Dual targeting in a new class of active ingredients

Abstract

The invention relates to compounds with carbonic anhydrase and histamine H3 receptor inhibitory activities.

Description

__________________________________________________________________________________ Dual Targeting In A New Class Of Active Ingredients__________________________________________________________________________________

[0001] The invention relates to compounds for the treatment of increased intraocular pressure (ocularhypertension, IOP, also known as glaucoma) and / or cancer, pharmaceutical compositions, in particulareye drop compositions, comprising these compounds, and medicinal kits comprising these pharmaceu- tical compositions, in particular eye drop compositions. Further, the invention relates to these com- pounds and pharmaceutical compositions, in particular eye drop compositions, for use as medicaments, in particular for use in the prevention or treatment of ocular hypertension.

[0002] Various causes lead to increased intraocular pressure (ocular hypertension, IOP, also known asglaucoma). The most common diseases are open angle glaucoma (frequent, chronic, slow progression, visual field loss) and narrow angle glaucoma (less frequent, sometimes painful glaucoma). Existing therapeutic principles are based on carbonic anhydrase inhibitors, beta blockers, alpha2-receptor ago- nists, prostaglandins and cholinergics. Some time ago, it was found that histamine H3-receptor antago- nists also exhibit a mode of action for the reduction of increased intraocular pressure. The inventorshave combined this mode of action with classical modes of action. Novel active ingredients are providedwhich exhibit such combined modes of action. The low-molecular-weight substances disclosed herein exhibit inhibitory effects at the histamine H3-receptors and at the relevant carbonic anhydrase isoen- zymes CAII and CAXII in the nanomolar concentration range. This combination of H3R / selective CA inhibitors is completely new and not described so far. The combination in a single compound has the advantages of uniform pharmacokinetics and improves the application possibilities. The simplicity of the compounds presented is on the one hand highly attractive, but may not outweigh the complexity of the pharmacological profile.

[0003] With respect to Germany alone, the number of patients in need for treatment of a glaucoma isestimated to be around three to five millions. Depending on the source, there are at least half a million patients who are at risk of becoming blind.

[0004] Compounds with carbonic anhydrase inhibitory activity are known.

[0005] Claudiu T. Supuran (2021) Carbonic anhydrase inhibitors: an update on experimental agents forthe treatment and imaging of hypoxic tumors, Expert Opinion on Investigational Drugs, 30:12, 1197- 1208 discloses carbonic anhydrase inhibitors for the treatment and imaging of hypoxic tumors.

[0006] Med Res Rev. 2020;40:2485–2565 discloses human carbonic anhydrase inhibitors and theirpharmacological applications.

[0007] Further, compounds with histamine H3 receptor inhibitory activity are known.

[0008] J. Ceras et al., European Journal of Medicinal Chemistry 52 (2012) 1-13, discloses sulfonylureaderivatives as H3 receptor antagonists.

[0009] Int. J. Mol. Sci. 2019, 20, 981 discloses the role of histamine H3 receptor antagonists on intra-ocular pressure reduction in rabbit models of transient ocular hypertension and glaucoma.

[0010] Khanfar MA, Affini A, Lutsenko K, Nikolic K, Butini S and Stark H (2016) Front. Neuro-sci.10:201 discloses multiple targeting approaches on histamine H3 receptor antagonists.

[0011] The known compounds, however, are not satisfactory in each and every aspect.

[0012] It is therefore an object of the invention to provide compounds which are advantageous overknown compounds, e.g. with respect to the treatment of increased intraocular pressure (ocular hyperten- sion, IOP, also known as glaucoma) and / or cancer.

[0013] This object has been achieved by the subject-matter of the patent claims.

[0014] It has been surprisingly found that by combining a pharmacophore of histamine H3-receptorantagonists with other already established pharmacophores (here: carbonic anhydrase) for glaucomatreatment, at least two modes of action can be combined in one molecule. Through the simultaneous attack of two target structures, broader applications and possibly improved therapeutic effects can berealized. New substances have been synthesized which are to be patented as a new group of drugs in-cluding their chemical structures (synthesis, etc.) and their therapeutic applications (elevated intraocularpressure).

[0015] A first aspect of the invention relates to a compound according to general formula (I)whereinZ is absent, -CH2- or N-R1; R1is (i) H, -[CH2]n-CH3or -C(H)([CH2]n-CH3)2, wherein, respectively independently, n is an integer from 0 to 18, or (ii) H, -[CH2]n-CH3, -C(H)([CH2]n-CH3)2, -C(=O)-[CH2]n-CH3, -C(=O)-[CH2]n- NH2, C(=O)-[CH2]n-NH([CH2]n-H)1 or C(=O)-[CH2]n-N([CH2]n-H)2, wherein, respectively inde- pendently, n is an integer from 0 to 12, preferably from 0 to 6 or preferably from 1 to 12, more preferably from 2 to 10, even more preferably from 3 to 8;X is N, CH or C-[CH2]n-CH3, wherein n is an integer from 0 to 18;Y is -O-CH2-CH2-CH2- (wherein preferably the -O-end is attached to X), -CH2-CH2-CH2-O- (whereinpreferably the -CH2-end is attached to X), -S-CH2-CH2-CH2- (wherein preferably the -S-end is at-tached to X), -CH2-CH2-CH2-S- (wherein preferably the -CH2-end is attached to X) or D;D is -O-, -S-, -C(=O)- or -[CH2]n-, wherein n is an integer from 0 to 18;A is (i) -O-, -S-, -S(O)1-2-, -C(=O)-O-, -C(=O)-, -C(=O)-NH-[CH2]n-, [-CH2]n-NH-[CH2]n-, -[CH2]n-;or (ii) -[CH2]n-O-[CH2]m-phenyl-, -[CH2]n-NH-[CH2]m-O-phenyl-, -[CH2]n-O-phenyl-, -[CH2]n-aziridinyl-, -[CH2]n-azetidinyl-, -[CH2]n-pyrrolidinyl-, -[CH2]n-imidazolidinyl-, -[CH2]n-pyra- zolidinyl-, -[CH2]n-piperidinyl-, -[CH2]n-piperazinyl-, -[CH2]n-triazolidinyl-, -[CH2]n-tetrazol- idinyl-, -[CH2]n-oxiranyl-, -[CH2]n-oxetanyl-, -[CH2]n-tetrahydrofuranyl-, -[CH2]n-tetrahydro- pyranyl-, -[CH2]n-thiiranyl-, -[CH2]n-thietanyl-, -[CH2]n-tetrahydrothiophenyl-, -[CH2]n-diaz- epanyl-, -[CH2]n-oxazolidinyl-, -[CH2]n-isoxazolidinyl-, -[CH2]n-thiazolidinyl-, -[CH2]n-iso- thiazolidinyl-, -[CH2]n-thiadiazolidinyl-, -[CH2]n-morpholinyl-, -[CH2]n-thiomorpholinyl-, re- spectively independently optionally mono-, di- or trisubstituted with -F, -Cl, -Br, -I, -OH or=O; wherein respectively independently, n and / or m is an integer from 0 to 18 with n+m ≤ 18; preferablyn and / or m is an integer from 0 to 8 with n+m ≤ 8;B is -L-(hetero-)aryl-SO2NH2 or -N(H)(R2);L is absent, -NH-, -C(=O)-NH-, -O-, -NH-[CH2]n- or -C(=O)-NH-[CH2]n-, wherein, respectively in-dependently, n is an integer from 0 to 18; (hetero-)aryl is (i) -pyrrolyl-, -indolyl-, -furyl- (-furanyl-), -benzofuranyl-, -thienyl- (-thiophenyl-), -ben-zothienyl-, -benzothiadiazolyl-, -benzooxadiazolyl-, -benzothiazolyl-, -benzooxazolyl-, -ben- zotriazolyl-, -benzodioxolanyl-, -benzodioxanyl-, -phthalazinyl-, -pyrazolyl-, -imidazolyl-, -thiazolyl-, -thiadiazolyl-, -oxazolyl-, -isoxazoyl-, -oxadiazolyl-, -pyridinyl-, -pyridazinyl-, -pyrimidinyl-, -pyrazinyl-, -pyranyl-, -indazolyl-, -purinyl, -indolizinyl-, -quinolinyl-, -iso- quinolinyl-, -quinazolinyl- or -benzthiazolyl-; or(ii) -phenyl-, -naphthyl-, -anthracenyl-, -phenanthrenyl-, -fluoroanthenyl-, -fluoroenyl, -indanyl-or -tetralinyl-; respectively independently optionally mono-, di- or trisubstituted with -F, -Cl, -Br, -I or -OH;R2is -S(=O)2NH2, -OH, -H, -[CH2]n-CH3, -C(=O)-OH or -C(=O)-O-[CH2]n-CH3, wherein, respec- tively independently, n is an integer from 0 to 18; preferably R2 is not -OH;or a physiologically acceptable salt thereof;for use in the prevention or treatment of (i) glaucoma or ocular hypertension, and / or (ii) eye diseases orconditions associated with elevated intraocular pressure, and / or (iii) cancer.

[0016] Another aspect of the invention relates to the use of a compound according to general formula(I) as defined above for the manufacture of a medicament for the prevention or treatment of preventionor treatment of (i) glaucoma or ocular hypertension, and / or (ii) eye diseases or conditions associated with elevated intraocular pressure, and / or (iii) cancer.

[0017] Another aspect of the invention relates to a method for the prevention or treatment of (i) glau-coma or ocular hypertension, and / or (ii) eye diseases or conditions associated with elevated intraocularpressure, and / or (iii) cancer, the method comprising administering a compound according to general formula (I) as defined above to a subject in need thereof.

[0018] In a preferred embodiment, the compound according to the invention has the general formula(I*)

[0019] In preferred embodiments, the compound according to the invention is selected from a com-pound according to general formula (1), (2) or (3)or a physiologically acceptable salt thereof; wherein, respectively independently,A is -S(O)1-2-, -C(=O)-O-, -C(=O)-, -C(=O)-NH-[CH2]n-, [-CH2]n-NH-[CH2]n-, -[CH2]n-,-[CH2]n-O-phenyl-, -[CH2]n-piperidinyl- or -[CH2]n-piperazinyl-, wherein -piperidinyl- or-piperazinyl- are optionally monosubstituted with =O, wherein, respectively independently, n is aninteger from 0 to 12, preferably from 1 to 12, more preferably from 2 to 10, even more preferably from 3 to 8;L is absent, -NH-, -C(=O)-NH-, -O-, -NH-[CH2]n- or -C(=O)-NH-[CH2]n-, wherein, respectively in-dependently, n is an integer from 0 to 12, preferably from 1 to 12, more preferably from 2 to 10, even more preferably from 3 to 8;(hetero-)aryl is(i) -pyrrolyl-, -indolyl-, -furyl- (-furanyl-), -benzofuranyl-, -thienyl- (-thiophenyl-), -ben-zothienyl-, -benzothiadiazolyl-, -benzooxadiazolyl-, -benzothiazolyl-, -benzooxazolyl-, -ben- zotriazolyl-, -benzodioxolanyl-, -benzodioxanyl-, -phthalazinyl-, -pyrazolyl-, -imidazolyl-, -thiazolyl-, -thiadiazolyl-, -oxazolyl-, -isoxazoyl-, -oxadiazolyl-, -pyridinyl-, -pyridazinyl-, -pyrimidinyl-, -pyrazinyl-, -pyranyl-, -indazolyl-, -purinyl-, -indolizinyl-, -quinolinyl-, -iso- quinolinyl-, -quinazolinyl- or -benzthiazolyl-, preferably -thiazolyl- or -thiadiazolyl-; or(ii) -phenyl-, -naphthyl-, -anthracenyl-, -phenanthrenyl-, -fluoroanthenyl-, -fluoroenyl-, -indanyl-or -tetralinyl-, preferably -phenyl- or -naphthyl-;respectively independently optionally monosubstituted with -F, -Cl, -Br, -I or -OH;D is -O-, -S- or -C(=O)-;R1is -[CH2]n-CH3 or -C(H)([CH2]n-CH3)2, wherein, respectively independently, n is an integer from 0 to 12, preferably from 1 to 12, more preferably from 2 to 10, even more preferably from 3 to 8; R2is -H, -[CH2]n-CH3, -OH, -S(=O)2NH2, -C(=O)-OH or -C(=O)-O-[CH2]n-CH3, wherein, respec- tively independently, n is an integer from 0 to 12, preferably from 1 to 12, more preferably from 2 to 10, even more preferably from 3 to 8; and / orX is N, CH or C-[CH2]n-CH3, wherein, respectively independently, n is an integer from 0 to 12, pref-erably from 1 to 12, more preferably from 2 to 10, even more preferably from 3 to 8.

[0020] In a preferred embodiment, n is, respectively independently, (i) 0, 1, 2, 3, 4, 5, 6 or 7; (ii) 0, 1,2, 3, 4, 5 or 6; (iii) 0, 1, 2, 3, 4 or 5; (iv) 0, 1, 2, 3 or 4; (v) 0, 1, 2 or 3; (vi) 0, 1 or 2; (vii) 1, 2, 3, 4, 5, 6or 7; (viii) 1, 2, 3, 4, 5 or 6; (ix) 1, 2, 3, 4 or 5; (x) 1, 2, 3 or 4; or (xi) 1, 2 or 3.

[0021] In a preferred embodiment, n is, respectively independently, an integer of from 0 to 6.

[0022] In preferred embodiments, the compound according to the invention is selected from a com-pound according to general formula (1A), (1B), (2A), (2B), (2B*), or (3)( ( ( ( (2( or a physiologically acceptable salt thereof;wherein, respectively independently, R1, R2, D, X, A and L are defined as above, and wherein R3 is -H,-F, -Cl, -Br, -I or -OH, preferably -H or -Cl; wherein in a more preferred embodiment, the compound according to the invention is selected from acompound according to general formula (1A), (1B), (2A), (2B), or (2B*); more preferably the compoundis selected from a compound according to general formula (1A), (1B), (2A), or (2B*).

[0023] In a preferred embodiment, respectively independently,A is -S(O)2-, -C(=O)-, -C(=O)-NH-CH2-CH2-, -CH2-NH-CH2-CH2-, -CH2-, -CH2-O-phenyl-, -CH2-piperidinyl- or -CH2-piperazinyl-, wherein -piperazinyl- is optionally monosubstituted with =O,L is -absent, -NH-, -C(=O)-NH-, -O-, -NH-CH2-, -NH-CH2-CH2- or -C(=O)-NH-CH2-CH2-,D is -O- or -C(=O)-,R1is -CH3 or -C(H)(CH3)2,R2 is -H, -OH or -S(=O)2NH2, preferably -H or -S(=O)2NH2, and / orX is N or CH.

[0024] In a preferred embodiment, the compound according to the invention is selected from,, ,r.

[0025] Preferred compounds according to the invention carry a sulfonamide moiety (i.e. -S(=O)2-NH2)as well as at least one tertiary amino group, preferably because X is N and / or Z is N-R1.

[0026] In preferred embodiments, the compound is for use in the prevention or treatment of- ocular hypertension; and / or- a glaucoma,- preferably a primary glaucoma, very preferably an open-angle glaucoma (POAG), a normal-ten-sion glaucoma, an angle-closure glaucoma, or a congenital glaucoma; or -preferably a secondary glaucoma, very preferably a neovascular glaucoma, a pigmentary glau-coma, an exfoliation glaucoma, or an uveitic glaucoma; or -preferably a glaucoma caused by an eye injury; or- preferably a glaucoma caused by a cataract or a tumor; and / or- other indications selected from the group consisting of retinal / cerebral edema, epilepsy, altitude sick-ness, renal disorders, retinitis pigmentosa, stroke, hypoxic tumors / metastasis, retinopathy and epi-lepsy.

[0027] In a preferred embodiment, the compound according to the invention is- provided in form of an eye drop composition, and / or- administered orally or topically via administration to the eye or eyes of a subject or patient, andpreferably topically via administration to the eye or eyes of a subject or patient.

[0028] In a preferred embodiment, the compound is for use in the prevention or treatment of cancer,preferably leukemia or a hypoxic tumor.

[0029] In a preferred embodiment, the compound according to the invention is administered (per-)orally, rectally, intravenously, intramuscularly, intraperitoneally, intrasternally, subcutaneously, by in- traarticular injection, by infusion, intravaginally, intracisternally, intraperitoneally, topically, buccally or extracorporeally.

[0030] In a preferred embodiment, the compound according to the invention is administered at leastonce daily, at least twice daily, at least thrice daily, at least four times a day, at least five times a day or at least six times a day; preferably once daily, twice daily, thrice daily, four times a day, five times a day or six times a day.

[0031] In a preferred embodiment, the compound according to the invention is administered in anamount of 0.3 µg / kg to 300 µg / kg, preferably 0.5 µg / kg to 200 µg / kg, more preferably 1 µg / kg to 100 µg / kg, and most preferably 5 µg / kg to 50 µg / kg, in each case based on the body weight of the subject or patient.

[0032] Another aspect of the invention relates to a compound which is selected from a compound ac-cording to general formula (1A), (1B), (2A), (2B), (2B*), or (3)(1 (2 (2 (2 ( or a physiologically acceptable salt thereof; whereinrespectively independently, with respect to general formulae (1A), (1B), (2A), (2B) and / or (2B*), R1,R3, D, X, A and L are defined as above; andwith respect to general formula (3), A and R2 are defined as above, with the proviso that the moiety -A-N(H)R2does not represent -S(=O)2NH2; wherein the compound is preferably selected from a compound according to general formula (1A), (1B),(2A), (2B), or (2B*); more preferably the compound is selected from a compound according to generalformula (1A), (1B), (2A), or (2B*).

[0033] Another aspect of the invention relates to a pharmaceutical composition,- preferably an ophthalmic composition, more preferably an eye drop composition, or- a composition for the treatment of cancer,comprising a compound according to the invention.

[0034] Another aspect of the invention relates to a kit comprising- the pharmaceutical composition according to the invention,- a package for containing the pharmaceutical composition according to the invention, and- instructions for administering the pharmaceutical composition according to the invention to a subject.

[0035] In preferred embodiments, the compound is selected from the group consisting of^ 4-((4-(3-(piperidin-1-yl)propoxy)benzyl)oxy)benzenesulfonamide;^ 4-(3-(piperidin-1-yl)propoxy)-N-(4-sulfamoylphenethyl)benzamide;^ 4-(3-(piperidin-1-yl)propoxy)benzenesulfonamide;^ 4-(3-(4-(pyridin-2-yl)piperazin-1-yl)propoxy)benzenesulfonamide;^ N‐((4‐(3‐(piperidin‐1‐yl)propoxy)phenyl)methyl)aminosulfonamide;^ 4-(3-(piperidin-1-yl)propoxy)-N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)benzamide;^ 4-((4-(3-(piperidin-1-yl)propoxy)benzyl)oxy)-N-(4-sulfamoylphenethyl)benzamide;^ N-(3-oxo-3-((5-sulfamoyl-1,3,4-thiadiazol-2-yl)amino)propyl)-4-(3-(piperidin-1-yl)propoxy)ben-zamide;^ 4-sulfamoylphenyl 4-(3-(piperidin-1-yl)propoxy)benzoate;^ 3-((4-(3-(piperidin-1-yl)propoxy)benzyl)amino)-N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)propena-mide;^ 4-(2-((4-(3-(piperidin-1-yl)propoxy)benzyl)amino)ethyl)benzenesulfonamide; and / ora physiologically acceptable salt thereof.

[0036] "Administration to the eye" preferably means topical application to the eye and / or surroundingtissues, particularly to the inner surface of the eye and the inner surface of the eyelids (including e.g.cornea, conjunctiva and sclera) of the subject or patient. "Administration to the eye" includes, for exam-ple, instillation administration, administration into conjunctival sac and conjunctival administration.

[0037] By "subject" or "patient" is preferably meant either a human or non-human animal, such as amammal. By "subject" is preferably meant any animal, including horses, dogs, cats, pigs, goats, rabbits,hamsters, monkeys, guinea pigs, rats, mice, lizards, snakes, sheep, cattle, fish, and birds. A human sub-ject may be referred to as a patient. For the purpose of the invention, the terms "subject" and "patient"may be used as synonyms.

[0038] The terms "treat", "treating" or "treatment" and other grammatical equivalents as used herein,preferably mean alleviating, abating, ameliorating, or preventing a disease, condition (e.g., conjunctivi- tis or other ocular diseases or infections) or symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regres- sion of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition, and are intended to include prophylaxis. The terms further include achieving a therapeutic benefit and / or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder.

[0039] The terms "prevent", "preventing" or "prevention" and other grammatical equivalents as usedherein, preferably mean to keep from developing, occur, hinder or avert a disease or condition symptomsas well as to decrease the occurrence of symptoms. The prevention may be complete (i.e., no detectable symptoms) or partial, so that fewer symptoms are observed than would likely occur absent treatment. The terms further include a prophylactic benefit. For a disease or condition to be prevented, the compo- sitions may be administered to a patient at risk of developing a particular disease, or to a patient reportingone or more of the physiological symptoms of a disease, even though a diagnosis of this disease maynot have been made.

[0040] The compound may be formulated for administration in any ocular formulation known to thoseof skill in the art. For example, the compound may be formulated as an eye drop composition, an inject-able formulation, an ointment, a spray, a gel, or a slow release formulation. In some embodiments, the formulation comprises at least 0.3 wt.-% of the compound, based on the total weight of the formulation.

[0041] In a preferred embodiment, the compound is formulated as an eye drop composition.

[0042] Certain ophthalmic compositions, such as eye drop compositions, are disclosed in EP 3452093,WO 2018 / 064354, WO 2019 / 138162, WO 2023 / 126636, WO 2023 / 079427 and WO 2023 / 152642.

[0043] The term "eye drop composition" preferably means a liquid or semisolid pharmaceutical com-position adapted to administration to the eye. An example of an eye drop composition is an ophthalmic aqueous solution to be administered dropwise to the eye.

[0044] In a preferred embodiment, the eye drop composition according to the invention comprises acompound according to general formula (I) or a pharmaceutically acceptable salt thereof as the soleactive ingredient.

[0045] In another preferred embodiment, the eye drop composition according to the invention com-prises in addition to a compound according to general formula (I) or a pharmaceutically acceptable saltthereof one or more other pharmacologically active compounds, preferably for treating increased intra-ocular pressure (ocular hypertension, IOP).

[0046] The eye drop composition according to the invention may be, for example, in a liquid or semi-solid form, such as in the form of a solution, emulsion or suspension.

[0047] Preferably, the eye drop composition according to the invention is in the form of an aqueoussolution adapted for administration to the eye of the subject or the patient. The eye drop composition,e.g. the aqueous solution, preferably comprises a compound according to general formula (I) or a phar-maceutically acceptable salt thereof in an amount of from about 0.001 wt.-% to about 10 wt.-%, morepreferably from about 0.01 wt.-% to about 5 % wt.-%, more preferably from about 0.05 wt.-% to about3 wt.-%, most preferably from about 0.1 wt.-% to about 2 wt.-%, in each case based on the total weightof the eye drop composition.

[0048] The eye drop composition may additionally comprise- (sterile) water,- a tonicity adjusting agent such as sodium chloride or mannitol,- pH adjusting agents or buffering agents such as sodium hydroxide, hydrochloric acid, citric acid / so-dium citrate, tartaric acid or fumaric acid,- antioxidants such as butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT),- chelating agents such as edetate disodium,- thickening agents such as polyvinylpyrrolidone (povidone), polyvinyl alcohol, polyethylene glycol,polyacrylic acid or a cellulose derivative such as sodium carboxymethylcellulose,- complexing agents such as cyclodextrins,- ion-pairing agents such as hyaluronic acid or glucuronic acid,- other ingredients commonly used in the preparation of eye drop compositions, and / or- or other related state-of-the-art drug formulation.

[0049] Preferably, the pH value of the eye drop composition is within the range of from about 3 toabout 8.5, preferably from about 3.5 to about 7.0, more preferably from about 4.0 to about 6.0.

[0050] The eye drop composition can be prepared e.g. by dissolving the active ingredient (i.e., a com-pound according to general formula (I) or a pharmaceutically acceptable salt thereof) and additional excipients (e.g., those defined above) to a vehicle, for example water, followed by pH adjustment, if necessary, and sterile filtering.

[0051] The eye drop composition is preferably given to the eye(s) of the subject or the patient from apackage, such as a prefilled bottle, ampoule or pipette in a volume ranging from about 0.01 ml to about 0.3 ml, more preferably from about 0.015 ml to about 0.2 ml, for example from about 0.02 ml to about 0.15 ml, of the eye drop composition.

[0052] Preferably, said package is an applicator, e.g. a squeezable prefilled single-use bottle, ampouleor pipette capable of dosing fixed volumes of the eye drop composition. The squeezable bottle, ampoule or pipette is preferably prepared form polymer material, such as LDPE. Preferably, the volume of the suitable bottle, ampoule or pipette ranges from about 0.5 ml to 5 ml. For example, about 0.5 ml to about 2 ml of the eye drop composition can be filled into single use blow fill seal (BFS) FDPE ampouleshaving volume of 0.5 ml, 1 ml or 2 ml.

[0053] In a preferred embodiment, a medicinal kit comprises- an eye drop composition according to the invention,- a package for containing this eye drop composition, e.g. a squeezable prefilled single-use bottle,ampoule or pipette capable of dosing fixed volumes of the eye drop composition, and- instructions for administering this eye drop composition on the eye(s) of a subject or patient.

[0054] The eye drop composition may be administered to one or both eyes of the subject or patient.

[0055] The eye drop composition is administered according to the need of the subject or patient, forexample daily or several times a day.

[0056] In a preferred embodiment, a compound according to general formula (I) or a pharmaceuticallyacceptable salt thereof is administered to the eye of a subject or patient in an amount of from 0.3 µg / kgto 300 µg / kg, preferably 0.5 µg / kg to 200 µg / kg, more preferably 1 µg / kg to 100 µg / kg, and most pref-erably 5 µg / kg to 50 µg / kg, in each case based on the body weight of the subject or patient.

[0057] In a preferred embodiment, administration of the eye drop composition comprises administeringone, two or more drops thereof, e.g. per day. In another preferred embodiment, the eye drop compositionis administered as long as it can sufficiently provide a desired efficacy, which can be administered in eye drops, at a frequency of 1 to 5 times a day in an amount of 1 to 2 drops each time, more preferably at a frequency of 2 to 4 times a day in an amount of 1 to 2 drops each time, and the most preferably once a day, before bedtime in an amount of 1 to 2 drops.

[0058] In a preferred embodiment, the size of a drop is between 10 and 100 µl. The drop size may beabout 10 µl, about 20 µl, about 30 µl, about 40 µl, about 50 µl, about 60 µl, about 70 µl., about 80 µl, about 90 µl., or about 100 µl.

[0059] In another preferred embodiment, the compounds according to the invention are administeredperorally.

[0060] The compounds according to the invention can be present in the form of a single stereoisomeror mixture thereof, the free compounds and / or their physiologically acceptable salts and / or solvates.

[0061] The compounds according to the invention can be chiral or achiral, depending on the substitutionpattern.

[0062] If the compounds according to the invention are chiral, then they are preferably present as race-mate or a mixture of stereoisomers or diastereomers or in enriched form of an enantiomer. In a preferredembodiment the enantiomer excess (ee) of the S-enantiomer amounts to at least 50% ee, more preferred at least 75% ee, more preferred at least 90% ee, most preferred at least 95% ee, and in particular at least 99% ee. In another preferred embodiment, the enantiomer excess (ee) of the R-enantiomer amounts to at least 50% ee, more preferred at least 75% ee, more preferred at least 90% ee, most preferred at least 95% ee, and in particular at least 99% ee.

[0063] Suitable methods for separating the enantiomers are known to the person skilled in the art. Pre-parative HPLC on chiral stationary phases and conversion into diastereomeric intermediates can begiven as examples. The conversion into diastereomeric intermediates can occur, for example, as salt formation by means of chiral, enantiomer-pure acids. After separation of the diastereomers thus formed, the salt can then be converted into the free base or another salt again.

[0064] Unless expressly specified, each reference to the compounds according to the invention coversall isomers in pure form and admixture with one another (e.g. stereoisomers, diastereomers, enantio- mers) in any desired mixture ratio.

[0065] Unless expressly specified, each reference to the compounds according to the invention coversthe free compounds (i.e. the forms that are not present in the form of salt) and all physiologically ac- ceptable salts.

[0066] For the purposes of the description, physiologically acceptable salts of the compounds accordingto the invention are present as salts with anions or acids of the respective compound with inorganic ororganic acids, which are physiologically acceptable - in particular on application in humans and / or mam-mals.

[0067] Examples of physiologically acceptable salts of specific acids are salts of: hydrochloric acid,hydrobromic acid, sulphuric acid, methane sulphonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, saccha-rinic acid, monomethyl sebacic acid, 5-oxo-proline, hexane-1-sulphonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl benzoic acid, α-liponic acid, acetylglycine, acetylsalicylic acid, hip- puric acid and / or aspartic acid. The hydrochloride, citrate and hemicitrate are particularly preferred.

[0068] Physiologically acceptable salts with cations or bases are salts of the respective compound - asanion with at least one, preferably inorganic, cation, which are physiologically acceptable - in particularon application in humans and / or mammals. Particularly preferred are the salts of the alkali and earth alkali metals, also ammonium salts, but in particular (mono-) or (di-) sodium, (mono-) or (di-) potas- sium, magnesium or calcium salts.

[0069] The compounds according to the invention are defined by substituents, e.g. by R1, R2 and X(substituents of the first generation), which are themselves possibly substituted (substituents of the sec- ond generation). Depending on the definition, these substituents of the substituents can themselves besubstituted again (substituents of the third generation) or be unsubstituted.

[0070] Another aspect of the invention relates to the compounds according to the invention as describedabove as medicaments.

[0071] Another aspect of the invention relates to pharmaceutical compositions or pharmaceutical dos-age forms comprising the compounds according to the invention as described above.

[0072] For the purpose of the invention, the terms "medicament", "pharmaceutical composition" and"pharmaceutical dosage form" may be used as synonyms.

[0073] Preferably, the pharmaceutical composition and / or medicament is solid, liquid or pasty and con-tains the compound according to the invention in an amount of from 0.001 to 99 wt. %, preferably from1.0 to 70 wt. %, based on the total weight of the pharmaceutical composition and / or medicament.

[0074] Preferably, the pharmaceutical composition and / or medicament contains the compound accord-ing to the invention in an amount of preferably from 0.001 to 99 wt. %, more preferably from 0.1 to 90 wt. %, yet more preferably from 0.5 to 80 wt. %, most preferably from 1.0 to 70 wt. % and in particular from 2.5 to 60 wt. %, based on the total weight of the pharmaceutical composition and / or medicament.

[0075] Preferably, the pharmaceutical compositions and / or medicaments comprise a compound accord-ing to the invention as described above, and a pharmaceutically acceptable carrier. The term "pharma-ceutically acceptable carrier", as used herein, means a non-toxic, inert solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of any type.

[0076] Some examples of materials which may serve as pharmaceutically acceptable carriers are sugarssuch as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents; alginic acid; pyrogen-free water; isotonicsaline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic com-patible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as releasing agents, coloring agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxi- dants may also be present in the composition, according to the judgment of one skilled in the art of formulations.

[0077] The pharmaceutical compositions and / or medicaments may be administered to subjects (e.g.,humans and other mammals) orally, perorally, parenterally, intraperitoneally, topically (as by powders, ointments or drops), buccally, extracorporeally, e.g. by dialysis, or as an oral or nasal spray. The term "parenterally," as used herein, refers to modes of administration, including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intraarticular injection and infusion.

[0078] Pharmaceutical compositions and / or medicaments for parenteral injection comprise pharmaceu-tically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions andsterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitableaqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (poly- ethylene glycol, propylene glycol, glycerol, and the like, and suitable mixtures thereof), vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate, or suitable mixtures thereof. Suitable fluidity of the composition may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0079] These pharmaceutical compositions and / or medicaments may also contain adjuvants, such aspreservative agents, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by various antibacterial and antifungal agents, for example, para- bens, phenol, chlorobutanol, sorbic acid, and the like. It also may be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the use of agents delaying absorption, for example, aluminum monos- tearate and gelatin.

[0080] In some cases, in order to prolong the effect of a drug, it is often desirable to slow the absorptionof the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug may depend upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, a parenterally administered drug form may be administered by dissolv- ing or suspending the drug in an oil vehicle.

[0081] Suspensions, in addition to the active compounds, may contain suspending agents, for example,polyoxyethylene sorbitol, ethoxylated isostearyl alcohols, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

[0082] If desired, and for more effective distribution, the compounds may be incorporated into slow-release or targeted-delivery systems such as polymer matrices, liposomes, and microspheres. They maybe sterilized, for example, by filtration through a bacteria-retaining filter or by incorporation of steriliz- ing agents in the form of sterile solid compositions, which may be dissolved in sterile water or some other sterile injectable medium immediately before use.

[0083] Injectable depot forms are made by forming microencapsulated matrices of the drug in biode-gradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release may be controlled. Depot inject- able formulations also are prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

[0084] The injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which may be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

[0085] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions maybe formulated according to the known art using suitable dispersing or wetting agents, suspending agents and the like. The sterile injectable preparation also may be a sterile injectable solution, suspension or emulsion in a nontoxic, parenterally acceptable diluent or solvent such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including syn-thetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation ofinjectables.

[0086] Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills,powders, and granules. In such solid dosage forms, one or more compounds is mixed with at least one inert pharmaceutically acceptable carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and salicylic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl al- cohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise bufferingagents.

[0087] Solid compositions of a similar type may also be employed as fillers in soft and hard-filledgelatin capsules using lactose or milk sugar as well as high molecular weight polyethylene glycols.

[0088] The solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared withcoatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical for- mulating art. They optionally may contain opacifying agents and also may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract in a delayed manner. Examples of materials useful for delaying release of the active agent may include polymeric substances and waxes.

[0089] Compositions for rectal or vaginal administration are preferably suppositories which may beprepared by mixing the compounds with suitable non-irritating carriers such as cocoa butter, polyeth- ylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0090] Liquid dosage forms for oral administration may include, but are not limited to, pharmaceuti-cally acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition tothe active compounds, the liquid dosage forms may contain inert diluents commonly used in the art suchas, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, iso- propyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sor- bitan, and mixtures thereof.

[0091] Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0092] Suspensions, in addition to the active compounds, may contain suspending agents, for example,ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

[0093] If desired, and for more effective distribution, the compounds may be incorporated into slow-release or targeted-delivery systems such as polymer matrices, liposomes, and microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporation of steriliz- ing agents in the form of sterile solid compositions, which may be dissolved in sterile water or some other sterile injectable medium immediately before use.

[0094] Dosage forms for topical or transdermal administration of a compound include ointments,pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. A desired compound isadmixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preserva- tives or buffers as may be required. Ophthalmic formulation, eardrops, eye ointments, powders andsolutions are also contemplated as being within the scope of this disclosure.

[0095] The ointments, pastes, creams and gels may contain, in addition to an active compound, animaland vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0096] Powders and sprays may contain, in addition to the compounds, lactose, talc, silicic acid, alu-minum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays additionally may contain customary propellants such as chlorofluorohydrocarbons.

[0097] Compounds also may be administered in the form of liposomes. As is known in the art, lipo-somes are generally derived from phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used. The present compositions in liposome form may contain, in addition to the compounds, stabilizers, pre- servatives, and the like. The preferred lipids are the natural and synthetic phospholipids and phosphati- dylcholines (lecithins) used separately or together. Methods to form liposomes are known in the art.

[0098] Dosage forms for topical administration of a compound according to the invention as describedabove include powders, sprays, ointments and inhalants. The active compound is mixed under sterileconditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propel-lants. Ophthalmic formulations, eye ointments, powders and solutions are also possible. Aqueous liquidcompositions may also be useful.

[0099] The compounds according to the invention are preferably administered once daily, twice daily,thrice daily or more often to a subject or patient in need thereof.

[0100] The compounds according to the invention are preferably administered orally, rectally, intrave-nously, intramuscularly, intraperitoneally, intrasternally, subcutaneously, by intraarticular injection, by infusion, intravaginally, intracisternally, intraperitoneally, topically, buccally or extracorporeally.

[0101] Another aspect of the invention relates to compounds according to the invention for use in thetreatment of ocular hypertension.

[0102] Another aspect of the invention relates to a kit comprising- a first pharmaceutical composition comprising a compound according to general formula (I); and- a second pharmaceutical composition comprising a second pharmacologically active compound,preferably a compound for treating ocular hypertension and / or which is preferably different from the compound according to general formula (I); wherein the first pharmaceutical composition and the second pharmaceutical composition are separate of one another.

[0103] Preferably, the first pharmaceutical composition and the second pharmaceutical composition ofsaid kit are for administration through the same route. In another embodiment of the invention, the first pharmaceutical composition is for administration through a different route than the second pharmaceu- tical composition.

[0104] Preferred administration routes for the first and second pharmaceutical composition of said kitare oral, peroral, rectal, parenteral, intravaginal, intracisternal, intraperitoneal, topical or bucal admin-istration to a patient.

[0105] Preferably, the first pharmaceutical composition and the second pharmaceutical composition ofsaid kit are administered to a patient subsequent to each other, wherein- the first pharmaceutical composition is administered first, followed by administration of the secondpharmaceutical composition, or- the second pharmaceutical composition is administered first, followed by administration of the firstpharmaceutical composition.

[0106] It is preferred that the period of time between the administration of the first pharmaceuticalcomposition and the second pharmaceutical composition, or vice versa, is at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours or at least 5 hours.

[0107] More preferred, the period of time between the administration of the first pharmaceutical com-position and the second pharmaceutical composition, or vice versa, is at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days or at least 8 days.

[0108] More preferred, the period of time between the administration of the first pharmaceutical com-position and the second pharmaceutical composition, or vice versa, is at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks or at least 8 weeks.

[0109] All aspects of the pharmaceutical composition and / or medicament comprising the compoundsaccording to the invention as described above also apply to the first pharmaceutical composition and the second pharmaceutical composition of said kit.

[0110] Another aspect of the invention relates to a process for the preparation of the compounds ac-cording to the invention. Suitable processes for the synthesis of the compounds according to the inven- tion are known in principle to the person skilled in the art.

[0111] The compounds according to the invention can be obtained via different synthesis routes. De-pending on the synthesis route, different intermediates are prepared and subsequently further reacted.

[0112] The following examples further illustrate the invention but are not to be construed as limitingits scope. Examples

[0113] The following compounds were synthesized and tested:

[0114] Solvents and chemicals were used as supplied from Sigma Aldrich (part of Merck KGa Group,Germany), VWR (Germany) or Fisher Scientific (USA).

[0115] All reactions were monitored by thin layer chromatography (TLC) using pre-coated TLC sheetsALUGRAM® Xtra SIL G / UV25420x20 cm (Macherey-Nagel, Germany). Elution of the plates was carried out using dichloromethane / methanol mixtures as eluting system. Visualization was achieved with UV light at 254 nm or by dipping into an ethanolic ninhydrin solution and heating with a hot air gun.

[0116] Microwave irradiation (MW) was conducted with Initiator+ Microwave System EU (Biotage,Sweden). Flash column chromatography was carried out with Biotage Isolera™ Spektra Systems withACI™ and Assist (Biotage, Sweden) using Biotage ® Sfär Silica D as normal phase or C18-Reversed phase silica gel for column chromatography, fully end-capped (Sigma Aldrich, Germany) as reversed phase. Mobile phase: mixtures of dichloromethane / methanol or water / methanol. Fractions from re- versed phase flash chromatography were freeze dried with CHRIST ALPHA 2-4 L D plus (Christ, Ger- many).

[0117] 1H and 13C NMR were measured with Bruker Avance III - 300 or Bruker Avance III - 600(Bruker, Germany). Measurements were conducted using deuterated solvents (CDCl3, DMSO-d6,MeOD or DMF-d7). Data is reported as chemical shifts δ (in ppm), multiplicity: s (singlet), d (doublet), dd (double of doublets), dt (double of triplets), t (triplet), q (quartet), p (pentet) or m (multiplet), coupling constants J (in Hz) and number of protons.

[0118] LC-MS measurements were conducted with Elute SP LC System (Bruker Daltonics, Germany)with vacuum degasser, binary pump, autosampler, column oven. Column: Intensity Solo 2 C18 (100 mm * 2.1 mm); Temperature: 40° C; MS-System: compact (Bruker Daltonics, Germany); Ionisation: electronspray; Polarity: positive; Scan range: m / z: 50-1300; Nebulizer: Nitrogen, 1,8 Bar; Dry Gas: Ni- trogen, 9 l / min, 220°C; Massrange mode: UltraScan. Data is reported as mass to charge ratio (m / z) of detected ion. All measured compounds show purity ≥ 95% (fraction area).

[0119] Elemental analysis (CHN) was performed with CHN-Rapid (Heraeus, Germany). Measured val-ues were within ± 0.4% of the theoretical values for the measured compounds.

[0120] Precursors A - G were synthesized according to Schemes 1 and 2.NH(i) N OH (ii) N ClA A AHCLHOScheme 1: Synthesis of precursors A – E. Reagents and conditions (i): K2CO3, KI, Aceton, reflux, 16 h; (ii): SOCl2, THF, reflux, 6 h; (iii): KOH, THF, MeOH,H2O, MW 70 °C, 15 minScheme 2: Synthesis of precursors F – G. Reagents and conditions (iv): conc. HCl, EtOH, reflux, 4 h; (v): EDC, TEA, Acetonitril, rt, 16 h; (vi): TFA, DCM, 0 °C –rt, 16 h

[0121] Reported compounds, unless otherwise stated, were synthesized according to general proce-dures 1 – 3.

[0122] General procedure 1: Alkylation of PhenolsTo a solution of alkylchloride hydrochloride (1 eq) and phenol (1.5 eq) in DMF was added potassium carbonate (3 eq) and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 18 hours. The crude suspension was filtrated and concentrated under vacuum. The crude mixture was purified using flash chromatography.

[0123] General procedure 2: HATU coupling

[0124] To a solution of acid (1 eq), amine (1 eq) and 1-[Bis(dimethylamino)methylene]-1H-1,2,3-tria-zolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 1.1 mmol) in DMF was added N,N-Diiso- propylethylamine (3 eq) at room temperature under nitrogen atmosphere. The reaction was stirred for 18 hours before quenching with water and extracted three times with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. The solvent was removedunder vacuum and the crude mixture was purified using flash chromatography.

[0125] General procedure 3: reductive amination

[0126] A stirred solution of Amine (1 eq) and Aldehyde (1.1 eq) in methanol was heated to refluxtemperature for 1 h. Then sodium borohydride (1.6 eq) was added portionwise at 0 °C and the resultingmixture was stirred under nitrogen atmosphere at room temperature for 3 hours before quenching with a few drops of water. The solvent was removed under vacuum and crude mixture was purified using flash chromatography.

[0127] 4-((4-(3-(piperidin-1-yl)propoxy)benzyl)oxy)benzenesulfonamideThis compound was synthesized according to general procedure 1 from B (3 mmol) and 4-hydroxyben-zenesulfonamide, purified on silica gel using flash chromatography (gradient 5-10% methanol in meth- ylene chloride) to obtain 4-((4-(3-(piperidin-1-yl)propoxy)benzyl)oxy)benzenesulfonamide as a white solid.ESI-LC / MS (m / z): [M+H]+ calculated for C21H28N2O4S 404.1770; found 405.22251H NMR (300 MHz, DMSO) δ 7.74 (d, J = 8.9 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 7.20 (s, 2H), 7.14 (d,J = 8.9 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 5.09 (s, 2H), 3.99 (t, J = 6.4 Hz, 2H), 2.47 – 2.21 (m, 6H), 1.95– 1.77 (m, 2H), 1.59 – 1.44 (m, 4H), 1.44 – 1.30 (m, 2H).13C NMR (151 MHz, DMSO) δ 160.73, 158.53, 136.23, 129.62, 128.18, 127.62, 114.83, 114.39, 69.34,65.93, 55.12, 54.09, 26.24, 25.56, 24.11.

[0128] 4-(3-(piperidin-1-yl)propoxy)-N-(4-sulfamoylphenethyl)benzamideThis compound was synthesized according to general procedure 2 from D (2 mmol) and 4-(2-ami-noethyl)benzenesulfonamide, purified on silica gel using flash chromatography (gradient 5-10% meth- anol in methylene chloride) to obtain 4-(3-(piperidin-1-yl)propoxy)-N-(4-sulfamoylphenethyl)ben- zamide as an off-white solid.ESI-LC / MS (m / z): [M+H]+ calculated for C23H31N3O4S 445.2035; found 446.22831H NMR (300 MHz, DMSO) δ 8.42 (t, J = 5.6 Hz, 1H), 7.83 – 7.69 (m, 4H), 7.42 (d, J = 8.4 Hz, 2H),7.28 (s, 2H), 6.97 (d, J = 8.9 Hz, 2H), 4.04 (t, J = 6.4 Hz, 2H), 3.54 – 3.44 (m, 2H), 2.91 (t, J = 7.0 Hz,2H), 2.47 – 2.23 (m, 6H), 1.93 – 1.80 (m, 2H), 1.56 – 1.44 (m, 4H), 1.44 – 1.32 (m, 2H).13C NMR (75 MHz, DMSO) δ 165.65, 160.85, 143.82, 141.98, 129.09, 128.88, 126.55, 125.65, 113.87,66.04, 54.94, 53.98, 40.32, 34.83, 26.03, 25.41, 23.96.

[0129] 4-(3-(piperidin-1-yl)propoxy)benzenesulfonamideThis compound was synthesized according to general procedure 1 from A (5 mmol) and 4-hydroxyben-zenesulfonamide, purified on silica gel using flash chromatography (gradient 5-10% methanol in meth- ylene chloride) to obtain 4-(3-(piperidin-1-yl)propoxy)benzenesulfonamide as an off-white solid.ESI-LC / MS (m / z): [M+H]+ calculated for C14H22N2O3S 298.1351; found 299.14621H NMR (300 MHz, DMSO) δ 7.73 (d, 2H), 7.19 (s, 2H), 7.07 (d, 2H), 4.06 (t, J = 6.4 Hz, 2H), 2.44 –2.22 (m, 6H), 1.86 (p, J = 6.7 Hz, 2H), 1.48 (p, J = 5.4 Hz, 4H), 1.42 – 1.30 (m, 2H)13C NMR (75 MHz, DMSO) δ 160.79, 136.27, 127.72, 114.51, 65.87, 53.58, 52.39, 23.85, 23.08, 22.16.

[0130] 4-(3-(4-(pyridin-2-yl)piperazin-1-yl)propoxy)benzenesulfonamideTo a stirred solution of 1-(pyridin-2-yl)piperazine (1 eq) and 6M NaOH (1.25 eq) in acetone 1-bromo- 3-chloropropane was added slowly at 0 °C. The resulting mixture was stirred at room temperature for 18 hours and concentrated under vacuum. The residue was taken up in water and extracted three times with methylene chloride. The organic layers were combined, washed with brine, and dried over anhy-drous sodium sulfate. The solvent was removed under vacuum to yield 1-(3-chloropropyl)-4-(pyridin-2-yl)piperazine as a transparent oil. Then this compound was synthesized according to general procedure1 from 1-(3-chloropropyl)-4-(pyridin-2-yl)piperazine (1 mmol) and 4-hydroxybenzenesulfonamide, pu- rified on silica gel using flash chromatography (gradient 5-10% methanol in methylene chloride) to obtain 4-(3-(4-(pyridin-2-yl)piperazin-1-yl)propoxy)benzenesulfonamide as a white solid.ESI-LC / MS (m / z): [M+H]+ calculated for C18H24N4O3S 376.1569; found 376.991H NMR (300 MHz, DMF) δ 8.16 (d, 1H), 7.86 (d, 2H), 7.57 (t, 1H), 7.25 (s, 2H), 7.15 (d, 2H), 6.86 (d, J = 8.7 Hz, 1H), 6.67 (dd, J = 7.1, 4.6 Hz, 1H), 4.20 (t, 2H), 3.54 (t, J = 5.2 Hz, 4H), 2.55 (t, J = 5.1 Hz, 6H), 2.02 (m, 2H).13C NMR (75 MHz, DMSO) δ 160.99, 159.02, 147.52, 137.44, 136.06, 127.65, 114.43, 112.94, 107.02,66.29, 54.30, 52.54, 44.59, 25.93.

[0131] N‐((4‐(3‐(piperidin‐1‐yl)propoxy)phenyl)methyl)aminosulfonamideThis compound was synthesized according to general procedure 3 from and C (2 mmol) and sulfuricdiamide (4eq) in ethanol, purified on silica gel using coloumn chromatography (gradient 5-10 % ammo- nia in methanol in methylene chloride) to obtain N‐((4‐(3‐(piperidin‐1-yl)propoxy)phenyl)methyl)ami- nosulfonamid.1H NMR (DMSO) δ 7.29 (d, J = 7.5, 2H), 7.00 (t, J = 6.3, 1H), 6.95 (d, J = 10.0, 2H), 6.65 (s, 2H), 4.07- 4.00 (m, 4H), 2.46-2.38 (m, 6H), 1.95-1.80 (m, 2H), 1.59-1.51 (m, 4H), 1.48-1.41 (m, 2H)13C NMR (DMSO) δ 157.65, 130.36, 128.92, 114.07, 65.87, 55.13, 54.08, 45.55, 26.28, 25.57, 24.11 CHN: calcd for C15H25N3O3S C, 55.02; H, 7.70; N, 12.83; S, 9.79; found C, 55.31; H, 7.78; N, 12.65; S, 9.60

[0132] 4-(3-(piperidin-1-yl)propoxy)-N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)benzamideTo a stirred suspension of E (1 mmol) and F (1 eq) in acetone pyridine (2.3 eq) was added dropwise at0 °C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 18 hours. The crude suspension was filtrated and the residue was purified using reversed phase flash chromatog- raphy (gradient 1-40 % methanol in water) to obtain 4-(3-(piperidin-1-yl)propoxy)-N-(5-sulfamoyl- 1,3,4-thiadiazol-2-yl)benzamide as a white solid.ESI-LC / MS (m / z): [M+H]+ calculated for C17H23N5O4S2425.1191; found 426.12821H NMR (300 MHz, DMSO) δ 8.15 (d, J = 8.6 Hz, 4H), 7.05 (d, J = 8.7 Hz, 2H), 4.15 (t, J = 6.0 Hz,2H), 3.21 – 2.82 (m, 6H), 2.31 – 2.06 (m, 2H), 2.00 – 1.65 (m, 4H), 1.64 – 1.38 (m, 2H).13C NMR (75 MHz, DMSO) δ 167.19, 166.46, 162.31, 161.43, 130.51, 126.44, 114.14, 65.43, 53.59,52.42, 23.74, 22.95, 21.78.

[0133] 4-((4-(3-(piperidin-1-yl)propoxy)benzyl)oxy)-N-(4-sulfamoylphenethyl)benzamide4-hydroxybenzoic acid and 4-(2-aminoethyl)benzenesulfonamide were reacted according to generalprocedure 2. The crude mixture was purified using flash chromatography (gradient 1-20% methanol in methylene chloride) to obtain 4-hydroxy-N-(4-sulfamoylphenethyl)benzamide. Then this compoundwas synthesized according to general procedure 1 from B (1 mmol) and 4-hydroxy-N-(4-sul-famoylphenethyl)benzamide, purified using reversed phase flash chromatography (gradient 5-60 % methanol in water) to obtain 4-((4-(3-(piperidin-1-yl)propoxy)benzyl)oxy)-N-(4-sul- famoylphenethyl)benzamide as a white solid.ESI-LC / MS (m / z): [M+H]+ calculated for C30H37N3O5S 551.2454; found 552.25451H NMR (300 MHz, DMSO) δ 8.45 (t, J = 5.6 Hz, 1H), 7.87 – 7.66 (m, 4H), 7.49 – 7.32 (m, 4H), 7.29(s, 2H), 7.12 – 6.89 (m, 4H), 5.06 (s, 2H), 4.01 (t, J = 6.3 Hz, 2H), 3.49 (q, J = 6.7 Hz, 3H), 2.91 (t, J =7.2 Hz, 2H), 2.70 – 2.54 (m, 6H), 2.05 – 1.81 (m, 2H), 1.57 (t, J = 5.6 Hz, 4H), 1.46 – 1.29 (m, 2H).13C NMR (75 MHz, DMSO) δ 165.67, 160.61, 158.35, 143.86, 142.01, 129.61, 129.13, 128.89, 128.58,126.78, 125.68, 114.38, 114.29, 75.80, 69.11, 54.61, 53.50, 34.85, 29.16, 24.68, 23.30.

[0134] N-(3-oxo-3-((5-sulfamoyl-1,3,4-thiadiazol-2-yl)amino)propyl)-4-(3-(piperidin-1-yl)propoxy)benzamideThis compound was synthesized according to general procedure 2 from D (1 mmol) and G, purified onsilica gel using reversed phase flash chromatography (gradient 5-60 % methanol in water) to obtain N- (3-oxo-3-((5-sulfamoyl-1,3,4-thiadiazol-2-yl)amino)propyl)-4-(3-(piperidin-1-yl)propoxy)benzamide as a white solid.ESI-LC / MS (m / z): [M+H]+ calculated for C20H28N6O5S2496.1563; found 497.16481H NMR (300 MHz, DMSO) δ 8.48 (t, J = 5.5 Hz, 1H), 8.32 (s, 2H), 7.85 – 7.75 (m, 2H), 7.02 – 6.93(m, 2H), 4.08 (t, J = 6.1 Hz, 2H), 3.64 – 3.50 (m, 2H), 3.05 – 2.86 (m, 6H), 2.81 (t, J = 6.7 Hz, 3H), 2.13– 1.96 (m, 2H), 1.75 – 1.57 (m, 4H), 1.57 – 1.40 (m, 2H).13C NMR (151 MHz, DMSO) δ 170.90, 165.90, 164.27, 161.31, 160.63, 129.07, 126.76, 114.00, 65.29,53.73, 52.62, 40.06, 35.37, 35.33, 23.96, 23.22, 21.85.

[0135] 4-sulfamoylphenyl 4-(3-(piperidin-1-yl)propoxy)benzoateTo a stirred solution of D (1 mmol), 4-hydroxybenzenesulfonamide (1 eq), 4-(dimethylamino)pyridine (0.05 eq) in DMF N,N'-dicyclohexylcarbodiimide (1.2 eq) was added dropwise. The resulting mixture was stirred at room temperature for 32 hours. The crude mixture was diluted with ethyl acetate and filtered through celite. The filtrate was concentrated under vacuum and purified using reversed phase flash chromatography (gradient 10-100 % methanol in water) to obtain 4-sulfamoylphenyl 4-(3-(piper- idin-1-yl)propoxy)benzoate as a white solid.ESI-LC / MS (m / z): [M+H]+ calculated for C21H26N2O5S 418.1562; found 419.16661H NMR (300 MHz, DMSO) δ 8.22 – 8.00 (m, 2H), 8.01 – 7.82 (m, 2H), 7.56 – 7.46 (m, 2H), 7.44 (s,2H), 7.21 – 7.02 (m, 2H), 4.13 (t, J = 6.3 Hz, 2H), 2.55 – 2.21 (m, 6H), 2.06 – 1.79 (m, 2H), 1.75 – 1.48(m, 4H), 1.48 – 1.27 (m, 2H).13C NMR (75 MHz, DMSO) δ 163.90, 163.32, 153.01, 141.61, 132.19, 127.35, 122.66, 120.40, 114.78,66.37, 54.69, 53.79, 29.37, 25.12, 23.72.

[0136] 3-((4-(3-(piperidin-1-yl)propoxy)benzyl)amino)-N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)propenamideThis compound was synthesized according to general procedure 3 from G (1 mmol) and C, purified onsilica gel using reversed phase flash chromatography (gradient 5-60 % methanol in water) to obtain 3- ((4-(3-(piperidin-1-yl)propoxy)benzyl)amino)-N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)propenamide as a white solid.ESI-LC / MS (m / z): [M+H]+ calculated for C20H30N6O4S2482.1770; found 483.18431H NMR (300 MHz, MeOD) δ 7.41 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 4.13 – 4.00 (m, 4H),3.18 (t, J = 6.3 Hz, 2H), 2.82 – 2.66 (m, 8H), 2.13 – 1.99 (m, 2H), 1.71 (p, J = 5.6 Hz, 4H), 1.57 (t, J =5.8 Hz, 2H).13C NMR (151 MHz, MeOD) δ 176.84, 163.87, 160.70, 132.00, 131.02, 115.94, 115.57, 67.09, 56.81,55.27, 51.90, 44.81, 34.81, 26.81, 25.95, 24.55.

[0137] 4-(2-((4-(3-(piperidin-1-yl)propoxy)benzyl)amino)ethyl)benzenesulfonamideThis compound was synthesized according to general procedure 3 from 2-aminoethyl)benzenesulfona-mide (1 mmol) and C, purified on silica gel using reversed phase flash chromatography (gradient 5-60% methanol in water) to obtain 4-(2-((4-(3-(piperidin-1-yl)propoxy)benzyl)amino)ethyl)benzenesulfon- amide as a white solid.ESI-LC / MS (m / z): [M+H]+ calculated for C23H33N3O3S 431.2243; found 432.23261H NMR (300 MHz, DMSO) δ 7.71 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.26 (s, 2H), 7.18 (d,J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 3.95 (t, J = 6.4 Hz, 2H), 3.62 (s, 2H), 2.84 – 2.63 (m, 4H), 2.41– 2.19 (m, 6H), 1.99 (s, 1H), 1.88 – 1.75 (m, 2H), 1.54 – 1.42 (m, 4H), 1.42 – 1.30 (m, 2H).13C NMR (151 MHz, DMSO) δ 157.37, 144.95, 141.72, 132.69, 129.03, 129.02, 125.57, 114.04, 65.83,55.19, 54.12, 52.21, 49.86, 35.53, 26.36, 25.61, 24.16.

[0138] 4-(2-((4-(4-methylpiperazine-1-carbonyl)benzyl)amino)ethyl)benzenesulfonamideFirst 4-(4-methylpiperazine-1-carbonyl)benzaldehyde was synthesized according to general procedure 2 from 1-methylpiperazine and 4-formylbenzoic acid. Then 4-(2-((4-(4-methylpiperazine-1-car-bonyl)benzyl)amino)ethyl)benzenesulfonamide was synthesized according to general procedure 3 from4-(2-aminoethyl)benzenesulfonamide and 4-(4-methylpiperazine-1-carbonyl)benzaldehyde, purified onsilica gel using reversed phase flash chromatography (gradient 5-40 % methanol in water) to obtain 4- (2-((4-(4-methylpiperazine-1-carbonyl)benzyl)amino)ethyl)benzenesulfonamide as a white solid. ESI-LC / MS (m / z): [M+H]+calcd. for C21H28N4O3S 416.1882; found 417.19551H NMR (600 MHz, MeOD) δ 7.81 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H), 7.40 – 7.35 (m, 4H),3.82 (s, 2H), 3.81 – 3.70 (m, 2H), 3.51 – 3.39 (m, 2H), 2.93 – 2.79 (m, 4H), 2.60 – 2.46 (m, 2H), 2.46 –2.36 (m, 2H), 2.32 (s, 3H).13C NMR (151 MHz, DMSO-d6) δ 169.01, 144.88, 142.49, 141.74, 134.11, 129.05, 127.75, 126.80,125.57, 52.42, 49.99, 45.61, 40.06, 39.94, 39.80, 39.66, 39.52, 39.38, 39.24, 39.10, 38.97, 35.54.

[0139] 1-(4-(3-(piperidin-1-yl)propoxy)benzyl)-N-(4-sulfamoylphenethyl)piperidine-4-carbox-amideTo a stirred suspension of ethyl piperidine-4-carboxylate (1 mmol) and B (1.1 eq) in acetonitrile N,N-diethylethanamine (3.3 eq) was added. The resulting mixture was stirred under reflux conditions for 3hours. The solvent was removed under vacuum and the crude mixture was dissolved in ethyl acetate and washed with 2M sodium hydroxide solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under vacuum to yield ethyl 1-(4-(3-(piperidin-1-yl)propoxy)benzyl)pi- peridine-4-carboxylate as a yellow oil. Then 1-(4-(3-(piperidin-1-yl)propoxy)benzyl)piperidine-4-carboxylate was dissolved in a mixture (1:1) of tetrahydrofuran and methanol and transferred to a microwave reactor vial. Potassium hydroxide (3 eq) was dissolved in water and added to the vial. The mixture reacted for 15 min at 70 °C in a microwave reactor and the organic solvents were removed under vacuum. The aqueous residue was neutralized with 4M hydrochloric acid solution and evaporated to dryness. The solid residue was dissolved in ethanol, filtered and the solvent removed under vacuum to obtain 1-(4-(3-(piperidin-1-yl)propoxy)benzyl)piper- idine-4-carboxylic acid. Then 1-(4-(3-(piperidin-1-yl)propoxy)benzyl)-N-(4-sulfamoylphenethyl)piperidine-4-carboxamide compound was synthesized according to general procedure 2 from 4-(2-aminoethyl)benzenesulfona- mide and 1-(4-(3-(piperidin-1-yl)propoxy)benzyl)piperidine-4-carboxylic acid, purified on silica gel us- ing reversed phase flash chromatography (gradient 5-60 % methanol in water) to obtain 1-(4-(3-(piper- idin-1-yl)propoxy)benzyl)-N-(4-sulfamoylphenethyl)piperidine-4-carboxamide as a white solid. ESI-LC / MS (m / z): [M+H]+calcd. for C29H42N4O4S 542.2927; found 543.29931H NMR (600 MHz, DMSO-d6) δ 7.81 (t, J = 5.7 Hz, 1H), 7.72 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.3 Hz,2H), 7.26 (s, 2H), 7.16 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 3.95 (t, J = 6.4 Hz, 2H), 3.33 (s,2H), 3.27 (q, J = 7.0 Hz, 2H), 2.82 – 2.68 (m, 4H), 2.40 – 2.15 (m, 6H), 2.05 – 1.93 (m, 1H), 1.89 – 1.75(m, 4H), 1.60 – 1.50 (m, 4H), 1.50 – 1.44 (m, 4H), 1.42 – 1.32 (m, 2H).13C NMR (151 MHz, DMSO-d6) δ 174.39, 157.59, 143.70, 142.05, 130.20, 129.92, 129.11, 125.58, 114.02, 65.82, 61.79, 55.18, 54.12, 52.56, 42.10, 40.06, 39.94, 39.80, 39.66, 39.52, 39.38, 39.24, 39.10, 34.80, 28.56, 26.36, 25.61, 24.16.

[0140] 4-((1-isopropylpiperidin-4-yl)oxy)-N-(4-sulfamoylphenethyl)benzamideTo a solution of methyl 4-hydroxybenzoate (1.7 mmol), 1-isopropylpiperidin-4-ol (1.3 eq) and tri- phenylphosphine (1.5) in tetrahydrofuran was added diethyl azodicarboxylate (40% in toluene; 1.5 eq) dropwise at 0 °C. The mixture was stirred at 0 °C for 15 min and continued stirring overnight at roomtemperature. After completion of the reaction, the reaction mixture was poured onto cold water the re- sulting solution was extracted with dichloromethane. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was removed under vacuum to obtain methyl 4-((1-isopropylpi- peridin-4-yl)oxy)benzoate. Then methyl 4-((1-isopropylpiperidin-4-yl)oxy)benzoate was dissolved in a mixture (1:1) of tetrahydro- furan and methanol and transferred to a microwave reactor vial. Potassium hydroxide (3 eq) was dis- solved in water and added to the vial. The mixture reacted for 15 min at 70 °C in a microwave reactor and the organic solvents were removed under vacuum. The aqueous residue was neutralized with 4M hydrochloric acid solution and evaporated to dryness. The solid residue was dissolved in ethanol, filtered and the solvent removed under vacuum to obtain 4-((1-isopropylpiperidin-4-yl)oxy)benzoic acid. Then 4-((1-isopropylpiperidin-4-yl)oxy)-N-(4-sulfamoylphenethyl)benzamide was synthesized accord- ing to general procedure 2 from 4-(2-aminoethyl)benzenesulfonamide and 4-((1-isopropylpiperidin-4- yl)oxy)benzoic acid to obtain 4-((1-isopropylpiperidin-4-yl)oxy)-N-(4-sulfamoylphenethyl)benzamide as a white solid. ESI-LC / MS (m / z): [M+H]+calcd. for C23H31N3O4S 445.2035; found 446.21081H NMR (600 MHz, DMSO-d6) δ 8.41 (t, J = 5.6 Hz, 1H), 7.80 – 7.70 (m, 4H), 7.42 (d, J = 8.4 Hz, 2H),7.28 (s, 2H), 6.98 (d, J = 8.9 Hz, 2H), 4.46 – 4.35 (m, 1H), 3.48 (q, J = 7.1 Hz, 2H), 2.91 (t, J = 7.2 Hz,2H), 2.75 – 2.63 (m, 3H), 2.38 – 2.27 (m, 2H), 2.01 – 1.89 (m, 2H), 1.65 – 1.47 (m, 2H), 0.97 (d, J =6.6 Hz, 6H).13C NMR (151 MHz, DMSO-d6) δ 165.67, 159.51, 143.86, 142.01, 129.12, 128.95, 126.49, 125.68, 114.95, 73.00, 53.58, 45.31, 40.37, 39.94, 39.80, 39.66, 39.52, 39.38, 39.24, 39.10, 34.86, 31.07, 18.11.

[0141] 4-(((4-(3-(piperidin-1-yl)propoxy)benzyl)amino)methyl)benzenesulfonamideThis compound was synthesized according to general procedure 3 from 4-(aminomethyl)benzenesul- fonamide and C, purified on silica gel using reversed phase flash chromatography (gradient 5-40 % methanol in water) to obtain 4-(((4-(3-(piperidin-1-yl)propoxy)benzyl)amino)methyl)benzenesulfona- mide as a white solid. ESI-LC / MS (m / z): [M+H]+calcd. for C22H31N3O3S 417.2086; found 418.21551H NMR (600 MHz, DMSO-d6) δ 7.76 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.28 (s, 2H), 7.23(d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 3.96 (t, J = 6.4 Hz, 2H), 3.71 (s, 2H), 3.59 (s, 2H), 2.66 (s,1H), 2.40 – 2.20 (m, 6H), 1.88 – 1.78 (m, 2H), 1.53 – 1.43 (m, 4H), 1.43 – 1.31 (m, 2H).13C NMR (151 MHz, DMSO-d6) δ 157.45, 145.16, 142.34, 132.42, 129.07, 128.12, 125.49, 114.09, 65.85, 55.18, 54.12, 51.53, 51.44, 39.94, 39.80, 39.66, 39.52, 39.38, 39.24, 39.10, 26.35, 25.61, 24.15.

[0142] 4-(3-(piperidin-1-yl)propoxy)-N-(4-sulfamoylbenzyl)benzamideThis compound was synthesized according to general procedure 2 from 4-(aminomethyl)benzenesul- fonamide and D, purified on silica gel using reversed phase flash chromatography (gradient 5-40 % methanol in water) to obtain 4-(3-(piperidin-1-yl)propoxy)-N-(4-sulfamoylbenzyl)benzamide as a white solid. ESI-LC / MS (m / z): [M+H]+calcd. for C22H29N3O4S 431.1879; found 432.19621H NMR (600 MHz, DMSO-d6) δ 8.98 (t, J = 6.0 Hz, 1H), 7.88 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 8.3 Hz, 2H), 7.30 (s, 2H), 7.01 (d, J = 8.8 Hz, 2H), 4.51 (d, J = 6.0 Hz, 2H), 4.11 (t, J= 6.0 Hz, 2H), 3.15 – 2.98 (m, 4H), 2.71 – 2.64 (m, 2H), 2.15 – 2.05 (m, 2H), 1.77 – 1.63 (m, 4H), 1.59– 1.42 (m, 2H).13C NMR (151 MHz, DMSO-d6) δ 165.72, 160.68, 143.96, 142.56, 129.14, 127.49, 126.56, 125.68,114.04, 65.22, 53.62, 52.53, 42.28, 39.94, 39.80, 39.66, 39.52, 39.38, 39.24, 39.10, 38.25, 23.83, 23.10.

[0143] 4-(3-(piperidin-1-yl)propoxy)-N-(4-sulfamoylphenyl)benzamideTo a stirred suspension of 4-aminobenzenesulfonamide (1 mmol) and potassium carbonate (1.5 eq) inacetone was added E (1.1 eq) dropwise at 0 °C. The resulting mixture was stirred at room temperatureunder nitrogen atmosphere for 1 hour. The crude suspension was filtrated and the residue was purified using reversed phase flash chromatography (gradient 1-40 % acetonitrile in water) to obtain 4-(3-(pi- peridin-1-yl)propoxy)-N-(4-sulfamoylphenyl)benzamide as a white solid. ESI-LC / MS (m / z): [M+H]+calcd. for C21H27N3O4S 417.1722; found 418.18161H NMR (600 MHz, DMSO-d6) δ 10.39 (s, 1H), 7.97 (d, J = 8.8 Hz, 2H), 7.94 (d, J = 8.8 Hz, 2H), 7.79(d, J = 8.8 Hz, 2H), 7.27 (s, 2H), 7.06 (d, J = 8.8 Hz, 2H), 4.09 (t, J = 6.4 Hz, 2H), 2.45 – 2.17 (m, 6H),1.93 – 1.81 (m, 2H), 1.54 – 1.44 (m, 4H), 1.44 – 1.30 (m, 2H).13C NMR (151 MHz, DMSO-d6) δ 165.22, 161.61, 142.37, 138.46, 129.80, 126.46, 126.27, 119.70, 114.12, 66.29, 55.05, 54.13, 39.94, 39.80, 39.66, 39.52, 39.38, 39.24, 39.10, 26.20, 25.62, 24.15.

[0144] The experimental data are summarized in the following Tables:Ki (nM)a, c Ki (nM)b, chCA I hCA II hCA IV hCA XII hCA XIV hH3R(-) (-) (-) (-) (-) (++)4-(3-(piperidin-1-yl)propoxy)-N-(3-piperidin-1-yl)propyl)benzenesul- fonamide; (Comparative compound 1) (-) (+++) (-) (+++) (-) (+++)4-((4-(3-(piperidin-1-yl)propoxy)benzyl)oxy)benzenesulfonamide (+) (+++) (-) (+++) (+) (+++)4-(3-(piperidin-1-yl)propoxy)-N-(4-sulfamoylphenethyl)benzamide(++) (+++) (-) (+++) (+) (+)4-(3-(piperidin-1-yl)propoxy)benzenesulfonamide (+) (+++) (+) (+++) (+) (-)4-(3-(4-(pyridin-2-yl)piperazin-1-yl)propoxy)benzenesulfonamide (Comparative compound 2) (-) (++) (-) (++) (+++) (++)N‐((4‐(3‐(piperidin‐1‐yl)propoxy)phenyl)methyl)aminosulfonamide aMean from 3 different assays, by a stopped flow technique (errors were in the range of ^ 5-10% of the reported values)bn = 3-4, [95% CI]cKivalues >1000 nM (-), < 1000 nM (+), <100 nM (++), < 10 nM (+++).The comparative compound 1 is an example without CA inhibitory potency and should demonstrate the limitations.The comparative compound 2 is an example without hH3R inhibitory potency and should demonstrate the limitations.Ki (nM)a, c Ki (nM)b, chCA I hCA II hCA IX hCA XII hH3R(+) (++) (++) (+++) (+)4-(3-(piperidin-1-yl)propoxy)-N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)benzamide (+) (++) (++) (++) (++)4-((4-(3-(piperidin-1-yl)propoxy)benzyl)oxy)-N-(4-sulfamoylphenethyl)ben- zamideKi (nM)a, c Ki (nM)b, chCA I hCA II hCA IX hCA XII hH3R(+) (++) (+++) (+++) (++)N-(3-oxo-3-((5-sulfamoyl-1,3,4-thiadiazol-2-yl)amino)propyl)-4-(3-(piperidin-1- yl)propoxy)benzamide (+) (+++) (+++) (++) (+++)4-sulfamoylphenyl 4-(3-(piperidin-1-yl)propoxy)benzoate (+) (++) (++) (++) (+++)3-((4-(3-(piperidin-1-yl)propoxy)benzyl)amino)-N-(5-sulfamoyl-1,3,4-thiadiazol- 2-yl)propenamideKi (nM)a, c Ki (nM)b, chCA I hCA II hCA IX hCA XII hH3R(++) (++) (++) (++) (+++)4-(2-((4-(3-(piperidin-1-yl)propoxy)benzyl)amino)ethyl)benzenesulfonamide (++) (++) (++) (+++) (+)4-(2-((4-(4-methylpiperazine-1-carbonyl)benzyl)amino)ethyl)benzenesulfona- mide (+) (++) (++) (++) (++)1-(4-(3-(piperidin-1-yl)propoxy)benzyl)-N-(4-sulfamoylphenethyl)piperidine-4- carboxamideKi (nM)a, c Ki (nM)b, chCA I hCA II hCA IX hCA XII hH3R(+) (++) (++) (++) (+)-((1-isopropylpiperidin-4-yl)oxy)-N-(4-sulfamoylphenethyl)benzamide (+++)-(((4-(3-(piperidin-1-yl)propoxy)benzyl)amino)methyl)benzenesulfonamide (++)-(3-(piperidin-1-yl)propoxy)-N-(4-sulfamoylbenzyl)benzamide (+++) -(3-(piperidin-1-yl)propoxy)-N-(4-sulfamoylphenyl)benzamideaMean from 3 different assays, by a stopped flow technique (errors were in the range of ^ 5-10% of the reported values)bn = 3-5cKivalues >1000 nM (-), < 1000 nM (+), <100 nM (++), < 10 nM (+++).

[0145] Ki values for different carbonic anhydrase (CA) isoforms were determined by an applied pho-tophysics stopped-flow instrument assaying the CA-catalyzed CO2hydration activity. For determination of the kinetic parameters and inhibition constants the CO2concentrations ranged from 1.7 to 17 nM. Phenol red was used as indicator at 557 nm, enzyme solutions and inhibitors were preincubated at roomtemperature and the assay was performed in buffer (20 mM Hepes, 20 mM Na2SO4, pH 7.5). The inhi-bition constants were calculated with GraphPad PRISM 3 using the Cheng-Prusoff equation. The results represent the mean from at least three independent experiments.

[0146] Ki values for human histamine H3 receptor (hH3R) were obtained by radioligand displacementassays on membrane fractions of HEK-293 cells stably expressing hH3R. The assay was performed with20 µg membrane fractions per well, [3H]-N-α-methylhistamine and titrations of test compounds. After90 minutes of incubation at room temperature while shaken continuously, membrane fractions with bound ligands were collected in filter mats and dried, radioactivity was determined by liquid scintillation counting. The Assay was performed in duplicates and repeated in at least three independent experiments. Ki values were calculated with GraphPad PRISM 6 using the Cheng-Prusoff equation. Mean values and 95% confidence intervals were converted to nanomolar concentrations.

Claims

Patent claims:

1. A compound according to general formula (I)wherein Zis absent, -CH2- or N-R1; R1is H, -[CH2]n-CH3, -C(=O)-[CH2]n-CH3or -C(H)([CH2]n-CH3)2, wherein, respectively inde- pendently, n is an integer from 0 to 18; Xis N, CH or C-[CH2]n-CH3, wherein n is an integer from 0 to 18;Y is -O-CH2-CH2-CH2-, -CH2-CH2-CH2-O-, -S-CH2-CH2-CH2-, -CH2-CH2-CH2-S- or D;D is -O-, -S-, -C(=O)- or -[CH2]n-, wherein n is an integer from 0 to 18;A is(i) -O-, -S-, -S(O)1-2-, -C(=O)-O-, -C(=O)-, -C(=O)-NH-[CH2]n-, [-CH2]n-NH-[CH2]n-,-[CH2]n-, or (ii) -[CH2]n-O-[CH2]m-phenyl-, -[CH2]n-NH-[CH2]m-O-phenyl-, -[CH2]n-O-phenyl-,-[CH2]n-aziridinyl-, -[CH2]n-azetidinyl-, -[CH2]n-pyrrolidinyl-, -[CH2]n-imidazoli- dinyl-, -[CH2]n-pyrazolidinyl-, -[CH2]n-piperidinyl-, -[CH2]n-piperazinyl-, -[CH2]n-tri- azolidinyl-, -[CH2]n-tetrazolidinyl-, -[CH2]n-oxiranyl-, -[CH2]n-oxetanyl-, -[CH2]n-tet- rahydrofuranyl-, -[CH2]n-tetrahydropyranyl-, -[CH2]n-thiiranyl-, -[CH2]n-thietanyl-, -[CH2]n-tetrahydrothiophenyl-, -[CH2]n-diazepanyl-, -[CH2]n-oxazolidinyl-, -[CH2]n- isoxazolidinyl-, -[CH2]n-thiazolidinyl-, -[CH2]n-isothiazolidinyl-, -[CH2]n-thiadiazoli- dinyl-, -[CH2]n-morpholinyl-, -[CH2]n-thiomorpholinyl-, respectively independently optionally mono-, di- or trisubstituted with -F, -Cl, -Br, -I, -OH or =O, andwherein respectively independently, n and / or m is an integer from 0 to 18 with n+m ≤ 18; Bis -L-(hetero-)aryl-SO2NH2 or -N(H)(R2); Lis absent, -NH-, -C(=O)-NH-, -O-, -NH-[CH2]n- or -C(=O)-NH-[CH2]n-, wherein, respec-tively independently, n is an integer from 0 to 18; (hetero-)aryl is (i) -pyrrolyl-, -indolyl-, -furyl- (-furanyl-), -benzofuranyl-, -thienyl- (-thiophenyl-), -ben-zothienyl-, -benzothiadiazolyl-, -benzooxadiazolyl-, -benzothiazolyl-, -benzooxazolyl-,-benzotriazolyl-, -benzodioxolanyl-, -benzodioxanyl-, -phthalazinyl-, -pyrazolyl-, -im- idazolyl-, -thiazolyl-, -thiadiazolyl-, -oxazolyl-, -isoxazoyl-, -oxadiazolyl-, -pyridinyl-, -pyridazinyl-, -pyrimidinyl-, -pyrazinyl-, -pyranyl-, -indazolyl-, -purinyl, -indolizinyl-, -quinolinyl-, -isoquinolinyl-, -quinazolinyl- or -benzthiazolyl-, or(ii) -phenyl-, -naphthyl-, -anthracenyl-, -phenanthrenyl-, -fluoroanthenyl-, -fluoroenyl, -in-danyl- or -tetralinyl-,respectively independently optionally mono-, di- or trisubstituted with -F, -Cl, -Br, -I or -OH; R2is -H, -[CH2]n-CH3, -OH, -S(=O)2NH2, -C(=O)-OH or -C(=O)-O-[CH2]n-CH3, wherein, re- spectively independently, n is an integer from 0 to 18; or a physiologically acceptable salt thereof; for use in the prevention or treatment of -glaucoma or ocular hypertension, and / or- eye diseases or conditions associated with elevated intraocular pressure, and / or- cancer.

2. The compound for use according to claim 1, which is according to general formula (I*)or a physiologically acceptable salt thereof; wherein A, B, X, Y and Z are defined according to claim 1;preferably selected from a compound according to general formula (1), (2) or (3)(3 or a physiologically acceptable salt thereof; wherein, respectively independently, Ais -S(O)1-2-, -C(=O)-O-, -C(=O)-, -C(=O)-NH-[CH2]n-, [-CH2]n-NH-[CH2]n-, -[CH2]n-,-[CH2]n-O-phenyl-, -[CH2]n-piperidinyl- or -[CH2]n-piperazinyl-, wherein -piperidinyl- or-piperazinyl- are optionally monosubstituted with =O, wherein, respectively independently,n is an integer from 0 to 12, preferably from 0 to 6 or preferably from 1 to 12, more preferably from 2 to 10, even more preferably from 3 to 8; Lis absent, -NH-, -C(=O)-NH-, -O-, -NH-[CH2]n- or -C(=O)-NH-[CH2]n-, wherein, respec-tively independently, n is an integer from 0 to 12, preferably from 0 to 6 or preferably from 1 to 12, more preferably from 2 to 10, even more preferably from 3 to 8; (hetero-)aryl is(i) -pyrrolyl-, -indolyl-, -furyl- (-furanyl-), -benzofuranyl-, -thienyl- (-thiophenyl-), -ben-zothienyl-, -benzothiadiazolyl-, -benzooxadiazolyl-, -benzothiazolyl-, -benzooxazolyl-, -benzotriazolyl-, -benzodioxolanyl-, -benzodioxanyl-, -phthalazinyl-, -pyrazolyl-, -im- idazolyl-, -thiazolyl-, -thiadiazolyl-, -oxazolyl-, -isoxazoyl-, -oxadiazolyl-, -pyridinyl-, -pyridazinyl-, -pyrimidinyl-, -pyrazinyl-, -pyranyl-, -indazolyl-, -purinyl-, -indolizinyl- ,-quinolinyl-, -isoquinolinyl-, -quinazolinyl- or -benzthiazolyl-, preferably -thiazolyl-or -thiadiazolyl-, or (ii) -phenyl-, -naphthyl-, -anthracenyl-, -phenanthrenyl-, -fluoroanthenyl-, -fluoroenyl-, -in-danyl- or -tetralinyl-, preferably -phenyl- or -naphthyl-,respectively independently optionally monosubstituted with -F, -Cl, -Br, -I or -OH; Dis -O-, -S- or -C(=O)-;R1 is H, -[CH2]n-CH3, -C(H)([CH2]n-CH3)2, -C(=O)-[CH2]n-CH3, -C(=O)-[CH2]n-NH2, C(=O)-[CH2]n-NH([CH2]n-H)1 or C(=O)-[CH2]n-N([CH2]n-H)2, wherein, respectively inde- pendently, n is an integer from 0 to 12, preferably from 0 to 6 or preferably from 1 to 12, more preferably from 2 to 10, even more preferably from 3 to 8; R2is -H, -[CH2]n-CH3, -OH, -S(=O)2NH2, -C(=O)-OH or -C(=O)-O-[CH2]n-CH3, wherein, re- spectively independently, n is an integer from 0 to 12, preferably from 0 to 6 or preferably from 1 to 12, more preferably from 2 to 10, even more preferably from 3 to 8; and / orX is N, CH or C-[CH2]n-CH3, wherein, respectively independently, n is an integer from 0 to 12,preferably from 0 to 6 or preferably from 1 to 12, more preferably from 2 to 10, even morepreferably from 3 to 8.

3. The compound for use according to claim 1 or 2, wherein, respectively independently, n and / orm is (i) 0, 1, 2, 3, 4, 5, 6 or 7; (ii) 0, 1, 2, 3, 4, 5 or 6; (iii) 0, 1, 2, 3, 4 or 5; (iv) 0, 1, 2, 3 or 4; (v)0, 1, 2 or 3; (vi) 0, 1 or 2; (vii) 1, 2, 3, 4, 5, 6 or 7; (viii) 1, 2, 3, 4, 5 or 6; (ix) 1, 2, 3, 4 or 5; (x)1, 2, 3 or 4; or (xi) 1, 2 or 3.

4. The compound for use according to any one of the preceding claims, which is selected from acompound according to general formula (1A), (1B), (2A), (2B), (2B*), or (3)(2 ( or a physiologically acceptable salt thereof; wherein, respectively independently, R1, R2, D, X, A and L are defined according to any one ofthe preceding claims and R3 is -H, -F, -Cl, -Br, -I or -OH, preferably -H or -Cl;wherein the compound for use is preferably selected from a compound according to general for- mula (1A), (1B), (2A), (2B), or (2B*); more preferably the compound for use is selected from acompound according to general formula (1A), (1B), (2A), or (2B*).

5. The compound for use according to any one of the preceding claims, wherein, respectively inde-pendently, Ais -S(O)2-, -C(=O)-, -C(=O)-NH-CH2-CH2-, -CH2-NH-CH2-CH2-, -CH2-, -CH2-O-phenyl-,-[CH2]n-piperidinyl- or -CH2-piperazinyl-, wherein -piperazinyl- is optionally monosubsti-tuted with =O, and wherein n is an integer from 0 to 18, preferably from 0 to 6, more prefer-ably from 0 to 3; Lis -absent, -NH-, -C(=O)-NH-, -O-, -NH-CH2-, -NH-CH2-CH2- or -C(=O)-NH-CH2-CH2-,D is -O- or -C(=O)-,R1is -CH3or -C(H)(CH3)2, R2 is -H, -OH or -S(=O)2NH2; preferably -H or -S(=O)2NH2;R3 is -H or -Cl; preferably -H, and / orX is N or CH.

6. The compound for use according to any one of the preceding claims, which is, ,r; preferably- ol- - mul- and / or a p ys o og ca y accepabe sa ereo .

7. The compound for use according to any one of the preceding claims, which is for use in theprevention or treatment of -ocular hypertension; and / or- a glaucoma,- preferably a primary glaucoma, very preferably an open-angle glaucoma (POAG), a nor-mal-tension glaucoma, an angle-closure glaucoma, or a congenital glaucoma; or -preferably a secondary glaucoma, very preferably a neovascular glaucoma, a pigmentaryglaucoma, an exfoliation glaucoma, or an uveitic glaucoma; or -preferably a glaucoma caused by an eye injury; or- preferably a glaucoma caused by a cataract or a tumor; and / or- other indications selected from the group consisting of retinal / cerebral edema, edema, epi-lepsy, altitude sickness, renal disorders, retinitis pigmentosa, stroke, retinopathy and cancer.

8. The compound for use according to claim 7, which is- provided as an eye drop composition, and / or- administered orally or topically via administration to the eye or eyes of a subject or patient,and preferably topically via administration to the eye or eyes of a subject or patient.

9. The compound for use according to any one of claims 1 to 6, which is for use in the preventionor treatment of cancer or metastasis, preferably leukemia or a hypoxic tumor.

10. The compound for use according to claim 9, which is administered orally, rectally, intravenously,intramuscularly, intraperitoneally, intrasternally, subcutaneously, by intraarticular injection, by infusion, intravaginally, intracisternally, intraperitoneally, topically, buccally or extracorporeally.

11. The compound for use according to any one of the preceding claims, which is administered atleast once daily, at least twice daily, at least thrice daily, at least four times a day, at least five times a day or at least six times a day; preferably once daily, twice daily, thrice daily, four times a day, five times a day or six times a day.

12. The compound for use according to any one of the preceding claims, which is administered in anamount of 0.3 µg / kg to 300 µg / kg, preferably 0.5 µg / kg to 200 µg / kg, more preferably 1 µg / kg to 100 µg / kg, and most preferably 5 µg / kg to 50 µg / kg, in each case based on the body weight of the subject or patient.

13. A compound which is selected from a compound according to general formula (1A), (1B), (2A),(2B), (2B*), or (3)(2 ( or a physiologically acceptable salt thereof; wherein, respectively independently, with respect to general formulae (1A), (1B), (2A), (2B) and / or (2B*),R1, R3, D, X, A and L are defined according to any one of claims 1 to 6; andwith respect to general formula (3), A and R2 are defined according to any one of claims 1 to 6,with the proviso that the moiety -A-N(H)R2does not represent -S(=O)2NH2; wherein the compound is preferably selected from a compound according to general formula (1A), (1B), (2A), (2B), or (2B*); more preferably the compound is selected from a compound according to general formula (1A), (1B), (2A), or (2B*).

14. A pharmaceutical composition comprising a compound according to claim 13; preferably an oph-thalmic composition, more preferably an eye drop composition, or a composition for the treatmentof cancer.

15. A kit comprising- the pharmaceutical composition according to claim 14,- a package for containing the pharmaceutical composition according to claim 14, and- instructions for administering the pharmaceutical composition according to claim 14 to a sub-ject.

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