CA2120028C

CA2120028C - Indol derivatives for the treatment of migrane

Info

Publication number: CA2120028C
Application number: CA002120028A
Authority: CA
Inventors: Dolors Fernandez Forner; Carles Puig Duran; Jose Prieto Soto; Armando Vega Noverola; Jacinto Moragues Mauri
Original assignee: Laboratorios Almirall SA
Current assignee: Almirall SA
Priority date: 1992-07-28
Filing date: 1993-07-19
Publication date: 1999-03-23
Anticipated expiration: 2013-07-19
Also published as: KR100191830B1; FI941413L; LU90758I2; RU2117667C1; ZA935316B; DE69323712D1; PL302917A1; ECSP930953A; EG20340A; US5565447A; FI109998B; MY113266A; DE10199016I1; NL300053I1; IL106387A; FI941413A0; NO180231B; DE10199016I2; CZ282659B6; AU4570793A

Abstract

A compound Or formula (I) wherein R1 and R2 each represents a hydrogen atom or an alkyl group, Z represents a ring selected from formula (II) in which n represents 4, 5 or 6; formula (111) and formula (IV) in which R1 represents hydrogen or an alkyl group and R4 represents an alkyl, methoxy, benzyl or R5NHCO group, R5 being an alkyl group; and Formula (V) in which R6 represents an alkyl group, and pharmaceutically acceptable salts thereof are useful in the treatment of migraine and other conditions. They are prepared by decàrboxylation of the corresponding indolyl-2-carboxylic acid.

Description

TI~IS INVENTION relate~ to new indol derivatives, methods for their preparation, compositions containing them and their use in medical treatment.

The mechanism involved in the genesis of a migraine attack is not known, but it ha~ been demon~trated that the large intracranial ve~els are distended during the headache phase. Some compounds like,ergotamine and serotonine (5-Hydroxytryptamine; 5-HT), have a vasoconstrictor action in the carotid vascular bed by an agonistic action at the "5-HTl-like"
receptor6. However, the lack of selectivity of the~e compound~
is the cause of undesirable and potentially dangerous ~ide-effect~.

In Briti6h Patent~ 2124210A and 2162522A, new anti-migraine compound~ have been di~closed and seem to stimulate more selectively a ~ub-population of "5-HT1-like" receptors.
Among the6e compound~, Sumatriptan of formula:

~ \ N ~

is available for migraine therapy. Thi8 compound pre6ents a high af~inity for 5-HT~ receptor but it has also a very important affinity for 5-HT~ receptor. Thi6 affinity for 5-HT~ receptor, cause6 hypotension by a central nervous sy6tem action and other side effects.
We have now found that the introduction of a nitrogen ring in the methanesulfonyl group provideg new anti-migraine compound that present a greater affinity for 5-HTlD recept~r than for 5-HTlA receptor and therefore, less side-effeCts ~., ~., ' 2120028 - 2 - w Accordingly, the present invention provides a cG~ou,-d of formula:
~R1 Z S~2 2 ~ CH2-~H2-N~ 2 (I) H

wherein Rl and R2 each represent a hydrogen atom or an alkyl group, Z represents a ring selected from:

II (C~2)n ~ n which _ represents 4, 5 or 6;

III A

IV ~ in which R3 represents hydrogen ~ N- or an alkyl group R~ represents R4 ~ an alkyl, methoxy, benzyl or R5 NHCO group, R5 being an ~ alkyl group; and R DOC-N N-V ~ in which R6 repreesents an alkyl group;
and pharmaceutically acceptable salts thereof.

The alkyl group mentioned in relation with the groups R~, R2, R3, R~, R5 and R6 in compounds of the invention, are usually "lower" alkyl, that is cont~;n;ng up to 6 and particularly up to 4 carbon atoms, the hydrocarbon chain being br~nche~ or straight.

SUBSTITUTE SHEET

W094/02460 2 I ~ O Q 2 8 PCT/EPg3/01901 The compounds of general formula I wherein R1 and R2 are alkyl groups and Z is II or V are preferred.

According to a feature of the present invention the indol derivatives of general formula I may be prepared by the process which comprises a decarboxylation of a carboxylic acid of general formula VI:
~R1 ~-502-CH2 ~ ~ 2 CH2 N~R2 (VI) H OOH

(wherein the various symbols are as defined above). The reaction is preferably carried out in an inert organic solvent as quinoline, tri-n-butylamine, N,N-dimethylacetamide or pyridine, in the presence of a catalyst as copper powder, cupric oxide, cuprous oxide or other copper derivatives, at a temperature between 100 and 2000C.

The intermediates VI used in the preparation of the compounds of the invention, were prepared by known processes described in the literature (A. Gonzalez, Synth.
Commun. (1991)), 21, 669; B.A. Howell, J. Chem. Ed. 176 (1984); H. Plieninger, Ber. (1950), 83, 268).

Indol derivatives of general formula I can be converted by methods known per ~e into acid addition salts with acids in appropriate solvents, for example acetone, alcohols, dioxane or tetrahydrofuran. Suitable acid addition salts are those derived from inorganic acids, for example the hydrochlorides and sulphates.

The experiments with usual test animals were conducted and evaluated in the following manner:

SUBSTITUTE SHEET

~ 028 - 4 -Doq saPhenous vein Isometric recordings were performed essentially as described by Humphrey et al ~1988). Briefly, lateral sArhenous vein ring preparations (3 mm. wide) removed from anaesthetized beagle dogs were suspended under 2g. resting tension, in 30 mL organ baths conta;n;ng Rrebs at 370C.
The experiments were carried out in the presence of 5-HT2, H1 and muscarinic antagonists and serotonin l~M was used as quantitative reference st~n~rd.

(Humphrey P.P.A.; Feniuk W.; Perren M.J.; Connor H.E.;
Oxford A.W.; Coates I.H. and Butina D. (1988). GR 43175, a selective agonist for the 5-HTl-like receptor in dog isolated ~r~enous vein. Br. J. Pharmac. 94, 1123-1132).

B; n~; n~ to 5HTlD recePtors Assays were performed essentially as described by Bruinvels et al. Varying amounts of tested drugs were added to 0.25 mL final volume reaction that included lOO~g of calf caudate nucleus membrane protein, 100 pM
(Serotonin-5-O-Carboxymethyl-Glycyl[l25I]Tyrosinamide (125I-GTI), 4 mM CaCl2 and 50 mM Tris HCl buffer, pH 7.4. After incubation at 370C for 30 minutes, samples were filtered under reduced pressure using glass fibre filters. The filters were washed with ice-cold buffer and dried. Non-specific b;n~;ng was defined as that obtained in the presence of lO~M 5HT. Trapped radioactivity was quantified using a gamma counter. Displacement curves were constructed and the concentration displacing 50% of radioligand was calculated for each tested compound using non-linear regression. Data from at least three different assays run in duplicate wa~ averaged.

SUBSTITUTE SHEET

(Bruinvels A.T.; Lery ~.; Palacio~ J.M. and Hoyer D.
(1992) 5-HT1D binding site~ in various species: similar pharmacological profile in dog, monkey, calf, guinea-pig and human brain membranes. Naunyn-Schmiedeberg's Arch.
Pharmacol. 346, 243-248).

Bindinq to 5HT1A receptors As~ay~ were performed essentially as de~cribed by Gozlan et al (1983). Varying amounts of te~ted drugs were added to 1 mL final volume reaction mixtures that included 100 ~g of rat hippocampus membrane protein, 0.5 nM lH-8-OH-DPAT, 4 mM CaCl2, O.1% ascorbic acid, 10 ~M pargyline and 50 mM Tris HCl buffer, p~ 7.4. After incubation at 250C
for 30 minute~, aamples ~ere filtered under reduced pressure using glass fibre filters. The filterG were wa~hed with ice-cold buffer and dried. Non-specific binding was defined a~ that obtained in the pre6ence of 10 ~M SHT. Radioactivity wa6 quantified by 6cintillation counting and data was handled as described for the 5HT~
binding as~ay. (Gozlan H.; El Me~tikawy S.; Pichat L.;
Glowinski J. and Hamon M. (1983). Identification of presynaptic serotonin autoreceptors u~ing~a new ligand:3H-PAT. Nature 305, 140-142).
The results of the tests described above, using compounds according to the invention (see Example8 below) and, as a comparison, Sumatripta~, are shown in Table I
below:

y ., i TABLE I. Results of different pharmacological test __________________________,_______________________________ Dog saphenou6' Binding IC50 nM
vein pD2 125I-GTI 3H-8-OH-DPAT SHTlA/
5HTlD
____________ ____________________________________________ Sumatriptan 6.06 + 0.01 10.4 + 1 460 + 67 44.2 1 6.06 + 0.03 10.7 + 0.4 825 + 69 77.

15 2 5.92 + 0.10 6.9 ~ 0.4 340 ~ O.S 49.3 11 6.47 + 0.03 3.2 + 0.3 850 + 40 265.6 ____________ ____________________________________________ From results presented above it can be concluded that the novel compounds of thi6 invention demonstrate binding selectivity for 5-~TlD receptor6 and vasoconstrictor capability mediated by an agonism on 5HTlD receptors.
According to the results this invention provides compounds with potential interest for the treatment or prevention of migraine and other headache associated with va6cular disorders (e.g. cluster headache and chronic paroxysmal hemicrania), with administration o~
substances or their withdrawal, and for the treatment or prevention of tensional cephaliar pain, movement disorders, depression and anxiety.

Thus, the present invention provides indol deri~atives of the formula I and pharmaceutically acceptable salts thereof, and pharmaceutical compo6ition6 comprising such ~erivatives and salts thereof, for u6e in the treatment or therapy of the human body.

Accordingly, the indol derivati~es of the formula I
and pharmaceutically acceptable 6alts thereof, and pharmaceutical compositions comprising such derivatives and salts thereof, may be used in a method of treatment ~ 7 ~

of disorders of the hum~n body which comprises administering to a recipient in need of such therapy an effective amount of said derivatives or salts thereof or said compositions.
s The present invention al~o provides ph~ ceutical compositions which comprise, as acti~e ingredient, at least one compound of general formula I, or a pharmacologically acceptable salt in association with a pharmaceutically acceptable carrier or diluent. The active ingredient may comprise 0.001% to 99% by weight, preferably 0.01~ to 90% by weight of the composition depending upon the nature of the formulation and whether further dilution i6 to be made prior to application.
Preferably the compositions are made up in a form suitable for oral, topical, percutaneous or parenteral admini6tration.

The pharmaceutically acceptable carriers or diluents which are admixed with the active compound, or compounds or salt6 of such compounds, to form the compositions of this in~-ention are well-known per se -and the actual excipients used depend inter alia on the intended method of administering the compositions.
Compositions of this invention are preferably adapted for admi~istration parenteral a~d per o~. In this case, the composition for oral administration may take the form of tablets, capsules or liquid preparations, such as mixtures, elixirs, syrups or su6pensiong, all cont A i n ~ ng one or more compounds of the invention; such preparations may be made by method6 well-known in the art.

The diluents which may be used in the preparation of the compositions include those liquid and solid diluents which are compatible with the active ingredient, 21~0~~

together with colouring or flavouring agents, if desired.
Tablets or capsules may conveniently contain between 1 and 200 mg of activeii~gredient or the equivalent amount of a salt thereof.
The liquid composition adapted for oral use may be in the form of solutions or suspensions. The solutions may be aqueous solutions of a soluble salt or other derivative of the active compound in association with, for example, sucrose to form a syrup. The suspensions may comprise an insoluble active compound of the invention or a pharmaceutically acceptable salt thereof in association with water, together with a susp~nd;ng agent or flavouring agent.
Compositions for parenteral injection may be prepared from soluble salts, which may or may not be freeze-dried and which may be dissolved in water or an appropriate parenteral injection fluid.
Effective doses are normally in the range of 10-600 mg of active ingredient per day.

The following Examples illustrate the preparation of compounds of the present invention.

To a solution of previously dried 1-~[2-carboxy-3-(2-dimethyla~;noethyl)-5-indolyl~meth~ne~ulphonyl]pyrrolidine (1.6 g; 0.0442 moles) in anhydrous quinoline (75 ml) and under atmosphere of nitrogen, cuprous oxide (160 mg; 0.0011 moles) was added. The reaction mixture was heated to l90oC for 15 minutes, stirred to room temperature, poured into a mixture of lN hydrochloric acid (150 ml) and ethyl SUBSTITUTE S~EET

W094/0~60 PCT/EP93/01901 acetate (50 ml), ~h~k~n and decanted. The aqueous solution was washed several times with ethyl acetate, then solid sodium bicarbonate was added until pH = 7.8, and washed with n-hexane to eliminate the quinoline. The aqueous solution was made alkaline with solid potassium carbonate and extracted with ethyl acetate. The organic solution was dried (Na2S0~), the solvent removed under reduced pressure when a dark oil was obtained (1.3 g;
yield 92%). This product was purified by column chromatography with silica gel and methylene chloride:ethanol:ammonium hydroxide (60:8:1) as eluent and a white $oam (0.8 g) of 1-[~3-(2-dimethylaminoethyl)-5-indolyl~meth~nesulphonyl]pyrrolidine was obtained.

To a solution of the above product (0.8 g) in acetone (30 ml), a few drops of hydrogen chloride saturated dioxan solution, were added. The precipitated solid was collected by filtration, washed with acetone and dried to give l-t[3-(2-dimethylaminoethyl)-5-indolyl]methanesulphonyl]-pyrrolidine hydrochloride (0.75 g). Melting point 218-2200C.

Further indol derivatives of general formula I as set out in Table 2 below were prepared according to the process disclosed in Example 1 but using the appropriately substituted reactants VI.

SUBSTITUTE SHEET

. ~

~. -COMPOUND Rl , R2 Z DERIVATIVE M.P oc No.
Rl=R2=CH3 II; n=4 HCl 218-220 Rl=R2=CH3 II; n=5 HCl 225-227(d) 3 Rl=R~=CH3 II; n=6 hydrogen 127-130(d) succinate 4 Rl=H;R2=CH3 II; n=4 HCl 177-178 Rl=R2=CH3 III HCl 231-232(d) 6 Rl=R2=CH3 IV; R3=H; hydrogen 151-153 R~=4-CH3 succinate IV; R3=
7 Rl=RZ=CH3R4=4-CH hydrogen 170-172 8 Rl=R2=CH3IV; R3=H; hydrogen 143-145 R4=methoxy succinate 9 Rl=R2=CH3 IV; R3=X; HCl 225-227 R~=benzyl . 25 10 Rl=R2=cH IV; R3zH; base 161-163 R4=H3CNHCo 11 Rl=R2=CH3 V; R6=C2Hs base 170-171 ,~,",=", 20,000 Ampoules each contA;ning 10 mg. of 1-[[3-(2-dimethylaminoethyl)-5-indolyl~methane~ulphonyl]piperidine hydrochloride (active ingredient) were preepared from the following formulation:

Active ingredient 200 g Sodium chloride 200 g 10 Water injectable grade q.~.40 litre~

Procedure The active ingredient and ~odium chloride were dis~olved in 40 litres of water, then pa~ed through a bacteria-retA;n;ng filter and filled under sterile conditions into 2 ml glaRs ampouleR in known manner.

SUBSTITUTE SHEET

Claims

1 . A compound of formula (I) wherein R1 and R2 each represents a hydrogen atom or an alkyl group containing up to 6 carbon atoms, Z represents a ring selected from:
in which ~ represents 4, 5 and 6;

in which R3 represents hydrogen or an alkyl group containing up to 6 carbon atoms and R4 represents an alkyl group containing up to 6 carbon atoms, methoxy, benzyl or R5NHCO group, R5 being an alkyl group containing up to 6 carbon atoms;
and in which R6 represents an alkyl group containing up to 6 carbon atoms, and pharmaceutically acceptable salts thereof.

2. A compound according to claim 1 in which R1 and R2 which are the same or different is each C1-4 alkyl, and Z is of the formula II.

3. 1-[[3-(2-dimethylaminoethyl)-5-indolyl]methane-sulphonyl3pyrrolidine;
1-[[3-(2-dimethylaminoethyl)-5-indolyl]methane-sulphonyl]piperidine; or 1-t[3-(2-dimethylaminoethyl)-S-indolyl]methane-sulphonyl]-4-ethoxycarbonyl piperazine;
or a hydrochloride salt thereof.

4. A process for the preparation of a compound of formula (I) wherein R1 and R2 each represents a hydrogen atom or an alkyl group containing up to 6 carbon atoms, Z represents a ring selected from:

in which ~ represents 4, 5 or 6;

in which R3 represents hydrogen or an alkyl group containing up to 6 carbon atoms and R4 represents an alkyl group containing up to 6 carbon atoms, methoxy, benzyl or R5NHCO group, R5 being an alkyl group containing up to 6 carbon atoms;
and in which R6 represents an alkyl group containing up to 6 carbon atoms;

and pharmaceutically acceptable salts thereof which process comprises a decarboxylation of a carboxylic acid of formula VI:

wherein Z, R1 and R2 are as defined above.

5. A composition comprising a compound according to any one of claims 1 to 3 mixed with a pharmaceutically acceptable carrier or diluent.

6. A compound according to any one of claims 1 to 3 or a composition according to claim 5 for use in a method of treatment of the human or animal body wherein the treatment is of migraine, headaches associated with vascular disorders headaches associated with the administration or withdrawal of substances to or from the body, tensional cephalic pain, movement disorders, depression or anxiety.

7. Use of a compound according to any one of claims 1 to 3 or a composition according to claim 5 for the manufacture of a medicament for the treatment of migraine, headaches associated with vascular disorders, headaches associated with the administration or withdrawal of substances to or from the body, tensional cephalic pain, movement disorders, depression or anxiety.