of formula V', with the proviso that when A is a group of formula III and B is -NH-, then D signifies a group of formula V', other than indol-3-yl carboxylic acid endo-8-methyl-8-aza-bicyclo[3.2.1]-oct-3-yl ester.
3. Use according to any one of claims 1 and 2 wherein the compound is indol-3-yl carboxylic acid endo-8-methyl-8-aza-bicyclo-[3.3.1]oct-3-yl-ester in free base form or in acid addition salt form.
4. Use according to any one of claims 1 and 2 wherein the compound is 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxy-benzamide.
5. Use according to any one of claims 1 and 2 wherein the compound is 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)-methyl]-4H-carbazol-4-one.
6. A pharmaceutical composition comprising (i) a 5-HT3 antagonist of formula I or formula Ia as defined in claim 1 and (ii) a pharmaceutically acceptable peptide.
7. A composition according to claim 6 wherein the composition is adapted for nasal administration.
8. A liquid nasal pharmaceutical composition containing a compound of formula I as defined in claim 1 wherein A is of formula II', a preservative, and a liquid diluent or carrier suitable for application to the nasal mucous membrane.
9. A composition according to claim 6 or 7 wherein the compound is of formula Ia as defined as claim 1.
10. A composition according to claim 6 or 7 wherein the 5-HT3 antagonist is 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxy-benzamide.
11. A composition according to claim 6 or 7 wherein the 5-HT3 antagonist is 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)-methyl]-4H-carbazol-4-one.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000616654A CA1334075C (en) | 1986-07-30 | 1992-09-09 | Therapeutic use of serotonin antagonists |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8618614 | 1986-07-30 | ||
| GB868618614A GB8618614D0 (en) | 1986-07-30 | 1986-07-30 | Treatment of psychiatric disorders |
| DE3626703 | 1986-08-07 | ||
| DEP3626703.1 | 1986-08-07 | ||
| CA000543271A CA1327750C (en) | 1986-07-30 | 1987-07-29 | Therapeutic use of serotonin-antagonists |
| CA000616654A CA1334075C (en) | 1986-07-30 | 1992-09-09 | Therapeutic use of serotonin antagonists |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000543271A Division CA1327750C (en) | 1986-07-30 | 1987-07-29 | Therapeutic use of serotonin-antagonists |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1334075C true CA1334075C (en) | 1995-01-24 |
Family
ID=27167756
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000616654A Expired - Fee Related CA1334075C (en) | 1986-07-30 | 1992-09-09 | Therapeutic use of serotonin antagonists |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1334075C (en) |
-
1992
- 1992-09-09 CA CA000616654A patent/CA1334075C/en not_active Expired - Fee Related
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| Date | Code | Title | Description |
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| MKLA | Lapsed |