AU3978899A

AU3978899A - Serotonergic 5HT, receptor compounds for treating ocular and CNS disorders

Info

Publication number: AU3978899A
Application number: AU39788/99A
Authority: AU
Inventors: Hwang-Hsing Chen; Thomas R. Dean; Jesse A. May; Najam A. Sharif
Original assignee: Alcon Laboratories Inc
Current assignee: Alcon Vision LLC
Priority date: 1998-05-19
Filing date: 1999-05-10
Publication date: 1999-12-06
Also published as: WO1999059499A2; CA2332505A1; JP2002515408A; WO1999059499A3; BR9910590A; CN1301161A; EP1079763A2

Description

WO 99/59499 PCT/US99/10179 SEROTONERGIC 5HT 7 RECEPTOR COMPOUNDS FOR TREATING OCULAR AND CNS DISORDERS 5 The present invention is directed to the use of compounds with serotonergic 5HT 7 receptor affinity (Compound) (some of which are novel), to improve blood flow to the optic nerve head and the retina, provide neuroprotection, lower intraocular pressure (IOP), and treat retinal diseases, such as, glaucoma, age related macular degeneration (ARMD), optic neuritis, ischemic disorders, diabetic retinopathy, and retinal edema. The Compounds are also useful o 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. Background of the Invention 5 Serotonin (5-hydroxy tryptamine; 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 Neurosci., 8:3713-3721, 1988]. 5HT can interact with at least seven major 5HT receptors (5HTi - 5HT 7 ) and additional subtypes within these families to initiate intracellular biochemical events such as stimulation of second messengers (e.g. cAMP, inositol trisphosphate) eventually leading to the final biological response, for example, tissue contraction or hormone release, etc. [Hoyer 5 et al., supra; Martin et al., Trends Pharmacol. Sci., 19:2-4, 1998]. Receptor subtypes within the 5HTI family are negatively coupled to adenylyl cyclase (AC) and cause inhibition of cAMP production, while 5HT 4 , 5HT 6 , and 5HT 7 receptors are positively coupled to AC and thus stimulate cAMP production when activated by 5HT [Martin et al., supra]. The receptors in the 5HT 2 family are positively coupled to phospholipase C (PLC) and thus 0 generate inositol phosphates and mobilize intracellular calcium when activated to mediate the effects of 5HT. The 5HT 3 receptor is unique in that it couples to an ion channel which gates sodium, potassium, and calcium [Hoyer et al., supra].

WO 99/59499 PCT/US99/10179 The human and animal 5HT 7 receptor has only recently been cloned, expressed, and shown to be present in various brain areas and peripheral tissues [Eglen et al., Trend Pharmacol. Sci., 18:104-107, 1997]. Recent studies have shown there to be four splice variants of the 5HT 7 receptor [Heidmann et al., J Neurochem., 68:1372-1381, 1997]. It has s been proposed that the 5HT 7 receptor may be involved in the pathophysiology of sleep disorders, depression, and other psychiatric disorders [Eglen et al., supra]. In the periphery, stimulation of 5HT 7 receptors results in relaxation of blood vessels and hence vasodilation [Eglen et al., supra]. Improving blood flow to the back of the eye, including the retina, the macula, and the optic nerve head is believed to be beneficial in the treatment of a number of 0 retinal diseases, 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., Ophthalmol., 5 95:1221-1226, 1988]. In addition, receptor binding sites for [ 3 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 5HT binding sites have been shown to be functionally coupled to second messenger generation in rabbits [Tobin and Osborne, SJ. Neurochem., 53:686-601, 1989 and Tobin et al., J. Neurosci, supra]. In the human ICB these binding sites are characterized as 5HTIA and 5HT 2 receptors [Barnet and Osborne, Exp. Eye Res., 57:209-216, 1993]. In addition, the presence of mRNAs for 5HTia and 5HT 7 receptors in the rabbit ICB have been reported [Chidlow et al., Invest. Ophthalmol. Vis. Sci., supra and Osborne and Chidlow, Ophthalmologica, 210:308-314, 1996]. The s precise functions of these receptors in the eye are unknown, especially the 5HT 7 subtype(s). 5HT or 5-carboxamidotryptamine (5-CT) topically applied to the rabbit eye raise intraocular pressure in the anterior chamber of the eye [Meyer-Bothling et al., Invest. Ophthalmol. Vis. Sci., 34:3035-3042, 1993]. By contrast, it has been shown that topically 0 applied 5HT lowers IOP [Krootila et al., J. Ocular Pharmacol., 3:279-290, 1987 (intracamerally 5HT raised IOP and caused breakdown of the blood-aqueous barrier)]. In addition, the 5HT uptake inhibitor, fluoxetine (Prozac*), also raises IOP in human subjects -2- WO 99/59499 PCTIUS99/10179 upon oral administration [Costagliola et al., Br. J. Ophthalmol., 80:678, 1996] and may cause glaucoma [Ahmad, Ann. Pharmacother., 25:436, 1992]. However, the 5HT receptor subtype(s) involved in the IOP-elevating effects of 5HT, 5-CT and fluoxetine are unknown. s Studies conducted in rabbits with 8-hydroxy DPAT and MKC-242 (5HTIA agonists) have shown these compounds lower IOP [Osborne and Chidlow, Ophthalmologica, 210:308-319, 1996, and EP 0771563-A2]. In addition, 5-methylurapidil (5HTIA agonist) lowered IOP in glaucomatous monkeys [Wang, et al., Curr. Eye Res., 16:679-775, 1997]. Both MKC-242 and 5-methylurapidil are relatively potent al receptor antagonists 10 (al antagonists are known to lower IOP in rabbits, monkeys, and man). The mechanism of action for lowering IOP by 5-methylurapidil has been attributed to its al antagonist activity and not its 5HTIA agonist activity [Wang, et al., Invest. Ophthal. Vis. Sci., 39(Suppl):2236 488, 1998]. U.S. Patent No. 5,693,654, discloses 5HT, receptor agonists for lowering IOP. W092/20333 discloses certain 5HT1A agonists for the treatment of glaucoma. 15 Methysergide (5HT 2 antagonist) lowered IOP in rabbits [Krootila, et al., Esp. Eye Res., supra]. Ketanserin (5HT2A/c antagonist), also with significant al antagonist activity, lowers IOP in rabbits and man [Chan, et al., J. Ocular Pharmacol., 1:137-147, 1985 and Costagliola, et al., Ex. Eye Res., 52:507-510, 1991]. Saprogrelate (5HT2A antagonist) lowers 20 IOP in rabbits and in man when dosed topically or orally [Mano, et al., Invest. Ophthal. Vis. Sci., 36(Suppl):3322- 3 0 9 , 1995, and Takenaka, et al., Invest Ophthal. Vis. Sci., 36(Suppl):33 9 0- 37 7 , 1995]. EP 522226 and U.S. Patent No. 5,290,781 disclose the use of ketanserin and its derivatives for treating ocular hypertension. U.S. Patent Nos. 5,290,781 and 5,106,555 discloses the use of certain 5HT 2 antagonists for lowering IOP. U.S. Patent 25 No. 5,652,272 discloses saprogrelate for reducing IOP. U.S. Patent No. 5,538,974 discloses opthalmic compositions of certain 5HT 2 antagonists for lowering IOP. U.S. Patent No. 5,011,846 discloses certain 5HT 3 receptor antagonists for treating glaucoma. 30 -3- WO 99/59499 PCT/US99/10179 WO 97/17345 discloses that particular compounds with 5HT 4 serotonergic receptor agonist or antagonist activity are useful for treating psychiatric, gastrointestinal, lower urinary, and cardiovascular disorders. The publication mentions the compounds may also be useful for glaucoma. 5 As evidenced by the previous discussion, it is not clear which serotonergic receptor activity is responsible for lowering IOP. Moreover, a number of these compounds are known to have activity at other receptors which are known to be involved in lowering IOP. Furthermore, it has not been cleared which receptor(s) might be responsible for increasing 10 blood flow and providing neuroprotection in the eye. Summary of the Invention The present invention is directed to Compounds, some of which are novel, that have is 5HT 7 receptor affinity, and the use of compounds with 5HT 7 receptor affinity to lower IOP, improve blood flow to the optic nerve head and the retina, provide neuroprotection, and control damage associated with diseases, such as, glaucoma, ARMD, optic neuritis, ischemic disorders, and retinal edema by functioning as neuroprotectants. Compositions of the compounds are contemplated for such uses. The Compounds are also useful for treating sleep 20 disorders, depression, and other psychiatric disorders, such as, schizophrenia, anxiety, obsessive compulsive disorder, circadian rhythm disorders, and centrally and peripherally mediated hypertension. Detailed Description Preferred Embodiments 25 It has been unexpectedly discovered that 5HT 7 receptors are present in the retina, choroid, and possibly the optic nerve head. Furthermore, sertonergic Compounds which possess a relatively high affinity (Ki = 0.01 - 200nM) for 5HT 7 receptors effectively lower elevated IOP. It is believed that these Compounds can improve blood flow, and provide 30 neuroprotection to the optic nerve head and the retina. The Compounds' (preferrably Compounds that are agonists or partial agonists) ability to improve blood flow to the optic nerve head and the retina and other characteristics are believed to render them -4- WO 99/59499 PCTIUS99/10179 neuroprotective. The novel Compounds disclosed herein are also useful for treating sleep disorders, depression, and other psychiatric disorders. Compounds found in the following applications are useful according to the present s 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 to solvates are useful for treating persons with the diseases and disorders previously described. Formula I 1 R ,, Aryl 8 (CR3R4) n--N 15 Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; 20 R 1 is H, OH, OC 1

.

3 alkyl, CI- 3 alkyl, C 1

.

3 alkyl substituted optionally with OH, or OCI- 3 alkyl;

R

2 is H, halogen, C 1

.

3 alkyl, CONRR 6 , S(=O)mC1.

3 alkyl, S(=0)2 NRR 6 , C 1

.

3 alkyl substituted optionally with OH, or OCI- 3 alkyl;

R

3 , R4 are independently H, C 1

.

3 alkyl, C 1

.

3 alkyl substituted optionally with OH or OC 1

.

3 alkyl; R , R6 are independently H, C 1

.

3 alkyl, C 2

-

3 alkyl substituted optionally with OH, OC 1

.

3 alkyl, or 25

R

5 and R 6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with C 1

.

3 alkyl, C 2

-

3 alkyl substituted optionally with OH or OCI- 3 alkyl; R7, R 8 are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected 30 from N, 0, S, such as pyrrolidine, piperidine,

A

3 -piperidein, piperazine, morpholine -5- -WO 99/59499 PCT/US99/10179 or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from CI- 3 alkyl, C 1

.

3 alkyl substituted optionally with OH, OCI- 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OC 1

-

3 alkyl, or C 1

.

3 alkyl, or substituted on nitrogen 5 with C 1

.

4 alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCi- 3 alkyl, or CI- 3 alkyl; n is 2 to 4 ; m is 0, 1 or 2. Formula II 10 8 R

CR

3 R) n N Aryl R R 0 0 Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; is R' is H, CI.

5 alkyl, C 3

-

5 alkenyl, an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH,

OC

1

.

3 alkyl, S(=O)mCI- 3 alkyl, halogen, CF 3 , or S(=0) 2

NRR

6 ; or C 2

-

5 alkyl substituted optionally with OH, OCi- 3 alkyl, S(=0)mC..- 3 alkyl or an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or 20 substituted optionally with OH, OC 1

-

3 alkyl, S(=O)mC- 3 alkyl, halogen, CF 3 , S(=0) 2 NR 5R6; or C 3

-

5 alkenyl substituted optionally with OH, OC 1

.

3 alkyl, or S(=O)mCi 3 alkyl; R2 is H, halogen, C 1

.

3 alkyl, S(=O)mCI- 3 alkyl, S(=0) 2

NRR

6 , or CI- 3 alkyl substituted optionally with OH, or OCI- 3 alkyl; 25 R 3 & R 4 are independently H, CI- 3 alkyl, or C 1

-

3 alkyl substituted optionally with OH or

OC

1

.

3 alkyl; R', R 6 are independently H, CI- 3 alkyl, C 2

-

3 alkyl substituted optionally with OH, OCI- 3 alkyl, or R 5 and R 6 can be joined together with saturated carbon atoms to form a 5 or 6 -6- WO 99/59499 PCT/US99/101 7 9 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with C 1

-

3 alkyl, C 2

-

3 alkyl substituted optionally with OH or OC 1

.

3 alkyl; R7, R' are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected s from N, 0, S, such as pyrrolidine, piperidine,

A

3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from Ci- 3 alkyl, C 1

.

3 alkyl, or C 1

-

3 alkyl, or substituted on nitrogen 10 with C 1 .4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen,

CF

3 , OC 1

.

3 alkyl, or C 1

-

3 alkyl; n is 2 to 4 ; m is 0 , 1 or 2. Formula III

R

1 0

R

8 (CR3R4---N R S R 0 0 15 R3 & R 4 are independently H, C 1

-

3 alkyl, or C 1

.

3 alkyl substituted optionally with OH or

OC

1

.

3 alkyl; R7, R' are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected 20 from N, 0, S, such as pyrrolidine, piperidine,

A

3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from C 1

.

3 alkyl, C 1

.

3 alkyl substituted optionally with OH, OC 1

.

3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OC 1

.

3 alkyl, or C 1

.

3 alkyl, or substituted on nitrogen 25 with C 14 alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen,

CF

3 , OC 1

-

3 alkyl, or C 1

-

3 alkyl; -7- WO 99/59499 PCT/US99/10179

R

9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with CiA alkyl, halogen, OCIAalkyl; R'" is Ci-alkyl, or Rio can be joined to R? to form a fused bicyclic ring system such as indoline; 5 n is 2 to 4 . Formula IV 0 0 \\ // 12 R N (CR3R 4 )--N R3 & R 4 are independently H, C 1

.

3 alkyl, or C 1

-

3 alkyl substituted optionally with OH or 10

OC

1

.

3 alkyl; R7, R' are together with the nitrogen atom to which they are attached incorporated into 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, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or 15 more substituents optionally selected from CI- 3 alkyl, C 1

.

3 alkyl substituted optionally with OH, OC 1

.

3 alkyl, or C 1

.

3 alkyl, or substituted on nitrogen with C 1 .4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen,

CF

3 , OC 1

.

3 alkyl, or C 1

-

3 alkyl; 20 R' is Ci- 3 alkyl, phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with CiA alkyl, halogen, OC 1 -alkyl; R1 2 is C 1 .4alkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-e]-1,2-thiazine, or 1,2-benzothiazine, or R can be joined to R" to form a fused bicyclic ring system such as 2,3-dihydro-benzo[c]isoxazole; 25 n is 2 to 4 . -8- WO 99/59499 PCT/US99/10179 The compounds of the present invention can be prepared using chemical synthesis procedures herein described. The preferred method for preparing compounds of Formula I is illustrated in Scheme I. For example, the thiazine alcohols 1, which can be prepared by methods described in U.S.Patents 5,344,929 and 5,470,973, or in J. Org. Chem. 31, 162 (1966), can be 5 selectively alkylated on the nitrogen atom at position two with, for example, a dihaloalkane using procedures known to the art to give 2, where X is a halogen atom such as chlorine, bromine, or iodine. Compounds 2 can be treated with amines by known procedures to provide compounds of Formula I (3) where R' is hydroxyl, further these alcohols 3 can be treated with an alkylhalide to effect alkylation on oxygen to provide the ethers, R, is alkoxy. 10 Alternately, 2 can be dehydrated by using methods described in U.S. Patent 5,538,966 to give compounds 4 which can be further reacted with amines to give compounds of Formula I where R' is hydrogen and the thiazine ring contains a double bond (5). Scheme I OH OH OH R2 N H R2 N (cH2)n-x HN7sR (CH2)nr-N 2 3 Ms20/DBNI R '1HNR 7

R

8 R R 8 N N A(cH2)-X H R N / "b e~ ''bc~ \ RCH)7 4 5 is Procedures for preparing compounds of Formula II are illustrated in Scheme II. For example, the 3-hydroxymethyl thiazine compounds 7 can be prepared from the esters 6 by methods described in U.S. Patent 5,538,966 [Equation (a)]. Further, compounds 7 can be aminated using a variety of well known procedures, such as initial activation of the hydroxyl group by forming a sulfonate ester, followed by reaction of this intermediate with the desired primary 20 or secondary amine to give compounds 8 of Formula II where R 3 and R 4 are hydrogen and n is 1 [Equation (b)]. Additionally, using 7 as an intermediate with which to initiate a suitable -9- WO 99/59499 PCTIUS99/10179 homologation sequence, compounds of Formula II wherein R 3 and R 4 are hydrogen and n is 2 or 3 can be prepared; an example of such a homologation sequence employing 7 is illustrated in Equations (c) and (d), respectively. 5 Scheme II (a)ROEtDIBAL-HR2O 67 22 R (b) R 2OlH . R7RO E a Aryl 7 8 2 2 R OH1.TsO/TEA RC (c) N'Ri2 aCN N O3. Hydrolysis a ' ,0 7 9 1. Borane 2. Ms 2 0/TEA 3. Aminej R OOH 10 10 -10- WO 99/59499 PCT/US99/10179 (d) R PBra R2R Br 7 11 1. Mg/THF 2. Ethylene Oxide 2R 2 OH Ary] 7 1. Ms201TEA O R2. AmnineArly eS0e 0R 13 12 The preparation of compounds of Formula III can be readily accomplished by procedures herein described. For example, reaction of the desired amine 14 with the appropriate haloalkylsulfonyl chloride 15 in an inert solvent in the presence of a suitable base [see e.g., J. s Med Chem. 40, 3217 (1997)] to give the haloalkylsulfonamide intermediate 16. Subsequent reaction of 16 with the appropriate primary or secondary amine employing known procedures, provides compounds 17 of Formula III. Scheme III R10 C,,CR)-'R10 C ( EtNH(iPr) 2 1 C 3

R

4 )_OI N acetone , (CR R) R H 0 0 R S 14 15 0 0 16

HNR

7

R

8 DMF/heat R10 , N

(CR

3

R

4 )-N R S R 0 0 17 10 -11- WO 99/59499 PCT/US99/10179 The preparation of compounds of Formula IV can be readily accomplished by procedures herein described. For example, reaction of the desired primary amine 18 with the appropriate sulfonyl chloride in an inert solvent in the presence of a suitable base provides the intermediate secondary sulfonamide 19 which can be alkylated by known procedures with the 5 appropriately substituted alkyldibromide to give the haloalkylsulfonamide intermediate 20. Subsequent reaction of 20 with the appropriate primary or secondary amine employing well known procedures provides compounds 21 of Formula IV. Scheme IV R1% NH RKSOc N. RK' ,(CR R 4 )Br N RioSO 2 CI N Br-(CR 3

R

4 ),-Br N H TEA O 0 NaH/DMF OU R* 20 18 19

HNR

7

R

8 DMF/heat

R

7 R N(CR 3

R

4 )--N N\8 21R O// ,R10 21R 10 It is evident that some of the Compounds of Formula I - IV will include asymmetric atoms, all enantiomers and diastereomers are contemplated. is 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 via an implant). The Compounds are preferrably incorporated into topical 20 ophthalmic formulations for delivery to the eye. The Compounds may be combined with ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic -12- WO 99/59499 PCTIUS99/10179 suspension or solution. Ophthalmic solution formulations may be prepared by dissolving a Compound in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the Compound. Furthermore, the ophthalmic solution may contain an agent to increase viscosity, 5 such as, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac. Gelling agents can also be used, including, but not limited to, gellan and xanthan gum. In order to prepare sterile ophthalmic ointment formulations, the active ingredient is combined with a preservative in an appropriate vehicle, such as, mineral oil, o liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations may 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 the published formulations for analogous ophthalmic preparations; preservatives and tonicity agents can be incorporated. The Compounds can be formulated for systemic (e.g. oral, I.V., I.M., subcutaneous) delivery s according to methods known to one skilled in the art. For systemic delivery the Compounds are delivered at concentrations of 0.005 - 1000 mg. per dose, preferrably 0.05 - 20.0, most preferrably 0.2 - 5 mg. per dose. The Compounds will be dosed 1-4 times per day according to the discretion of a skilled clinician. For ophthalmic medications the Compounds are preferably formulated as topical ophthalmic suspensions or solutions, with a pH of about 5 to 8. The Compounds will normally be contained in these formulations in an amount .01% to 5% by weight, but preferably in an amount of .25% to 2% by weight. Thus, for topical presentation 1 to 2 drops of these formulations would be delivered to the surface of the eye 1 to 4 times per day 5 according to the routine discretion of a skilled clinician. 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. -13- WO 99/59499 PCT/US99/10179 Example 1 6-Chloro-2-[4-[4-(2H-benzimidazo-2-oxo-1-yl)piperidin-1-yl]butyl] 2H-thieno[3,2-e]- 1,2-thiazine 1,1-dioxide Hydrochloride cN ~ N K N 0 0 H C I 5 Step 1. A solution 6-chloro-3,4-dihydro-2H-thieno[3,2-e]- 1,2-thiazine-4-ol 1,1-dioxide (9.0 g, 37.6 mmol) in dimethylformamide (200 mL, anhydrous) and sodium hydride (60% in oil, 1.66 g, 41.5 mmol) was reacted with 1,4-dibromobutane at 00. The reaction was stirred in an ice bath for 30 min and then it was allowed to warm to room temperature and stir for three days. The mixture was poured into ice water (400 mL) and extracted with diethyl ether (2 x o 200 mL). The combined organic layers were washed with water (200 mL), brine (200 mL) and then were dried over magnesium sulfate and evaporated. The resulting residue was purified by silica gel flash chromatography with hexane/ethyl acetate (7:3) to give 6-chloro 3,4-dihydro-2-(4-bromobutyl)-2H-thieno[3,2-e]-1,2-thiazine-4-ol 1,1-dioxide as a colorless oil (10.62 g, 75%); the 1 H NMR was consistent with the structure. 5 Step 2. The product from Step 1 (10.6 g, 28.3 mmol) was dissolved in tetrahydrofuran (anhydrous, 400 mL) and treated with triethyl amine (9.88 mL, 70.9 mmol) and methane sulfonic anhydride (9.86 g, 56.6 mmol) at room temperature and stirred for one hour. The suspension was concentrated and taken up in dimethylformamide (anhydrous, 120 mL). This o mixture was heated at 1600 for 45 min. The reaction mixture was poured into ice water (300 ml) and extracted with dichloromethane (300 mL). The organic layer was washed with water (2 x 200 mL), dried over magnesium sulfate and evaporated to a brown oil. After silica flash chromatography with hexane/ethyl acetate 6-chloro-2-(4-bromobutyl)-2H-thieno[3,2-e]-1,2 thiazine 1,1-dioxide was obtained as a yellow oil (4.97 g, 49%); the 1 H NMR. was consistent 5 with the structure. Step 3. A solution of 4-(2H-benzimidazo-2-oxo-1-yl)piperidine (0.30 mmol) in DMF (1.6 mL, anhydrous) and triethyl amine (0.5 mL) was treated with the product of Step 2 (0.103 g, -14- WO 99/59499 PCT/US99/10179 0.29 mmol) and stirred at 700 for 20 hours and then at room temperature for two days. The reaction mixture was diluted with ethyl acetate (3 mL) and water (4 mL). Saturated sodium bicarbonate (1 mL) 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 give a residue that s was dissolved in ethanol and treated with 1 N hydrochloric acid in ether. After evaporation the desired product was obtained as a white solid (69.2 mg, 45%): 'H NMR and MS (M + H 493) were consistent with the structure. By following the procedures of Example 1, but replacing 4-(2H-benzimidazo-2-oxo- 1 o 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. 1. 6-Chloro-2-[4-(4-phenylpiperazin-1-yl)butyl]-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide s hydrochloride; 2. 6-Chloro-2-[4-[4-(2-fluorophenyl)piperazin-1-yl]butyl]-2H-thieno[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-thieno[3,2-e]- 1,2 thiazine 1,1-dioxide hydrochloride; o 4. 6-Chloro-2-[4-[4-hydroxypiperidin-1-yl]butyl]-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide hydrochloride. By following the procedures of Example 1, but replacing the 1,4-dibromobutane in Step 1 with 1,3-dibromopentane and 4-(2H-benzimidazo-2-oxo-1-yl)piperidine in Step 3 with the s 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. 5. 6-Chloro-2-[3-[4-phenylpiperazin-1-yl]propyl]-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide hydrochloride; o 6. 6-Chloro-2-[3-[4-(3-trifluoromethylphenyl)piperazin-1-yl]propyl]-2H-thieno[3,2-e]-1,2 thiazine 1,1-dioxide hydrochloride; -15- WO 99/59499 PCT/US99/10179 7. 6-Chloro-2-[3-[4-(2-fluorophenyl)piperazin- 1 -yl]propyl]-2H-thieno[3,2-e]- 1,2-thiazine 1,1-dioxide hydrochloride; 8. 6-Chloro-2-[3-[4-(2H-benzimidazol-2-oxo)piperidin-1-yl]propyl]-2H-thieno[3,2-e]-1,2 thiazine 1,1-dioxide hydrochloride. 5 Example 2 3-(4-Methylpiperidin-1-yl)propylsulfonyl-2,3-dihydro-1H-indole Hydrochloride CH, SN NO HCI 0 Step 1. To a solution of indoline (4.00 g, 33.6 mmol) in 100 mL of acetone at O'C was o added 3-chloropropanesulfonyl chloride (5.95 g, 33.6 mmol) with stirring. A solid precipitated from the solution. Diisopropylethylamine (4.33 g, 33.6 mmol) was added in two portions and the reaction mixture became a homogenous solution. The mixture was stirred for 30 min, warmed to ambient temperature, and evaporated to dryness. The crude mixture was combined with a saturated aqueous solution of sodium bicarbonate and extracted s with ethyl acetate (2 x 100 mL). Chromatography on silica (10% to 25% ethyl acetate/hexane) gave an oil which solidified on standing (7.68 g, 77%, mp 53-53'C). Step 2. A mixture of the product of Step 1 (200 mg, 0.77 mmol) and 0.5 M solution of 4 methylpiperidine (4 mL, 2.0 mmol) was heated at 35'C for 60 h. The reaction mixture was D 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 though 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 give the hydrochloride salt (220 mg, 80 %): MS(ES) 323 (M+H). s By following the procedures of Example 2, but replacing 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. -16- WO 99/59499 PCT/US99/10179 1. 3-[4--(3-Chlorophenyl)piperazin- 1 -yl]propylsulfonyl-2,3-dihydro- 1H-indole; 2. 3-(3-Methylpiperidin- 1 -yl)propylsulfonyl-2,3 -dihydro- 1 H-indole; 3. 3-(1,2,3,4-Tetrahydroisoquinolin-2-yl)propylsulfonyl-2,3-dihydro-1H-indole; s 4. 3-[4-(3-Trifluoromethylphenyl)piperazin- 1 -yl]propylsulfonyl-2,3-dihydro- 1 H-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- 1 H-indole; 7. 3-[4-(2-Methoxyphenyl)piperazin-1-yl]propylsulfonyl-2,3-dihydro-1H-indole; 8. 3-[4-(4-Methoxyphenyl)piperazin- 1 -yl]propylsulfonyl-2,3 -dihydro- 1 H-indole; o 9. 3-[4-(2-Chlorophenyl)piperazin- 1 -yl]propylsulfonyl-2,3-dihydro-1H-indole. By following the procedures of Example 2, but replacing 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 5 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-trifluoromethylphenyl)piperazin-1-yl]propylsulfonamide; 12. N-Methyl-N-phenyl-3-(4-phenylpiperazin- 1 -yl)propylsulfonamide; o 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; 15. 3-[4-(2-Chlorophenyl)piperazin- 1-yl]- N-methyl-N-phenyl-propylsulfonamide By following the procedures of Example 2, but replacing the 3-chloropropanesulfonyl 5s 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 this compound were consistent with the assigned structure. 16. 2-(3-Methylpiperidin-1-yl)ethylsulfonyl-2,3-dihydro-1H-indole. 10 -17- WO 99/59499 PCT/US99/10179 Example 3 N-[3-[4-(3-Chlorophenyl)piperazin-1-yl]propyl]-N-(4-methoxyphenyl) propanesulfonamide Hydrochloride o' / /CH 3 HHOI HHCIN Nf Cl 5 Step 1. To a solution ofp-anisidine (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 nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was washed with a saturated aqueous solution of sodium bicarbonate (100 mL), water, and dried over magnesium sulfate. o The organic layer was evaporated to give an oil that was mixed with a solution of hexane and ethyl acetate (3:1) to afford a crystalline solid (7.97 g). The mother liquid was chromatographed on silica (hexane/ethyl acetate, 4:1) to give a solid (2.27 g, 92%): mp 72'C; MS(-ES) 228 (M-H). 5 Step 2. To the product of Step 1 (3.50 g, 15.3 mmol) in anhydrous dimethylformamide (80 mL) at O'C was added sodium hydride (60 % suspension in mineral oil, 0.672 g, 16.8 mmol) under a nitrogen atmosphere. The suspension was stirred for 30 min and 1,3-dibromopropane (9.27 g, 45.9 mmol) was added over 1 min. The reaction was stirred for 3 h, mixed with a saturated aqueous solution of sodium bicarbonate (200 mL) and extracted with ethyl acetate 0 (3 x 100 mL). The combined extracts were dried and evaporated to dryness. Chromatography on silica (20% ethyl acetate in hexane) gave a colorless oil (4.33 g, 8 1%): MS(+ES) 352 (M+H). Step 3. To a solution of the product of Step 2 (0.175 g, 0.50 mmol) in anhydrous 1s 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 0 C for 18 h. The cooled reaction mixture was extracted with ethyl acetate (2 x 1 mL) and the combined extracts were washed with a saturated aqueous solution of sodium -18- WO 99/59499 PCTIUS99/10179 bicarbonate, dried and evaporated to an oil which was treated with a 1.0 M solution of hydrogen chloride gas in ether to give the corresponding salt (0.11 g, 44%): MS(ES) 466 (M+). s By following the procedures of Example 3, but replacing 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-(4-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. By following the procedures of Example 3, but replacing the 1,3-dibromopropane in Step 2 with 1,4-dibromobutane and the 1-(3-chlorophenyl)piperazine in Step 3 with 1,2,3,4 -19- WO 99/59499 PCT/US99/10179 tetrahydroisoquinoline, 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 1-4 times per day according to the discretion of a skilled clinician. EXAMPLE 4 Ingredients Amount (wt %) 5HT 7 Compound 0.01 -2% Hydroxypropyl methylcellulose 0.5% Dibasic sodium phosphate (anhydrous) 0.2% Sodium chloride 0.5% Disodium EDTA (Edetate disodium) 0.01% Polysorbate 80 0.05% Benzalkonium chloride 0.01% Sodium hydroxide / Hydrochloric acid For adjusting pH to 7.3 - 7.4 Purified water q.s. to 100% -20- WO 99/59499 PCT/US99/10179 EXAMPLE 5 Ingredients Amount (wt %) 5HT 7 Compound 0.01 -2% Hydroxypropyl methylcellulose 0.5% Cremophor EL 0.1% Tromethamine, USP, AR 0.64% Mannitol, USP 3.0% Boric acid, USP 0.3% Dibasic sodium phosphate (anhydrous) 0.2% Sodium chloride 0.5% Disodium EDTA (Edetate disodium) 0.01% Polysorbate 80 0.05% Benzalkonium chloride 0.01% Sodium hydroxide / Hydrochloric acid For adjusting pH to 7.3 - 7.4 Purified water q.s. to 100% 5 EXAMPLE 6 Ingredients Amount (wt %) 5HT 7 Compound 0.01 -2% Methyl cellulose 4.0% Dibasic sodium phosphate (anhydrous) 0.2% Sodium chloride 0.5% Disodium EDTA (Edetate disodium) 0.01% Polysorbate 80 0.05% Benzalkonium chloride 0.01% Sodium hydroxide / Hydrochloric acid For adjusting pH to 7.3 - 7.4 Purified water q.s. to 100% -21- WO 99/59499 PCTIUS99/10179 EXAMPLE 7 Ingredients Amount (wt %) 5HT 7 Compound 0.01 -2% Hydroxypropyl-p-cyclodextrin 4.0% Dibasic sodium phosphate (anhydrous) 0.2% Sodium chloride 0.5% Disodium EDTA (Edetate disodium) 0.01% Polysorbate 80 0.05% Benzalkonium chloride 0.01% Sodium hydroxide / Hydrochloric acid For adjusting pH to 7.3 - 7.4 Purified water q.s. to 100% s EXAMPLE 8 Ingredients Amount (wt %) 5HT 7 Compound 0.01 -2% Xanthan gum 0.5-6.0% Dibasic sodium phosphate (anhydrous) 0.2% Sodium chloride 0.5% Disodium EDTA (Edetate disodium) 0.01% Polysorbate 80 0.05% Benzalkonium chloride 0.01% Sodium hydroxide / Hydrochloric acid For adjusting pH to 7.3 - 7.4 Purified water q.s. to 100% -22- WO 99/59499 PCT/US99/10179 EXAMPLE 9 Ingredients Amount (wt %) 5HT 7 Compound 0.01 -2% Guar gum 0.4- 6.0% Dibasic sodium phosphate (anhydrous) 0.2% Sodium chloride 0.5% Disodium EDTA (Edetate disodium) 0.01% Polysorbate 80 0.05% Benzalkonium chloride 0.01% Sodium hydroxide / Hydrochloric acid For adjusting pH to 7.3 - 7.4 Purified water q.s. to 100% 5 EXAMPLE 10 Ingredients Amount (wt %) 5HT 7 Compound 0.01 -2% Tyloxapol 0.2-4.0% Dibasic sodium phosphate (anhydrous) 0.2% Sodium chloride 0.5% Disodium EDTA (Edetate disodium) 0.01% Polysorbate 80 0.05% Benzalkonium chloride 0.01% Sodium hydroxide / Hydrochloric acid For adjusting pH to 7.3 - 7.4 Purified water q.s. to 100% -23- WO 99/59499 PCT/US99/10179 EXAMPLE 11 Ingredients Amount (wt %) 5HT 7 Compound 0.01 -2% White petrolatum and mineral oil and Ointment consistency lanolin Dibasic sodium phosphate (anhydrous) 0.2% Sodium chloride 0.5% Disodium EDTA (Edetate disodium) 0.01% Polysorbate 80 0.05% Benzalkonium chloride 0.01% Sodium hydroxide / Hydrochloric acid For adjusting pH to 7.3 - 7.4 5 EXAMPLE 12 Formulation for Oral Administration 10 Tablet: 0.2 - 5 mg. of 5HT 7 Compound with inactive ingredients such as cornstarch, lactose, colloidal silicon dioxide, microcrystalline cellulose, and magnesium sterate can be formulated according to procedures known to those skilled in the art of tablet formulation. -24-

Claims

1. A compound of the formula: 1 R Aryl 8 (CR3R) n-N 0 0 R Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; 0 R' is H, OH, OC 1 . 3 alkyl, CI- 3 alkyl, Ci- 3 alkyl substituted optionally with OH, or OCi- 3 alkyl; R2 is H, halogen, C1. 3 alkyl, CONR R6, S(=0)mCi- 3 alkyl, S(=0) 2 NR 5 R 6 , Ci- 3 alkyl substituted optionally with OH, or OCI- 3 alkyl; R 3 , R 4 are independently H, CI- 3 alkyl, Ci- 3 alkyl substituted optionally with OH or OCI. 3 alkyl; R 5 , R 6 are independently H, CI. 3 alkyl, C 2 - 3 alkyl substituted optionally with OH, OCI 3 alkyl, or 5 R 5 and R 6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with CI. 3 alkyl, C 2 - 3 alkyl substituted optionally with OH or OCI- 3 alkyl; R7, R 8 are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from CI. 3 alkyl, Ci- 3 alkyl substituted optionally with OH, OCI 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI- 3 alkyl, or CI 3 alkyl, or substituted on nitrogen s with C1.4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI. 3 alkyl, or CI- 3 alkyl; n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates. 0 -25- WO 99/59499 PCT/US99/10179

2. A compound of the formula: 2___ 8 R s CRR)n N Aryl | R A ,1 /\\ R 0 0 5 Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; R 1 is H, C 1 . 5 alkyl, C 3 . 5 alkenyl, an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OCi- 3 alkyl, S(=O)mCi. 3 alkyl, halogen, CF 3 , or S(=0) 2 NR 5 R 6 ; or C 2 -salkyl 1o substituted optionally with OH, OCI. 3 alkyl, S(=0)mC. 3 alkyl or an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OCi- 3 alkyl, S(=O)mCi 3 alkyl, halogen, CF 3 , S(=0) 2 NR 5 R 6 ; or C 3 .salkenyl substituted optionally with OH, OCI. 3 alkyl, or S(=O)mC1. 3 alkyl; 1s R2 is H, halogen, Ci- 3 alkyl, S(=O)mC1. 3 alkyl, S(=0) 2 NRR 6 , or CI 3 alkyl substituted optionally with OH, or OCi- 3 alkyl; R & R are independently H, Ci- 3 alkyl, or Ci- 3 alkyl substituted optionally with OH or OCi- 3 alkyl; R 5 , R 6 are independently H, CI 3 alkyl, C 2 - 3 alkyl substituted optionally with OH, OCi- 3 alkyl, 20 or R 5 and R 6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with Ci- 3 alkyl, C 2 - 3 alkyl substituted optionally with OH or OCI. 3 alkyl; R 7 , R 8 are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected 25 from N, 0, S, such as pyrrolidine, piperidine, A3-piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from Ci- 3 alkyl, CI. 3 alkyl substituted optionally with OH, OCI. 3 alkyl, phenyl which can be unsubstituted or substituted -26- WO 99/59499 PCTIUS99/10179 optionally with halogen, CF 3 , OCi- 3 alkyl, or CI. 3 alkyl, or substituted on nitrogen with C1.4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI. 3 alkyl, or Ci- 3 alkyl; n is 2 to 4; s m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates.

3. A compound of the formula: R 10R R(CR3R4)-N R 9-N"Sn \R7 30 4 0o R3 & R are independently H, CI. 3 alkyl, or CI. 3 alkyl substituted optionally with OH or OC 1 . 3 alkyl; R7, R are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, A3-piperidein, piperazine, morpholine is or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from C 1 . 3 alkyl, CI. 3 alkyl substituted optionally with OH, OCi- 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCi- 3 alkyl, or C1. 3 alkyl, or substituted on nitrogen with C1.4alkoxy or phenyl which can be unsubstituted or substituted optionally with 2o halogen, CF 3 , OCi- 3 alkyl, or Ci. 3 alkyl; R 9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with C1.4 alkyl, halogen, OC1.4alkyl; R'O is C1.4alkyl, or R' 0 can be joined to R9 to form a fused bicyclic ring system such as indoline; 25 n is 2 to 4 and any pharmaceutically acceptable salts and solvates. -27- WO 99/59499 PCT/US99/10179

4. A Compound of the formula: 0 0 R 111N -S--R (CR 3 R4)-N 5 R 3 & R4 are independently H, CI. 3 alkyl, or Ci- 3 alkyl substituted optionally with OH or OCI. 3 alkyl; R 7, R are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine o or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from CI. 3 alkyl, Ci- 3 alkyl substituted optionally with OH, OCi - 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OC 1 .3alkyl, or CI 3 alkyl, or substituted on nitrogen with C14alkoxy or phenyl which can be unsubstituted or substituted optionally with s halogen, CF 3 , OC 1 . 3 alkyl, or C 1 . 3 alkyl; R" is C 1 . 3 alkyl, phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with Ci4 alkyl, halogen, OCI.4alkyl; R is C14alkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-e]-1,2-thiazine, or 1,2-benzothiazine, or R can be joined to R to form a fused bicyclic ring system 0o such as 2,3-dihydro-benzo[c]isoxazole; n is 2 to 4 and any pharmaceutically acceptable salts and solvates. -28- WO 99/59499 PCT/US99/10179

5. A method for lowering IOP which comprises administering to a person in need thereof, a composition comprising an effective amount of a compound of the formula: 1 R 2 Aryl 8 ,N 3 (CR3R4) nNs O O R7 5 Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; R' is H, OH, OCi- 3 alkyl, Ci- 3 alkyl, CI. 3 alkyl substituted optionally with OH, or OCI. 3 alkyl; 0o R2 is H, halogen, Ci. 3 alkyl, CONRR 6 , S(=O)mC1. 3 alkyl, S(=0) 2 NR 5 R 6 , CI- 3 alkyl substituted optionally with OH, or OCi- 3 alkyl; R3, R4 are independently H, C,. 3 alkyl, Ci. 3 alkyl substituted optionally with OH or OCi- 3 alkyl; R 5 , R6 are independently H, Ci- 3 alkyl, C 2 . 3 alkyl substituted optionally with OH, OCi- 3 alkyl, or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6 i5 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with CI. 3 alkyl, C 2 - 3 alkyl substituted optionally with OH or OCI-3alkyl; R7, R are together with the nitrogen atom to which they are attached incorporated into 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, piperazine, morpholine to or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from CI. 3 alkyl, CI. 3 alkyl substituted optionally with OH, OCI. 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OC1. 3 alkyl, or C1. 3 alkyl, or substituted on nitrogen with C1.4alkoxy or phenyl which can be unsubstituted or substituted optionally with 2s halogen, CF 3 , OCI. 3 alkyl, or CI- 3 alkyl; n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates. -29- WO 99/59499 PCTIUS99/10179

6. A method for lowering IOP which comprises administering to a person in need thereof, a composition comprising an effective amount of a compound of the formula: 8 R SCRR -N Aryl R /k R 5 0 0 Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; RI is H, Ci.salkyl, C 3 -salkenyl, an aromatic ring such as phenyl, thienyl, pyridyl, and o imidazoyl which is either unsubstituted or substituted optionally with OH, OCI. 3 alkyl, S(=O)mCi- 3 alkyl, halogen, CF 3 , or S(=0) 2 NR 5 R 6 ; or C 2 -salkyl substituted optionally with OH, OCi- 3 alkyl, S(=O)mCi- 3 alkyl or an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OCi- 3 alkyl, S(=0)mC. 3 alkyl, halogen, CF 3 , S(=0) 2 s NR R ; or C 3 -salkenyl substituted optionally with OH, OCi- 3 alkyl, or S(=O)mCi. 3 alkyl; R2 is H, halogen, C 1 .3alkyl, S(=O)mC- 3 alkyl, S(=0) 2 NRsR 6 , or CI 3 alkyl substituted optionally with OH, or OCI. 3 alkyl; R 3 & R 4 are independently H, CI. 3 alkyl, or Ci. 3 alkyl substituted optionally with OH or o OCI- 3 alkyl; R 5 , R 6 are independently H, Ci- 3 alkyl, C 2 - 3 alkyl substituted optionally with OH, OCI. 3 alkyl, or R 5 and R 6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with Ci - 3 alkyl, C 2 - 3 alkyl substituted optionally with OH or OCI- 3 alkyl; s R

7, R are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or -30- WO 99/59499 PCT/US99/10179 more substituents optionally selected from CI. 3 alkyl, CI. 3 alkyl substituted optionally with OH, OCI. 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI. 3 alkyl, or Ci- 3 alkyl, or substituted on nitrogen with CI.4alkoxy or phenyl which can be unsubstituted or substituted optionally with 5 halogen, CF 3 , OCi. 3 alkyl, or Ci- 3 alkyl; n is 2 to 4; mis 0, 1 or2 and any pharmaceutically acceptable salts and solvates. 0 7. A method for lowering IOP which comprises administering to a person in need thereof, a composition comprising an effective amount of a compound of the formula: R 10 Ra8 (CR 3 R 4 )-N R9' S R7 O O R 3 & R4 are independently H, CI. 3 alkyl, or CI. 3 alkyl substituted optionally with OH or OC 1 . 3 alkyl; R 7, R are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, A3-piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from CI. 3 alkyl, CI. 3 alkyl substituted 0 optionally with OH, OCi- 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCi- 3 alkyl, or Ci- 3 alkyl, or substituted on nitrogen with Ci.4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCi- 3 alkyl, or Ci- 3 alkyl; R 9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted s with C.4 alkyl, halogen, OC14alkyl; R" 0 is C1.4alkyl, or R' 0 can be joined to R9 to form a fused bicyclic ring system such as indoline; n is 2 to 4 -31- WO 99/59499 PCT/US99/10179 and any pharmaceutically acceptable salts and solvates.

8. A method for lowering IOP which comprises administering to a person in need thereof, a composition comprising an effective amount of a compound of the formula: 5 0 0 RM S-R" N Ra (CR3R 4 );-N R 3 & R 4 are independently H, CI 3 alkyl, or CI. 3 alkyl substituted optionally with OH or OC 1 . 3 alkyl; R 7, R are together with the nitrogen atom to which they are attached incorporated into a 0 heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from CI 3 alkyl, Ci- 3 alkyl substituted optionally with OH, OCI. 3 alkyl, phenyl which can be unsubstituted or substituted 5 optionally with halogen, CF 3 , OCI. 3 alkyl, or CI. 3 alkyl, or substituted on nitrogen with CI. 4 alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCi- 3 alkyl, or CI. 3 alkyl; R"' is C1. 3 alkyl, phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with C1. 4 alkyl, halogen, OC1. 4 alkyl; 0 12R is Ci. 4 alkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-e]-1 ,2-thiazine, or 1,2-benzothiazine, or R can be joined to R" to form a fused bicyclic ring system such as 2,3-dihydro-benzo[c]isoxazole; n is 2 to 4 and any pharmaceutically acceptable salts and solvates. 5 -32- WO 99/59499 PCT/US99/10179

9. A method for improving blood flow to the optic nerve head and the retina which comprises administering to a person in need thereof, a composition comprising an effective amount of a compound of the formula: 1 R Aryl 8 3 (CR3R 4 ) n-N 0 0 R Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; R' is H, OH, OCi- 3 alkyl, C1.. 3 alkyl, C1.. 3 alkyl substituted optionally with OH, or OCi- 3 alkyl; R2 is H, halogen, C 1 . 3 alkyl, CONRR 6 , S(=O)mCi- 3 alkyl, S(=O) 2 NR 5 R 6 , CI. 3 alkyl substituted optionally with OH, or OCI. 3 alkyl; R 3 , R 4 are independently H, Ci- 3 alkyl, Ci- 3 alkyl substituted optionally with OH or OCI. 3 alkyl; R 5 , R 6 are independently H, CI- 3 alkyl, C 2 - 3 alkyl substituted optionally with OH, OCI 3 alkyl, or R 5 and R 6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with CI. 3 alkyl, C 2 - 3 alkyl substituted optionally with OH or OCI. 3 alkyl; R 7 , R' are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from CI 3 alkyl, Ci- 3 alkyl substituted optionally with OH, OCi- 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCi- 3 alkyl, or CI. 3 alkyl, or substituted on nitrogen with C1.4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI- 3 alkyl, or CI. 3 alkyl; n is 2 to 4; mis 0, 1 or2 and any pharmaceutically acceptable salts and solvates. -33- WO 99/59499 PCTIUS99/10179

10. A method for improving blood flow to the optic nerve head and the retina which comprises administering to a person in need thereof, a composition comprising an effective amount of a compound of the formula: 5 8 R s CR 3 R -N Aryl | R /fe\ R 0 0 Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; 0 R 1 is H, Ci.salkyl, C 3 .salkenyl, an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OCI. 3 alkyl, S(=O)mCi- 3 alkyl, halogen, CF 3 , or S(=0) 2 NR 5 R 6 ; or C 2 -salkyl substituted optionally with OH, OCi. 3 alkyl, S(=0)mC. 3 alkyl or an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or s substituted optionally with OH, OCi- 3 alkyl, S(=O)mCi. 3 alkyl, halogen, CF 3 , S(=0) 2 NR R ; or C 3 .salkenyl substituted optionally with OH, OCI. 3 alkyl, or S(=O)mC1. 3 alkyl; R is H, halogen, CI- 3 alkyl, S(=O)mCI. 3 alkyl, S(=0) 2 NR R 6 , or CI. 3 alkyl substituted optionally with OH, or OCi - 3 alkyl; 0R 3 & R 4 are independently H, Ci. 3 alkyl, or Ci- 3 alkyl substituted optionally with OH or OCi- 3 alkyl; R 5 , R 6 are independently H, CI. 3 alkyl, C 2 - 3 alkyl substituted optionally with OH, OCI. 3 alkyl, or R 5 and R 6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted 5 optionally with CI. 3 alkyl, C 2 - 3 alkyl substituted optionally with OH or OC.. 3 alkyl; R , R 8 are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine -34- WO 99/59499 PCT/US99/10179 or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from CI. 3 alkyl, CI. 3 alkyl substituted optionally with OH, OCi- 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OC1. 3 alkyl, or Ci.- 3 alkyl, or substituted on nitrogen with C1.4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCi - 3 alkyl, or CI. 3 alkyl; n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates.

11. A method for improving blood flow to the optic nerve head and the retina which comprises administering to a person in need thereof, a composition comprising an effective amount of a compound of the formula: 1 /(CR3R 4 ),-N R 9,N S n \R 7 R 3 & R4 are independently H, Ci- 3 alkyl, or Ci- 3 alkyl substituted optionally with OH or OCI. 3 alkyl; R 7 , R 8 are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected D from N, 0, S, such as pyrrolidine, piperidine, 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from Ci- 3 alkyl, Ci- 3 alkyl substituted optionally with OH, OCI. 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCi- 3 alkyl, or Ci. 3 alkyl, or substituted on nitrogen 5 with CI.4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCi- 3 alkyl, or CI. 3 alkyl; -35- WO 99/59499 PCT/US99/10179 R 9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with CI.4 alkyl, halogen, OCI.4alkyl; R10 is CI.4alkyl, or R'O can be joined to R9 to form a fused bicyclic ring system such as indoline; s n is 2 to 4 and any pharmaceutically acceptable salts and solvates.

12. A method for improving blood flow to the optic nerve head and the retina which comprises administering to a person in need thereof, a composition comprising an effective o amount of a compound of the formula: 0 0 RM S-RU N /R (CR 3 R 4 );-N R & R 4 are independently H, CI. 3 alkyl, or Ci. 3 alkyl substituted optionally with OH or OCI- 3 alkyl; R , R are together with the nitrogen atom to which they are attached incorporated into a s heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, A3-piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from CI. 3 alkyl, C 1 . 3 alkyl substituted optionally with OH, OCI. 3 alkyl, phenyl which can be unsubstituted or substituted to optionally with halogen, CF 3 , OCI. 3 alkyl, or CI. 3 alkyl, or substituted on nitrogen with C14alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI- 3 alkyl, or CI. 3 alkyl; R" is C 1. 3 alkyl, phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with C 1 . 4 alkyl, halogen, OC14alkyl; Zs R 12 is C14alkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-e]-1,2-thiazine, or 1,2-benzothiazine, or R can be joined to R to form a fused bicyclic ring system such as 2,3-dihydro-benzo[c]isoxazole; -36- WO 99/59499 PCT/US99/10179 n is 2 to 4 and any pharmaceutically acceptable salts and solvates.

13. A method for treating retinal diseases which comprises administering to a person in need thereof, a composition comprising an effective amount of a compound of the formula: 1 R Aryl 8 \\ (CR nR 4 )N 0 0 R Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; R' is H, OH, OCI- 3 alkyl, CI. 3 alkyl, Ci- 3 alkyl substituted optionally with OH, or OCi- 3 alkyl; R2 is H, halogen, Ci- 3 alkyl, CONRR 6 , S(=0)mCI. 3 alkyl, S(=0) 2 NR R6, CI. 3 alkyl substituted optionally with OH, or OCi - 3 alkyl; R 3 , R 4 are independently H, C1. 3 alkyl, Ci - 3 alkyl substituted optionally with OH or OC1. 3 alkyl; R 5 , R 6 are independently H, CI. 3 alkyl, C 2 - 3 alkyl substituted optionally with OH, OCI. 3 alkyl, or R 5 and R 6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with CI- 3 alkyl, C 2 - 3 alkyl substituted optionally with OH or OCi- 3 alkyl; D R 7 , R 8 are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, A3-piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from Ci- 3 alkyl, CI.3alkyl substituted s optionally with OH, OC1.I 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCi. 3 alkyl, or C1. 3 alkyl, or substituted on nitrogen with Cl.4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI- 3 alkyl, or C . 3 alkyl; n is 2 to 4; -37- WO 99/59499 PCT/US99/10179 m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates.

14. A method for treating retinal diseases which comprises administering to a person s in need thereof, a composition comprising an effective amount of a compound of the formula: 8 R s CRR -- 1 Aryl | R /yk\ R 0 0 Wherein the dashed bond represents a single or double bond; 0 Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; R 1 is H, CI. 5 alkyl, C 3 . 5 alkenyl, an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OC 1 . 3 alkyl, S(=O)mC1i 3 alkyl, halogen, CF 3 , or S(=0) 2 NR 5 R 6 ; or C 2 -salkyl substituted optionally with OH, OCi. 3 alkyl, S(=0)mC. 3 alkyl or an aromatic ring 5 such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OCi- 3 alkyl, S(=0)mCi- 3 alkyl, halogen, CF 3 , S(=0) 2 NR 5 R 6 ; or C 3 - 5 alkenyl substituted optionally with OH, OCI. 3 alkyl, or S(=O)mC1. 3 alkyl; 26 R2 is H, halogen, CI. 3 alkyl, S(=O)mCI. 3 alkyl, S(=0) 2 NR 5 R 6 , or CI. 3 alkyl substituted 0 optionally with OH, or OCI. 3 alkyl; R & R 4 are independently H, Ci- 3 alkyl, or CI. 3 alkyl substituted optionally with OH or OCi- 3 alkyl; R 5 , R 6 are independently H, Ci- 3 alkyl, C 2 - 3 alkyl substituted optionally with OH, OCI. 3 alkyl, or R 5 and R 6 can be joined together with saturated carbon atoms to form a 5 or 6 Z5 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with C 1 . 3 alkyl, C 2 - 3 alkyl substituted optionally with OH or OCI. 3 alkyl; R 7 , R 8 are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected -38- WO 99/59499 PCT/US99/10179 from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from Ci. 3 alkyl, CI. 3 alkyl substituted optionally with OH, OCi. 3 alkyl, phenyl which can be unsubstituted or substituted s optionally with halogen, CF 3 , OCi- 3 alkyl, or CI. 3 alkyl, or substituted on nitrogen with CI.4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI. 3 alkyl, or Ci. 3 alkyl; n is 2 to 4; m is 0, 1 or 2 10 and any pharmaceutically acceptable salts and solvates.

15. A method for treating retinal diseases which comprises administering to a person in need thereof, a composition comprising an effective amount of a compound of the formula: R 10 yR8 I (CR3R4)--N R N' S R O O 15 R3 & R4 are independently H, CI. 3 alkyl, or CI. 3 alkyl substituted optionally with OH or OCI- 3 alkyl; R7, R are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected 20 from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from Ci- 3 alkyl, CI. 3 alkyl substituted optionally with OH, OC1- 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI. 3 alkyl, or CI. 3 alkyl, or substituted on nitrogen 25 with CI. 4 alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OC1. 3 alkyl, or C 1 . 3 alkyl; R 9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with C 1 . 4 alkyl, halogen, OC 1.4alkyl; -39- WO 99/59499 PCT/US99/10179 R'O is C1.4alkyl, or R10 can be joined to R9 to form a fused bicyclic ring system such as indoline; n is 2 to 4 and any pharmaceutically acceptable salts and solvates. 5

16. A method for treating retinal diseases which comprises administering to a person in need thereof, a composition comprising an effective amount of a compound of the formula: 0 0 \// 12 R N S-R /R (CR3R 4 )--N 0 R & R are independently H, C1. 3 alkyl, or Ci- 3 alkyl substituted optionally with OH or OCI- 3 alkyl; R7, R are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine is or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from Ci- 3 alkyl, CI. 3 alkyl substituted optionally with OH, OCi- 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI. 3 alkyl, or Ci- 3 alkyl, or substituted on nitrogen with C1.4alkoxy or phenyl which can be unsubstituted or substituted optionally with zo halogen, CF 3 , OCI. 3 alkyl, or Ci- 3 alkyl; R" is C 1 - 3 alkyl, phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with C1.4 alkyl, halogen, OCI.4alkyl; R is CI4alkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-e]-1,2-thiazine, or 1,2-benzothiazine, or R can be joined to R" to form a fused bicyclic ring system is such as 2,3-dihydro-benzo[c]isoxazole; n is 2 to 4 and any pharmaceutically acceptable salts and solvates. -40- WO 99/59499 PCTIUS99/10179

17. A composition for lowering IOP comprising a pharmaceutically effective amount of a compound of the formula: 1 R Aryl 8 A341 (CR3R,-N O O R7 Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; 1o R' is H, OH, OC 1 . 3 alkyl, CI. 3 alkyl, CI 3 alkyl substituted optionally with OH, or OCI 3 alkyl; R2 is H, halogen, Ci- 3 alkyl, CONRsR6, S(=O)mCI. 3 alkyl, S(=0) 2 NR 5 R 6 , CI. 3 alkyl substituted optionally with OH, or OCi- 3 alkyl; R(, R 4 are independently H, Ci- 3 alkyl, Ci- 3 alkyl substituted optionally with OH or OCI. 3 alkyl; R 5 , R 6 are independently H, Ci- 3 alkyl, C 2 - 3 alkyl substituted optionally with OH, OCI. 3 alkyl, or is R 5 and R 6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with CI. 3 alkyl, C 2 - 3 alkyl substituted optionally with OH or OCI. 3 alkyl; R', R 8 are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected 20 from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from Ci- 3 alkyl, CI. 3 alkyl substituted optionally with OH, OC 1 . 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI. 3 alkyl, or CI 3 alkyl, or substituted on nitrogen 25 with C .4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI. 3 alkyl, or CI 3 alkyl; n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates. -41- WO 99/59499 PCT/US99/10179

18. A composition for lowering IOP comprising a pharmaceutically effective amount of a compound of the formula: 8 R . CRR n Aryl |R f e\ R 0 0 5 Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; RI is H, Ci- 5 alkyl, C 3 .salkenyl, an aromatic ring such as phenyl, thienyl, pyridyl, and 10 imidazoyl which is either unsubstituted or substituted optionally with OH, OCI. 3 alkyl, S(=0)mC.. 3 alkyl, halogen, CF 3 , or S(=0) 2 NR 5 R 6 ; or C 2 -salkyl substituted optionally with OH, OCI. 3 alkyl, S(=O)mC1. 3 alkyl or an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OCi- 3 alkyl, S(=O)mCI- 3 alkyl, halogen, CF 3 , S(=0) 2 15 NR 5 R 6 ; or C 3 -salkenyl substituted optionally with OH, OCi- 3 alkyl, or S(=O)mCl. 3 alkyl; 2 56 R2 is H, halogen, C 1 . 3 alkyl, S(=O)mCI. 3 alkyl, S(=0) 2 NR R , or C1. 3 alkyl substituted optionally with OH, or OCi- 3 alkyl; R 3 & R4 are independently H, Ci. 3 alkyl, or C1. 3 alkyl substituted optionally with OH or 20 OCi- 3 alkyl; R , R6 are independently H, CI. 3 alkyl, C 2 - 3 alkyl substituted optionally with OH, OCI. 3 alkyl, or R5 and R 6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with Ci- 3 alkyl, C 2 - 3 alkyl substituted optionally with OH or OCi- 3 alkyl; 25 R7, R are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or -42- WO 99/59499 PCTIUS99/10179 more substituents optionally selected from CI. 3 alkyl, CI. 3 alkyl substituted optionally with OH, OCI. 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCi- 3 alkyl, or Ci- 3 alkyl, or substituted on nitrogen with C1.4alkoxy or phenyl which can be unsubstituted or substituted optionally with s halogen, CF 3 , OCI. 3 alkyl, or CI. 3 alkyl; n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates. 1o

19. A composition for lowering IOP comprising a pharmaceutically effective amount of a compound of the formula: R 10 R8 1 (CR3R4)--N R S R7 O O R 3 & R 4 are independently H, CI 3 alkyl, or Ci- 3 alkyl substituted optionally with OH or OCI. 3 alkyl; 1s R 7 , R 8 are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from Ci- 3 alkyl, CI. 3 alkyl substituted 20 optionally with OH, OC. 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCi- 3 alkyl, or Ci- 3 alkyl, or substituted on nitrogen with C1 4 alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OC 1 - 3 alkyl, or CI. 3 alkyl; R 9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted 25 with C14 alkyl, halogen, OC.4alkyl; RI' is C 1 4alkyl, or R10 can be joined to R? to form a fused bicyclic ring system such as indoline; -43- WO 99/59499 PCTIUS99/10179 n is 2 to 4 and any pharmaceutically acceptable salts and solvates.

20. A composition for lowering IOP comprising a pharmaceutically effective amount s of a compound of the formula: 0 0 \\~ >/ 12 RM O I-S R 8 N (CR 3 R 4 ),-N R 3 & R 4 are independently H, CI 3 alkyl, or CI. 3 alkyl substituted optionally with OH or OCI- 3 alkyl; R', R' are together with the nitrogen atom to which they are attached incorporated into a o heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from Ci- 3 alkyl, Ci. 3 alkyl substituted optionally with OH, OC 1 . 3 alkyl, phenyl which can be unsubstituted or substituted 5 optionally with halogen, CF 3 , OCI 3 alkyl, or CI. 3 alkyl, or substituted on nitrogen with C1.4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCi - 3 alkyl, or CI. 3 alkyl; R 1 is C 1 . 3 alkyl, phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with C1.4 alkyl, halogen, OC1.4alkyl; to R is C1.4alkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-e]-1,2-thiazine, or 1,2-benzothiazine, or R can be joined to R1 to form a fused bicyclic ring system such as 2,3-dihydro-benzo[c]isoxazole; n is 2 to 4 and any pharmaceutically acceptable salts and solvates. 15

21. A composition for improving blood flow to the optic nerve head and the retina comprising a pharmaceutically effective amount of a compound of the formula: -44- WO 99/59499 PCTIUS99/10179 R * Aryl 8 3 1 S (CR3R4) n-N, O O R7 5 Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; R' is H, OH, OC 1 . 3 alkyl, C1. 3 alkyl, Ci- 3 alkyl substituted optionally with OH, or OCI. 3 alkyl; 2 56 R2 is H, halogen, C 1 . 3 alkyl, CONR R , S(=O)mCi- 3 alkyl, S(=0) 2 NR 5 R 6 , Ci- 3 alkyl substituted optionally with OH, or OCI. 3 alkyl; o R 3 , R 4 are independently H, Ci- 3 alkyl, Ci- 3 alkyl substituted optionally with OH or OCI.. 3 alkyl; R 5 , R 6 are independently H, CI 3 alkyl, C 2 - 3 alkyl substituted optionally with OH, OCI. 3 alkyl, or R 5 and R 6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with CI. 3 alkyl, C 2 - 3 alkyl substituted optionally with OH or OCi- 3 alkyl; 5s R 7 , R 8 are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from Ci- 3 alkyl, Ci- 3 alkyl substituted zo optionally with OH, OCI. 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI. 3 alkyl, or CI 3 alkyl, or substituted on nitrogen with C1 4 alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCi- 3 alkyl, or CI. 3 alkyl; n is 2 to 4; 25 r mis 0, 1 or 2 and any pharmaceutically acceptable salts and solvates.

22. A composition for improving blood flow to the optic nerve head and the retina comprising a pharmaceutically effective amount of a compound of the formula: -45- WO 99/59499 PCT/US99/10179 8 R RR CRR -N 4 Aryl | R /fe\ R 0 0 Wherein the dashed bond represents a single or double bond; s Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; R' is H, C 1 5 alkyl, C 3 . 5 alkenyl, an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OC 1 . 3 alkyl, S(=O)mCi. 3 alkyl, halogen, CF 3 , or S(=0) 2 NR 5 R 6 ; or C 2 - 5 alkyl substituted optionally with OH, OCi- 3 alkyl, S(=O)mCi. 3 alkyl or an aromatic ring to such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OCi- 3 alkyl, S(=O)mCi. 3 alkyl, halogen, CF 3 , S(=0) 2 NRR 6 ; or C 3 . 5 alkenyl substituted optionally with OH, OCi- 3 alkyl, or S(=O)mC1. 3 alkyl; 26 R2 is H, halogen, Ci. 3 alkyl, S(=O)mCi. 3 alkyl, S(=0) 2 NR 5 R 6 , or Ci. 3 alkyl substituted 15 optionally with OH, or OCi. 3 alkyl; R 3 & R 4 are independently H, C1.I 3 alkyl, or Ci- 3 alkyl substituted optionally with OH or OCI- 3 alkyl; R', R6 are independently H, Ci- 3 alkyl, C 2 - 3 alkyl substituted optionally with OH, OCI. 3 alkyl, or R 5 and R 6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with Ci- 3 alkyl, C 2 - 3 alkyl substituted optionally with OH or OCi. 3 alkyl; R', R are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine 25 or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from Ci- 3 alkyl, CI. 3 alkyl substituted optionally with OH, OCi- 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI. 3 alkyl, or CI. 3 alkyl, or substituted on nitrogen -46- WO 99/59499 PCTIUS99/10179 with C1.4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCi- 3 alkyl, or CI. 3 alkyl; n is 2 to 4; mis 0, 1 or2 s and any pharmaceutically acceptable salts and solvates.

23. A composition for improving blood flow to the optic nerve head and the retina comprising a pharmaceutically effective amount of a compound of the formula: R 10 /R 8 (CR3R4);-N R S R O O 10 R 3 & R 4 are independently H, CI. 3 alkyl, or CI- 3 alkyl substituted optionally with OH or OCI. 3 alkyl; R7, R8 are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected is from N, 0, S, such as pyrrolidine, piperidine, A3-piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from CI- 3 alkyl, Ci- 3 alkyl substituted optionally with OH, OCI. 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI. 3 alkyl, or CI. 3 alkyl, or substituted on nitrogen 20 with CI. 4 alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI. 3 alkyl, or CI- 3 alkyl; R 9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with CI.4 alkyl, halogen, OC14alkyl; R" is C 14alkyl, or R1 can be joined to R? to form a fused bicyclic ring system such as 2s indoline; n is 2 to 4 and any pharmaceutically acceptable salts and solvates. -47- WO 99/59499 PCTIUS99/10179

24. A composition for improving blood flow to the optic nerve head and the retina comprising a pharmaceutically effective amount of a Compound of the formula: 0 0 \\< > / 12 R N '-S-R R (CR 3 R 4 );-N R 3 & R4 are independently H, CI. 3 alkyl, or Ci- 3 alkyl substituted optionally with OH or s OC 1 . 3 alkyl; R 7 , R 8 are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or o more substituents optionally selected from Ci- 3 alkyl, CI. 3 alkyl substituted optionally with OH, OCi- 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCi- 3 alkyl, or CI. 3 alkyl, or substituted on nitrogen with C1.4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCi- 3 alkyl, or Ci- 3 alkyl; s R" is C 1 . 3 alkyl, phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with CI.4 alkyl, halogen, OC1.4alkyl; R is C1.4alkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-e]-1,2-thiazine, or 1,2-benzothiazine, or R can be joined to R" to form a fused bicyclic ring system such as 2,3-dihydro-benzo[c]isoxazole; 0o n is 2 to 4 and any pharmaceutically acceptable salts and solvates.

25. A composition for treating retinal diseases comprising a pharmaceutically effective amount of a compound of the formula: -48- WO 99/59499 PCT/US99/10179 1 R Aryl 8 A347 (CR3R) n N O O R7 Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; s R' is H, OH, OCI. 3 alkyl, CI 3 alkyl, CI- 3 alkyl substituted optionally with OH, or OCI. 3 alkyl; R2 is H, halogen, C 1 . 3 alkyl, CONRR 6 , S(=O)mCI. 3 alkyl, S(=0) 2 NR 5 R 6 , CI. 3 alkyl substituted optionally with OH, or OCI. 3 alkyl; R 3 , R 4 are independently H, CI. 3 alkyl, CI. 3 alkyl substituted optionally with OH or OCI. 3 alkyl; R 5 , R6 are independently H, Ci- 3 alkyl, C 2 - 3 alkyl substituted optionally with OH, OCI. 3 alkyl, or 10 R' and R 6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with Ci- 3 alkyl, C 2 - 3 alkyl substituted optionally with OH or OCi- 3 alkyl; R 7 , R' are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected 15 from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from CI. 3 alkyl, Ci- 3 alkyl substituted optionally with OH, OCI. 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCi- 3 alkyl, or CI 3 alkyl, or substituted on nitrogen 20 with C14alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI. 3 alkyl, or Ci - 3 alkyl; n is 2 to 4; misO, 1 or2 and any pharmaceutically acceptable salts and solvates. 2s

26. A composition for treating retinal diseases comprising a pharmaceutically effective amount of a compound of the formula: -49- WO 99/59499 PCT/US99/10179 8 R S CRR n Aryl | R /S\\ R 0 0 Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; 5 R1 is H, Ci. 5 alkyl, C 3 - 5 alkenyl, an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OCI- 3 alkyl, S(=O)mCi- 3 alkyl, halogen, CF 3 , or S(=0) 2 NR 5 R 6 ; or C 2 - 5 alkyl substituted optionally with OH, OCi - 3 alkyl, S(=O)mCi- 3 alkyl or an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or O substituted optionally with OH, OCI. 3 alkyl, S(=O)mCi.. 3 alkyl, halogen, CF 3 , S(=0) 2 NR 5 R 6 ; or C 3 -salkenyl substituted optionally with OH, OCI. 3 alkyl, or S(=O)mC1. 3 alkyl; 26 R is H, halogen, CI. 3 alkyl, S(=O)mCi. 3 alkyl, S(=0) 2 NRR 6 , or CI- 3 alkyl substituted optionally with OH, or OCi- 3 alkyl; 5 R 3 & R 4 are independently H, Ci- 3 alkyl, or Ci- 3 alkyl substituted optionally with OH or OCi- 3 alkyl; R 5 , R 6 are independently H, Ci- 3 alkyl, C 2 - 3 alkyl substituted optionally with OH, OCI- 3 alkyl, or R 5 and R 6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted o optionally with C 1 . 3 alkyl, C 2 - 3 alkyl substituted optionally with OH or OC 1 . 3 alkyl; R 7 , R 8 are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or s more substituents optionally selected from CI. 3 alkyl, CI. 3 alkyl substituted optionally with OH, OCI. 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI. 3 alkyl, or Ci- 3 alkyl, or substituted on nitrogen -50- WO 99/59499 PCT/US99/10179 with CI.4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI. 3 alkyl, or CI. 3 alkyl; n is 2 to 4; m is 0, 1 or 2 s and any pharmaceutically acceptable salts and solvates.

27. A composition for treating retinal diseases comprising a pharmaceutically effective amount of a compound of the formula: N (CR3R4)-N R 9 IlN S n \R7 O O D R 3 & R are independently H, CI. 3 alkyl, or CI. 3 alkyl substituted optionally with OH or OCI. 3 alkyl; R 7, R are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine 5 or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from Ci- 3 alkyl, Ci. 3 alkyl substituted optionally with OH, OC 1 . 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OC .. 3 alkyl, or C1.. 3 alkyl, or substituted on nitrogen with C14alkoxy or phenyl which can be unsubstituted or substituted optionally with 0 halogen, CF 3 , OCI- 3 alkyl, or Ci- 3 alkyl; R 9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with C 1 . 4 alkyl, halogen, OC1. 4 alkyl; R1 0 is C 1 . 4 alkyl, or R' can be joined to R! to form a fused bicyclic ring system such as indoline; 5 n is 2 to 4 and any pharmaceutically acceptable salts and solvates. -51- WO 99/59499 PCT/US99/10179

28. A composition for treating retinal diseases comprising a pharmaceutically effective amount of a compound of the formula: 0 0 R 11 NIS-R2 N (CR3R4);-N R 3 & R 4 are independently H, Ci- 3 alkyl, or Ci- 3 alkyl substituted optionally with OH or 5 OCI- 3 alkyl; R 7 , R 8 are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, A3-piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or o more substituents optionally selected from Ci- 3 alkyl, Ci- 3 alkyl substituted optionally with OH, OCI. 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCi. 3 alkyl, or CI. 3 alkyl, or substituted on nitrogen with Ci 4 alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI. 3 alkyl, or Ci- 3 alkyl; s R" 1 is C 1 . 3 alkyl, phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with CIA alkyl, halogen, OC1. 4 alkyl; R is CI alkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-e] -1,2-thiazine, or 1,2-benzothiazine, or R can be joined to R" to form a fused bicyclic ring system such as 2,3-dihydro-benzo[c]isoxazole; .0 n is 2 to 4 and any pharmaceutically acceptable salts and solvates.

29. A method for improving blood flow to the optic nerve head or the retina which comprises administering to a person in need thereof, a composition comprising a 5s pharmaceutically effective amount of a compound with 5HT 7 receptor affinity. -52- WO 99/59499 PCTIUS99/10179

30. A composition for improving blood flow to the optic nerve head or the retina comprising a pharmaceutically effective amount of a compound with 5HT 7 receptor affinity.

31. A method for providing neuroprotection to the optic nerve head or the retina which comprises administering to a person in need thereof, a composition comprising a pharmaceutically effective amount of a compound with 5HT 7 receptor affinity.

32. A composition for providing neuroprotection to the optic nerve head or the retina comprising a pharmaceutically effective amount of a compound with 5HT 7 receptor affinity.

33. A method for treating retinal diseases which comprises administering to a person in need thereof, a composition comprising a pharmaceutically effective amount of a compound with 5HT 7 receptor affinity. s

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

35. A composition for treating retinal diseases comprising a pharmaceutically D effective amount of a compound with 5HT 7 receptor affinity.

36. The composition of Claim 35 wherein the retinal diseases are selected from the group consisting of glaucoma, age related macular degeneration, optic neuritis, ischemic disorders, diabetic retinopathy, and retinal edema. 5

37. A method for lowering IOP which comprises administering to a person in need thereof, a composition comprising a pharmaceutically effective amount of a compound with 5HT 7 receptor affinity. o

38. A composition for lowering IOP comprising a pharmaceutically effective amount of a compound with 5HT 7 receptor affinity. -53- WO 99/59499 PCTIUS99/10179

39. A method for treating persons suffering from a sleeping disorder, depression, schizophrenia, anxiety, circadian rhythm disorders, and centrally and peripherally mediated hypertension, which comprises, administering a composition comprising a pharmaceutically effective amount of a compound of the formula: 5 R ,, Aryl 8 A 3 S (CR3R ) -N O O R7 Wherein the dashed bond represents a single or double bond; 10 Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; R' is H, OH, OC 1 . 3 alkyl, CI. 3 alkyl, Ci. 3 alkyl substituted optionally with OH, or OCI. 3 alkyl; R2 is H, halogen, CI. 3 alkyl, CONRR 6 , S(=0)mCi. 3 alkyl, S(=0) 2 NR 5 R 6 , CI. 3 alkyl substituted optionally with OH, or OCI 3 alkyl; R 3 , R 4 are independently H, Ci- 3 alkyl, CI. 3 alkyl substituted optionally with OH or OCi- 3 alkyl; is R , R 6 are independently H, CI 3 alkyl, C 2 - 3 alkyl substituted optionally with OH, OCI 3 alkyl, or R 5 and R 6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with CI. 3 alkyl, C 2 - 3 alkyl substituted optionally with OH or OCI. 3 alkyl; R 7 , R 8 are together with the nitrogen atom to which they are attached incorporated into a 20 heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from CI. 3 alkyl, CI. 3 alkyl substituted optionally with OH, OCI. 3 alkyl, phenyl which can be unsubstituted or substituted 25 optionally with halogen, CF 3 , OCI. 3 alkyl, or CI. 3 alkyl, or substituted on nitrogen with C1.4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI. 3 alkyl, or CI. 3 alkyl; n is 2 to 4; m is 0, 1 or 2 -54- WO 99/59499 PCT/US99/10179 and any pharmaceutically acceptable salts and solvates.

40. A method for treating persons suffering from a sleeping disorder, depression, schizophrenia, anxiety, obsessive compulsive disorder, circadian rhythem disorders, and 5 centrally and peripherally mediated hypertension which comprises, administering a composition comprising a pharmaceutically effective amount of a compound of the formula: 8 R sCRR n-N\ Aryl R /yS\ R 0 0 o Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; R' is H, CI.salkyl, C 3 .salkenyl, an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OCi- 3 alkyl, S(=O)mC. 3 alkyl, halogen, CF 3 , or S(=O) 2 NR 5 R 6 ; or C 2 -salkyl s substituted optionally with OH, OC1. 3 alkyl, S(=0)mC. 3 alkyl or an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OCI. 3 alkyl, S(=0)mCI1 3 alkyl, halogen, CF 3 , S(=0) 2 NRR 6 ; or C 3 . 5 alkenyl substituted optionally with OH, OCI. 3 alkyl, or S(=O)mC1. 3 alkyl; 0o R2 is H, halogen, CI. 3 alkyl, S(=O)mC. 3 alkyl, S(=0) 2 NR 5 R 6 , or CI. 3 alkyl substituted optionally with OH, or OCI 3 alkyl; R 3 & R 4 are independently H, CI- 3 alkyl, or CI- 3 alkyl substituted optionally with OH or OC 1 . 3 alkyl; R 5 , R 6 are independently H, CI. 3 alkyl, C 2 - 3 alkyl substituted optionally with OH, OCi- 3 alkyl, Zs or R 5 and R 6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with C 1 . 3 alkyl, C 2 - 3 alkyl substituted optionally with OH or OCi- 3 alkyl; -55- WO 99/59499 PCT/US99/10179 R 7, R are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or 5 more substituents optionally selected from CI. 3 alkyl, Ci- 3 alkyl substituted optionally with OH, OC I- 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCi- 3 alkyl, or CI 3 alkyl, or substituted on nitrogen with C1.4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI.. 3 alkyl, or Ci- 3 alkyl; o n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates.

41. A method for treating persons suffering from a sleeping disorder, depression, s schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, and centrally and peripherally mediated hypertension which comprises, administering a composition comprising a pharmaceutically effective amount of a compound of the formula: R 10 R 8 S /(CR3R 4 )-N O O R 3 & R are independently H, C1- 3 alkyl, or CI. 3 alkyl substituted optionally with OH or o OCI- 3 alkyl; R 7, R are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or 5 more substituents optionally selected from CI. 3 alkyl, CI. 3 alkyl substituted optionally with OH, OCI 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI. 3 alkyl, or CI. 3 alkyl, or substituted on nitrogen -56- WO 99/59499 PCT/US99/10179 with CI. 4 alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI. 3 alkyl, or CI. 3 alkyl; R9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with C 1 . 4 alkyl, halogen, OC1.4alkyl; 5 R' is C1..4alkyl, or R10 can be joined to R9 to form a fused bicyclic ring system such as indoline; n is 2 to 4 and any pharmaceutically acceptable salts and solvates. 0

42. A method for treating persons suffering from a sleeping disorder, depression, schizophrenia, anxiety, obsessive compulsive disorder, circadian rhythm disorders, and centrally and peripherally mediated hypertension which comprises, administering a composition comprising a pharmaceutically effective amount of a compound of the formula: 0 0 R1 NS-R R N (CR3R4);-N 5 R 3 & R 4 are independently H, CI 3 alkyl, or CI. 3 alkyl substituted optionally with OH or OCI- 3 alkyl; R', R are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected 0o from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from Ci. 3 alkyl, Ci- 3 alkyl substituted optionally with OH, OCI. 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCi- 3 alkyl, or Ci- 3 alkyl, or substituted on nitrogen as with C1.4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI. 3 alkyl, or CI. 3 alkyl; -57- WO 99/59499 PCT/US99/10179 R 1 is C 1 . 3 alkyl, phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with C1.4 alkyl, halogen, OC1.4alkyl; R is C 1 . 4 alkyl or a fused bicyclic heteroaromatic ring such as thieno [3,2-e] -1,2-thiazine, or 1,2-benzothiazine, or R can be joined to R" to form a fused bicyclic ring system s such as 2,3-dihydro-benzo[c]isoxazole; n is 2 to 4 and any pharmaceutically acceptable salts and solvates.

43. A composition comprising a pharmaceutically effective amount of a compound D of the formula: 1 R Aryl 8 A . 3 (CR3R 4 ) -N 0 0 R Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; s RI is H, OH, OCi- 3 alkyl, C1. 3 alkyl, Ci. 3 alkyl substituted optionally with OH, or OCI. 3 alkyl; R is H, halogen, Ci. 3 alkyl, CONR R6, S(=O)mCI. 3 alkyl, S(=0) 2 NR R6, CI. 3 alkyl substituted optionally with OH, or OCi- 3 alkyl; R 3 , R 4 are independently H, C .. 3 alkyl, Ci- 3 alkyl substituted optionally with OH or OC1. 3 alkyl; R 5 , R 6 are independently H, Ci- 3 alkyl, C 2 - 3 alkyl substituted optionally with OH, OCi. 3 alkyl, or 0 R 5 and R 6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with CI. 3 alkyl, C 2 - 3 alkyl substituted optionally with OH or OCI. 3 alkyl; R7, R are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected 5 from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from Ci- 3 alkyl, CI- 3 alkyl substituted optionally with OH, OCI. 3 alkyl, phenyl which can be unsubstituted or substituted -58- WO 99/59499 PCT/US99/10179 optionally with halogen, CF 3 , OCi- 3 alkyl, or Ci- 3 alkyl, or substituted on nitrogen with C 14 alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCi.. 3 alkyl, or CI. 3 alkyl; n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates in a pharmaceutically acceptable carrier.

44. A composition comprising a pharmaceutically effective amount of a compound of the formula: IR8 R s CRR) -- N 7 Aryl | R /yS\ R 0 0 Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; R' is H, CI 5 alkyl, C 3 . 5 alkenyl, an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OCI- 3 alkyl, S(=O)mCi- 3 alkyl, halogen, CF 3 , or S(=0) 2 NR 5 R 6 ; or C 2 - 5 alkyl substituted optionally with OH, OCI- 3 alkyl, S(=O)mCl. 3 alkyl or an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OCI. 3 alkyl, S(=O)mCi.. 3 alkyl, halogen, CF 3 , S(=0) 2 NR 5 R 6 ; or C 3 - 5 alkenyl substituted optionally with OH, OCi- 3 alkyl, or S(=O)mC1. 3 alkyl; R2 is H, halogen, C 1 . 3 alkyl, S(=O)mC- 3 alkyl, S(=0) 2 NR 5 R 6 , or CI. 3 alkyl substituted optionally with OH, or OCI. 3 alkyl; R 3 & R are independently H, CI. 3 alkyl, or Ci-3alkyl substituted optionally with OH or OC 1 - 3 alkyl; R 5 , R 6 are independently H, CI- 3 alkyl, C 2 - 3 alkyl substituted optionally with OH, OCI- 3 alkyl, or R and R 6 can be joined together with saturated carbon atoms to form a 5 or 6 -59- WO 99/59499 PCT/US99/10179 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with CI. 3 alkyl, C 2 . 3 alkyl substituted optionally with OH or OCI. 3 alkyl; R , R are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected s from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from CI. 3 alkyl, CI. 3 alkyl substituted optionally with OH, OCI. 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI. 3 alkyl, or Ci. 3 alkyl, or substituted on nitrogen o with C14alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI 3 alkyl, or CI. 3 alkyl; n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates in a pharmaceutically acceptable 5 carter.

45. A composition comprising a pharmaceutically effective amount of a compound of the formula: R 10 Ra8 1 (CR3R4)-N R S R O O o R 3 & R4 are independently H, Ci- 3 alkyl, or CI. 3 alkyl substituted optionally with OH or OCi- 3 alkyl; R , R 8 are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine Zs or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from CI. 3 alkyl, CI. 3 alkyl substituted optionally with OH, OCI. 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCi - 3 alkyl, or CI- 3 alkyl, or substituted on nitrogen -60- WO 99/59499 PCT/US99/10179 with C1.4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCI. 3 alkyl, or CI. 3 alkyl; R 9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with C1.4 alkyl, halogen, OC1.4alkyl; R' 0 is C1.4alkyl, or R10 can be joined to R9 to form a fused bicyclic ring system such as indoline; n is 2 to 4 and any pharmaceutically acceptable salts and solvates in a pharmaceutically acceptable carrier.

46. A composition comprising a pharmaceutically effective amount of a compound of the formula: 0 0 \\ 1 )S/ 12 R N /R (CR 3 R 4 )-N R 3 & R 4 are independently H, Ci- 3 alkyl, or CI. 3 alkyl substituted optionally with OH or OCI- 3 alkyl; R 7 , R 8 are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, 0, S, such as pyrrolidine, piperidine, A 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from Ci.. 3 alkyl, Ci- 3 alkyl substituted optionally with OH, OCi- 3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCi- 3 alkyl, or CI. 3 alkyl, or substituted on nitrogen with CI.4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OCi- 3 alkyl, or Ci- 3 alkyl; R 11 is C 1 . 3 alkyl, phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with C1.4 alkyl, halogen, OC1.4alkyl; -61- WO 99/59499 PCT/US99/10179 R is Cl-alkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-e]-1,2-thiazine, or 1,2-benzothiazine, or R can be joined to R" to form a fused bicyclic ring system such as 2,3-dihydro-benzo[c]isoxazole; n is 2 to 4 s and any pharmaceutically acceptable salts and solvates in a pharmaceutically acceptable carter.

47. The Compound of Claim 1 selected from the group consisting of: 6-Chloro-2-[4-[4-(2H-benzimidazo-2-oxo-1-yl)piperidin-1-yl]butyl]-2H-thieno[3,2-e]-1,2 o thiazine 1,1-dioxide; 6-Chloro-2-[4-(4-phenylpiperazin-1-yl)butyl]-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide; 6-Chloro-2-[4-[4-(2-fluorophenyl)piperazin-1-yl]butyl]-2H-thieno[3,2-e]-1,2-thiazine 1,1 dioxide; 6-Chloro-2-[3-[4-(3-trifluoromethylphenyl)piperazin-1-yl]propyl]-2H-thieno[3,2-e]-1,2 5 thiazine 1,1-dioxide; 6-Chloro-2-[3-[4-(2H-benzimidazol-2-oxo)piperidin-1-yl]propyl]-2H-thieno[3,2-e]-1,2 thiazine 1,1-dioxide.

48. The Compound of Claim 3 selected from the group consisting of: 0 3-[4-(3-Chlorophenyl)piperazin-1-yl]propylsulfonyl-2,3-dihydro-1H-indole; 3-(1,2,3,4-Tetrahydroisoquinolin-2-yl)propylsulfonyl-2,3-dihydro-1H-indole; 3-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]propylsulfonyl-2,3-dihydro-1H-indole; 3-[4-(2-Methoxyphenyl)piperazin-1-yl]propylsulfonyl-2,3-dihydro-1H-indole; 3-(1,2,3,4-Tetrahydroisoquinolin-2-yl)-N-methyl-N-phenyl-propylsulfonamide; 5

49. The Compound of Claim 4 selected from the group consisting of: N-[3-[4-(3-Chlorophenyl)piperazin-1-yl]propyl]-N-(4-methoxyphenyl)-propanesulfonamide; 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; o 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. -62-