MXPA00011211A

MXPA00011211A - Serotonergic 5ht7

Info

Publication number: MXPA00011211A
Application number: MXPA/A/2000/011211A
Authority: MX
Inventors: Thomas R Dean; A May Jesse; Najam A Sharif; Chen Hwanghsing
Original assignee: Alcon Laboratories Inc; Chen Hwanghsing; Thomas R Dean; A May Jesse; Najam A Sharif
Priority date: 1998-05-19
Filing date: 2000-11-15
Publication date: 2001-07-31

Abstract

Compounds with 5HT7 receptor affinity (some of which are novel) useful for lowering IOP, improving blood flow to the optic nerve head and the retina, providing neuroprotection, and treating retinal diseases are disclosed. The Compounds are also useful for treating sleep disorders, depression, and other psychiatric disorders, such as, schizophrenia, anxiety, obsessive compulsive disorder, circadian rhythm disorders, and centrally and peripherally mediated hypertension. Compositions and methods for their use are also disclosed.

Description

SEROTONINERGIC COMPOUNDS WITH RECEIVER 5HT7 TO TREAT OCULAR ANOMALIES X OF THE SNC The present invention is directed to the use of compounds with affinity to the serotonergic 5HT7 (compound) receptor (some of which are novel), to improve blood flow to the head of the optic nerve and the retina, to provide neuroprotection, to reduce intraocular pressure (IOP), and treat retinal abnormalities, such as glaucoma, age-related macular degeneration (ARMD), optic neuritis, ischemic abnormalities, diabetic retinopathy and retinal edema. The compounds are also useful to treat sleep abnormalities, depression and other psychiatric conditions such as schizophrenia, anxiety, obsessive-compulsive disorder, circadian rhythm disorders and central and peripherally mediated hypertension.

BACKGROUND OF THE INVENTION Serotonin (5-hydroxytryptamine; 5HT) is an endogenous biogenic amine with a well-defined neurotransmitter function in many tissues of the body including the eye [Zifa and Fillion, Pharmacol, Rev., 44: 401-458, 1992; Hoyer et al., Pharmacol. Rev., 46: 157-203, 1994; Tobin et al., J. Neurosa. , 8: 3713-3721, 1988]. 5HT can interact with at least seven important 5HT receptors (5HT? -5HT7) and additional subtypes within these families to initiate intracellular biochemical events such as the stimulation of secondary messengers (eg, cAMP, inositol triphosphate) originating from last to the final biological response, for example, tissue contraction or release of the hormone, etc. [Hoyer et al., Supra; Martin et al., Trends Pharmacol. Sci. , 19: 2-4, 1988]. The receptor subtypes within the 5HT family! are negatively coupled with adenylyl cyclase (AC) and cause inhibition of cAMP production, whereas 5HT4, 5HT6 and 5HT7 receptors are positively attenuated to AC and thus stimulate the production of cAMP when activated with 5HT [Martin et al., supra] receptors in the 5HT2 family are positively coupled to phospholipase C (PLC) and thus generate inositol phosphates and mobilize intracellular calcium when activated to mediate the effects of 5HT. The 5HT3 receptor is unique in that it is coupled to an ion channel that is the gateway of sodium, potassium and calcium [Hoyer et al., Supra]. The human and animal 5HT7 receptor has recently been cloned, expressed and shown to be present in different areas of the brain and peripheral tissues [Eglen et al. Trend Pharmacol. Sci. , 18: 104-107, 1997].

Recent studies have shown that there may be four splice variants of the 5HT7 receptor [Heidman et al., J. Neurochem. , 68: 1372-1381, 1997]. It has been proposed that the 5HT7 receptor may be involved in the pathophysiology of sleep disorders, depression and other psychiatric disorders [Eglen et al., Supra]. In the periphery, the stimulation of the 5HT7 receptors causes relaxation of the blood vessels and therefore vasodilation [Eglen et al., Supra]. It is considered that the improvement of blood flow to the back of the eye, including the retina, macula and macula and the head of the optic nerve, is beneficial in the treatment of different retinal abnormalities, for example, glaucoma, ARMD, and diabetic retinopathy [Chiou, et al., J. Ocular Pharmacol 9: 13-24 (1993)]. Serotonergic nerves innervate the eye [Tobin et al., J. Neurosci. , 8: 3713-3721, 1988] and 5HT has been found in the aqueous humor of human eyes [Martin et al., Ophthamol. , 95: 1221-1226, 1988]. In addition, receptor binding sites for [H] 5HT have been demonstrated and pharmacologically characterized in the iris ciliary body (ICB) of rabbits [Mallorga and Sugrue, Curr. Eye Res. , 6: 527-532, 1987 and Chidlow et al., Invest. Ophthalmol. Vis Sci. , 36: 2238-2245, 1995]. These binding sites of 5HT have been shown to be functionally coupled with the generation of second messengers in rabbits [Tobin Osborne, J Neurochem. , 53: 686-601, 1989 and Tobin et al., J Neurosci, supra]. In human ICB these binding sites are characterized as 5HT? Ft and 5HT2 receptors [Barnet, and Osborne Exp. Eye Res. , 57: 209-216, 1993]. In addition, the presence of mRNAs for the 5HTα and 5HT7 receptors in the rabbit ICB has already been reported [Chidlow et al., Invest. Ophthalmol. Vis. Sci. supra and Osborne and Chidlow, Ophthalmologica, 210: 308-314, 1996]. The precise functions of these receptors in the eye are unknown, especially of the 5HT subtype (s). 5HT or 5-carboxamidotriptamna [5-CT] normally applied to the eye of the rabbit increases intraocular pressure in the anterior chamber of the eye [Meyer-Bothling et al., Invest, Aphthamol. Vis. Sic. , 34: 3035-3042, 1993]. On the contrary, it has been shown that normally the applied 5HT reduces the IOP [Krootila et al., J. Ocular Pharmacol. , 3: 729-290, 1987 (5HT intracamerally increased IOP and caused rupture of the blood-aqueous barrier)]. In addition, the inhibitor of 5HT uptake, fluoxetine (Prozac®), also increases IOP in humans with oral administration [Costagliola et al., Ophthalmol. , 80: 678, 1996] and can cause glaucoma [Ahmad, Ann. Pharmacother. , 25: 436, 1992]. However, the subtype (s) of the 5HT receptors involved in the effects of raising the IOP of 5HT, 5-CT and fluoxetine are unknown.

Studies in rabbits with 8-hydroxy DPAT and MKC-242 (5HT? A agonists) have shown that these compounds reduce IOP [Osborne and Chidlow, Ophthamlogica, 210: 308-319, 1996, and EP 0771563-A2]. In addition, 5-methylurapidil (5HT1A agonist) reduced IOP in glaucomatous monkeys [Wang et al., Curr. Eye Res., 16: 679-775, 1997]. Both MKC-242 and 5-methylurapidil are relatively potent antagonists of the al receptor (antagonists of al are known to reduce IOP in rabbits, monkeys and man). The mechanism of action for reducing IOP by 5-methylurapidil has been attributed to its antagonist activity and not to its 5HTlñ agonist activity [Wang et al., Invest. Ophthal. Vis. Sci. 39 (suppl): 2236-488, 1998]. U.S. Patent No. 5,693,654, describes 5HT? Receptor agonists. to reduce the IOP. W092 / 29333 discloses certain 5HT? A agonists for the treatment of glaucoma.

Methiserbed (5H? 2 antagonist reduced IOP in rabbits [Krootila, et al., Esp. Eye Res. Supra] .Ketanserin (5HT2A / C antagonist), also with significant antagonist activity, reduces IOP in rabbits and man [Chan, et al., J. Ocular Pharmacol., 1: 137-147, 1985 and Costagliola, et al., Exp. Eye Res., 52: 507-510, 1991] .Saprogrelate (antagonist of 5HTñ) reduces IOP in rabbits and in man when dosed topically or orally [Mano et al., Invest. Ophthal., Vis. Sci., 36 (Suppl): 3322-309, 1995, and Takenaka, et al., Invest. Ophthal. Vis. Sci. , 36 (Suppl): 3390-377, 1995]. EP 522226 and U.S. Patent No. 5,290,781 describe the use of ketanserin and its derivatives for the treatment of ocular hypertension. U.S. Patent Nos. 5,290,781 and 5,106,555 describe the use of certain 5HT2 antagonists to reduce IOP. U.S. Patent No. 5,652.27 describes saprogrelate to reduce IOP. U.S. Patent No. 5,538,974 discloses ophthalmic compositions of certain 5HT2 antagonists to reduce IOP. U.S. Patent No. 5,011,846 discloses certain 5HT3 receptor antagonists for the treatment of glaucoma. WO 97/17345 discloses that particular compounds with 5HT4 serotonergic receptor agonist or antagonist activity are useful for the treatment of psychiatric, gastrointestinal, minor urinary and cardiovascular disorders. The publication mentions that the compounds may also be useful for glaucoma. As described in the above, it is not clear that the serotonergic receptor activity is responsible for the reduction of the IOP. In addition, it is known that many of these compounds have activity in other receptors known to be involved in the reduction of IOP.

In addition, it has not been made clear that receptor (s) could be responsible for the increase in blood flow and for providing neuroprotection in the eye.

SUMMARY OF THE INVENTION The present invention is directed to compounds, some of which are novel, that have affinity to the 5HT7 receptor, and the use of compounds with affinity for the 5HT7 receptor to reduce IOP, improve blood flow to the head of the optic nerve and the retina, provide neuroprotection and control the damage associated with diseases such as glaucoma, ARMD, optic neuritis, ischemic anomalies and retinal edema functioning as neuroprotectors. The compositions of the compounds are contemplated for such uses. The compounds are also useful for the treatment of sleep disorders, depression and other psychiatric disorders such as schizophrenia, anxiety, obsessive-compulsive disorders, circadian rhythm disorders and central and peripherally mediated hypertension.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Unexpectedly, it has been discovered that 5HT7 receptors are present in the retina, choroid and possibly the head of the optic nerve. In addition, Serotoninergic compounds that possess a relatively high affinity (rZ = 0.01 -200 nM) for 5HT7 receptors do indeed reduce elevated IOP. It is considered that these compounds can improve blood flow and provide neuroprotection to the head of the optic nerve and the retina. The ability of compounds (preferably compounds that are agonists or partial agonists) to improve blood flow to the head of the optic nerve and the retina and other features, is believed to make them neuroprotective. The novel compounds described herein are also useful for treating sleep abnormalities, depression and other psychiatric disorders. The compounds found in the following applications are useful in accordance with the present invention and are incorporated herein by reference: EP 738513-Al; WO 97/29097; WO 97/48681; WO 97/49695; and WO 98/00400. Specific compounds include: LY-215840, SB-258719, and DR-4004. The following novel compounds and their pharmaceutically acceptable salts and solvates are useful for treating people with the diseases and disorders described above. and.,. "« ^ Formula I: wherein the dotted link represents a single or double bond; Aryl means a fused phenyl or monocyclic heteroaromatic ring; R is H, OH, O-C1-3 alkyl, C3_3 alkyl, C3_3 alkyl optionally substituted with OH, or OC3_3alkyl; R 2 is H, halogen, C 1 -C 3 alkyl, CONR 5 R 6, S (= 0) m-C 1-3 alkyl, S (= 0> 2NR R, C 1-3 alkyl optionally substituted with OH or O-alkyl C1-3; R, R are independently H, C1-3 alkyl, C1-3 alkyl optionally substituted with OH or O-alkyl C1-3; R, R are independently H, C1-3 alkyl, C2-3 alkyl optionally substituted with OH, O-C1-3 alkyl; or R5 and R6 may be linked together with saturated carbon atoms to form a 5- or 6-membered ring and the carbon atoms may be optionally unsubstituted or substituted with C1-3alkyl, C2-3alkyl optionally substituted with OH or O-C1-3 alkyl; R, R are together with the nitrogen atom to which they are attached incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be unsubstituted or substituted on the carbon with one or more substituents optionally selected from C1-3alkyl, C3_3alkyl optionally substituted with OH, O-C1alkyl -3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C1-3 alkyl or C1-3 alkyl, or substituted on nitrogen with C1-C4 alkoxy or phenyl which may be unsubstituted or substituted optionally with halogen, CF3, O-C ?_3 alkyl or Cj_3 alkyl; n is from 2 to 4; m is 0, 1 or 2.

Formula II wherein the dotted union represents a single or double bond; Aryl means a fused phenyl or a monocyclic heteroaromatic ring; R is H, C ?5 alkyl, C3_5 alkenyl, an aromatic ring such as phenyl, thienyl, pyridyl and imidazolyl which is unsubstituted or optionally substituted with OH, O-C1-3 alkyl, S (= 0) m C? -3 alkyl, halogen, CF3 or S (= 0) 2 NR5R6; or C2-3 alkyl, optionally substituted with OH O-C ?3 alkyl, S (= 0) m C ?3 alkyl, or an aromatic ring such as phenyl, thienyl, pyridyl and imidazolyl which is unsubstituted or substituted optionally with OH, O-C3-3 alkyl, S (= 0) m C1-3 alkyl, halogen, CF3, S (= 0) 2NR5R6; or C3-5 alkenyl optionally substituted with OH, O-C 1-3 alkyl or S (= 0) m C 1-3 alkyl; R 2 is H, halogen, C 1-3 alkyl, S (= 0) m C 1-3 alkyl, S (= 0) 2NR5R6; or C 1-3 alkyl optionally substituted with OH, or O-C 1-3 alkyl; R and R are independently H, C1-3 alkyl or C1-3 alkyl optionally substituted with OH or O-C3 alkyl; R5, R6 are independently H, C1-3 alkyl, C2-3 alkyl optionally substituted with OH, O-alkyl C1-3, or R5 and R may be linked together with saturated carbon atoms to form a 5- or 6-membered ring and the carbon atoms may be not optionally substituted or substituted with C1-3alkyl, C2-3alkyl optionally substituted with OH or O-C1-3alkyl; R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be unsubstituted or substituted on the carbon with one or more substituents optionally selected from C? _3 alkyl, C1-3 alkyl optionally substituted with OH, C1-O-alkyl -3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C3_3alkyl or C3_3alkyl, or substituted on the nitrogen with C1-C4alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C1-3alkyl or C1-3alkyl; n is 2 to 4; m is 0, 1 or 2.

Formula III R3 and R4 are independently H, C3_3alkyl or C3_3alkyl optionally substituted with OH or O-alkyl C1-3; R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be substituted or unsubstituted on the carbon with one or more substituents optionally selected from C1-3alkyl, C1-3alkyl optionally substituted with OH, O-C1alkyl ? _3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C3-alkyl or C1-3 alkyl, or substituted on the nitrogen with C3-C4 alkoxy or phenyl which may not be optionally substituted or substituted with halogen, CF3, O-C1-3alkyl or C1-3alkyl; R9 is phenyl or a monocyclic heteroaromatic ring which may be unsubstituted or substituted with C1-4alkyl, halogen, O-C1-alkyl; R10 is C? _ Alkyl, or R may be attached to R to form a fused bicyclic ring system such as indolino [sic]; n is 2 to 4.

Formula IV R4 and R are independently H, C3 alkyl or C3-3 alkyl optionally substituted with OH or O-alkyl C1-3; R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be substituted or unsubstituted on the carbon with one or more substituents optionally selected from C1-3alkyl, C1-3alkyl optionally substituted with OH, O-C1alkyl -3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C1-3 alkyl or C1-3 alkyl, or substituted on the nitrogen with C1-C alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-alkyl C? _3 or C1-3 alkyl; R11 is C1-3 alkyl, phenyl or a monocyclic heteroaromatic ring which may be unsubstituted or substituted with C 1-4 alkyl, halogen, O-C 1-4 alkyl; 12 R is C 1-4 alkyl or a heteroaromatic, bicyclic ring, fused as thien [3, 2-e] -1,2-thiazine, or 1, 2-benzothiazine, or R 12 may be linked to R 11 to form a bicyclic ring system, fused such as 2,3-dihydro-benzo [c] isoxazole; n is 2 to 4. The compounds of the present invention can be prepared using the chemical synthesis methods described herein. The preferred method for preparing the compounds of the formula I is illustrated in Scheme I. For example, the thiazine alcohols I, which can be prepared by the methods described in U.S. Patent Nos. 5,344,929 and 5,470,973, or in J. Org. Chem. 31, 162 (1966), can be selectively alkylated at the nitrogen atom at the 2-position with, for example, a dihaloalkane using the procedures known in the art, to obtain, 2, wherein X is a halogen atom such as chlorine, bromine or iodine, the compounds 2 can be treated with amines by known processes to provide the compounds of the formula I (3) wherein R is hydroxyl, further these alcohols 3 can be treated with an alkyl halide to effect alkylation on the oxygen to provide the ethers, R is alxoxi. Otherwise, 2 can be dehydrated using the methods that are described in US Pat. No. 5,538,966 to obtain the compounds 4 which can furthermore be reacted with amines to obtain the compounds of the formula I wherein R is hydrogen and the thiazine ring contains a double bond (5).

Scheme I The processes for preparing the compounds of the formula II are illustrated in Scheme II. For example, the 3-hydroxymethylthiazamine compounds 7 can be prepared from the esters 6 by the methods that are described in U.S. Patent 5,538,966 [Equation (a)]. In addition, the compounds 7 can be aminated using some of the well-known procedures, such as the initial activation of the hydroxyl group to form a sulfonate ester, followed by the reaction of this intermediary with the desired primary or secondary amine 3 4 to obtain compounds 8 of formula II, wherein R and R are hydrogen, and n is 1 [Equation (b)]. In addition, by using 7 as an intermediate with which a suitable homologation sequence is initiated, it is possible to prepare the compounds of the formula II, wherein R and R are hydrogen and n is 2 or 3; an example of such homologation sequence using 7 is illustrated in equations (c) and (d), respectively.

Scheme II The preparation of compounds III can be carried out easily by the methods described herein. For example, the reaction of the desired amine 14 with the appropriate haloalkylsulfonyl chloride 15 in an inert solvent, in the presence of a convenient base [see, for example, J. Med. Chem. 40, 3217 (1997)] to obtain the haloalkylsulfonamide intermediate 16. subsequent reaction of 16 with the appropriate primary or secondary amine using the known procedures provides compounds 17 of formula III. jUgjg ** ^ - "^ sS -" - ^ » Scheme III The preparation of the compounds of the formula IV can be easily carried out by the methods described herein. For example, the reaction of the desired primary amine with the appropriate sulfonyl chloride in an inert solvent, in the presence of a suitable base, provides the secondary sulfonamide intermediate 19 which can be alkylated by known procedures with the alkyl dibromide suitably substituted for obtaining the haloalkylsulfonamide intermediate 20. Subsequent reaction of 20 with the appropriate primary or secondary amine using well-known procedures provides compounds 21 of formula IV.

Scheme IV It is evident that some of the compounds of formula I-IV will include asymmetric atoms, all enantiomers and diastereomers are contemplated. The term "heteroaromatic ring" refers to thiophene, furan, pyrrole, pyridine, pyrimidine, pyridazine and pyrazine.

The compounds can be administered systemically or locally to the eye (e.g., topically, intracamerally or by an implant). Preferably, the compounds are incorporated into topical ophthalmic formulations for delivery to the eye. The compounds can be combined with ophthalmologically acceptable preservatives, surfactants, viscosity improvers, penetration enhancers, buffers, sodium chloride and water to form a sterile, aqueous, ophthalmic solution or suspension. Formulations for the ophthalmic solution can ^ ^^^ Jt ^,. * - *., - ^ - "á- prepare by dissolving a compound in an isotonic, physiologically acceptable aqueous buffer solution. In addition, the ophthalmic solution may include an ophthalmologically acceptable surfactant to help dissolve the compound. In addition, the ophthalmic solution may contain an agent for increasing the viscosity, such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone or the like, to improve the retention of the formulation in the conjunctival sac. It is also possible to use gelling agents including, but not limited to, gellan and xanthan gum. To prepare sterile ophthalmic ointment formulations, the active ingredient is combined with a preservative in a suitable vehicle, such as mineral oil, liquid lanolin or white petrolatum. Sterile gel ophthalmic formulations can be prepared by suspending the active ingredient in a hydrophilic base prepared from the combination of, for example, carbopol-940 or the like, according to published formulations for analogous ophthalmic preparations; It can incorporate preservatives and agents to confer tonicity. The compounds can be formulated for systemic delivery (eg, oral, IV, IM, subcutaneous) according to methods known to those skilled in the art. For him systemic delivery, the compounds are supplied in concentrations of 0.005-1000 mg per dose, preferably 0.05-20.0, most preferably 0.2-5 mg per dose. The compounds will be dosed 1 to 4 times per day according to the criteria of the expert physician. Ophthalmic medications of the compounds are preferably formulated as suspensions or ophthalmic solutions with a pH of about 5 to 8. The compounds will normally be contained in these formulations in an amount of 0.01% to 5% by weight, but preferably in an amount from 0.25% to 2% by weight. Thus, for topical presentation of one to two drops of these formulations would be delivered to the surface of the eye from 1 to 4 times a day according to the physician's criteria. The preferred compounds are those set forth in examples 1, 1.1, 1.2, 1.6, 1.8, 2.3, 2.7, 2.10, 2.1, 2.4, 3, 3.1, 3.11, 3.5 and 3.10.

Example 1 6-Chloro-2- [4- [4- (2H-benzimidazo-2-oxo-l-yl) piperidin-1-yl] butyl] -2H-thieno [3,2-e] -l hydrochloride , 2-thiazine 1,1-dioxide Step 1. A solution of 1,1-dioxide of 6-chloro-3,4-dihydro-2H-thien [3,2-e] -1,2-thiazine-4-ol (9.0 g, 37.6 mmol) in dimethylformamide (200 ml, anhydrous) and sodium hydride (60% in oil, 1.66 g, 1.5 mmol) was reacted with 5 1, 4-dibromobutane at 0 ° [sic]. The reaction was stirred in an ice bath for 30 minutes and then allowed to warm to room temperature and stirred for three days. The mixture was poured into ice water (400 ml) and extracted with diethyl ether (2 x 200 ml). The combined organic layers were washed with water (200 ml), brine (200 ml) and then dried over magnesium sulphate and evaporated. The resulting residue was purified by flash chromatography on silica gel with hexane / ethyl acetate (7: 3) to obtain 6-chloro-3,4-dihydro-2- (4-5-bromobutyl) 1,1-dioxide. 2H-thien [3,2-e] -1,2-thiazine-4-ol as a colorless oil (10.62 g, 75%); H NMR was consistent with the structure. Step 2. The product of Step 1 (10.28 g, 28.3 mmol) was dissolved in tetrahydrofuran (anhydrous, 400 ml) and treated 0 with triethylamine (9.88 ml, 70.9 mmol) and methanesulfonic anhydride (9.86 g, 56.6 mmol) at room temperature and stirred for one hour. The suspension was concentrated and taken in dimethylformamide (anhydrous, 120 ml). This mixture was heated to 160 ° [sic] for 45 minutes, the reaction mixture was poured into ice water (300 ml) and extracted _t ^^ MU6ií ^ fc-_ with dichloromethane (300 ml). The organic layer was washed with water 82 x 200 ml), dried over magnesium sulphate and evaporated to a brown oil. After flash chromatography on silica with hexane / ethyl acetate, 6-chloro-2- (4-bromobutyl) -2H-thien [3,2-e] -1,2-thiazine 1,1-dioxide was obtained as a yellow oil (4.97 g, 49%); H NMR was consistent with the structure. Step 3. A solution of 4- (2H-benzimidazo-2-oxo-l-yl) piperidine (0.30 mmol) in DMF (1.6 ml, anhydrous) and triethylamine (0.5 ml) was treated with the product from Step 2 (0.103). g, 0.29 mmol) and stirred at 70 ° [sic] for 20 hours and then at room temperature for two days. The reaction mixture was diluted with ethyl acetate (3 ml) and water (3 ml). Saturated sodium bicarbonate (1 ml) [sic] was added and the layers were mixed followed by removal of the aqueous layer. The organic layer was washed with water (6 ml) and evaporated to obtain a residue which was dissolved in ethanol and treated with IN hydrochloric acid in ether. After evaporation the desired product was obtained as a white solid (69.2 mg, 45%): 1 H NMR and MS (M + H 493) were consistent with the structure. Following the procedures of Example 1, but replacing 4- (2H-benzimidazo-2-oxo-1-yl) piperidine in Step 3 with the appropriate amine, the following compounds were prepared. The 1H NMR spectrum and the mass spectrum for each of these compounds were consistent with the assigned structure. 1,1-dioxide 6-chloro-2- [4- (4-phenylpiperazin-1-yl) butyl] -2H-thien [3,2-e] -1,2-thiazine hydrochloride; 2. 6-chloro-2- [4- [4- (4-fluorophenyl) piperazin-l-yl] butyl] -2H-thien [3,2-e] -1,2-thiazine 1,1-dioxide hydrochloride; 3. 6-chloro-2- [4- [4-hydroxy-4- (4-chlorophenyl) piperidin-1-yl] butyl] -2H-thien [3, 2-e] -1 1,1-dioxide , 2- thiazine hydrochloride; 4. 6-chloro-2- [4- [4-hydroxypiperidin-1-yl] butyl] -2H-thien [3,2-e] -1,2-thiazine hydrochloride 1,2-dioxide; Following the procedures of Example 1, but replacing 1,4-dibromobutane in Step 1 with 1,3-dibromopentane and 4- (2H-benzimidazo-2-oxo-l-yl) piperidine in Step 3 with the appropriate amine , the following compounds were prepared. The H NMR spectrum and the mass spectrum for each of these compounds were consistent with the assigned structure. 5. 6-chloro-2- [3- [4-phenylpiperazin-1-yl] propyl] -2H-thien [3,2-e] -1,2-thiazine hydrochloride 1,1-dioxide; 6. 6-Chloro-2- [3- [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl] propyl] -2-dioxide [3, 2-e] -1,2- thiazine hydrochloride; 7. 6-chloro-2- [3- [4- (2-fluorophenyl) piperazin-1-yl] propyl] -2H-thien [3,2-e] -1,2-thiazine 1,1-dioxide hydrochloride; 8. 6-Chloro-2- [3- [4- (2H-benzimidazole-2-oxo) piperidin-1-yl] propyl] -2H-thien [3, 2-e] -1,2-1,2-dioxide -thiazine hydrochloride; EXAMPLE 2 3- (4-Methylpiperidin-1-yl) propylsulfonyl-2, 3-dihydro-1H-indole hydrochloride Step 1. To a solution of indoline (4.00 g, 33.6 mmol) in 100 ml of acetone at 0 ° C was added 3-chloropropanesulfonyl chloride (5.95 g, 33.6 mmol) with stirring. I precipitate a solid of the solution. Diisopropylethylamine (4.33 g, 33.6 mmol) was added in two portions and the reaction mixture became a homogeneous solution. The mixture was stirred for 30 minutes, warmed to room temperature and evaporated to dryness. The crude mixture was combined with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (2 x 100 ml). Chromatography on silica gel (10% to 25% ethyl acetate / hexane) gave an oil that solidified with the well (7.68 g, 77%, pp. 53-53 ° C [sic]).

Step 2. A mixture of the product of Step 1 (200 mg, 0.77 mmol) and a 0.5 M solution of 4-methylpiperidine (4 mL, 2.0 mmol) was heated at 35 ° C for 60 hours. The reaction mixture was combined with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (2 x 10 ml). The extracts were dried and evaporated to dryness. The crude product was filtered through a short silica column and treated with a 1.0 M solution of hydrogen chloride gas in ether. The solid was filtered and dried to obtain the hydrochloride salt (220 mg, 80%): MS (ES) 323 (M + H).

Following the procedures of Example 2, but substituting 2-methylpiperidine in Step 2 with the appropriate amine, the following compounds were prepared. The H NMR spectrum and the mass spectrum for each of these compounds were consistent with the assigned structure. 1. 3- [4- (3-Chlorophenyl) piperazin-1-yl] propylsulfonyl-2, 3-dihydro-lN-indole; 2. 3- (3-Methylpiperidin-1-yl) propylsulfonyl-2,3-dihydro-1H-indole; 3. 3- (1,2,3,4-Tetrahydroisoquinolin-2-yl) propylsulfonyl-2,3-dihydro-lH-indole; 4. 3- [4- (3-Trifluoromethylphenyl) piperazin-1-yl] propylsulfonyl-2,3-dihydro-1H-indole; 5. 3- (4-Phenylpiperazin-1-yl) propylsulfonyl-2,3-dihydro-1H-indole; - ^^ "^ 6. 3- [4- (2-Fluorophenyl) piperazin-1-yl] propylsulfonyl-2, 3-dihydro-1H-indole; 7. 3- [4- (2-Methoxyphenyl) piperazin-1-yl] propylsulfonyl-2, 3-dihydro-1H-indole; 5 8. 3- [4- (4-Methoxyphenyl) piperazin-1-yl] propylsulfonyl-2, 3-dihydro-1H-indole; 9. 3- [4- (2-Chlorophenyl) piperazin-1-yl] propylsulfonyl-2, 3-dihydro-1H-indole. Following the procedures of Example 2, but substituting the indoline in Step 1 with N-methylaniline and the 4-methylpiperidine in Step 2 with the appropriate amine, the following compounds were prepared. The H NMR spectrum and the mass spectrum for each of these compounds were consistent with the assigned structure. 10. 3- (1,2,3,4-Tetrahydroisoquinolin-2-yl) -N-methyl-N-phenyl-propylsulfonamide; 11. N-Methyl-N-phenyl-3- [4- (3-trifluoromethyl) piperazin-1-yl] propylsulfonamide; 12. N-Methyl-N-phenyl-3- (4-phenylpiperazin-1-yl) propylsulfonamide; 13. 3- [4- (2-Fluorophenyl) piperazin-1-yl] -N-methyl-N-phenyl-propylsulfonamide; 14. N-Methyl-3- [4- (2-methoxyphenyl) piperazin-1-yl] -N-phenyl-propylsulfonamide; 25 15. 3- [4- (2-Chlorophenyl) piperazin-1-yl] -N-methyl-N-phenyl- propylsulfonamide. Following the procedures of Example 2, but substituting the 3-chloropropanesulfonyl chloride in step 1 with 2-chloroethanesulfonyl chloride and the 4-methylpiperidine in Step 2 with 3-methylpiperidine, the following compound was prepared. The H NMR spectrum and the mass spectrum for each of these compounds were consistent with the assigned structure. 16. 2- (3-methylpiperidin-1-yl) ethylsulfonyl-2,3-dihydro-1H-indole.

Example 3 N- [3- [4- (3-Chlorophenyl) piperazin-1-yl] propyl] -N- (4-methoxyphenyl) -propanesulfonamide hydrochloride Step 1. ? a solution of p-amsiama (6.00 g, 48.7 mmol) and triethylamine (5.91 g, 58.4 mmol) in methylene chloride (200 ml) at 0 ° C was added propylsulfonyl chloride (7.64 g, 53.6 mmol) with stirring under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The mixture was washed with a saturated aqueous solution of ^^^^. sodium bicarbonate (100 ml), water and dried over magnesium sulfate. The organic layer was evaporated to obtain an oil which was mixed with a solution of hexane and ethyl acetate (3.1) to yield a crystalline solid (7.97 g). The mother liquor was subjected to chromatography on silica gel (hexane / ethyl acetate, 4: 1) to obtain a solid (2.27 g, 92%): p. F. 72 ° C; MS (-ES) 228 (M-H). Step 2. For the product from Step 1 (3.50 g, 15.3 mmol) in anhydrous dimethylformamide (80 ml) at 0 ° C, sodium hydride (60% suspension in mineral oil, 0.672 g, 16.8 mmol) was added under an atmosphere of nitrogen. The suspension was stirred for 30 minutes and 1,3-dibromopropane (9.27 g, 45.9 mmol) was added during one minute. The reaction was stirred for three hours, mixed with a saturated aqueous solution of sodium bicarbonate (200 ml) and extracted with ethyl acetate (3 x 100 ml). The combined extracts were dried and evaporated to dryness. Chromatography on silica (20% ethyl acetate in hexane) yielded a colorless oil (4.33 g, 81%): MS. { ES) 352 (M + H). Step 3. To a solution of the product from Step 2 (0.175 g, 0.50 mmol) in anhydrous dimethylformamide (1 ml) was added a 0.5 M solution of 1- (3-chlorophenyl) piperazine in dimethylformamide (1.1 ml, 0.55 mmol) and triethylamine (0.20 ml). This mixture was heated at 60 ° C for 18 hours. The cooled reaction mixture was extracted with ethyl acetate as t ^? ^ k. ethyl acetate (2 x 1 ml) and the combined extracts were washed with a saturated aqueous solution of sodium bicarbonate, dried and evaporated to an oil which was treated with a 1.0 M solution of hydrogen chloride gas in ether to obtain the corresponding salt (0.11 g, 44%): MS (ES) 466 (M +). Following the procedures of Example 3, but substituting 1- (3-chlorophenyl) piperazine in Step 3 with the appropriate amine, the following compounds were prepared. The H NMR spectrum and the mass spectrum for each of these compounds were consistent with the assigned structure. 1. N- [3- (1,2,3,4-Tetrahydroisoquinolin-2-yl) propyl] -N- (-methoxyphenyl) propanesulfonamide; 2. N- [3- (3-Hydroxymethylpiperidin-1-yl) propyl] -N- (4-methoxyphenyl) -propanesulfonamide; 3. N- (4-Methoxyphenyl) -N- [3- (morpholin-4-yl) propyl] -propanesulfonamide; 4. N- (4-Methoxyphenyl) -N- [3- (2-methylpiperidin-1-yl) propyl] -propanesulfonamide; 5. N- [3- [4- (3-Chlorophenyl) piperazin-1-yl] propyl] -N- (4-methoxyphenyl) propanesulfonamide; 6. N- (4-Methoxyphenyl) -N- [3- [4- (3-trifluoromethylphenyl) piperazin-1-yl] propyl] -propanesulfonamide; 7. N- [3- (4-phenylpiperazin-1-yl) propyl] -N- (4-methoxyphenyl) -propanesulfonamide; 8. N- [3- [4- (2-Fluorophenyl) piperazin-1-yl] propyl] -N- (4-methoxyphenyl) propanesulfonamide; 9. N- [3- [4- (4-Methoxyphenyl) piperazin-1-yl] propyl] -N- (4-methoxyphenyl) propanesulfonamide; 10. N- [3- [4- (2-Methoxyphenyl) piperazin-1-yl] propyl] -N- (4-methoxyphenyl) propanesulfonamide; 11. N- [3- [4- (2-Chlorophenyl) piperazin-1-yl] propyl] -N- (4-methoxyphenyl) propanesulfonamide; 12. N- [3- [4- (2H-Benzimidazo-2-oxo-1-yl) piperidin-1-yl] propyl] -N- (4-methoxyphenyl) propanesulfonamide. Following the procedures of Example 3, but substituting 1,3-dibromopropane in Step 2 with 1,4-dibromobutane and 1- (3-chlorophenyl) piperazine in Step 3 with 1, 2, 3, 4-tetrahydroizoquinoline, the following compound was prepared. The H NMR spectrum and the mass spectrum for this compound were consistent with the assigned structure. 13. N- [4- (1, 2, 3, 4-tetrahydroisoquinolin-2-yl) butyl] -N- (4-methoxyphenyl) -methanesulfonamide. The following topical ophthalmic formulations are useful according to the present invention administered 1 to 4 times a day according to the judgment of the skilled physician. lUtaÉI-Jííftt ^ BK EXAMPLE 4 EXAMPLE 5 EXAMPLE 6 EXAMPLE 7 EXAMPLE 8 EXAMPLE 9 EXAMPLE 10 EXAMPLE 11 - - ^ t ~ - »-" EXAMPLE 12 Formulation for oral administration Tablet: 0.2-5 mg of compound 5HT7 with inactive ingredients such as corn starch, lactose, colloidal silicon dioxide, microcrystalline cellulose and magnesium stearate can be formulated according to procedures known to those skilled in the art. of the tablet formulation. ^^ b ausau ^ attí.

Claims

1. A compound of the formula: wherein the dotted link represents a single or double bond; Aryl means a fused phenyl or monocyclic heteroaromatic ring; R is H, OH, O-C de3 alkyl, C1-3 alkyl, alkyl C1-3 optionally substituted with OH, or O-C1-3alkyl; R2 is H, halogen, C? -3 alkyl, CONR5R6, S (= 0) m-C? _3 alkyl, S (= 0> 2NR R, C1-3 alkyl optionally substituted with OH or O-alkyl) of C1-3; R3, R4 are independently H, C? -3 alkyl, C1-3 alkyl optionally substituted with OH or O-alkyl of C1-3; R, R are independently H, C ?3 alkyl, C2-3 alkyl optionally substituted with OH, O-C alquilo3 alkyl, - or R and R may be linked together with saturated carbon atoms to form a ring of 5 or 6 members and the carbon atoms may be optionally unsubstituted or substituted with alkyl of C1-3, C2-3 alkyl optionally substituted by OH or O-C1-3alkyl; R, R are together with the nitrogen atom to which they are attached incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be unsubstituted or substituted on the carbon with one or more substituents optionally selected from C1-3alkyl, Cj._3alkyl optionally substituted with OH, O-C1alkyl -3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C3_3 alkyl or C1-3 alkyl, or substituted on nitrogen with C1-C4 alkoxy or phenyl which may be unsubstituted or substituted optionally with halogen, CF3, O-C3_3alkyl or C1-3alkyl; n is from 2 to 1; m is 0, 1 or 2 and any of the pharmaceutically acceptable salts and solvates. H ^

2. A compound of the formula: wherein the dotted union represents a single or double bond; Aryl means a fused phenyl or a monocyclic heteroaromatic ring; R is H, C1-5 alkyl, C3_5 alkenyl, an aromatic ring such as phenyl, thienyl, pyridyl and imidazolyl which is unsubstituted or optionally substituted with OH, O-C1-3 alkyl, S (= 0) m C 1-3 alkyl, halogen, CF 3 or S (= 0) 2 NR 5 R 6; or C2-3 alkyl, optionally substituted with OH O-C1-3 alkyl, S (= 0) m C1-3 alkyl, or an aromatic ring such as phenyl, thienyl, pyridyl and imidazolyl which is unsubstituted or substituted optionally with OH, O-C 1 -C 3 alkyl, S (= 0) m C 1-3 alkyl, halogen, CF 3, S (= 0> 2NR 5 R, or C 3 5 alkenyl optionally substituted with OH, O-alkyl C3.-3 or S (= 0) m C 1-3 alkyl, R 2 is H, halogen, C 1-3 alkyl, S (= 0) m C 1-3 alkyl, S (= 0) 2 NR R; of C1-3 optionally substituted with OH, or O-C1-3 alkyl: R and R are independently H, C1-3 alkyl or alkyl - "" - - ^? T ^ mt ae? T ÍHíii ^ í í ib? m iWtk of C1-3 optionally substituted with OH or O-alkyl of C1-3; R, R are independently H, C1-3 alkyl, C2-3 alkyl optionally substituted by OH, O-C3 alkyl, or R and R may be linked together with saturated carbon atoms to form a ring of 5 or 6 members and the carbon atoms may be unsubstituted or optionally substituted with C 1-3 alkyl, C 2-3 alkyl optionally substituted with OH or O-C 1-3 alkyl; R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be substituted or unsubstituted on the carbon with one or more substituents optionally selected from C1-3alkyl, C1-3alkyl optionally substituted with OH, O-C1alkyl -3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C1-3alkyl or C1-3alkyl, or substituted on the nitrogen with C1-C4alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C1-3alkyl or C1-3alkyl; n is 2 to 4; m is O, 1 or 2 and any of the pharmaceutically acceptable salts and solvates.

3. A compound of the formula: R and R are independently H, C3 alkyl or C3-3 alkyl optionally substituted with OH or O-alkyl C1-3; R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be substituted or unsubstituted on the carbon with one or more substituents optionally selected from C1-3alkyl, C1-3alkyl optionally substituted with OH, O-C1alkyl -3. phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C1-3alkyl or C1-3alkyl, or substituted on the nitrogen with C1-C4alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-alkyl C? _3 or C? _3 alkyl, -9 R is phenyl or a monocyclic heteroaromatic ring which may be unsubstituted or substituted by C1_alkyl, halogen, O_C? - alkyl; R is C 1-4 alkyl, or R may be attached to R to form a fused bicyclic ring system such as indolino [sic]; n is 2 to 4 and any of the pharmaceutically acceptable salts and solvates.

4. A compound of the formula: R and R are independently H, C ?3 alkyl or C 1-3 alkyl optionally substituted with OH or O-alkyl C1-3 R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be substituted or unsubstituted ^ ÉÍM £ -átlHk.-Mi at the carbon with one or more substituents optionally selected from C1-3alkyl, C1_3alkyl optionally substituted with OH, OC3-3alkyl, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O -C3 alkyl or C1-3 alkyl, or substituted on the nitrogen with C1-C4 alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C3 alkyl or C1-6 alkyl 3; R is C 1-3 alkyl, phenyl or a monocyclic heteroaromatic ring which may be unsubstituted or substituted with C 1 -4 alkyl, halogen, C 1 -4 alkyl; R 12 is C 1-4 alkyl or a heteroaromatic, bicyclic ring, fused as thien [3, 2-e] -1,2-thiazine, or 1,2-benzothiazine, or R 12 may be attached to R 11 to form a bicyclic ring system, fused such as 2, 3-dihydro-benzo [c] isoxazole; n is 2 to 4 and any of the pharmaceutically acceptable salts and solvates.

5. A method for reducing IOP, which is to administer to a person in need thereof, a composition containing an effective amount of a compound of the formula: wherein the dotted link represents a single or double bond; Aryl means a fused phenyl or monocyclic heteroaromatic ring; R is H, OH, O-C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkyl optionally substituted with OH, or O-C 1-3 alkyl; R2 is H, halogen, C1-3alkyl, CONR5R6, S (= 0) m-C1-3alkyl, S (= 0> 2NRR, C1-3alkyl optionally substituted with OH or O-C1alkyl) -3; R 3, R 4 are independently H, C 1-3 alkyl, C 0-3 alkyl optionally substituted with OH or O-alkyl C1-3; R, R are independently H, C? _3 alkyl, C2-3 alkyl optionally substituted with OH, O-C1-3 alkyl; or R and R can be linked together with saturated carbon atoms to form a 5- or 6-membered ring and the carbon atoms can be optionally unsubstituted or substituted with C? _3 alkyl, C2-3 alkyl optionally substituted with OH or O-C1-3 alkyl; R7, R are together with the nitrogen atom to which they are riÉia-Uiíi ^ lHtMI MÉb united incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be unsubstituted or substituted on the carbon with one or more substituents optionally selected from C1-3alkyl, C1-3alkyl optionally substituted with OH, O-alkyl C? _3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C3_3alkyl or C3_3alkyl, or substituted on nitrogen with C1-C4alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C3_3alkyl or C1-3alkyl; n is from 2 to 4; m is 0, 1 or 2 and any of the pharmaceutically acceptable salts and solvates.

6. A method for reducing IOP, which is to administer to a person in need thereof, a composition containing an effective amount of a compound of the formula: - ^^ - "^^ - ^ flfil aggUl wherein the dotted union represents a single or double bond; Aryl means a fused phenyl or a monocyclic heteroaromatic ring; R is H, C1-5 alkyl, C3-5 alkenyl, an aromatic ring such as phenyl, thienyl, pyridyl and imidazolyl which is unsubstituted or optionally substituted with OH, O-C1-3 alkyl, S (= 0 ) m C 1-3 alkyl, halogen, CF 3 or S (= 0) 2 NR 5 R 6; or C2-3 alkyl, optionally substituted with OH O-C1-3 alkyl, S (= 0) m C3_3 alkyl, or an aromatic ring such as phenyl, thienyl, pyridyl and imidazolyl which is unsubstituted or substituted optionally with OH, O-C 1-3 alkyl, S (= 0) m C 1-3 alkyl, halogen, CF 3, S (= 0) 2 NR 5 R 6; or C3_5 alkenyl optionally substituted with OH, O-C1-3 alkyl or S (= 0) m C1-3 alkyl; R 2 is H, halogen, C 3 alkyl, S (= 0) m C 1-3 alkyl, S (= 0) 2NR5R6; or C 1-3 alkyl optionally substituted with OH, or O-C 1-3 alkyl; R and R4 are independently H, C3 alkyl or C1-3 alkyl optionally substituted with OH or O-alkyl C1-3; R5, R6 are independently H, C1-3 alkyl, C2-3 alkyl optionally substituted with OH, O-C1-3 alkyl, or R and R may be attached to each other with atoms * "« * • "• ***» • "- - -J-- saturated carbon to form a 5- or 6-membered ring and the carbon atoms may be unsubstituted or optionally substituted with C 1 -C 3 alkyl, C 2 -3 alkyl optionally substituted with OH or O-C 1-3 alkyl; R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be substituted or unsubstituted on the carbon with one or more substituents optionally selected from C1-3alkyl, C1-3alkyl optionally substituted with OH, O-C1alkyl -3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C1-3 alkyl or C3-3 alkyl, or substituted on the nitrogen with C1-C4 alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C3 alkyl or C1-3 alkyl; n is 2 to 4; m is 0, 1 or 2 and any of the pharmaceutically acceptable salts and solvates. JM ÉIÉÉtl y, ...-- ^ * "-

7. A method for reducing IOP, which is to administer to a person in need thereof, a composition containing an effective amount of a compound of the formula: R3 and R4 are independently H, C3_3alkyl or C3_3alkyl optionally substituted with OH or O_C3_3alkyl; R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be substituted or unsubstituted on the carbon with one or more substituents optionally selected from C1-3 alkylC 1 -C 3 alkyl optionally substituted with OH, O-C 1-3 alkyl, phenyl which may be unsubstituted or optionally substituted with halogen, CF 3, O-C 3 alkyl or C 1-3 alkyl, or substituted on the nitrogen with C 1 -C 4 alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF 3, O-C 1-3 alkyl or C 3 alkyl; 11 11 rri 1 '• - I? G - ^ maaagfafc R is phenyl or a monocyclic heteroaromatic ring which may be unsubstituted or substituted with C 1-4 alkyl, halogen, O-C 1-4 alkyl; R is C 1-4 alkyl, or R 10 may be attached to R to form a fused bicyclic ring system such as indolino [sic]; n is 2 to 4 and any of the pharmaceutically acceptable salts and solvates.

8. A method for reducing IOP, which is to administer to a person in need thereof, a composition containing an effective amount of a compound of the formula: R and R are independently H, C3_3alkyl or C3_alkyl optionally substituted with OH or OC3_3alkyl; R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, γ3-piper? Dein [sic], piperazine, morpholine or ^^^ thiomorpholine which may be unsubstituted or substituted on the carbon with one or more substituents optionally selected from C? _3 alkyl, C1-3 alkyl optionally substituted with OH, C? -3 alkyl, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C3-alkyl or C3 alkyl, or substituted on the nitrogen with C1-C4 alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O -alkyl of C? _3 or C1-3 alkyl; R is C 1-3 alkyl, phenyl or a monocyclic heteroaromatic ring which may be unsubstituted or substituted with C 1-4 alkyl, halogen, C 1-4 alkyl; R 12 is C 1-4 alkyl or a heteroaromatic, bicyclic ring, fused as thien [3, 2-e] -1,2-thiazine, or 1,2-benzothiazine, or R may be attached to R to form a bicyclic ring system, fused such as 2, 3-dihydro-benzo [c] isoxazole; n is 2 to 4 and any of the pharmaceutically acceptable salts and solvates.

9. A method for improving blood flow to the head of the optic nerve and the retina, which consists of administering to a person in need thereof, a composition containing an effective amount of a compound of the formula: wherein the dotted link represents a single or double bond; Aryl means a fused phenyl or monocyclic heteroaromatic ring; R is H, OH, O-C de3 alkyl, C ?3 alkyl, alkyl C? _3 optionally substituted with OH, or O-C1-3alkyl; R 2 is H, halogen, C 1 -C 3 alkyl, CONR 5 R 6, S (= 0) R-C 3 alkyl, S (= 0) 2 NRR, C 1-3 alkyl optionally substituted with OH or O- C 0 alkyl; R 3, R 4 are independently H, C 1-3 alkyl, C 3 alkyl, optionally substituted with OH or O-alkyl C1-3; R, R are independently H, C1-3 alkyl, C2-3 alkyl optionally substituted with OH, O-C1-3 alkyl; or R and R can be linked together with saturated carbon atoms to form a 5- or 6-membered ring and the carbon atoms can be optionally unsubstituted or substituted with C 1-3 alkyl, C 2-3 alkyl optionally substituted with OH or O-C1-3 alkyl; ^ u mm R, R are together with the nitrogen atom to which they are attached incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be unsubstituted or substituted on the carbon with one or more substituents optionally selected from C? _3 alkyl, C? _3 alkyl optionally substituted with OH, O-C alkyl ? _3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C3_3alkyl or C1-3alkyl, or substituted on nitrogen with C1-C4alkoxy or phenyl which may be unsubstituted or substituted optionally with halogen, CF3, O-C1-3alkyl or C1-3alkyl; n is from 2 to 4; m is 0, 1 or 2 and any of the pharmaceutically acceptable salts and solvates.

10. A method for improving blood flow to the head of the optic nerve and the retina, which consists of administering to a person in need thereof, a composition containing an effective amount of a compound of the formula: nm 'm mt, t? m a¡i ßM íti.Élm¡ i¡m * ^ mílt ^ i * ¡im ¡?? ß wherein the dotted union represents a single or double bond; Aryl means a fused phenyl or a monocyclic heteroaromatic ring; R is H, C ?5 alkyl, C3-5 alkenyl, an aromatic ring such as phenyl, thienyl, pyridyl and imidazolyl which is unsubstituted or optionally substituted with OH, O-C1-3 alkyl, S (= 0 ) m C 1 _ 3 alkyl, halogen, CF 3 or S (= 0) 2 NR 5 R 6; or C2-3 alkyl, optionally substituted with OH O-C1-3 alkyl, S (= 0) m C3_3 alkyl, or an aromatic ring such as phenyl, thienyl, pyridyl and imidazolyl which is unsubstituted or substituted optionally with OH, O-C 1-3 alkyl, S (= 0) m C 1-3 alkyl, halogen, CF 3, S (= 0> 2NRR; or C3-5 alkenyl optionally substituted with OH, O-C ?3 alkyl or S (= 0) m C3-3 alkyl; R2 is H, halogen, C1-6 alkyl 3, S (= 0) m C1-3 alkyl, S (= 0) 2NR5R6; or C 1-3 alkyl optionally substituted with OH, or O-C 1-3 alkyl; R3 and R4 are independently H, C1-3 alkyl or C1-3 alkyl optionally substituted with OH or O-alkyl What is it? C? -3; R, R are independently H, C1-3 alkyl, C2-3 alkyl optionally substituted by OH, O-C3 alkyl, or R and R may be linked together with saturated carbon atoms to form a ring of 5 or 6 members and the carbon atoms may be unsubstituted or optionally substituted with C1-3 alkyl, C2-3 alkyl optionally substituted with OH or O-C3 alkyl, -R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be substituted or unsubstituted on the carbon with one or more substituents optionally selected from C1-3alkyl, C1-3alkyl optionally substituted with OH, O-C1alkyl -3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C1-3alkyl or C1-3alkyl, or substituted on the nitrogen with C1-C4alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C3_3alkyl or C1-3alkyl; n is 2 to 4; m is O, 1 or 2 and any of the pharmaceutically acceptable salts and solvates.

11. A method for improving blood flow to the head of the optic nerve and the retina, which consists of administering to a person in need thereof, a composition containing an effective amount of a compound of the formula: R and R are independently H, C 1-3 alkyl or C 1-3 alkyl optionally substituted with OH or O-alkyl C1-3; R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, β3-piperidein [ sic], piperazine, morpholine or thiomorpholine which may be unsubstituted or substituted on the carbon with one or more substituents optionally selected from C? _3alkyl, C? _3alkyl optionally substituted with OH, O-C1-3alkyl, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C1-3 alkyl or C 1-3 alkyl, or substituted on the nitrogen with C 1 -C 4 alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF 3, O-alkyl C? _3 or C1-3 alkyl; R is phenyl or a monocyclic heteroaromatic ring which may be unsubstituted or substituted by alkyl C1-4, halogen, O-C1-4 alkyl; R is C1- alkyl, or R may be attached to R to form a fused bicyclic ring system such as indolino [sic]; n is 2 to 4 and any of the pharmaceutically acceptable salts and solvates.

12. A method for improving blood flow to the head of the optic nerve and the retina, which consists of administering to a person in need thereof, a composition containing an effective amount of a compound of the formula: R 3 and R 4 are independently H, C 1 -C 3 alkyl or C 1-3 alkyl optionally substituted with OH or O-C 1-3 alkyl; R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be substituted or unsubstituted on the carbon with one or more substituents optionally selected from C1-3alkyl, C1_3alkyl optionally substituted with OH, C1-Oalkyl -3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C3_3 alkyl or C1-3 alkyl, or substituted on the nitrogen with C1-C4 alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C3_3alkyl or C1-3alkyl; R is C 1-3 alkyl, phenyl or a monocyclic heteroaromatic ring which may be unsubstituted or substituted with C 1-4 alkyl, halogen, O-C 1- alkyl; R12 is C4_4 alkyl or a heteroaromatic, bicyclic ring, fused as thien [3, 2-e] -1, 2-thiazine, or 12 1, 2-benzothiazine, or R can be attached to R to form a bicyclic ring system, fused such as 2,3-dihydro-benzo [c] isoxazole; n is 2 to 4 and any of the salts and solvates pharmaceutically g tfg acceptable

13. A method for treating diseases of the retina, which consists of administering to a person in need thereof, a composition containing an effective amount of a compound of the formula: 10 wherein the dotted link represents a single or double bond; Aryl means a fused phenyl or monocyclic heteroaromatic ring; R is H, OH, O-C? _3 alkyl, C 1-3 alkyl, C?? _3 alkyl optionally substituted with OH, or O-C 1-3 alkyl; R2 is H, halogen, C1-3 alkyl, CONR5R6, S (= 0) - C1-3 alkyl, S (= 0) NR5R6, C1-3 alkyl optionally substituted with OH or O- C1 alkyl -.3; R3, R4 are independently H, C1-3 alkyl, alkyl 20 of C? _3 optionally substituted with OH or O-alkyl of C1-3; R5, Rd are independently H, C ?3 alkyl, C2-3 alkyl optionally substituted with OH, O-alkyl C1-3; or R and R can be linked together with atoms 25 saturated carbon to form a ring of 5 or 6 members and the carbon atoms may be optionally unsubstituted or substituted with C3 alkyl, C2-3 alkyl optionally substituted with OH or OC3-3 alkyl; R, R are together with the nitrogen atom to which they are attached incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholma which may be unsubstituted or substituted on the carbon with one or more substituents optionally selected from C1-3alkyl, C3_3alkyl optionally substituted with OH, O-C1alkyl -3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C1-3 alkyl or C1-3 alkyl, or substituted on nitrogen with C1-C4 alkoxy or phenyl which may be unsubstituted or substituted optionally with halogen, CF3, O-C1-3alkyl or C1-3alkyl; n is from 2 to 4; m is 0, 1 or 2 and any of the pharmaceutically acceptable salts and solvates.

14. A method to treat diseases of the retina, which consists of administering to a person in need of a ». ~ -a - this one, a composition containing an effective amount of a compound of the formula: wherein the dotted union represents a single or double bond; Aryl means a fused phenyl or a monocyclic heteroaromatic ring; R is H, C1-5 alkyl, C3-5 alkenyl, an aromatic ring such as phenyl, thienyl, pyridyl and imidazolyl which is unsubstituted or optionally substituted with OH, O-C1-3 alkyl, S (= 0 ) m C 1-3 alkyl, halogen, CF 3 or S (= 0) NR 5 R 6; or C2-3 alkyl, optionally substituted with OH O-C1-3 alkyl, S (= 0) m C1-3 alkyl, or an aromatic ring such as phenyl, thienyl, pyridyl and imidazolyl which is unsubstituted or substituted optionally with OH, O-C 1-3 alkyl, S (= 0) m C 1-3 alkyl, halogen, CF 3, S (= 0) 2NR5R6; or C3_5 alkenyl optionally substituted with OH, O-C1-3 alkyl or S (= 0) m C1-3 alkyl; R is H, halogen, C 1-3 alkyl, S (= 0) m C 1-3 alkyl, S (= 0> 2NR5R; or C1-3alkyl optionally substituted with OH, or O-C1-3alkyl; R4 and R are independently H, C3_3alkyl or C3_3alkyl optionally substituted with OH or O-alkyl C1-3; R, R are independently H, C ?3 alkyl, C2-3 alkyl optionally substituted with OH, O-C alquilo -3 alkyl, or R and R may be linked together with saturated carbon atoms to form a ring of 5 or 6 members and the carbon atoms may be unsubstituted or optionally substituted with C 1-3 alkyl, C 2-3 alkyl optionally substituted with OH or O-C1-3 alkyl; R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be substituted or unsubstituted on the carbon with one or more substituents optionally selected from C1-3 alkyl. C1-3alkyl optionally substituted with OH, O-C1-3alkyl, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C3_3alkyl or C1-3alkyl, or substituted on the nitrogen with C 1 -C alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF 3, O-alkyl aail - - "" .- ** ** »- ** - .. C? _3 or C? _3 alkyl; n is 2 to 4; m is 0, 1 or 2 and any of the pharmaceutically acceptable salts and solvates.

15. A method for treating diseases of the retina, which is to administer to a person in need thereof, a composition containing an effective amount of a compound of the formula: R 3 and R 4 are independently H, C 1-3 alkyl or C 1-3 alkyl optionally substituted with OH or O-alkyl C1-3; R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, pipepdine,? -piperidein [sic], piperazine, morphol or thiomorpholine which may be unsubstituted or substituted on the carbon with one or more substituents optionally selected from C1-3alkyl, C1-3alkyl optionally substituted with OH, O-C1alkyl -3, aiíadiuai-i? íai-u phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C1-3alkyl or C3_3alkyl, or substituted on the nitrogen with C1-C4alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-alkyl C1-3 or C3 alkyl; R is phenyl or a monocyclic heteroaromatic ring which may be unsubstituted or substituted by C 1-4 alkyl, halogen, O-C 1-4 alkyl; R is C 1-4 alkyl, or R may be attached to R to form a fused bicyclic ring system such as indolino [sic]; n is 2 to 4 and any of the pharmaceutically acceptable salts and solvates.

16. A method for treating diseases of the retina, which is to administer to a person in need thereof, a composition containing an effective amount of a compound of the formula: R and R are independently H, C 1-3 alkyl or C 1-3 alkyl optionally substituted with OH or O-alkyl - - iTMfir --tit? rr-111-rtr C? -3; R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be substituted or unsubstituted on the carbon with one or more substituents optionally selected from C1-3alkyl, C1-3alkyl optionally substituted with OH, O-C1alkyl ? 3, phenyl which may be unsubstituted or optionally substituted with halogen, CF 3, O-C 3 alkyl or C 1-3 alkyl, or substituted on the nitrogen with C 1 -C alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C ?3 alkyl or C1-3 alkyl; R is C 1-3 alkyl, phenyl or a monocyclic heteroaromatic ring which may be unsubstituted or substituted with C 1-4 alkyl, halogen, C 1-4 alkyl; 12 R is C4_4alkyl or a heteroaromatic, bicyclic ring, fused as thien [3, 2-e] -1, 2-thiazine, or 1, 2-benzothiazine, or R1 may be attached to R to form a bicyclic ring system, fused such as 2,3-dihydro-benzo [c] isoxazole; n is 2 to 4 jgigg and any of pharmaceutically acceptable salts and solvates.

17. A composition for reducing IOP, which contains a pharmaceutically effective amount of a compound of the formula: wherein the dotted link represents a single or double bond; Aryl means a fused phenyl or monocyclic heteroaromatic ring; R is H, OH, O-C 1 -C 3 alkyl, C 1 -C 3 alkyl, C 1 -C 3 alkyl optionally substituted with OH, or O-C 3 alkyl, R is H, halogen, C 1-3 alkyl, CONRR, S (= 0) m-C1-3alkyl, S (= 0) 2NRR, C3_3alkyl optionally substituted with OH or O- C3_3alkyl; R, R are independently H, C? _3 alkyl, C? _3 alkyl optionally substituted with OH or O-alkyl C1-3; R, R are independently H, C ?3 alkyl, C2-3 alkyl optionally substituted with OH, O-alkyl C1-3; or R and R can be linked together with saturated carbon atoms to form a ring of 5 or 6 sbjaaÉ Ul ßm members and the carbon atoms may be optionally unsubstituted or substituted by C1-3alkyl, C2-3alkyl optionally substituted by OH or O-C3alkyl; R, R are together with the nitrogen atom to which they are attached incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be unsubstituted or substituted on the carbon with one or more substituents optionally selected from C1-3alkyl, C3_3alkyl optionally substituted with OH, O-C1alkyl -3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C1-3 alkyl or C1-3 alkyl, or substituted on nitrogen with C1-C4 alkoxy or phenyl which may be unsubstituted or substituted optionally with halogen, CF3, O-C3_3alkyl or C1-3alkyl; n is from 2 to 4; m is 0, 1 or 2 and any of the pharmaceutically acceptable salts and solvates.

18. A composition for reducing IOP, which contains a pharmaceutically effective amount of a compound of the aMIMiiiiíÉÉf-il 11 iiíÉilil 1 1 1 1 ilíl - || II formula: where the dotted union represents a single or double bond; Aryl means a fused phenyl or a monocyclic heteroaromatic ring; R is H, C1-5 alkyl, C3-5 alkenyl, an aromatic ring such as phenyl, thienyl, pyridyl and imidazolyl which is unsubstituted or optionally substituted with OH, O-C1-3 alkyl, S (= 0 ) m C 1-3 alkyl, halogen, CF 3 or S (= 0) 2 NR 5 R 6; or C2-3 alkyl, optionally substituted with OH O-C1-3 alkyl, S (= 0) m C1-3 alkyl, or an aromatic ring such as phenyl, thienyl, pyridyl and imidazolyl which is unsubstituted or substituted optionally with OH, O-C 1-3 alkyl, S (= 0) m C 1-3 alkyl, halogen, CF 3, S (= 0) 2 NRR; or C3-5 alkenyl optionally substituted with OH, O-C ?_3 alkyl or S (= 0) m C 1-3 alkyl; 2 R is H, halogen, C 1-3 alkyl, S (= 0) m C 1-3 alkyl, S (= 0) 2 NR 5 R; or C 1-3 alkyl optionally substituted with OH, or O-C 1-3 alkyl; R and R are independently H, C1-3 alkyl or alkyl I'Ii? fMr B "'ir -iiiift .a ^ Bja ^^ j ^ g ^^ of C? _3 optionally substituted with OH or O-C1-3alkyl; R, R are independently H, C1-3 alkyl, C2-3 alkyl optionally substituted by OH, O-C3 alkyl, or R and R may be linked together with saturated carbon atoms to form a ring of 5 or 6 members and the carbon atoms may be unsubstituted or optionally substituted with C ?3 alkyl, C2-3 alkyl optionally substituted with OH or O-C ?3 alkyl; R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be unsubstituted or substituted on the carbon with one or more substituents optionally selected from C? _3 alkyl, C 1-3 alkyl optionally substituted with OH, O-C1 alkyl -3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C3 alkyl or C1-3 alkyl, or substituted on the nitrogen with C1-C4 alkoxy or phenyl which may be unsubstituted or substituted optionally with halogen, CF3, O-C ?3 alkyl or C ?3 alkyl; n is 2 to 4; m is O, 1 or 2 and any of the pharmaceutically acceptable salts and solvates.

19. A composition for reducing IOP, which contains a pharmaceutically effective amount of a compound of the formula: R and R are independently H, C 1-3 alkyl or C 1 -C 3 alkyl optionally substituted with OH or O-C 1-3 alkyl; R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be unsubstituted or substituted on the carbon with one or more substituents optionally selected from C? _3 alkyl, C? _3 alkyl optionally substituted with OH, C1-O-alkyl -3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C1-3 alkyl or C3_3 alkyl, or substituted on the nitrogen with ^^^^^ t t ^ u mmitm C 1 -C 4 alkoxy or phenyljx which may be unsubstituted or optionally substituted with halogen, CF 3, O-alkyl C? _3 or C1-3 alkyl; R is phenyl or a monocyclic heteroaromatic ring which may be unsubstituted or substituted with alkyl of C1-4, halogen, O-C 4 alkyl; R is C 1-4 alkyl, or R may be attached to R to form a fused bicyclic ring system such as indolino [sic]; n is 2 to 4 and any of the pharmaceutically acceptable salts and solvates.

20. A composition for reducing IOP, which contains a pharmaceutically effective amount of a compound of the formula: R 3 and R 4 are independently H, C 1 -C 3 alkyl or C 1-3 alkyl optionally substituted with OH or O-alkyl C1-3; R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second hetero atom • ?? • -? mrt M-nt.1 - j¡ || MiIM tMaA¡MM, J M¡M | rMi ^^ i ^ BMÍMttrtiiMfa selected from N, 0, S, as pyrrolidine, piperidine,? -piperidein [sic] -, piperazine, morpholine or thiomorpholine which may be unsubstituted or substituted on the carbon with one or more substituents optionally selected from C 1-3 alkyl, C 1 -C 3 alkyl optionally substituted with OH, O-alkyl C1-3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C1-3alkyl or C1-3alkyl, or substituted on the nitrogen with C1-C4alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-alkyl C? _3 or C_3 alkyl; R is C 1-3 alkyl, phenyl or a monocyclic heteroaromatic ring which may be unsubstituted or substituted with C 1-4 alkyl, halogen, O-C 1 alkyl; R is C 1-4 alkyl or a heteroaromatic, bicyclic ring, fused as thien [3, 2-e] -1,2-thiazine, or 1, 2-benzothiazine, or R 12 may be linked to R 11 to form a bicyclic ring system, fused such as 2,3-dihydro-benzo [c] isoxazole; n is 2 to 4 and any of the pharmaceutically acceptable salts and solvates.

21. A composition to improve blood flow to the head of the optic nerve and the retina, which contains Tfi ittÉmwr iiíiiffiíiiir a pharmaceutically effective amount of a compound of the formula: wherein the dotted link represents a single or double bond; Aryl means a fused phenyl or monocyclic heteroaromatic ring; R is H, OH, O-C 1 alkyl, C 3 alkyl, alkyl C? _3 optionally substituted with OH, or O-C1-3alkyl; R2 is H, halogen, alkyl of .3, CONR5R6, S (= 0) m-alkyl of C? _3, S (= 0) 2NR R, alkyl of C1-3 optionally substituted with OH or 0- alkyl of C1 -3; 3 4 R, R are independently H, C 1-3 alkyl, C 1-3 alkyl optionally substituted with OH or O-alkyl R, R are independently H, C3 alkyl, C2-3 alkyl optionally substituted with OH, O-C3 alkyl; or R and R can be linked together with saturated carbon atoms to form a 5- or 6-membered ring and the carbon atoms can be optionally unsubstituted or substituted with C 1-3 alkyl, C 2-3 alkyl optionally substituted with OH -ffff-TMI-- flí- iMlll '- Jf-¿- ^ ^ .- > ^ ~ M or O-alkyl of C? _3; R, R are together with the nitrogen atom to which they are attached incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be unsubstituted or substituted on the carbon with one or more substituents optionally selected from C 1-3 alkyl, C 1-3 alkyl optionally substituted with OH, O-alkyl C? _3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C1-3 alkyl or C1-3 alkyl, or substituted on nitrogen with C1-C4 alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-alkyl C1-3 or C1-3 alkyl; n is from 2 to 4; m is 0, 1 or 2 and any of the pharmaceutically acceptable salts and solvates.

22. A composition for improving blood flow to the head of the optic nerve and the retina, which contains a pharmaceutically effective amount of a compound of the formula: a ^ j ^ wherein the dotted union represents a single or double bond; Aryl means a fused phenyl or a monocyclic heteroaromatic ring; R is H, C1-5 alkyl, C3_5 alkenyl, an aromatic ring such as phenyl, thienyl, pyridyl and imidazolyl which is unsubstituted or optionally substituted with OH, O-C ?3 alkyl, S (= 0) m C? -3 alkyl, halogen, CF3 or S (= 0) 2 NR5R6; or C2-3 alkyl, optionally substituted with OH O-C ?3 alkyl, S (= 0) m C 1-3 alkyl, or an aromatic ring such as phenyl, thienyl, pyridyl and imidazolyl which is unsubstituted or substituted optionally with OH, O-alkyl of C? _3, S (= 0) m alkyl of C1-3, halogen, CF3, S (= 0> 2NRR; or C3-5 alkenyl optionally substituted with OH, O-C 1-3 alkyl or S (= 0) m C 1-3 alkyl; R is H, halogen, C alquilo alkyl; 3, S (= 0) m alkyl of C? _3, S (= 0> 2NR5R6; or C! _3 alkyl optionally substituted with OH, or O-C de3 alkyl; R and R are independently H, C 1-3 alkyl or C ?3 alkyl optionally substituted with OH or O-alkyl of C? -3; R, R are independently H, C3_3alkyl, C2_3alkyl optionally substituted with OH, C_3_O-alkyl, or R and R may be linked together with saturated carbon atoms to form a 5 or 6 membered ring and the carbon atoms may be unsubstituted or optionally substituted with C ?3 alkyl, C2-3 alkyl optionally substituted with OH or O-C? -3 alkyl, - R, R are , together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or 15 thiomorpholine which may be substituted or unsubstituted on the carbon with one or more substituents optionally selected from C 1-3 alkyl, C 1-3 alkyl optionally substituted with OH, C 1-3 alkyl, phenyl which may be unsubstituted or replaced Optionally with halogen, CF3, O-C3_3alkyl or C3_alkyl, or substituted on the nitrogen with C1-C4alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-alkyl of C? _3 or C1-3 alkyl; 25 n is 2 to 4; -MI "» m r MÉH n ptwn 1 í- --a-mi --- * j? M ^ ** á * á? Mt ^ * i í m is O, 1 or 2 and any of the pharmaceutically acceptable salts and solvates.

23. A composition for improving blood flow to the head of the optic nerve and the retina, which contains a pharmaceutically effective amount of a compound of the formula: 3 4 R and R are independently H, C 1-3 alkyl or C 1-3 alkyl optionally substituted with OH or O-alkyl C1-3; R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine,? -pipepdem [sic], piperazine, morphol or thiomorpholine which may be unsubstituted or substituted on the carbon with one or more substituents optionally selected from C1-3alkyl, C1-3alkyl optionally substituted with OH, O-C1alkyl -3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C1-3 alkyl or C3_3 alkyl, or substituted on the nitrogen with C.sub.4 -C.sub.4 alkoxy or phephyl which may be unsubstituted or optionally substituted with halogen, CF.sub.3, O-alkyl C? -3 or C? _3 alkyl; R is phenyl or a monocyclic heteroaromatic ring which may be unsubstituted or substituted with alkyl of C1-4, halogen, O-C4 alkyl; R is C 4 alkyl, or R may be attached to R to form a fused bicyclic ring system such as indolino [sic]; n is 2 to 4 and any of the pharmaceutically acceptable salts and solvates.

24. A composition for improving blood flow to the head of the optic nerve and the retina, which contains a pharmaceutically effective amount of a compound of the formula: R and R are independently H, C ?3 alkyl or C ?3 alkyl optionally substituted with OH or O-alkyl C1-3; R7, R8 are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be substituted or unsubstituted on the carbon with one or more substituents optionally selected from C1-3alkyl, C1-3alkyl optionally substituted with OH, O-C1alkyl -3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C1-3 alkyl or C1-3 alkyl, or substituted on the nitrogen with C1-C alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-alkyl C1-3 or C1-3 alkyl; R is C3_3alkyl, phenyl or a monocyclic heteroaromatic ring which may be unsubstituted or substituted by C ?_alkyl, halogen, C_4_Oalkyl; R12 is C4_4 alkyl or a heteroaromatic, bicyclic ring, fused as thien [3, 2-e] -1,2-t-azine, or 1, 2-benzothiazine, or R can be attached to R to form a bicyclic ring system, fused such as 2,3-dihydro-benzo [c] isoxazole; n is 2 to 4 and any of the pharmaceutically acceptable salts and solvates.

25. A composition for treating diseases of the retina containing a pharmaceutically effective amount of a compound of the formula: wherein the dotted link represents a single or double bond; Aryl means a fused phenyl or monocyclic heteroaromatic ring; R is H, OH, 0-alkyl of C? _3, C? _3 alkyl, alkyl of C? _3 optionally substituted with OH, or O-C1-3alkyl; R2 is H, halogen, C-3 alkyl, CONR5R6, S (= 0) m-C 1-3 alkyl, S (= 0> 2NRR, C 1-3 alkyl optionally substituted with OH or 0-C alkyl) _ 3; R 3, R 4 are independently H, C ?3 alkyl, C ?3 alkyl optionally substituted with OH or O-alkyl C1-3; R, R are independently H, C1-3 alkyl, C2-3 alkyl optionally substituted with OH, O-C1-3 alkyl; or R and R can be linked together with saturated carbon atoms to form a 5- or 6-membered ring and the carbon atoms can be optionally unsubstituted or substituted with C? _3 alkyl, C2-3 alquilo alkyl optionally substituted with OH or O-alkyl of C? _3; R, R are together with the nitrogen atom to which they are attached incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be unsubstituted or substituted on the carbon with one or more substituents optionally selected from C1-3alkyl, C3_3alkyl optionally substituted with OH, O-alkyl C1-3, phenyl which can be unsubstituted or optionally substituted with halogen, CF3, O-C1-3alkyl or C? -3alkyl, or substituted on nitrogen with C1-C4alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-alkyl C1-3 or C1-3 alkyl; n is from 2 to 1; m is 0, 1 or 2 and any of the pharmaceutically acceptable salts and solvates.

26. A composition for treating diseases of the retina that contains a pharmaceutically effective amount of a compound of the formula: wherein the dotted union represents a single or double bond; Aryl means a fused phenyl or a monocyclic heteroaromatic ring; R is H, C1-5 alkyl, C3-5 alkenyl, an aromatic ring such as phenyl, thienyl, pyridyl and imidazolyl which is unsubstituted or optionally substituted with OH, O-C1-3 alkyl, S (= 0 ) m C 1 _ 3 alkyl, halogen, CF 3 or S (= 0) 2 NR 5 R 6; or C2_3 alkyl, optionally substituted with OH O-C1-3alkyl, S (= 0) m C1-3alkyl, or an aromatic ring such as phenyl, thienyl, pyridyl and imidazolyl which is unsubstituted or optionally substituted with OH, O-C 1-3 alkyl, S (= 0) m C 1-3 alkyl, halogen, CF 3, S (= 0> 2NRR; or C3_5 alkenyl optionally substituted with OH, O-C ?3 alkyl or S (= 0) m C alquilo3 alkyl; R 2 is H, halogen, C? _3 alkyl, S (= 0) m C 1-3 alkyl, S (= 0) 2 NR 5 R 6, or C 1 -C 3 alkyl optionally substituted with OH, or O-C 1-3 alkyl, and RR 4 ssoonn iinnddeeppeennddiieenntteemmeennttee H, C 1-3 alkyl or C_3 alkyl optionally substituted with OH or O-alkyl of R, R are independently H, C1-3 alkyl, C2-3 alkyl optionally substituted with OH, O-C1-3 alkyl, or R and R may be linked together with saturated carbon atoms to form a ring of 5 or 6 members and the carbon atoms may be unsubstituted or optionally substituted with C] _3 alkyl, C2_3 alkyl optionally substituted with OH or 0-C_3 alkyl; R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be substituted or unsubstituted on the carbon with one or more substituents optionally selected from C1-3alkyl, C1-3alkyl optionally substituted with OH, O-C1alkyl -3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C3_3 alkyl or C1-3 alkyl, or substituted on the nitrogen with C1-C4 alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C3_3alkyl or C3_3alkyl; n is 2 to 4; m is O, 1 or 2 and any of the pharmaceutically acceptable salts and solvates.

27. A composition for treating diseases of the retina that contains a pharmaceutically effective amount of a compound of the formula: R 3 and R 4 are independently H, C 1-3 alkyl or C 1 -C 3 alkyl optionally substituted with OH or O-alkyl C1-3; R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O,,, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be substituted or unsubstituted on the carbon with one or more substituents optionally selected from C1-3alkyl, C1-3alkyl optionally substituted with OH, O-C1alkyl -3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C3 alkyl or C1-3 alkyl, or substituted on the nitrogen with C1-C4 alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-alkyl C1-3 or C1-3 alkyl; R is phenyl or a monocyclic heteroaromatic ring which may be unsubstituted or substituted by C 1-4 alkyl, halogen, C 1-4 alkyl; R is C 4 alkyl, or R may be attached to R to form a fused bicyclic ring system such as indolino [sic]; n is 2 to 4 and any of the pharmaceutically acceptable salts and solvates.

28. A composition for treating diseases of the retina that contains a pharmaceutically effective amount of a compound of the formula: R and R are independently H, C 1-3 alkyl or C 1-3 alkyl optionally substituted with OH or O-alkyl C1-3; R7, R8 are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, ^^ ¡^ ¡^^^ H ^ s ^^ ? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be substituted or unsubstituted on the carbon with one or more substituents optionally selected from C1-3alkyl, C1-3alkyl optionally substituted with OH, O-C1alkyl -3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C1-3alkyl or C1-3alkyl, or substituted on the nitrogen with C1-C4alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-alkyl C! _3 or C? _3 alkyl; R is C3_3alkyl, phenyl or a monocyclic heteroaromatic ring which may be unsubstituted or substituted by C1_4alkyl, halogen, C1_4alkyl; R 12 is C 1-4 alkyl or a heteroaromatic, bicyclic ring fused as thien [3, 2-e] -1,2-thiazine, or 1, 2-benzothiazine, or R 12 may be attached to R 11 to form a bicyclic ring system, fused such as 2,3-dihydro-benzo [c] isoxazole; n is 2 to 4 and any of the pharmaceutically acceptable salts and solvates.

29. A method for improving blood flow to the head of the optic nerve or the retina, which consists of administering to a person in need thereof, a ai ^ i_¡áiaBaí composition containing a pharmaceutically effective amount of a compound with affinity for the 5HT7 receptor.

30. A composition for improving blood flow to the head of the optic nerve or retina contains a pharmaceutically effective amount of a compound with affinity for the 5HT7 receptor.

31. A method for providing neuroprotection to the head of the optic nerve or the retina, which is to administer to a person in need thereof, a composition containing a pharmaceutically effective amount of a compound with affinity for the 5HT receptor.

32. A composition for providing neuroprotection for the head of the optic nerve or retina contains a pharmaceutically effective amount of a compound with affinity for the 5HT receptor.

33. A method for treating diseases of the retina, which consists of administering to a person in need thereof a composition containing a pharmaceutically effective amount of a compound with affinity for the 5HT7 receptor.

34. The method of claim 1, wherein the disease of the retina is selected from the group consisting of: glaucoma, age-related macular degeneration, optic neuritis, ischemic disorders, and retinal edema.

35. A composition for treating diseases of the retina, which contains a pharmaceutically effective amount of a compound with affinity for the 5HT7 receptor.

36. The composition of claim 35, wherein the diseases of the retina are selected from the group consisting of: glaucoma, age-related macular degeneration, optic neuritis, ischemic disorders, and retinal edema.

37. A method for reducing IOP, which comprises administering to a person in need thereof, a composition containing a pharmaceutically effective amount of a compound with affinity for the 5HT receptor.

38. A composition for reducing IOP contains a pharmaceutically effective amount of a compound with affinity for the 5HT receptor.

39. A method for treating persons suffering from sleep disorders, depression, schizophrenia, anxiety, circn rhythm disorders, and central and peripheral-mediated hypertension, which consists of administering a composition containing a pharmaceutically effective amount of a compound of the formula: where the dotted link represents a single link or double; Aryl means a fused phenyl or monocyclic heteroaromatic ring; R is H, OH, O-C de3 alkyl, C ?3 alkyl, C ?3 alkyl optionally substituted with OH, or O-C C3 alkyl; R is H, halogen, C-3 alkyl, CONR5R6, S (= 0) m-C alquilo-3 alkyl, S (= 0> 2NRR, C 1-3 alkyl optionally substituted with OH or O-alkyl) C? _3, -R 3, R 4 are independently H, C 1-3 alkyl, C 1-3 alkyl optionally substituted with OH or O-alkyl C1-3; R, R are independently H, C1-3 alkyl, C2-3 alkyl optionally substituted with OH, O-C1-3 alkyl; or R and R can be linked together with saturated carbon atoms to form a 5- or 6-membered ring and the carbon atoms can be optionally unsubstituted or substituted with C? _3 alkyl, C2-3 alkyl optionally substituted with OH or O-alkyl of C? _3, -R, R are together with the nitrogen atom to which they are attached incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, as can it be pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be unsubstituted or substituted on carbon with one or more substituents optionally selected from C 1-3 alkyl, C 1-3 alkyl optionally substituted with OH, C 1-3 alkyl, phenyl which may be unsubstituted or optionally substituted with halogen, CF 3, O - C3_3 alkyl or C3_3alkyl, or substituted on nitrogen with C1-C4alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C3_3alkyl or C1_4alkyl 3; n is from 2 to 4; m is 0, 1 or 2 and any of the pharmaceutically acceptable salts and solvates.

40. A method for treating persons suffering from sleep disorders, depression, schizophrenia, anxiety, obsessive-compulsive disorders, circadian rhythm disorders, and central and peripheral-mediated hypertension, consisting of administering a composition containing a pharmaceutically effective amount of a compound of the formula: wherein the dotted union represents a single or double bond; Aryl means a fused phenyl or a monocyclic heteroaromatic ring; R is H, C ?5 alkyl, C3_5 alkenyl, an aromatic ring such as phenyl, thienyl, pyridyl and imidazolyl which is unsubstituted or optionally substituted with OH, O-C ?3 alkyl, S (= 0) m C1-3 alkyl, halogen, CF3 or S (= 0) 2NRR6; or C2-3 alkyl, optionally substituted with OH O-C ?3 alkyl, S (= 0) m C 1-3 alkyl, or an aromatic ring such as phenyl, thienyl, pyridyl and imidazolyl which is unsubstituted or substituted optionally with OH, O-C alquilo_3 alkyl, S (= 0) m C 1-3 alkyl, halogen, CF 3, S (= 0) 2NRR; or C3-5 alkenyl optionally substituted with OH, O-C 1-3 alkyl or S (= 0) m C 1-3 alkyl; R is H, halogen, C alquilo _3 alkyl, S (= 0) to C 1-3 alkyl, S (= 0> 2NR R) or C1-3 alkyl optionally substituted with OH, or O-C3 alkyl, -R and R4 are independently H, C3_3 alkyl or optionally substituted C3_3 alkyl with OH or O-alkyl of C1-3 R, R are independently H, C ?3 alkyl, optional C2-3 alkyl substituted with OH, O-C1-3 alkyl, or R and R may be linked together with atoms of saturated carbon to form a 5- or 6-membered ring and the carbon atoms may be unsubstituted or optionally substituted with C? _3alkyl, C2-3 alquiloalkyl optionally substituted by OH or O-C? _alkyl; R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, 3 ? -piperidein [sic], piperazm, morpholine or thiomorpholine which may be substituted or unsubstituted on the carbon with one or more substituents optionally selected from C1-3alkyl, C1-3alkyl optionally substituted with OH, O-C1alkyl -3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C1-3alkyl or C1-3alkyl, or substituted on the nitrogen with C1-C4alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C3_3 alkyl or C3 alkyl; n is 2 to 4; m is 0, 1 or 2 and any of the pharmaceutically acceptable salts and solvates.

41. A method to treat people suffering from sleep disorders, depression, schizophrenia, anxiety, obsessive-compulsive disorders, circadian rhythm disorders, and central and peripheral-mediated hypertension, which consists of administering a composition containing a pharmaceutically effective amount of a compound of the formula: R and R are independently H, C3 alkyl or C1-3 alkyl optionally substituted with OH or OC3 1-3 alkyl; R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be substituted or unsubstituted on the carbon with one or more substituents optionally selected from C? _3 alkyl, C 1-3 alkyl optionally substituted with OH, O-C alquilo alkyl -3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C3_3 alkyl or C3_3 alkyl, or substituted on the nitrogen with C 1 -C 4 alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF 3, O-alkyl C1-3 or C1-3 alkyl; R is phenyl or a monocyclic heteroaromatic ring which may be unsubstituted or substituted with alkyl of C -4, halogen, O-C 1 alkyl; R is C 1-4 alkyl, or R may be attached to R to form a fused bicyclic ring system such as indolino [sic]; n is 2 to 4 and any of the pharmaceutically acceptable salts and solvates.

42. A method for treating persons suffering from sleep disorders, depression, schizophrenia, anxiety, obsessive-compulsive disorders, circadian rhythm disorders, and central and peripheral-mediated hypertension, consisting of administering a composition containing a pharmaceutically effective amount of a compound of the formula: R3 and R4 are independently H, C1-3 alkyl or C3-3 alkyl optionally substituted with OH or O-alkyl C? -3; R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be unsubstituted or substituted on the carbon with one or more substituents optionally selected from C ?3 alkyl, C alquilo3 alkyl optionally substituted with OH, O-C1- alkyl 3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C3_3alkyl or C1-3alkyl, or substituted on the nitrogen with C1-C4alkoxy or phenyl which may be unsubstituted or substituted optionally with halogen, CF3, O-C1-3alkyl or C1-3alkyl; R is C 1-3 alkyl, phenyl or a monocyclic heteroaromatic ring which may be unsubstituted or substituted with C 1-4 alkyl, halogen, C 1-4 alkyl; R 12 is C 1-4 alkyl or a heteroaromatic, bicyclic ring fused as thien [3, 2-e] -1,2-thiazine, or 1, 2-benzothiazine, or R 12 may be linked to R 11 to form a bicyclic ring system, fused such as 2,3-dihydro-benzo [c] isoxazole; n is 2 to 4 ^ Mgg ^^^^ and any of pharmaceutically acceptable salts and solvates.

43. A composition containing a pharmaceutically effective amount of a compound of the formula: wherein the dotted link represents a single or double bond; Aryl means a fused phenyl or monocyclic heteroaromatic ring; R is H, OH, O-C1-3 alkyl, C3_3 alkyl, C3_3 alkyl optionally substituted with OH, or OC3_3alkyl; R 2 is H, halogen, C 1-3 alkyl, CONR 5 R 6, S (= 0) m-C 1-3 alkyl, S (= 0) 2 NRR, C 3 alkyl optionally substituted with OH or O-C 1-3 alkyl; R, R are independently H, C ?3 alkyl, C3 alkyl optionally substituted with OH or O-C ?3 alkyl; R5, Rd are independently H, C ?3 alkyl, C2-3 alkyl optionally substituted with OH, O-alkyl C1-3; or R5 and R6 can be linked together with saturated carbon atoms to form a 5- or 6-membered ring and the carbon atoms can be * < ** - - - -Y-- optionally unsubstituted or substituted by C1-3alkyl, C2-3alkyl optionally substituted with OH or O-C1-3alkyl; R, R are together with the nitrogen atom to which they are attached incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be unsubstituted or substituted on the carbon with one or more substituents optionally selected from C1-3alkyl, C3_3alkyl optionally substituted with OH, O-alkyl C? -3, phenyl which can be unsubstituted or optionally substituted with halogen, CF3, O-C? _3 alkyl or C1-3 alkyl, or substituted on nitrogen with C1-C4 alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-alkyl C? _3 or C1-3 alkyl; n is from 2 to 4; m is 0, 1 or 2 and any of the pharmaceutically acceptable salts and solvates in a pharmaceutically acceptable carrier.

44. A composition containing a pharmaceutically effective amount of a compound of the formula: - "- '< * -" * - wherein the dotted union represents a single or double bond; Aryl means a fused phenyl or a monocyclic heteroaromatic ring; R is H, C1-5 alkyl, C3-5 alkenyl, an aromatic ring such as phenyl, thienyl, pyridyl and imidazolyl which is unsubstituted or optionally substituted with OH, O-C ?3 alkyl, S (= 0 ) m C 1-3 alkyl, halogen, CF 3 or S (= 0) 2 NR 5 R 6; or C2-3 alkyl, optionally substituted with OH O-C ?3 alkyl, S (= 0) m C 1-3 alkyl, or an aromatic ring such as phenyl, thienyl, pyridyl and imidazolyl which is unsubstituted or substituted optionally with OH, O-alkyl of C? _3, S (= 0) m alkyl of C1-3, halogen, CF3, S (= 0) 2NRR; or C3_5 alkenyl optionally substituted with OH, O-C 1-3 alkyl or S (= 0) m C 1-3 alkyl; R is H, halogen, C 1-3 alkyl, S (= 0) m C 1-3 alkyl, S (= 0> 2NR5R6; or C ?_3 alkyl optionally substituted with OH, or O-C de_3 alkyl; R and R4 are independently H, C ?_3 alkyl or C 1-3 alkyl optionally substituted with OH or O-alkyl of C? -3; R, R are independently H, C1-3 alkyl, C2-3 alkyl optionally substituted by OH, O-C3 alkyl, or R and R may be linked together with saturated carbon atoms to form a ring of 5 or 6 members and the carbon atoms may be unsubstituted or optionally substituted with C 1-3 alkyl, C 2-3 alkyl optionally substituted with OH or O-C 1-3 alkyl; R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be substituted or unsubstituted on the carbon with one or more substituents optionally selected from C1-3alkyl, C1-3alkyl optionally substituted with OH, O-C1alkyl _3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C3 alkyl or C3 alkyl, or substituted on the nitrogen with C1-C4 alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen , CF3, O-C3 alkyl or C3-3 alkyl; n is 2 to 4; m is 0, 1 or 2 and any of the pharmaceutically acceptable salts and solvates in a pharmaceutically acceptable carrier.

45. A composition containing a pharmaceutically effective amount of a compound of the formula: R 3 and R 4 are independently H, C 1 -C 3 alkyl or C 1 -C 3 alkyl optionally substituted with OH or O-alkyl C1-3; R, R are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine,? -piperidein [sic], piperazine, morpholine or thiomorpholine which may be unsubstituted or substituted on the carbon with one or more substituents optionally selected from C? _3 alkyl, C1-3 alkyl optionally substituted with OH, C1-O-alkyl -3, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C1-3alkyl or C1-3alkyl, or substituted on the nitrogen with C1-C4alkoxy or phenyl which may be unsubstituted or ^ ÉÉÉ ^^^ saa ^ optionally substituted with halogen, CF3, O-alkyl C? _3 or C1-3 alkyl; R is phenyl or a monocyclic heteroaromatic ring which may be unsubstituted or substituted by C? _4 alkyl, halogen, C--4 OO-alkyl; R is C 1-4 alkyl, or R may be attached to R to form a fused bicyclic ring system such as indolino [sic]; n is 2 to 4 and any pharmaceutically acceptable salts and solvates in a pharmaceutically acceptable carrier.

46. A composition containing a pharmaceutically effective amount of a compound of the formula: R and R are independently H, C3 alkyl or C3-3 alkyl optionally substituted with OH or O-C1-3 alkyl; R7, R8 are, together with the nitrogen atom to which they are attached, incorporated in a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine,? 3-piperidein [sic], piperazine, morpholine or - - "- '- ^ - thiomorpholine which may be unsubstituted or substituted on the carbon with one or more substituents optionally selected from C? -3 alkyl, C1-3 alkyl optionally substituted with OH, 0-C? _3 alkyl, phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O-C1-3alkyl or C3_3alkyl, or substituted on the nitrogen with C1-C4alkoxy or phenyl which may be unsubstituted or optionally substituted with halogen, CF3, O- C3 alkyl or C1-3 alkyl; R is C3_3alkyl, phenyl or a monocyclic heteroaromatic ring which may be unsubstituted or substituted by C1_4alkyl, halogen, C1_4alkyl; R 12 is C 1-4 alkyl or a heteroaromatic, bicyclic ring, fused as thien [3, 2-e] -1,2-thiazine, or 1, 2-benzot? Az? Na, or R 12 can be attached to R11 to form a bicyclic ring system, fused such as 2,3-dihydro-benzo [c] isoxazole; n is 2 to 4 and any pharmaceutically acceptable salts and solvates in a pharmaceutically acceptable carrier.

47. The compound of claim 1 selected from the group consisting of: 6-chloro-2- [4- [4- (2H-benzimidazo-2-oxo-l-yl) piperidin-1-yl] butyl] -2H -thien [3, 2-e] -1,2-thiazine 1,1-dioxide; 6-chloro-2- [4- (4-phenylpiperazin-1-yl) butyl] -2 H -thien [3,2-e] -1,2-thiazine 1,1-dioxide; 6-chloro-2- [4- [4- (2-fluorophenyl) piperazin-1-yl] butyl] -2H-thien [3,2-e] -1,2-thiazine 1,1-dioxide; 6-chloro-2- [3- [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl] -propyl] -2H-thien [3,2-e] -1,2-thiazine-1,1-dioxide; 6-chloro-2- [3- [4- (2H-benzimidazol-2-oxo) -piperidin-1-yl] propyl] -2H-thien [3,2-e] -1,2-thiazine 1.1 -dioxide.

48. The compound of claim 3 selected from the group consisting of: 3- [4- (3-chlorophenyl) piperazin-1-yl] propylsulfonyl-2,3-dihydro-lH-indole; 3- (1, 2, 3, 4-tetrahydroisoquinolin-2-yl) propylsulfonyl-2,3-dihydro-lH-indole; 3- [4- (3-trifluoromethylphenyl) piperazin-1-yl] propylsulfonyl-2,3-dihydro-1H-indole; 3- [4- (2-methoxyphenyl-Jpiperazin-1-yl] -propylsulfonyl-2,3-dihydro-lH-indole; 3- (1, 2, 3, 4-tetrahydroisoquinolin-2-yl) -N-methyl-N phenyl-propylsulfonamide

49. The compound of claim 4 selected from the group consisting of: N- [3- [4- (3-chlorophenyl) piperazin-1-yl] propyl] -N- (4-methoxyphenyl) - propansulfonamide; N- [3- (1, 2,3,4-tetrahydroisoquinolin-2-yl) propyl] -N- (4- ^ methoxyphenyl) -propanesulfonamide; N- [3- [4- (3-chlorophenyl) piperazin-1-yl] propyl] -N- (4-methoxyphenyl) -propanesulfonamide; [sic] N- [3- [4- (2-methoxyphenyl) piperazin-1-yl] propyl] -N- (4-methoxyphenyl) -propanesulfonamide; N- [3- [4- (2-chlorophenyl) piperazin-1-yl] propyl] -N- (4-methoxyphenyl) -propanesulfonamide;