Ergoline derivatives and their use as somatostatin receptor antagonists

The invention provides compounds of formula I ##STR1## wherein R.sub.1 to R.sub.6 are as defined in the description, and a process for preparing them. The compounds of formula I are useful as pharmaceuticals.

The present invention relates to novel ergoline derivatives, their
 preparation, their use as pharmaceuticals and pharmaceutical compositions
 comprising them.
 More particularly the present invention provides a compound of formula I
 ##STR2##
 wherein
 R.sub.1 is hydrogen, (C.sub.1-4)akyl or a group of formula
 ##STR3##
 wherein n is 1 to 4 and R.sub.7 is fluorine, chlorine, hydroxy,
 (C.sub.1-4)alkyl or (C.sub.1-4)alkoxy,
 R.sub.2 is hydrogen, chlorine, bromine, iodine, (C.sub.1-4)alkyl or
 (C.sub.1-4)alkylthio,
 R.sub.3 is hydrogen or (C.sub.1-4)alkyl,
 R.sub.4 is (i) a group of formula
 ##STR4##
 wherein R.sub.8 is fluorine, chlorine, nitro or cyano, R.sub.9 and R.sub.10
 independently, are hydrogen, fluorine, chlorine, nitro or cyano and
 R.sub.11 is (C.sub.1-4)alkyl or (C.sub.2-5)alkenyl, or (ii) a group of
 formula
 ##STR5##
 wherein each X independently is O or S, and
 R.sub.5 and R.sub.6 are each hydrogen or form together a further bond
 between the two carbon atoms on which they are located,
 provided that R.sub.8 is not 4-NO.sub.2 if R.sub.1, R.sub.2, R.sub.9 and
 R.sub.10 are hydrogen, R.sub.3 is methyl and R.sub.5 and R.sub.6 form
 together a further bond between the two carbon atoms on which they are
 located, and that R.sub.8 is not chlorine if R.sub.1, R.sub.2, R.sub.9 and
 R.sub.10 are hydrogen and R.sub.3 is methyl,
 in free base or acid addition salt form.
 The invention includes the enantiomers as well as their mixtures, e.g. the
 epimeric or racemic mixtures which may be present on account of the
 asymrnetrical carbon atoms in positions 5, 8 and 10. The configuration
 [5R,10R] is preferred (5R corresponding to a 5.beta. hydrogen). The
 configuration 8.beta. is also preferred.
 The above-defined alkyl, alkoxy and alkylthio groups preferably represent
 methyl, methoxy and methylthio.
 In a further aspect, the invention provides a process for the production of
 the compounds of formula I and their acid addition salts, whereby a
 compound of formula II
 ##STR6##
 wherein R.sub.1, R.sub.2, R.sub.3, R.sub.5 and R.sub.6 are as defined above
 and M is H or an alkali metal, is reacted with a compound of formula III
 ##STR7##
 wherein R.sub.4 is as defined above, and the compounds of formula I thus
 obtained are recovered in free base or acid addition salt form.
 The reaction can be effected according to known amide formation methods,
 for example as described in Example 1. In formula II, M as an alkali metal
 is for example sodium.
 Working up the reaction mixtures obtained according to the above process
 and purification of the compounds thus obtained may be carried out in
 accordance to known procedures.
 Acid addition salts may be produced from the free bases in known manner,
 and vice versa. Suitable acid addition salts for use in accordance with
 the present invention include for example the hydrochloride.
 The starting compounds of formula III may be produced by reacting
 piperazine with a compound of formula R.sub.4 --Cl, e.g. as described in
 Example 1.
 The compounds of formulae II and R.sub.4 --Cl are known or may be produced
 in analogous manner to known procedures.
 Compounds of the invention, e.g. compounds of formula I and their
 pharmaceutically acceptable acid addition salts, hereinafter referred to
 as agents of the invention, exhibit interesting pharmacological properties
 when tested in vitro using SRIF receptor expressing cell cultures and in
 animals, and are therefore useful as pharmaceuticals.
 In particular the agents of the invention bind to somatostatin receptors.
 More particularly they are selective antagonists at Somatostatin sst.sub.1
 receptors, previously called SSTR-1 receptors (see Hoyer et al., TIPS,
 1995, 16; 86-88), as determined in radioligand binding and second
 messenger studies [see for example K Kaupmann et al., FEBS LETTERS 1993,
 331: 53-59].
 The agents of the invention are therefore useful for treatment in anxiety,
 depression, schizophrenia, neurodegenerative diseases such as dementia,
 for the treatment of tumors and for vascular disorders and immunological
 diseases.
 The usefulness of the agents of the invention in these indications is
 confirmed in a range of standard tests as indicated below:
 At doses of about 0.3 to 3 mg/kg p.o., the agents of the invention increase
 exploratory behavior of mice in the open half of the half enclosed
 platform, a model which is predictable for anxiolytic activity
 (Psychopharmacology, 1986, 89:31-37).
 In the same half enclosed platform model, the agents of the invention at
 the above indicated doses also increase vigilance of the mice. The
 compounds are therefore indicated for the treatment of depression,
 schizophrenia and dementia, in particular of senile dementia of the
 Alzheimer type (SDAT).
 In the intruder mouse test [Triangle, 1982, 21:95-105; J. Clin. Psychiatry,
 1994, 55:9 (suppl. B) 4-7], the agents of the invention increase
 non-social behavior, social investigation and sex, and reduce defensive
 ambivalence in the treated intruder mouse at doses of about 1 to about 10
 mg/kg s.c., suggesting an antidepressant profile like carbamazepine and
 lithium, a neuroleptic profile like clozapine and an anxiolytic profile
 like diazepam.
 Furthermore at about 3 to about 30 mg/kg p.o. the agents of the invention
 reduce aggressive behavior (attacks, chases, bites) in the Matched Pairs
 Situation test in mice [Dixon et al., J. Clin. Psychiatry 55: (9) [Suppl.
 B] 4-7 (1994)]. Since as mentioned above they additionally attenuate
 defensive behaviors in the intruder mouse test, the compounds of the
 invention exhibit an ethopharmacological profile which is very similar to
 that of carbamazepine, lithium chloride and clozapine. They are therefore
 indicated for the treatment of affective disorders including bipolar
 disorders e.g. manic-depressive psychoses, extreme psychotic states e.g.
 mania, schizophrenia, and excessive mood swings where behavioral
 stabilization is desired. In addition, the compounds are indicated in
 anxiety states, generalized anxiety as well as social and agoraphobia, as
 well as those behavioral states characterized by social withdrawal e.g.
 negative symptoms.
 In addition, the agents of the invention improve the performance in the
 step-down passive avoidance paradigm in mice following both pre- (p.o.)
 and post-trial (i.p.) adrnnistration of about 0.01 to about 10 mg/kg,
 enhance retrieval-performance in the step-through passive avoidance test
 (p.o.) [Mondadori et al., Behav. Neural. Biol. 60: 62-68 (1993)] and
 partially counteract electroshock-induced amnesia (p.o.) [Mondadori et
 al., Physiol. & Behav. 18: 1103-1109 (1997)]. Finally the agents
 specifically enhance social recognition of familiar, but not unfamiliar
 juvenile rats at doses of about 0.03 to about 3 mg/kg p.o. These findings
 indicate that the agents facilitate learning and memory at low doses.
 These features combined with the marked anti-aggressive properties and
 sociotropic effects suggest that the agents of the invention are effective
 in the treatment of attention deficit and hyperactivity disorders (ADHD).
 The agents of the invention are also effective in the treatment of various
 kinds of tumors, particularly of sst.sub.1 receptor bearing tumors, as
 indicated in proliferation tests with various different cancer cell lines
 and in tumor growth experiments in nude mice with hormone dependent tumors
 [see for example: G. Weckbecker et al., Cancer Research 1994, 54:
 6334-6337]. Thus the compounds are indicated in the treatment of, for
 example, cancers of the breast, the prostate, the colon, the pancreas, the
 brain and the lung (small cell lung cancer).
 For all the above mentioned indications, the appropriate dosage will of
 course vary depending upon, for example, the compound employed, the host,
 the mode of administration and the nature and severity of the condition
 being treated. However, in general, satisfactory results in animals are
 indicated to be obtained at a daily dosage of from about 0.1 to about 10
 mg/kg animal body weight. In larger mammals, for example humans, an
 indicated daily dosage is in the range from about 5 to about 200 mg,
 preferably about 10 to about 100 mg of the compound conveniently
 administered in divided doses up to 4 times a day or in sustained release
 form.
 The agents of the invention may be administered in free form or in
 pharmaceutically acceptable salt form. Such salts may be prepared in
 conventional manner and exhibit the same order of activity as the free
 compounds.
 The present invention furthermore provides a pharmaceutical composition
 comprising an agent of the invention in association with at least one
 pharmaceutically acceptable diluent or carrier. Such compositions may be
 formulated in conventional manner. Unit dosage forms contain, for example,
 from about 0.25 to about 50 mg of an agent according to the invention.
 The agents of the invention may be administered by any conventional route,
 for example parenterally e.g. in form of injectable solutions or
 suspensions, or enterally, preferably orally, e.g. in the form of tablets
 or capsules, or nasally.
 For all above indications the preferred compound is the compound of example
 1 below. Said compound has high affinity for native rat sst.sub.1
 receptors (pIC.sub.50 =9.7) and native and recombinant human sst.sub.1
 receptors (pIC.sub.50 =9.0 and 8.8 respectively), without significant
 activity for a wide range of neurotransmitter receptors. At 3-30 mg/kg
 p.o., the compound clearly lowers aggressive behavior in the
 above-mentioned Matched Pairs Situation test and reverses social
 withdrawal in the above-mentioned intruder mouse test. These effects are
 also observed with the standard anti-manic drugs lithium and carbamazepine
 at 3-30 mg/kg s.c., indicating similar therapeutic effects in man.
 However, lithium and carbamazepine were found to be less potent and are
 known to have considerable drawbacks such as a narrow therapeutic window
 and slow onset of action.
 The preferred indications are depression, anxiety, affective disorders,
 including bipolar disorders, e.g. mania, and ADHD.
 In accordance with the foregoing, the present invention also provides an
 agent of the invention for use as a pharmaceutical, e.g. for the treatment
 of depression, anxiety, bipolar disorders and ADHD.
 Moreover the present invention provides an agent of the invention, for the
 manufacture of a medicament for the treatment of any condition mentioned
 above, e.g. depression, anxiety, bipolar disorders and ADHD.
 In still a further aspect the present invention provides a method for the
 treatment of any condition mentioned above, e.g. depression, anxiety,
 bipolar disorders and ADHD in a subject in need of such treatment, which
 comprises administering to such subject a therapeutically effective amount
 of an agent of the invention.

The following examples illustrate the invention. The temperatures are given
 in degrees Celsius and are uncorrected.
 EXAMPLE 1
 [5R, 8R,
 10R]-2-Bromo-9,10-dihydro-lysergic-acid-4-(1-methyl-1H-pyrid-6-on-2-yl)-pi
 perazine-amide
 a) 2-Chloro-1-methyl-pyrid-6-one
 51.82 g of 2-chloro-pyrid-6-one (400 mmol) and 12.7. g of 83%
 sodium-hydride dispersion in mineral oil (440 mmol) are reacted in 400 ml
 absolute dimnethylfomamide at room temperature under argon for 15 minutes.
 32.4 ml methyl-iodide (520 mmol) are added dropwise and stirring is
 continued at 50.degree. for 5 hours. The reaction mixture is evaporated on
 a rotary evaporator until the solvent starts to distill from a bath of
 60.degree..
 b) 4-(1-methyl-1H-pyrid-6-on-2-yl)-piperazine
 The crude solution of 2-chloro-1-methyl-pyrid-6-one obtained under a) is
 mixed with 103 g piperazine (1.2 mol) and reacted at 110.degree. for 6
 hours. The solvent is removed on a rotary evaporator at 70.degree. under
 0.01 Torr. Removal of the excess of piperazine is effected by partitioning
 between 16% natrium chloride in water and toluene/1-propanol--50/50. The
 title compound is crystallized as hydrogen-oxalate salt from 2-propanol
 and as free base from toluene. Mp=108.degree..
 c) [5R, 8R,
 10R]-2-Bromo-9,10-dihydro-lysergic-acid-4-(1-methyl-1H-pyrid-6-on-2-yl)-pi
 perazine-amide
 2.794 g (8 mmol) of [5R, 8R, 10R]-2-Bromo-9,10-dihydro-lysergic-acid are
 suspended in 19.1 ml 38% propane-phosphonic-acid anhydride in
 dimethylformamide (24 mmol) and 8 ml absolute pyridine, and stirred for 15
 minutes at room temperature. After addition of 1.546 g
 4-(1-methyl-1H-pyrid-6-on-2-yl)-piperazine (8 mmol), stirring is continued
 overnight. The reaction mixture is partitioned between
 toluene/2-propanol--60/40 and 2 M aqueous ammonia, the organic layer
 evaporated and chromatographed on 24 g silicagel with
 toluene/ethanol/conc. aqueous ammnonia--90/0.9/0.1. The main component is
 recrystallized from ethyl-acetate. Mp=250-253.degree. (decomposition);
 [.alpha.].sub.D,20 =-94.3.degree. (0.5% in dimethylformamide).
 The compounds of formula I defined below and in which the configuration is
 [5R,8R,10R] are produced in analogous manner to example 1.
 In the following compounds, R.sub.5 and R.sub.6 are hydrogen.