Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/08—Bridged systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
  • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
  • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
  • C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
  • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
  • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
  • C07D451/06—Oxygen atoms
  • C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the present invention relates to azabicyclo and diazepine derivatives useful as modulators of muscarinic receptors and methods of treating disease using same.
• the muscarinic receptor is a target for the excitatory neurotransmitter acetylcholine, and was named based on the selective activation of the receptor by muscarine.
• the muscarinic receptor is widely distributed throughout human tissues, and is further classified into subtypes of Ml to M5.
• the modulation of muscarinic receptors has been considered a therapeutic target for disorders ranging from overactive bladder to cognitive disorders (Abrams et al., Br. J Pharmacol 2006 July; 148(5): 565-578).
• Myopia is an ocular refractive error caused by excessive growth of the eye in a longitudinal direction. This elongation of the eye causes the visual image to be focused in front of the retina and typically results in blurred vision of distant objects.
• the non-selective muscarinic antagonist atropine has been reported to be effective as a topical 1% drop in the treatment of myopia. (Chua et al., Ophthalmology 2006 Dec; 113(12):2285-91). However, numerous side effects were reported, including mydriasis (dilation of the pupil) and blurring of near vision due to cycloplegia (inability to accommodate).
• corrective lenses represent the primary means for ameliorating eye-length disorders such as myopia.
• lenses optically correct the refractive errors without treating the underlying cause which is excessive growth of the eye. Thus, there remains a need for methods to treat disorders relating to excessive growth of the eye.
• the invention provides compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof and combinations thereof, which compounds are muscarinic modulators.
• the invention further provides methods of treating, preventing, or ameliorating disorders relating to excessive growth of the eye, comprising administering to a subject in need thereof an effective amount of a muscarinic modulator.
• Various embodiments of the invention are described herein.
• A O or NRs
• R 1 and R 2 are independently substituted as H, D, hydroxyl, alkoxy, nitrile, halogen atoms, C1-C20, preferably C1-C10, straight, branched or cyclo alkyl groups optionally substituted with halogen atoms; or
• R 1 and R 2 are independently substituted as phenyl or benzyl groups being optionally substituted with one or more substituents selected form C1-C20, preferably C1-C10, straight, branched or cyclo alkyl groups, halo alkyl groups, hydroxyl, alkoxy, nitrile, nitro, amino, amide, ester, sulfone, sulfoxide, sulfonamide, and halogen atoms; or
• R 1 and R 2 are independently substituted with a heterocyclic saturated, unsaturated or aromatic 5- or 6-member ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur and being optionally substituted with one or more substituents selected form C1-C20, preferably C1-C10, straight, branched or cyclo alkyl, halo alkyl groups, hydroxyl, alkoxy, nitrile, nitro, amino, amide, ester, sulfone, sulfoxide or halogen atoms; R 3 and R 4 are independently substituted with hydrogen, C1-C10 straight or branched or cyclo alkyl or halo alkyl groups or
• R 3 and R 4 can combine to form 3- to 6-membered rings
• R 5 H or C1-C20, preferably C1-C10, straight or branched alkyl groups, C1-C10 straight or branched haloalkyl groups;
• X ⁇ ONC , -O-Y-Z, -S-Y-Z, or -NRs-Y-Z;
• Y is a bivalent radical having the following meaning: a) Straight or branched Ci - C20 alkyl, preferably Ci - C10 alkyl, being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxyl, and -ONO2; b) -C(O) (Ci - Cio alkyl) - or -C(0)(CH 2 )nC(0)0 -(Ci - C10 alkyl) - or -(C1-C10 alkyl) -;
• n is an integer from 0 to 20;
• R 6 and R 7 are independently H or Ci-Cio straight or branched alkyl groups, Ci-Cio straight or branched haloalkyl groups; or
• R 6 and R 7 can combine to form 3- to 6-membered rings:
• Z is a monovalent radical having the following meaning: a)
• R 8 and R 9 are independently substituted as Ci - C20 alkyl, preferably Ci - C10 alkyl, being optionally substituted with one or more substituents selected from hydroxyl, amino, ester, carboxylic acid, and halogen atoms; or
• R 8 and R 9 can combine to form 3- to 6-membered rings containing one or more heteroatoms, which are selected from the group consisting of:
• the compound of formula (I) has the following formula (IA):
• R 1 H, D, OH, halogen, Ci-Cio straight or branched alkyl, phenyl or benzyl, a heterocyclic saturated, unsaturated or aromatic 5- or 6-member ring, containing one or more heteroatoms selected from nitrogen, oxygen and sulfur;
• X -ONO2, -O-Y-Z, -S-Y-Z, or -NRs-Y-Z; and Y and Z are as defined above.
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutically effective amount (preferably from about 0.01 to about 10.0 weight percent of, more preferably from about 0.01 to about 5 weight/volume percent of or from about 0.1 to 5.0 weight percent of) (a) a compound of the present invention and/or (b) a pharmaceutically acceptable salt thereof; and (2) one or more pharmaceutically acceptable carriers.
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising: (1) a compound of the present invention and/or a pharmaceutically acceptable salt thereof; and (2) one or more pharmaceutically acceptable carriers.
• the invention provides a combination, in particular a pharmaceutical combination, comprising: (1) a therapeutically effective amount of (preferably from about 0.01 to about 10.0 weight percent, more preferably from about 0.01 to about 5 weight/volume percent of or from about 0.1 to 5.0 weight percent of) (a) a compound of the present invention and/or (b) a pharmaceutically acceptable salt thereof; and (2) one or more therapeutically active agents.
• a combination, in particular a pharmaceutical combination comprising: (1) a compound of the present invention and/or a pharmaceutically acceptable salt thereof; and (2) one or more therapeutically active agents.
• FIGURE 1A is a 3 ⁇ 4 NMR spectrum of (7i?,3i?,5,S)-8-Methyl-8-azabicyclo[3.2.1]octan-3- yl 2-fluoro-3-(nitrooxy)-2-phenylpropanoate.
• FIGURE IB is a 13 C NMR spectrum of
• FIGURE 2A is a 3 ⁇ 4 NMR spectrum of 2-Fluoro-3-(((77?,37?,55 -8-methyl-8- azabicyclo[3.2.1]octan-3-yl)oxy)-3-oxo-2-phenylpropyl 6-(nitrooxy)hexanoate.
• FIGURE 2B is a 13 C NMR spectrum of 2-Fluoro-3-(((77?,37?,5,S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-3- oxo-2-phenylpropyl 6-(nitrooxy)hexanoate.
• FIGURE 3 A is a 3 ⁇ 4 NMR spectrum of (77?,37?,5,S)-8-Methyl-8-azabicyclo[3.2.1]octan-3- yl 2-methyl-3-(nitrooxy)-2-phenylpropanoate.
• FIGURE 3B is a 13 C NMR spectrum of
• FIGURE 4A is a 3 ⁇ 4 NMR spectrum of 2-Methyl-3-(((77?,37?,5S)-8-methyl-8- azabicyclo[3.2.1]octan-3-yl)oxy)-3-oxo-2-phenylpropyl-6-(nitrooxy)hexanoate.
• FIGURE 4B is a 13 C NMR spectrum of 2-Methyl-3-(((77?,37?,5,S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)- 3-oxo-2-phenylpropyl-6-(nitrooxy)hexanoate.
• FIGURE 5A is a 3 ⁇ 4 NMR spectrum of (77?,37?,5,S)-8-Methyl-8-azabicyclo[3.2.1]octan-3- yl 2-benzyl-3-(nitrooxy)-2-phenylpropanoate.
• FIGURE 5B is a 13 C NMR spectrum of
• FIGURE 6A is a 3 ⁇ 4 NMR spectrum of 2-Benzyl-3-(((77?,37?,55 8-methyl-8- azabicyclo[3.2.1]octan-3-yl)oxy)-3-oxo-2-phenylpropyl-6-(nitrooxy)hexanoate.
• FIGURE 6B is a 13 C NMR spectrum of 2-Benzyl-3-(((77?,37?,5,S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)- 3-oxo-2-phenylpropyl-6-(nitrooxy)hexanoate.
• FIGURE 7 A is a 3 ⁇ 4 NMR spectrum of 6-((l l-(2-(4-Methylpiperazin-l-yl)acetyl)-l lH- benzo[e]pyrido[3,2-b][l,4]diazepin-6-yl)oxy)hexyl nitrate.
• FIGURE 7B is a 13 C NMR spectrum of 6-((l l-(2-(4-Methylpiperazin-l-yl)acetyl)-l lH-benzo[e]pyrido[3,2-b][l,4]diazepin-6- yl)oxy)hexyl nitrate.
• the invention relates to classes of compounds each having an atropine or pirenzepine residue and pharmaceutically acceptable salts thereof.
• the invention provides a compound of formula (I) or (II):
• A O or NRs
• R 1 and R 2 are independently substituted as H, D, hydroxyl, alkoxy, nitrile, halogen atoms,
• C1-C20 preferably C1-C10, straight, branched or cyclo alkyl groups optionally substituted with halogen atoms; or
• R 1 and R 2 are independently substituted as phenyl or benzyl groups being optionally substituted with one or more substituents selected form C1-C20, preferably C1-C10, straight, branched or cyclo alkyl groups, halo alkyl groups, hydroxyl, alkoxy, nitrile, nitro, amino, amide, ester, sulfone, sulfoxide, sulfonamide, and halogen atoms; or
• R 1 and R 2 are independently substituted with a heterocyclic saturated, unsaturated or aromatic 5- or 6-member ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur and being optionally substituted with one or more substituents selected form C1-C20, preferably C1-C10, straight, branched or cyclo alkyl, halo alkyl groups, hydroxyl, alkoxy, nitrile, nitro, amino, amide, ester, sulfone, sulfoxide or halogen atoms; R 3 and R 4 are independently substituted with hydrogen, C1-C10 straight or branched or cyclo alkyl or halo alkyl groups or
• R 3 and R 4 can combine to form 3- to 6-membered rings
• R 5 H or C1-C20, preferably C1-C10, straight or branched alkyl groups, C1-C10 straight or branched haloalkyl groups;
• X - ⁇ 2, - ⁇ - ⁇ - ⁇ , -S-Y-Z, or -NRs-Y-Z;
• Y is a bivalent radical having the following meaning: a) Straight or branched Ci - C20 alkyl, preferably Ci - C10, being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxyl, and -ONO2; b) -C(O) (Ci - Cio alkyl) - or -C(0)(CH 2 )nC(0)0 -(Ci - C10 alkyl) - or -(C1-C10 alkyl) -; d)
• n is an integer from 0 to 20;
• R 6 and R 7 are independently H or C1-C10, straight or branched alkyl groups, C1-C10 straight or branched haloalkyl groups ; or
• R 6 and R 7 can combine to form 3- to 6-membered rings
• Z is a monovalent radical having the following meaning: a)
• R 8 and R 9 are independently substituted as Ci - C20 alkyl, preferably Ci - C10, being optionally substituted with one or more substituents selected from hydroxyl, amino, ester, carboxylic acid, and halogen atoms; or
• R 8 and R 9 can combine to form 3- to 6-membered rings containing one or more heteroatoms which are selected from the group consisting of:
• the compound of formula (I) has formula (IA):
• R 1 H, D, OH, halogen, Ci - C10 straight or branched alkyl, phenyl or benzyl, a heterocyclic saturated, unsaturated or aromatic 5- or 6-member ring, containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;
• X -ONO2, -O-Y-Z, -S-Y-Z, or -NRs-Y-Z; and Y and Z are as described above.
• the invention relates to a method of treating a mammalian subject having or at risk of having an ocular disorder, comprising administering to the subject an effective amount of a compound according to formula (I) or formula (II).
• the term "compounds of the present invention” or “compound of the present invention” refers to compounds of formula (I) or formula (II), subformulae thereof, and exemplified compounds, and salts thereof, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers and isotopically labeled compounds (including deuterium substitutions), as well as inherently formed moieties.
• an effective amount of the compounds of the invention refers to that amount of a therapeutic compound necessary or sufficient to perform its intended function within a mammal, e.g., treat a muscarinic receptor associated disorder, or a disease state in a mammal.
• An effective amount of the therapeutic compound can vary according to factors such as the amount of the causative agent already present in the mammal, the age, sex, and weight of the mammal, and the ability of the therapeutic compounds of the present invention to affect the muscarinic receptor associated disorder in the mammal.
• factors such as the amount of the causative agent already present in the mammal, the age, sex, and weight of the mammal, and the ability of the therapeutic compounds of the present invention to affect the muscarinic receptor associated disorder in the mammal.
• One of ordinary skill in the art would be able to study the aforementioned factors and make a determination regarding the effective amount of the therapeutic compound without undue experimentation.
• an in vitro or in vivo assay also can be used to determine an "effective amount" of the therapeutic compounds described infra.
• the ordinarily skilled artisan would select an appropriate amount of the therapeutic compound for use in the aforementioned assay or as a therapeutic treatment.
• ophthalmically compatible refers to formulations, polymers and other materials and/or dosage forms which are suitable for use in contact with the ocular tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio as determined by one of ordinary skill in the art.
• a pharmaceutical composition is a composition suitable for pharmaceutical use.
• a composition suitable for pharmaceutical use may be sterile, homogeneous and/or isotonic.
• Pharmaceutical compositions may be prepared in certain embodiments in an aqueous form, for example in a pre-filled syringe or other single- or multi-dose container.
• the pharmaceutical compositions of the invention are ophthalmically compatible and suitable for ophthalmic administration to a human subject by, for example, topical or other known methods of delivery.
• the pharmaceutical compositions of the invention are suitable for intravitreal administration.
• the pharmaceutical compositions of the invention are suitable for administration by intravitreal infusion.
• the pharmaceutical compositions are administered orally.
• alkyl is intended to include branched, straight chain and cyclic, substituted or unsubstituted saturated aliphatic hydrocarbon groups.
• Alkyl groups can comprise about 1 to about 24 carbon atoms ("C1-C24"), about 7 to about 24 carbon atoms (“C7-C24”), about 8 to about 24 carbon atoms (“C8-C24”), or about 9 to about 24 carbon atoms (“C9-C24”).
• Alkyl groups can also comprise about 1 to about 8 carbon atoms (“Ci-Cs”), about 1 to about 6 carbon atoms (“C1-C6”), or about 1 to about 3 carbon atoms (“C1-C3").
• C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl and n-hexyl radicals.
• C2-6alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to six carbon atoms, which is attached to the rest of the molecule by a single bond.
• C2-C20 alkenyl and “C2-Cioalkenyl” are to be construed accordingly.
• Examples of C2-6alkenyl include, but are not limited to, ethenyl, prop-l-enyl, but-l-enyl, pent-l-enyl, pent- 4-enyl and penta-l,4-dienyl.
• C2-6alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to six carbon atoms, and which is attached to the rest of the molecule by a single bond.
• C2-4alkynyl is to be construed accordingly. Examples of C2-6alkynyl include, but are not limited to, ethynyl, prop- 1 -ynyl, but- 1 -ynyl, pent- 1 -yny 1, pent-4-ynyl and penta- 1 ,4-diyny 1.
• Ci-6alkoxy refers to a radical of the formula -ORa where Ra is a Ci-6alkyl radical as generally defined above.
• Ci-6alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, and hexoxy.
• Halogen refers to bromo, chloro, fluoro or iodo.
• heterocyclyl refers to a stable 5- or 6- membered non-aromatic monocyclic ring radical which comprises 1, 2, or 3, heteroatoms individually selected from nitrogen, oxygen and sulfur.
• the heterocyclyl radical may be bonded via a carbon atom or heteroatom.
• heterocyclyl include, but are not limited to, azetidinyl, oxetanyl, pyrrolinyl, pyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, piperazinyl, tetrahydropyranyl, morpholinyl or perhydroazepinyl.
• heteroaryl refers to a 5- or 6-membered aromatic monocyclic ring radical which comprises 1, 2, 3 or 4 heteroatoms individually selected from nitrogen, oxygen and sulfur.
• the heteroaryl radical may be bonded via a carbon atom or heteroatom.
• heteroaryl include, but are not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidyl or pyridyl.
• novel pharmaceutical formulations in particular novel pharmaceutical formulations in which the active ingredient comprises a muscarinic modulator of the formula (I) or formula (II) or pharmaceutically acceptable salts or stereoisomers thereof:
• A O or NRs
• R 1 and R 2 are independently substituted as H, D, hydroxyl, alkoxy, nitrile, halogen atoms, C1-C20, preferably C1-C10, straight, branched or cyclo alkyl groups optionally substituted with halogen atoms; or
• R 1 and R 2 are independently substituted as phenyl or benzyl groups being optionally substituted with one or more substituents selected form C1-C20, preferably C1-C10, straight, branched or cyclo alkyl groups, halo alkyl groups, hydroxyl, alkoxy, nitrile, nitro, amino, amide, ester, sulfone, sulfoxide, sulfonamide, and halogen atoms; or
• R 1 and R 2 are independently substituted with a heterocyclic saturated, unsaturated or aromatic 5- or 6-member ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur and being optionally substituted with one or more substituents selected form C1-C20, preferably C1-C10, straight, branched or cyclo alkyl, halo alkyl groups, hydroxyl, alkoxy, nitrile, nitro, amino, amide, ester, sulfone, sulfoxide or halogen atoms; R 3 and R 4 are independently substituted with hydrogen, C1-C10 straight or branched or cyclo alkyl or halo alkyl groups or
• R 3 and R 4 can combine to form 3- to 6-membered rings
• R 5 H or C1-C20, preferably C1-C10, straight or branched alkyl groups, C1-C10 straight or branched haloalkyl groups;
• Y is a bivalent radical having the following meaning: a) Straight or branched alkyl, preferably, being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxyl, and -ONO2; b) -C(O) (Ci - Cio alkyl) - or -C(0)(CH 2 )nC(0)0 -(Ci - C10 alkyl) - or -(C1-C10 alkyl) -; d)
• n is an integer from 0 to 20;
• R 6 and R 7 are independently H or C1-C10, straight or branched alkyl groups, C1-C10 straight or branched haloalkyl groups ; or
• R 6 and R 7 can combine to form 3- to 6-membered rings
• Z is a monovalent radical having the following meaning: a)
• R 8 and R 9 are independently substituted as Ci - C20 alkyl, preferably Ci - C10, being optionally substituted with one or more substituents selected from hydroxyl, amino, ester, carboxylic acid, and halogen atoms; or
• R 8 and R 9 can combine to form 3- to 6-membered rings containing one or more heteroatoms, which are selected from the group consisting of:
• the compound of formula (I) has the following formula (IA):
• R 1 H, D, OH, halogen, Ci - C10 straight or branched alkyl, phenyl of benzyl, a heterocyclic saturated, unsaturated or aromatic 5- or 6-member ring, containing one or more heteroatoms selected from nitrogen, oxygen and sulfur;
• W N or CH;
• X -ONO2, - ⁇ - ⁇ - ⁇ , -S-Y-Z, or -NR5-Y-Z; and
• Y and Z have the same meanings as described above.
• compounds of formula (I) and formula (II) are selected from the group consisting of:
• Additional compounds of the present invention include the following:
• the invention relates to a method of treating a mammalian subject having or at risk of having an ocular disorder, said method comprising administering to the subject an effective amount of a compound according to formula (I) or formula (II).
• the ocular disorder is myopia.
• 6-(Nitrooxy)hexanoic acid To a solution of 6-bromohexanoic acid (50.0 g, 0.26 mol) in MeCN (250 mL) was added silver nitrate (65.3 g, 0.38 mol) and the suspension stirred at 50°C for 3 h. The reaction mixture was cooled to RT and filtered and the filtrate was concentrated in vacuo causing more solids to precipitate. The residue was diluted with DCM, filtered and the filtrate washed with water. The organic fraction was washed with brine, dried (MgS0 4 ) and concentrated in vacuo to give the product as a straw coloured oil (40.1 g, 88%).
• 6-Chloro-6-oxohexyl nitrate To a solution of 6-(nitrooxy)hexanoic acid (2.5 g, 14.1 mmol) in DCM at RT was added 1 drop of DMF followed by oxalyl chloride (1.8 mL, 21.1 mmol), causing effervescence. The reaction mixture was stirred at RT for 1.5 h. and was then concentrated in vacuo to produce the product as a semi-solid (2.76 g, quant.). The material was used crude in the next step.
• 6-Chloro-l lH-benzo[e]pyrido[3,2-b][l,4]diazepine 500 mg, 2.37 mmol was added to a stirred solution of 6-hydroxyhexyl nitrate (739 mg, 4.53 mmol) in DCM (2 mL) at RT. The reaction mixture was warmed to 30°C for 30 min and then partitioned between ⁇ 2 ⁇ and DCM. DCM extracts were washed with saturated brine, dried (Na2S0 4 ), filtered and evaporated.
• the compounds of the present invention may be incorporated in various formulations for delivery.
• topical formulations can be used and can include ophthalmically acceptable preservatives, surfactants, viscosity enhancers, buffers, sodium chloride, and water to form aqueous ophthalmically compatible solutions and suspensions.
• Systemic formulations for example, orally ingested tablets
• formulations for intraocular injection are also contemplated.
• Topical ophthalmically compatible aqueous solutions, suspensions, ointments, and gels are the preferred dosage forms for the treatment of ocular diseases in the front of the eye (the cornea, iris, trabecular meshwork); or ocular diseases of the back of the eye if the compound can be formulated such that it can be delivered topically and is able to penetrate the tissues in the front of the eye.
• a compound according to formula (I) will normally be contained in these formulations in an amount from about 0.01 to about 10.0 weight/percent.
• Preferable concentrations for topical administration range from about 0.1 to about 5.0 weight/percent.
• these formulations are delivered to the surface of the eye one to six times a day, depending on the routine discretion of the skilled clinician.
• Systemic administration for example, in the form of tablets is useful for the treatment of ocular disease particularly of the back of the eye, for example, the retina.
• the compounds of the present invention are preferably incorporated into ophthalmically compatible formulations for delivery to the eye.
• the compounds may be combined with ophthalmically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution.
• Ophthalmic solution formulations may be prepared by dissolving a compound in a physiologically acceptable isotonic aqueous buffer.
• the ophthalmic solution may include an ophthalmically acceptable surfactant to assist in dissolving the compound.
• the ophthalmic solution may contain an agent to increase viscosity 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.
• the active ingredient is combined with a preservative in an appropriate vehicle such as mineral oil, liquid lanolin, or white petrolatum.
• Sterile ophthalmic gel formulations may be prepared by suspending the compound in a hydrophilic base prepared from the combination of, for example, carbopol-974, or the like, according to the published formulations for analogous ophthalmic formulations; preservatives and tonicity agents can be incorporated.
• the pharmaceutical compositions may include one or more buffering agent(s) or pH adjusting agent(s) to provide improved pH control.
• a pharmaceutical composition of the invention has a pH between 5.0 and 8.0, between 5.0 and 7.0, between 6.0 and 8.0, or between 6.0 and 7.0.
• the pH of a pharmaceutical composition of the invention is about 6.3 to about 7.3.
• an aqueous pharmaceutical composition of the invention has an approximately neutral pH of about 6.8.
• contemplated excipients which may be utilized in the pharmaceutical compositions of the invention include, for example, antimicrobial agents, antioxidants, antistatic agents, lipids such as phospholipids or fatty acids, steroids such as cholesterol, protein excipients such as serum albumin (human serum albumin), recombinant human albumin, gelatin, casein, salt-forming counterions such sodium and the like.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
• the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein.
• solvates and hydrates are generally considered compositions.
• pharmaceutically acceptable carriers are sterile.
• the pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc.
• compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions).
• the pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.
• the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with one or more of: a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) absorbents, colorants, flavors and sweeteners. Tablets may be either film coated or enteric coated according to methods known in
• compositions of the invention may include an additional therapeutic agent in addition to compounds of the present invention.
• Further therapeutic agents may include, for instance, other compounds and antibodies useful for treating ocular diseases.
• Pharmaceutical compositions of the invention can be administered to a patient.
• the term "subject” or “patient” refers to human and non-human mammals, including but, not limited to, primates, rabbits, pigs, horses, dogs, cats, sheep, and cows.
• a subject or patient is a human.
• compositions for example, topical, intravitreal, oral, IV, intracameral, and other methods known to those of skill in the art.
• administration will typically be via a syringe.
• a delivery device e.g. a syringe
• a pharmaceutical composition of the invention e.g., pre-filled syringe.
• Patients will receive an effective amount of a compound according to formula (I) as the principal active ingredient.
• ocular inserts or films are used to deliver a compound of the present invention.
• a compound of formula (I) is formulated in a polymeric ocular insert comprising one or more mucoadhesive polymers that are biocompatible with the ocular surface and tear film of the eye.
• the thickness of the tear film may increase for at least 30 minutes post- insertion.
• the one or more mucoadhesive polymers may be selected from the group comprising: hyaluronic acid (in acid or salt form), hydroxypropylmethylcellulose (HPMC), methylcellulose, tamarind seed polysaccharide (TSP), guar, hydroxypropyl guar (HP guar), scleroglucan poloxamer, poly(galacturonic) acid, sodium alginate, pectin, xanthan gum, xyloglucan gum, chitosan, sodium carboxymethylcellulose, polyvinyl alcohol, polyvinyl pyrrolidine, carbomer, polyacrylic acid and combinations thereof.
• the one or more mucoadhesive polymers may be HP guar, hyaluronic acid, and sodium hyaluronate.
• the invention further provides a method for delivering a compound according to formula (I) to a patient, comprising a step of administering to the patient a pharmaceutical composition of the invention one or more times daily.

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