The present invention relates to new pharmacologically active polycyclic indanylimidazole derivatives and pharmaceutically acceptable salts and esters thereof, as well as to pharmaceutical compositions containing them.
It is known that several derivatives of imidazole have affinity for alpha1 and/or alpha2 adrenoceptors. Accordingly, for example, WO-A-97 12874 describes imidazole-substituted (1,2,3,4-tetrahydro-1-naphthalenyl)- and (2,3-dihydro-1H-inden-1-yl)-derivatives which are stated to possess affinity for alpha2 adrenoceptors, most of them being selective alpha2 adrenoceptor agonists. EP-A-0 717 037 describes 4-(1,2,3,4-tetrahydro-1-naphthalenyl)- and 4-(2,3-dihydro-1H-inden-1-yl)-1H-imidazole derivatives which possess alfa2 adrenoceptor agonistic and alpha1 adrenoceptor antagonistic activity. Furthermore, the imidazole derivatives disclosed in EP-A-0 183 492 are known as alpha2 adrenoceptor antagonists. Compounds acting on the said alpha adrenoceptors may exert a wide variety of peripheral and/or CNS (central nervous system) effects in mammals.
The inventors have now found that the present polycyclic indanylimidazole derivatives of the invention exhibit affinity for alpha2 adrenoceptors so that they can be useful in the treatment of various diseases or conditions wherein the alpha2 adrenoceptors are involved. Such diseases or conditions include various disorders of the central nervous system (CNS), i.e. neurological, psychiatric or cognition disorders, as well as various disorders of the peripheric system, e.g. diabetes, orthostatic hypotension, lipolytic disorders (such as obesity) or sexual dysfunction.
The polycyclic indanylimidazole derivatives of the invention can be represented by the following formula (I): 
wherein
xe2x80x94Axe2x80x94 forms, together with the two carbon atoms to which it is attached, a ring system being a partially or fully saturated monocyclic carbocyclic ring of 3 to 7 ring atoms or a partially or fully saturated bicyclic bridged carbocyclic ring of 6 to 10 ring atoms, wherein each of the said ring systems formed by xe2x80x94Axe2x80x94 is optionally fused with a benzene ring which is optionally substituted with one to three substituent(s) R1;
each R1 is independently halogen, OH, NH2, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, (C1-6)alkoxy, halo-(C1-6)alkyl, OHxe2x80x94(C1-6)alkyl, mono- or di(C1-6)alkylamino or OHxe2x80x94(C1-6)alkoxy(C1-6)alkoxy;
each R2 is independently halogen, OH, xe2x95x90O, xe2x95x90CH2, NH2, (C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkoxy, halo-(C1-6)alkyl, OHxe2x80x94(C1-6)alkyl, NH2xe2x80x94(C1-6)alkyl or mono- or di(C1-6)alkylamino;
R3 is H, F, OH, xe2x95x90O, xe2x95x90CH2, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, (C1-6)alkoxy, halo-(C1-6)alkyl, NH2 or mono- or di(C1-6)alkylamino;
m is 0, 1, 2 or 3; and
t is 0, 1, 2 or 3;
or a pharmaceutically acceptable ester or salt thereof.
The invention also includes mixtures of compounds defined above.
In one possible subgroup of compounds of formula (I), the said ring formed by xe2x80x94Axe2x80x94 is a fully saturated monocyclic carbocyclic ring moiety of 3, 4, 5, 6 or 7 ring atoms, e.g. cyclopropa, cyclobuta, cyclopenta, cyclohexa or cyclohepta, such as cyclopropa, cyclopenta, cyclohexa or cyclohepta, fused to the indane backbone structure. In another possible subgroup of the compounds of formula (I), xe2x80x94Axe2x80x94 forms a fused, partially saturated monocyclic carbocyclic ring system of 5, 6 or 7 ring atoms, which contains one double bond, e.g. a fused cyclopentene or cyclohexene ring. The said fully or partially saturated carbocyclic ring system fused to the indan backbone can optionally be substituted with one to three, e.g. one or two, such as one, substituent(s) R2 as defined above, and/or further be fused with an unsubstituted benzene ring or with a benzene ring substituted with one to three substituents R1 as defined above.
In another possible subgroup of the compounds of formula (I), xe2x80x94Axe2x80x94 forms a fused, fully or partially saturated bicyclic bridged carbocyclic ring system of 6 to 10 ring atoms, e.g. of 7 or 8 ring atoms, such as a fused bicyclo[2.2.1]heptane or bicyclo[2.2.2]octane ring. The said bridged carbocyclic ring moiety can optionally be substituted with one to three, e.g. one or two, such as one, substituent(s) R2 as defined above and/or further be fused with an unsubstituted benzene ring or with a benzene ring substituted with one to three substituents R1 as defined above.
The following subgroups (1) to (6) of compounds of formula I taken alone or in any combination with each other are possible,
(1) m is 0 or 1; e.g. 0
(2) m is 1 and R2 is halogen, OH, xe2x95x90O, NH2, xe2x95x90CH2, (C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkoxy, halo-(C1-6)alkyl, OHxe2x80x94(C1-6)alkyl, NH2xe2x80x94(C1-6)alkyl or mono- or di(C1-6)alkylamino; e.g. OH, xe2x95x90O, xe2x95x90CH2, (C1-6)alkyl, or (C1-6)alkoxy; e.g. OH, xe2x95x90O, xe2x95x90CH2 or (C1-6)alkyl; such as (C1-6)alkyl or xe2x95x90CH2;
(3) t is 0 or 1; e.g. 0;
(4) t is 1 and R1 is selected from halogen, OH, NH2, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, (C1-6)alkoxy, halo-(C1-6)alkyl, OHxe2x80x94(C1-6)alkyl, mono- or di(C1-6)alkylamino or OHxe2x80x94(C1-6)alkoxy(C1-6)alkoxy; e.g. halogen, OH, (C1-6)alkyl, (C1-6)alkoxy and OHxe2x80x94(C1-6)alkoxy(C1-6)alkoxy; such as halogen, e.g. F, OH, (C1-6)alkoxy and OHxe2x80x94(C1-6)alkoxy(C1-6)alkoxy;
(5) R3 is selected from H, OH, xe2x95x90O, xe2x95x90CH2, (C1-6)alkyl, (C2-6)alkenyl and (C1-6)alkoxy; e.g. H, OH, xe2x95x90O, xe2x95x90CH2 and (C1-6)alkyl; such as H, OH and xe2x95x90O; e.g. H; and
(6) the xe2x80x94Axe2x80x94 ring fused to the indan ring is further fused with an unsubstituted benzene ring or a benzene ring substituted with one to three, e.g. one, substituents R1 as defined above, e.g. under (4).
A possible subgroup of the compounds of formula I are compounds of formula Ia 
wherein R1, R2, R3, m and t are as defined above and n is 1,2,3, 4 or 5.
In a subgroup of compounds Ia, m is 0. In another subgroup of compounds Ia, m is 1 and R2 is selected from halogen, OH, xe2x95x90O, xe2x95x90CH2, (C1-6)alkyl and (C1-6)alkoxy; e.g. OH, xe2x95x90O, xe2x95x90CH2 and (C1-6)alkyl; such as (C1-6)alkyl and xe2x95x90CH2. In a further subgroup of compounds Ia, t is 0. In another subgroup of compounds Ia, t is 1 and R1 is selected from halogen, OH, (C1-6)alkyl, (C1-6)alkoxy and OHxe2x80x94(C1-6)alkoxy(C1-6)alkoxy; such as halogen, OH, (C1-6)alkoxy and OHxe2x80x94(C1-6)alkoxy(C1-6)alkoxy; such as halogen, e.g. F, OH and (C1-6)alkoxy. In a subgroup of compounds Ia, R3 is selected from H, OH, xe2x95x90O, (C1-6)alkyl, (C2-6)alkenyl and (C1-6)alkoxy; e.g. H, OH, xe2x95x90O and (C1-6)alkyl; such as H, OH and xe2x95x90O; e.g. H. In one embodiment of the compounds of formula Ia, the carbocyclic ring fused to the indan ring is further fused with an unsubstituted or substituted benzene ring. The substituted benzene ring bears one to three, e.g. one, substituent(s) R1 as defined above; e.g. each R1 is independently halogen, OH, (C1-6)alkyl, (C1-6)alkoxy or OHxe2x80x94(C1-6)alkoxy(C1-6)alkoxy; such as halogen, OH, (C1-6)alkoxy and OHxe2x80x94(C1-6)alkoxy(C1-6)alkoxy; such as halogen, e.g. F, OH or (C1-6)alkoxy.
Another possible subgroup of the compounds of formula I are compounds of formula Ib 
wherein R1, R2, R3 and t are as defined above; m is 0, 1 or 2; txe2x80x2 is 0, 1, 2 or 3; p is 0, 1, 2 or 3; and v is0, 1, 2 or 3, with the proviso that p+v is 1, 2 or 3.
In a subgroup of compounds Ib, (a) p is 0 and v is 1, 2 or 3, or (b) v is 0 and p is 1, 2 or 3.
A subgroup of compounds Ib are compounds of formula Ibxe2x80x2. 
wherein R1, R2, R3 and t are as defined above; m is 0, 1 or 2; txe2x80x2 is 0, 1, 2 or 3; and v is 1, 2 or 3.
In a subgroup of compounds of formula Ib, m is 0; or m is 1 and R2 is halogen, e.g. F or Cl, or (C1-6)alkyl; e.g. (C1-6)alkyl. Preferably, t and/or txe2x80x2 is 0 or 1, e.g. 0. R3 is e.g. H. In one embodiment of the compounds Ib, v is 1 or 2.
The compounds of formula I and the subgroups Ia and Ib, as well as the pharmaceutically acceptable esters and salts thereof, are referred to below as the compounds of the invention, unless otherwise indicated.
The compounds of the invention may have chiral carbon atom(s) in their structure. The invention includes within its scope all the possible stereoisomers of the compounds I, including geometric isomers, e.g. Z and E isomers (cis and trans isomers), and optical isomers, e.g. diastereomers and enantiomers. Furthermore, the invention includes in its scope both the individual isomers and any mixtures thereof, e.g. racemic mixtures. The individual isomers may be obtained using the corresponding isomeric forms of the starting material or they may be separated after the preparation of the end compound according to conventional separation methods. For the separation of, for example, optical isomers, e.g. enantiomers, from the mixture thereof the conventional resolution methods, e.g. fractional crystallisation, may be used.
Physiologically acceptable salts may be prepared by known methods. The pharmaceutically acceptable salts, e.g. acid addition salts, are the usual organic and inorganic salts in the art. Furthermore, the OH- or amino-functionality, when present in the compounds of the invention, can be converted to a pharmaceutically acceptable ester or, respectively, a pharmaceutically acceptable amide with pharmaceutically acceptable acids by known methods. Examples of such pharmaceutically acceptable acids are e.g. aliphatic acids or aromatic acids which are conventional in the field of pharmaceuticals and which retain the pharmacological properties of the free form.
Terms employed herein have the following meanings: A halogen or halo refers to fluorine, chlorine, bromine or iodine. The term (C1-C6)alkyl as employed herein as such or as part of another group includes both straight, and branched chain radicals of up to 6 carbon atoms, for example of 1, 2, 3 or 4 carbon atoms. The term (C1-C6)alkoxy as such or as part of another group refers to xe2x80x94O(C1-C6)alkyl, wherein (C1-C6)alkyl is as defined above. The term (C2-C6)alkenyl includes both straight and branched chain radicals of up to 6 carbon atoms, for example of 2, 3 or 4 carbon atoms, containing double bond(s), e.g. one double bond. The term (C2-C6)alkynyl includes both straight and branched chain radicals of up to 6 carbon atoms, for example of 2, 3 or 4 carbon atoms, containing triple bond(s), e.g. one triple bond. The term halo-(C1-C6)alkyl refers to (C1-C6)alkyl radical, as defined above, that is substituted by one or more halo radicals as defined above, e.g. trifluoromethyl, difluoromethyl etc.
The compounds of the invention can be prepared by a variety of synthetic routes analogously or according to the methods known in the literature using suitable starting materials. In general, the compounds of the invention can be prepared e.g. analogously or according to the scheme 1: 
wherein xe2x80x94Axe2x80x94 is as defined above except a 3-membered carbocycle; and R1, R2, R3, t and m are as defined above.
According to the reaction route of scheme 1, a compound V is formed either by reacting a compound III with acetic anhydride to obtain a compound IV (see V. E. Dehmlow et al., Liebigs Ann. Chem., 1977, p.1617-1624, or R. M. Manyik et al., J. Am. Chem. Soc., vol.75, 1953, p.5030-5032), which is then reacted with Br2 in a suitable solvent, e.g. methanol. The compound V thus obtained is reacted with formamide to form an end compound I, wherein R3 is xe2x95x90O (compound Id). The said xe2x95x90O as R3 in the compound Id can then further be converted to another R3 of the invention in a manner known in the art. For example, it can be reduced in a suitable solvent to a compound Ie using suitable reducing agent, e.g. NaBH4 or it can be reduced e.g. with H2NNH2 to a compound If, wherein R3 is H (see B. C. Ranu and U. Jana, J. Org. Chem., vol.64, 1999, p.6380-6386). Also the OH-group of the compound Ie can further be converted to another functionality R3 of the invention. The above steps can be carried out at room or elevated temperature in a manner known in the art.
Scheme 2 illustrates an alternative route for preparing compounds I: 
wherein R1, R2, m and t are as defined above and xe2x80x94Axe2x80x94 is as defined above except 3- or 4-membered carbocycle.
Accordingly, a starting compound VI is reduced with a suitable reducing agent, e.g. NaBH4, in a conventional manner, in a suitable solvent, e.g. ethanol, to a corresponding alcohol VII, which is then cyclized in a known manner to the end compound Ig using a strong acid, e.g. MeSO3H.
A further alternative route for preparing compounds of formula 1, wherein xe2x80x94Axe2x80x94 forms a fused saturated monocyclic carbocycle of 5 ring atoms (i.e. cyclopenta), is illustrated in scheme 3: 
wherein R1, R3 and t are as defined above, R4 is H or (C1-6)alkyl, Hal is a halogen, e.g. Br, and Rxe2x80x2 is a (C1-6)alkyl, e.g. ethyl
Accordingly, a compound VII is reacted with a compound II in the presence of a base, e.g. potassium carbonate, to form an ester IX, which is reacted first with bromine and then with formamide to form compound X. The resulted compound X is cyclized according to McMurry reaction in a suitable solvent, e.g. THF, in the presence of a catalyst, e.g. titanium(0) (produced in situ). The carbonyl group of the compounds of formula Ixe2x80x2 can, if desired, further be reduced in a conventional manner to obtain a corresponding alcohol compound Ih of the invention. An optional well known elimination of water from the said alcohol compound Ih results in compounds of formula Ii. The double bond can further be hydrogenated in a usual manner to obtain a corresponding saturated compound Ij. The above-mentioned ketone or alcohol functionality can also be converted with another suitable alternative given for R2 in a manner known in the art. Each of the above reactions can be carried out in a suitable reaction temperature, e.g., at room or elevated temperature.
A further alternative route for preparing compounds of formula I, wherein xe2x80x94Axe2x80x94 forms a fused, partially or fully saturated monocyclic carbocycle of 3 ring atoms (i.e., cyclopropa ring); and m is 0, is illustrated in scheme 4: 
wherein R1, R3 and t are as defined above; and Rxe2x80x3 is a conventional protecting group for xe2x95x90NH in the imidazole ring, e.g., benzyl, xe2x80x94CPh3 (trityl) or SO2NMe2.
Accordingly, xe2x95x90NH of the imidazole moiety of a compound XI is protected in a conventional manner. The resulted compound XII can be converted to a corresponding cyclopropa-fused compound XIII analogously to e.g. the Simmons-Smith procedure using ZnEt2 in a suitable solvent, e.g. CH2Cl2 (see e.g. P. T. Kaye is and W. E. Molema, Synt. Commun., vol.29(11), 1999, p.1889-1902). The compound XIII is finally deprotected in a conventional manner to obtain the end compound Ic. Each of the above reactions are carried out in a suitable reaction temperature, e.g. at room or elevated temperature.
Generally, if applicable, a substituent as R1, R2 and/or R3 in a compound of formula I prepared according to the above reaction schemes can be converted in a conventional manner to another substituent of the invention.
The starting materials of formulae III, VI, VIII and XI are commercially available or can be prepared via a variety of known synthetic routes known in the literature.
For example the starting material of formula III for the synthetic route of scheme 1 can be e.g. prepared analogously or according to scheme 5a: 
wherein xe2x80x94Axe2x80x94 is as defined above except 3- or 4-membered carbocycle; and R1, R2, m and t are as defined above.
Accordingly, a compound XIV is reacted with an optionally (R1)t-substituted benzene in a suitable solvent, e.g. dichloromethane, analogously to the Friedel-Crafts acylation procedure to obtain a compound XV. The compound XV is then reacted in a suitable solvent, e.g. dichlormethane, with bromine in acidic reaction conditions, whereby compound XVII is formed, which is then cyclized in a known manner in the presence of a strong acid, e.g. H2SO4, to obtain a starting compound III (see e.g. H. O. House et al., J. Am. Chem. Soc., vol.82, 1960, p.1457-1462). Each of the above reactions are carried out in a suitable reaction temperature, e.g. at room or elevated temperature.
A further route for preparing starting compounds of formula III is illustrated in scheme 5b: 
wherein R1 and t are as defined above, Ra and Rb are independently H or as defined for R2 above, and c is 1 or 2.
Accordingly, compound XIVxe2x80x2 is reacted via a bromine derivative XVxe2x80x2 to a compound XVIIxe2x80x2, e.g., analogously to a procedure described by P. E. Hansen and K. Undheim in Acta Chem.Scand., vol.27(3), 1973, p.1112-1113. The compound XVIIxe2x80x2 is then reacted with a diene derivative analogously to a known Diels-Alder procedure (cf. e.g. S. Gosh and S. Saha, Tetrahedron, vol.41, 1985, p.349-355). The above reaction steps are carried out in suitable temperatures and solvents obvious for a skilled person.
The starting compound of formula VI for the synthetic route of scheme 2 can be, for example, prepared analogously or according to scheme 6: 
wherein R1, R2, m and t are as defined above and xe2x80x94Axe2x80x94 is as defined above except 3- or 4-membered carbocycle.
Accordingly, a compound XVIII is acylated in acidic conditions to obtain a compound XIX which is then reacted with a benzyl bromide derivative in the presence of a base, e.g. potassium carbonate, in a suitable solvent. The resulted compound XX is reacted with bromine in a suitable solvent, e.g. methanol. The compound XXI thus obtained is allowed to react with formamide to form a starting compound VI. Each of the above reactions are carried out in a suitable reaction temperature, e.g., at room or elevated temperature.
The starting material for the synthetic route of scheme 3 (e.g., compound VIII) and also the starting material for the synthetic route of scheme 4 (e.g., compound XI) can be e.g. prepared analogously or according to the methods described in EP-A-0 183 492, the contents of which are hereby incorporated by reference.
Furthermore, the starting materials for preparing the above compounds III, VI, VIII, XI, XIVxe2x80x2 and the diene derivatives described in scheme 5b are commercially available or can be prepared analogously or according to the methods described in the literature (see the above cited EP-A-0 183 492).
It is obvious to a skilled person that, in the above reactions, any starting material or intermediate can be protected, if necessary, in a manner well known in the chemical field. Any protected functionality is subsequently deprotected in a usual manner.
The above described synthetic routes are meant to illustrate the preparation of the compounds of the invention and the preparation is by no means limited thereto, i.e., other synthetic methods that are within the general knowledge of a skilled person are also possible.
The compounds of the invention may be converted, if desired, into their pharmaceutically acceptable salt or ester form using methods well known in the art.
The compounds of the invention show interesting pharmacological properties, namely they exhibit affinity for alpha2 adrenoceptors. This activity is demonstrated in the pharmacological tests presented below.
Antagonist Activity on Alpha2 Adrenoceptors (alpha2AR) in Rat Vas Deferens in Vitro
Rats were killed by CO2-suffocation. Vas deferentia were dissected out and both prostatic halves were removed to tissue chambers containing Krebs-solution of the following composition (mM): NaCl 118, KCl 4.7, CaCl2 2.5, KH2PO4 1.2, MgSO4 0.6, NaHCO3 25, glucose 11.1, aerated by 5% carbogen, temperature 37xc2x0 C., pH 7.4. Propranolol 260 g/l and desipramine 2 g/ml were added to prevent the possible effects on alpha-adrenergic receptors and to prevent re-uptake of released norepinephrine, respectively. Preparations were tied to the bottom hooks of the incubation chambers and the to isometric force-displacement transducers above. Electrical stimulation was started after the equilibrium period/5 minutes under a resting tension of 0.5 g) by introducing field stimulation with the following parameters: twin-pulses, voltage 70 V, frequency 0.2 Hz, delay 5 ms, duration 2 ms. As soon as the electrically induced twitch response was stabilised, the test compounds were administered by a cumulative fashion with half logarithmic increments at five minutes intervals. Inhibition of the electrically evoked contractions was measured as the response to alpha2AR agonists. Antagonist was administered into the incubation medium at least five minutes before agonist. Meansxc2x1SEM of percentage inhibition were calculated in the absence and in the presence of antagonist and expressed as dose-response curves. In order to express the antagonist potency, pA2-value was calculated. The results of the test are reported in table 1.
In general, the compounds of the invention exhibiting alpha2-antagonistic activity may be useful for therapeutical indications in which alpha2-antagonists are used. They may also be used for reversal of the effects of alpha2-agonists.
Accordingly, the compounds of the invention may be useful, for example, in the treatment of different neurological, psychiatric and cognition disorders. Furthermore, they may be used in the treatment of various peripheral disorders, e.g. diabetes, orthostatic hypotension, lipolytic disorders (such as obesity) or sexual dysfunction.
The compounds of the invention may be administered enterally, topically or parenterally.
The compounds of the invention may be formulated alone or together with another active ingredient and/or together with a pharmaceutically acceptable diluent, carrier and/or excipient in different pharmaceutical unit dosage forms, e.g. tablets, capsules, solutions, emulsions and powders etc., depending on the route of administration, using conventional techniques. The pharmaceutically acceptable diluent, carrier and/or excipient can be selected from those conventionally used in the field of pharmaceuticals noticing the chosen route of administration.
The amount of the active ingredient varies from 0.01 to 75 weight-% depending on i.a. the type of the dosage form.
The specific dose level of the compounds of the invention depends on several factors such as the compound to be administered, the species, age and the sex of the subject to be treated, the condition to be treated and on the route and method of administration. Accordingly, the dosage for parenteral administration is typically from 0.5 xcexcg/kg to 10 mg/kg per day and that for oral administration is typically from 5 xcexcg/kg to 100 mg/kg for an adult male.
The present invention also provides a compound of the invention or an ester or salt thereof for use in a method of treatment of human or animal body.
The present invention further provides a compound of the invention or an ester or salt thereof for use as alpha-2 antagonist, i.a. in the treatment of diseases and conditions where alpha-2 antagonists are indicated to be used, e.g. in the treatment of above indicated diseases and conditions. The use of the compounds of the invention for the manufacture of a medicament to be used for the above indications is also provided. The invention further relates to a method for the treatment of above indicated conditions or diseases, by administering to a subject in need of such treatment an effective amount of the compound of the invention or a pharmaceutically acceptable ester or salt thereof.
USPTO Backgrounds
USPTO Backgrounds