US20210253547A1 - Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds - Google Patents
Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds Download PDFInfo
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- US20210253547A1 US20210253547A1 US17/244,786 US202117244786A US2021253547A1 US 20210253547 A1 US20210253547 A1 US 20210253547A1 US 202117244786 A US202117244786 A US 202117244786A US 2021253547 A1 US2021253547 A1 US 2021253547A1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
-
- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Definitions
- the present invention relates to beta and gamma-amino isoquinoline amide compounds and substituted benzamide compounds that affect the function of kinases in a cell and that are useful as therapeutic agents or with therapeutic agents.
- these compounds are useful in the treatment of eye diseases such as glaucoma, for the treatment of cardiovascular diseases, and for diseases characterized by abnormal growth, such as cancers.
- G proteins guanine nucleotide-binding proteins
- GPCRs G-protein coupled receptors
- ⁇ -adrenergic receptors ⁇ -adrenergic receptors
- opioid receptors cannabinoid receptors
- prostaglandin receptors The biological effects of activating these receptors is not direct but is mediated by a host of intracellular proteins. The importance of these secondary proteins has only recently been recognized and investigated as intervention points in disease states. One of the most important classes of these downstream effectors is the “kinase” class.
- kinases thus play important roles in the regulation of various physiological functions.
- kinases have been implicated in a number of disease states, including, but not limited to: cardiac indications such as angina pectoris, essential hypertension, myocardial infarction, supraventricular and ventricular arrhythmias, congestive heart failure, atherosclerosis, renal failure, diabetes, respiratory indications such as asthma, chronic bronchitis, bronchospasm, emphysema, airway obstruction, upper respiratory indications such as rhinitis, seasonal allergies, inflammatory disease, inflammation in response to injury, rheumatoid arthritis.
- cardiac indications such as angina pectoris, essential hypertension, myocardial infarction, supraventricular and ventricular arrhythmias, congestive heart failure, atherosclerosis, renal failure, diabetes
- respiratory indications such as asthma, chronic bronchitis, bronchospasm, emphysema, airway obstruction
- upper respiratory indications such as
- Other conditions include chronic inflammatory bowel disease, glaucoma, hypergastrinemia, gastrointestinal indications such as acid/peptic disorder, erosive esophagitis, gastrointestinal hypersecretion, mastocytosis, gastrointestinal reflux, peptic ulcer, Zollinger-Ellison syndrome, pain, obesity, bulimia nervosa, depression, obsessive-compulsive disorder, organ malformations (e.g., cardiac malformations), neurodegenerative diseases such as Parkinson's Disease and Alzheimer's Disease, multiple sclerosis, Epstein-Barr infection and cancer (Nature Reviews Drug Discovery 2002, 1: 493-502). In other disease states, the role of kinases is only now becoming clear.
- the retina is a complex tissue composed of multiple interconnected cell layers, highly specialized for transforming light and color into electrical signals that are perceived by the brain. Damage or death of the primary light-sensing cells, the photoreceptors, results in devastating effects on vision.
- the cellular and molecular mechanisms leading from the primary mutations to photoreceptor apoptosis are not well understood, but may involve the wnt pathway (AS hackam “The Wnt Signaling Pathway in Retinal Degeneration” IUBMB Life Volume 57, Number 6/June 2005).
- tyrosine-kinase inhibitor STI571 (Gleevec) in the treatment of chronic myelogenous leukaemia (Nature Reviews Drug Discovery 2003, 2: 296-313) has spurred considerable efforts to develop other kinase inhibitors for the treatment of a wide range of other cancers (Nature Reviews Cancer 2003, 3: 650-665).
- the balance between the initiation and the inactivation of intracellular signals determines the intensity and duration of the response of the receptors to stimuli such as agonists.
- the mediation or regulation of the physiological function mediated or regulated by the G proteins to which the receptors are coupled is reduced or prevented.
- the receptors when agonists are administered to treat a disease or condition by activation of certain receptors, the receptors relatively quickly become desensitized from the action of the GRKs such that agonist administration may no longer result in therapeutic activation of the appropriate receptors. At that point, administration of the agonist no longer enables sufficient or effective control of or influence on the disease or condition intended to be treated.
- R 1 and R 2 are, independently, hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 carbonyl, C 1 -C 4 carbonylamino, C 1 -C 4 alkoxy, C 1 -C 4 sulfonyl, C 1 -C 4 sulfonylamino, C 1 -C 4 thioalkyl or C 1 -C 4 carboxyl; or R 1 and R 2 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms, or R 1 and R 3 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms; and wherein one of R 3 and R 4 is an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, C 1 -C 8 alkyl, C 2 -C 8
- R 1 and R 2 are, independently, hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 carbonyl, C 1 -C 4 carbonylamino, C 1 -C 4 alkoxy, C 1 -C 4 sulfonyl, C 1 -C 4 sulfonylamino, C 1 -C 4 thioalkyl or C 1 -C 4 carboxyl; or R 1 and R 2 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms; or R 1 and R 3 combine to form a heterocycloalkyl ring of at least 5 and at least 8 member atoms; and wherein one of R 3 , R 4 and R 5 is an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, C 1 -C 8 alkyl, C 2
- R 1 , R 2 and R 4 are, independently, hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 carbonyl, C 1 -C 4 carbonylamino, C 1 -C 4 alkoxy, C 1 -C 4 sulfonyl, C 1 -C 4 sulfonylamino, C 1 -C 4 thioalkyl or C 1 -C 4 carboxyl; or R 1 and R 2 combine to form an alkyl or heteroalkyl ring of at least 5 and at most 8 member atoms, or R 1 and R 3 combine to form an alkyl or heteroalkyl ring of at least 5 and at most 8 member atoms; and wherein one of the R 3 groups is an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, C 1 -C 8 alkyl, C 1
- composition comprising a compound according to Formula I, II, or III as described above, and a carrier.
- a method of treating a disease comprising administering to a subject in need of treatment effective amount of a compound according to Formula I, II, or III as described above, wherein the disease is selected from the group consisting of eye disease, bone disorder, obesity, heart disease, hepatic disease, renal disease, pancreatitis, cancer, myocardial infarct, gastric disturbance, hypertension, fertility control, disorders of hair growth, nasal congestion, neurogenic bladder disorder, gastrointestinal disorder, and dermatological disorder.
- a method of modulating kinase activity comprising contacting a cell with a compound according to the Formula I, II or III in an amount effective to modulate kinase activity
- Beta- and gamma-amino isoquinolines and benzamides are provided.
- Alkyl refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups. “Alkyl” may be exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl and the like. Alkyl groups may be substituted or unsubstituted. More than one substituent may be present. Substituents may also be themselves substituted. When substituted, the substituent group is preferably but not limited to C 1 -C 4 alkyl, aryl, heteroaryl, amino, imino, cyano, halogen, alkoxy or hydroxyl. “C 1 -C 4 alkyl” refers to alkyl groups containing one to four carbon atoms.
- Alkenyl refers to an unsaturated aliphatic hydrocarbon moiety including straight chain and branched chain groups. Alkenyl moieties must contain at least one alkene. “Alkenyl” may be exemplified by groups such as ethenyl, n-propenyl, isopropenyl, n-butenyl and the like. Alkenyl groups may be substituted or unsubstituted. More than one substituent may be present. When substituted, the substituent group is preferably alkyl, halogen or alkoxy. Substitutients may also be themselves substituted.
- C 2 -C 4 alkenyl refers to alkenyl groups containing two to four carbon atoms.
- Alkynyl refers to an unsaturated aliphatic hydrocarbon moiety including straight chain and branched chain groups. Alkynyl moieties must contain at least one alkyne. “Alkynyl” may be exemplified by groups such as ethynyl, propynyl, n-butynyl and the like. Alkynyl groups may be substituted or unsubstituted. More than one substituent may be present. When substituted, the substituent group is preferably alkyl, amino, cyano, halogen, alkoxyl or hydroxyl. Substituents may also be themselves substituted.
- C 2 -C 4 alkynyl refers to alkynyl groups containing two to four carbon atoms.
- Acyl or “carbonyl” refers to the group —C(O)R wherein R is alkyl; alkenyl; alkynyl, aryl, heteroaryl, carbocyclic, heterocarbocyclic; C 1 -C 4 alkyl aryl or C 1 -C 4 alkyl heteroaryl.
- C 1 -C 4 alkylcarbonyl refers to a group wherein the carbonyl moiety is preceded by an alkyl chain of 1-4 carbon atoms.
- Alkoxy refers to the group —O—R wherein R is acyl, alkyl alkenyl, alkyl alkynyl, aryl, carbocyclic; heterocarbocyclic; heteroaryl, C 1 -C 4 alkyl aryl or C 1 -C 4 alkyl heteroaryl.
- Amino refers to the group —NR′R′ wherein each R′ is, independently, hydrogen, amino, hydroxyl, alkoxyl, alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, C 1 -C 4 alkyl aryl or C 1 -C 4 alkyl heteroaryl.
- the two R′ groups may themselves be linked to form a ring.
- the R′ groups may themselves be further substituted, in which case the group also known as guanidinyl is specifically contemplated under the term ‘amino”.
- Aryl refers to an aromatic carbocyclic group. “Aryl” may be exemplified by phenyl. The aryl group may be substituted or unsubstituted. More than one substituent may be present. Substituents may also be themselves substituted. When substituted, the substituent group is preferably but not limited to heteroaryl; acyl, carboxyl, carbonylamino, nitro, amino, cyano, halogen, or hydroxyl.
- Carboxyl refers to the group —C( ⁇ O)O—C 1 -C 4 alkyl.
- Carbonyl refers to the group —C(O)R wherein each R is, independently, hydrogen, alkyl, aryl, cycloalkyl; heterocycloalkyl; heteroaryl, C 1 -C 4 alkyl aryl or C 1 -C 4 alkyl heteroaryl.
- Carbonylamino refers to the group —C(O)NR′R′ wherein each R′ is, independently, hydrogen, alkyl, aryl, cycloalkyl; heterocycloalkyl; heteroaryl, C 1 -C 4 alkyl aryl or C 1 -C 4 alkyl heteroaryl.
- the two R′ groups may themselves be linked to form a ring.
- C 1 -C 4 alkyl aryl refers to C 1 -C 4 alkyl groups having an aryl substituent such that the aryl substituent is bonded through an alkyl group.
- C 1 -C 4 alkyl aryl may be exemplified by benzyl.
- C 1 -C 4 alkyl heteroaryl refers to C 1 -C 4 alkyl groups having a heteroaryl substituent such that the heteroaryl substituent is bonded through an alkyl group.
- Carbocyclic group or “cycloalkyl” means a monovalent saturated or unsaturated hydrocarbon ring.
- Carbocyclic groups are monocyclic, or are fused, spiro, or bridged bicyclic ring systems.
- Monocyclic carbocyclic groups contain 3 to 10 carbon atoms, preferably 4 to 7 carbon atoms, and more preferably 5 to 6 carbon atoms in the ring.
- Bicyclic carbocyclic groups contain 8 to 12 carbon atoms, preferably 9 to 10 carbon atoms in the ring.
- Carbocyclic groups may be substituted or unsubstituted. More than one substituent may be present. Substituents may also be themselves substituted.
- Preferred carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and cycloheptyl. More preferred carbocyclic groups include cyclopropyl and cyclobutyl. The most preferred carbocyclic group is cyclopropyl. Carbocyclic groups are not aromatic.
- Halogen refers to fluoro, chloro, bromo or iodo moieties.
- the halogen is fluoro, chloro, or bromo.
- Heteroaryl or “heteroaromatic” refers to a monocyclic or bicyclic aromatic carbocyclic radical having one or more heteroatoms in the carbocyclic ring. Heteroaryl may be substituted or unsubstituted. More than one substituent may be present. When substituted, the substituents may themselves be substituted. Preferred but non limiting substituents are aryl, C 1 -C 4 alkylaryl, amino, halogen, hydroxy, cyano, nitro, carboxyl, carbonylamino, or C 1 -C 4 alkyl.
- Preferred heteroaromatic groups include tetrazoyl, triazolyl, thienyl, thiazolyl, purinyl, pyrimidyl, pyridyl, and furanyl. More preferred heteroaromatic groups include benzothiofuranyl; thienyl, furanyl, tetrazoyl, triazolyl, and pyridyl.
- Heteroatom means an atom other than carbon in the ring of a heterocyclic group or a heteroaromatic group or the chain of a heterogeneous group.
- heteroatoms are selected from the group consisting of nitrogen, sulfur, and oxygen atoms.
- Groups containing more than one heteroatom may contain different heteroatoms.
- Heterocarbocyclic group or “heterocycloalkyl” or “heterocyclic” means a monovalent saturated or unsaturated hydrocarbon ring containing at least one heteroatom.
- Heterocarbocyclic groups are monocyclic, or are fused, spiro, or bridged bicyclic ring systems.
- Monocyclic heterocarbocyclic groups contain 3 to 10 carbon atoms, preferably 4 to 7 carbon atoms, and more preferably 5 to 6 carbon atoms in the ring.
- Bicyclic heterocarbocyclic groups contain 8 to 12 carbon atoms, preferably 9 to 10 carbon atoms in the ring.
- Heterocarbocyclic groups may be substituted or unsubstituted.
- Preferred heterocarbocyclic groups include epoxy, tetrahydrofuranyl, azacyclopentyl, azacyclohexyl, piperidyl, and homopiperidyl. More preferred heterocarbocyclic groups include piperidyl, and homopiperidyl. The most preferred heterocarbocyclic group is piperidyl. Heterocarbocyclic groups are not aromatic.
- “Hydroxy” or “hydroxyl” means a chemical entity that consists of —OH. Alcohols contain hydroxy groups. Hydroxy groups may be free or protected. An alternative name for hydroxy is hydroxyl.
- Linker means a linear chain of n member atoms where n is an integer of from 1 to 4.
- Member atom means a carbon, nitrogen, oxygen or sulfur atom. Member atoms may be substituted up to their normal valence. If substitution is not specified the substituents required for valency are hydrogen.
- Rings means a collection of member atoms that are cyclic. Rings may be carbocyclic, aromatic, or heterocyclic or heteroaromatic, and may be substituted or unsubstituted, and may be saturated or unsaturated. More than one substituent may be present. Ring junctions with the main chain may be fused or spirocyclic. Rings may be monocyclic or bicyclic. Rings contain at least 3 member atoms and at most 10 member atoms. Monocyclic rings may contain 3 to 7 member atoms and bicyclic rings may contain from 8 to 12 member atoms. Bicyclic rings themselves may be fused or spirocyclic.
- Thioalkyl refers to the group —S— alkyl.
- “Sulfonyl” refers to the —S(O) 2 R′ group wherein R′ is alkoxy, alkyl, aryl, carbocyclic, heterocarbocyclic; heteroaryl, C 1 -C 4 alkyl aryl or C 1 -C 4 alkyl heteroaryl.
- “Sulfonylamino” refers to the —S(O) 2 NR′R′ group wherein each R′ is independently alkyl, aryl, heteroaryl, C 1 -C 4 alkyl aryl or C 1 -C 4 alkyl heteroaryl.
- “Pharmaceutically acceptable carrier” means a carrier that is useful for the preparation of a pharmaceutical composition that is: generally compatible with the other ingredients of the composition, not deleterious to the recipient, and neither biologically nor otherwise undesirable.
- “A pharmaceutically acceptable carrier” includes both one and more than one carrier. Embodiments include carriers for topical, ocular, parenteral, intravenous, intraperitoneal intramuscular, sublingual, nasal and oral administration. “Pharmaceutically acceptable carrier” also includes agents for preparation of aqueous dispersions and sterile powders for injection or dispersions.
- Excipient as used herein includes physiologically compatible additives useful in preparation of a pharmaceutical composition.
- Examples of pharmaceutically acceptable carriers and excipients can for example be found in Remington Pharmaceutical Science, 16 th Ed.
- “Therapeutically effective amount” as used herein refers to a dosage of the compounds or compositions effective for influencing, reducing or inhibiting the activity of or preventing activation of a kinase. This term as used herein may also refer to an amount effective at bringing about a desired in vivo effect in an animal, preferably, a human, such as reduction in intraocular pressure.
- administering refers to administration of the compounds as needed to achieve the desired effect.
- Eye disease as used herein includes, but is not limited to, glaucoma, allergy, cancers of the eye, neurodegenerative diseases of the eye, and dry eye.
- disease or condition associated with kinase activity is used to mean a disease or condition treatable, in whole or in part, by inhibition of one or more kinases.
- controlling the disease or condition is used to mean changing the activity of one or more kinases to affect the disease or condition.
- contacting a cell is used to mean contacting a cell in vitro or in vivo (i.e. in a subject, such as a mammal, including humans, rabbits, cats and dogs).
- the beta-amino isoquinoline amide compounds may be represented by Formula I:
- R 1 and R 2 are, independently, hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 carbonyl, C 1 -C 4 carbonylamino, C 1 -C 4 alkoxy, C 1 -C 4 sulfonyl, C 1 -C 4 sulfonylamino, C 1 -C 4 thioalkyl or C 1 -C 4 carboxyl; or R 1 and R 2 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms, or R 1 and R 3 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms; and wherein one of R 3 and R 4 is an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, C 1 -C 8 alkyl, C 2 -C 8
- R 1 and R 2 are methyl groups or hydrogens, R 4 is an aryl or heteroaryl group and R 3 and X 2 are hydrogen.
- R 1 is a cycloalkyl group, and R 2 is hydrogen and R 3 are methyl and X 1 is a hydroxyl group.
- the gamma-amino isoquinoline amide compounds may be represented by Formula II:
- R 1 and R 2 are, independently, hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 carbonyl, C 1 -C 4 carbonylamino, C 1 -C 4 alkoxy, C 1 -C 4 sulfonyl, C 1 -C 4 sulfonylamino, C 1 -C 4 thioalkyl or C 1 -C 4 carboxyl; or R 1 and R 2 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms; and wherein one of R 3 , R 4 and R 5 is an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, and the other two of R 3 , R 4
- R 1 and R 2 are methyl groups or hydrogens, R 4 is an aryl or heteroaryl group and R 3 and X 2 are hydrogen.
- R 1 is a cycloalkyl group, and R 2 is a hydrogen and R 3 are methyl and X 1 is a hydroxyl group.
- the benzamide compounds may be represented by Formula III:
- R 1 , R 2 and R 4 are, independently, hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 carbonyl, C 1 -C 4 carbonylamino, C 1 -C 4 alkoxy, C 1 -C 4 sulfonyl, C 1 -C 4 sulfonylamino, C 1 -C 4 thioalkyl or C 1 -C 4 carboxyl; or R 1 and R 2 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms, or R 1 and R 3 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms; and wherein one of the R 3 groups is an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, C 1 -C 8 alkyl, C 2
- R 1 and R 2 are methyl groups or hydrogens, R 3 is an aryl or heteroaryl group and R 4 and X 2 are hydrogen.
- R 1 is a cycloalkyl group, and R 2 is a hydrogen and R 3 are methyl and X 1 is a fluoride or a hydrogen.
- n is 1 to 3. Alternatively, n is 2.
- the beta or gamma-amino isoquinoline amide or substituted benzamide compounds may be synthesized by the general Schemes 1-7 set forth below:
- the selected acid (S1) is reduced with an appropriate agent such as borane then activated as the tosylate to form the desired intermediate (S2).
- the tosylate (S2) is reacted with the sodium cyanide in DMSO to generate the nitrile (S3) directly which is then hydrolyzed with sodium hydroxide to form the one-carbon longer amino acid (S4).
- alpha amino acids are transformed into beta amino acids and beta amino acids are turned into gamma, and gamma to delta in turn.
- the selected acid (S4) is activated with an appropriate agent such as EDC then coupled to a 6-aminoisoquinoline (S5) using standard coupling procedures to form the desired intermediate (S6).
- the amine (S6) is reacted with the HCl in methylene chloride to generate the amide (S7) directly.
- (S6) is subjected to reductive amination conditions to generate the N,N-disubstituted compounds of type (S8).
- Benzamidines are synthesized using the procedures outlined in Scheme 2, but substituting the para-amino benzamide of choice for the amino isoquinoline, as shown in Scheme 3.
- benzamide compounds may be synthesized by the general Schemes 6-7 set forth below:
- the appropriate acid is converted to its acid chloride with oxalyl chloride then reacted with ammonia gas or another amine to give the amide.
- the nitro group is reduced to the aniline with hydrogen or another reducing agent.
- the aniline is coupled with an appropriate acid using standard coupling procedures such as EDC and DMAP in pyridine.
- the aniline is coupled with an appropriate acid using standard coupling procedures such as EDC and DMAP in pyridine.
- the ester is then converted to the corresponding primary amide using formamide and NaOMe in DMF or to a substituted amide by heating with the appropriate amine in a solvent such as MeOH.
- Boc 2 O means di-tert-butyl-dicarbonate
- DMAP means dimethyl aminopyridine
- DMSO means dimethyl sulfoxide
- HATU means 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
- LDA means lithium diisopropyl amide
- DMF is dimethylformamide
- THF is tetrahydrofuran
- EDC means N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride.
- the compounds of the above Formulae and compositions including them have kinase inhibitory activity and are thus useful in modulating the action of kinases, and in treatment and/or prevention of diseases or conditions influenced by kinases.
- the above Formulae and compositions may be used to modulate (e.g., influence or inhibit) the action of kinases either in a cell in vitro or in a cell in a living body in vivo.
- a method is provided of inhibiting the action of a kinase comprising applying to a medium such as an assay medium or contacting with a cell either in a cell in vitro or in a cell in a living body in vivo an effective inhibitory amount of a compound according to Formulae I or II or III.
- the kinase inhibited is a rho kinase.
- Compounds according to Formulae I or II or III are used in methods of inhibiting kinases in a cell, a tissue or a subject such as a human comprising contacting the cell with an amount of one or more of the compounds of the present invention effective to inhibit the kinase.
- the compounds are administered in a pharmaceutically acceptable composition, such as in or with a pharmaceutically acceptable carrier.
- the compounds of the present invention are used in methods for modulating the action of a kinase in a cell comprising contacting the cell with amount of one or more compounds according to Formulae I or II or III effective to modulate the action of a kinase in a cell.
- the compounds of the present invention are administered in a pharmaceutically acceptable composition, such as in or with a pharmaceutically acceptable carrier.
- Treatment or prevention of diseases or conditions for which the compounds of the present invention may be useful includes any of the diseases or conditions associated with kinase activity or diseases or conditions affected by kinases. Examples of these types of diseases include retinal degradation, glaucoma, cardiovascular diseases and cancer.
- the compounds of the present invention will be administered in conjunction with one or more additional therapeutic agents.
- additional therapeutic agents include, but are not limited to, beta blockers, alpha-agonists, carbonic anhydrase inhibitors, prostaglandin-like compounds, miotic or cholinergic agents, or epinephrine compounds.
- Beta blockers These reduce the production of aqueous humor. Examples include levobunolol (Betagan), timolol (Betimol, Timoptic), betaxolol (Betoptic) and metipranolol (OptiPranolol).
- Alpha-agonists These reduce the production of aqueous humor and increase drainage.
- Examples include apraclonidine (Iopidine) and brimonidine (Alphagan).
- Carbonic anhydrase inhibitors These also reduce the production of aqueous humor.
- examples include dorzolamide (Trusopt) and brinzolamide (Azopt).
- Prostaglandin-like compounds These eyedrops increase the outflow of aqueous humor. Examples include latanoprost (Xalatan), bimatoprost (Lumigan) and travoprost (Travatan).
- Miotic or cholinergic agents These also increase the outflow of aqueous humor.
- examples include pilocarpine (Isopto Carpine, Pilopine) and carbachol (Isopto Carbachol).
- Epinephrine compounds such as dipivefrin (Propine), also increase the outflow of aqueous humor.
- the additional therapeutic agent or agents can be administered simultaneously or sequentially with the compounds of the present invention. Sequential administration includes administration before or after the compounds of the present invention. In some embodiments, the additional therapeutic agent or agents can be administered in the same composition as the compounds of the present invention. In other embodiments, there can be an interval of time between administration of the additional therapeutic agent and the compounds of the present invention.
- an additional therapeutic agent with a compound of the present invention will enable lower doses of the other therapeutic agents to be administered for a longer period of time.
- Compounds of the present invention may be obtained in the form of various salts or solvates.
- the salts physiologically acceptable salts or salts available as raw materials are used.
- compositions may include one or more of the isoforms of the compounds of the present invention.
- each enantiomer or diastereomer may be separately used, or they may be combined in any proportion.
- tautomers all possible tautomers are specifically contemplated.
- compositions for use in accordance with the present invention may be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients.
- the compounds and their physiologically acceptable salts and solvates may be formulated for administration by, for example, solid dosing, eyedrop, in a topical oil-based formulation, injection, inhalation (either through the mouth or the nose), implants, or oral, buccal, parenteral or rectal administration.
- Techniques and formulations may generally be found in “Remington's Pharmaceutical Sciences”, (Meade Publishing Co., Easton, Pa.).
- composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral) or topical administration (e.g., local application on the skin, ocular, liposome delivery systems, or iontophoresis).
- systemic administration e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral
- topical administration e.g., local application on the skin, ocular, liposome delivery systems, or iontophoresis.
- Carriers for systemic administration typically comprise at least one of a) diluents, b) lubricants, c) binders, d) disintegrants, e) colorants, f) flavors, g) sweeteners, h) antioxidants, j) preservatives, k) glidants, m) solvents, n) suspending agents, o) wetting agents, p) surfactants, combinations thereof, and others. All carriers are optional in the systemic compositions.
- Ingredient a) is a diluent.
- Suitable diluents for solid dosage forms include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitol; and sorbitol.
- the amount of ingredient a) in the systemic or topical composition is typically about 50 to about 90%.
- Ingredient b) is a lubricant.
- Suitable lubricants for solid dosage forms are exemplified by solid lubricants including silica, talc, stearic acid and its magnesium salts and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma .
- the amount of ingredient b) in the systemic or topical composition is typically about 5 to about 10%.
- Ingredient c) is a binder.
- Suitable binders for solid dosage forms include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose.
- the amount of ingredient c) in the systemic composition is typically about 5 to about 50%, and in ocular solid dosing forms up to 99%.
- Ingredient d) is a disintegrant.
- Suitable disintegrants for solid dosage forms include agar, alginic acid and the sodium salt thereof, effervescent mixtures, croscarmelose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins.
- the amount of ingredient d) in the systemic or topical composition is typically about 0.1 to about 10%.
- Ingredient e) for solid dosage forms is a colorant such as an FD&C dye.
- the amount of ingredient e) in the systemic or topical composition is typically about 0.005 to about 0.1%.
- Ingredient 0 for solid dosage forms is a flavor such as menthol, peppermint, and fruit flavors.
- the amount of ingredient 0, when used, in the systemic or topical composition is typically about 0.1 to about 1.0%.
- Ingredient g) for solid dosage forms is a sweetener such as aspartame and saccharin.
- the amount of ingredient g) in the systemic or topical composition is typically about 0.001 to about 1%.
- Ingredient h) is an antioxidant such as butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), and vitamin E.
- BHA butylated hydroxyanisole
- BHT butylated hydroxytoluene
- the amount of ingredient h) in the systemic or topical composition is typically about 0.1 to about 5%.
- Ingredient j) is a preservative such as benzalkonium chloride, methyl paraben and sodium benzoate.
- the amount of ingredient j) in the systemic or topical composition is typically about 0.01 to about 5%.
- Ingredient k) for solid dosage forms is a glidant such as silicon dioxide.
- the amount of ingredient k) in the systemic or topical composition is typically about 1 to about 5%.
- Ingredient m) is a solvent, such as water, isotonic saline, ethyl oleate, glycerine, hydroxylated castor oils, alcohols such as ethanol, and phosphate buffer solutions.
- the amount of ingredient m) in the systemic or topical composition is typically from about 0 to about 100%.
- Ingredient n) is a suspending agent.
- Suitable suspending agents include AVICEL® RC-591 (from FMC Corporation of Philadelphia, Pa.) and sodium alginate.
- the amount of ingredient n) in the systemic or topical composition is typically about 1 to about 8%.
- Ingredient o) is a surfactant such as lecithin, Polysorbate 80, and sodium lauryl sulfate, and the TWEENS® from Atlas Powder Company of Wilmington, Del.
- Suitable surfactants include those disclosed in the C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp. 587-592; Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239.
- the amount of ingredient o) in the systemic or topical composition is typically about 0.1% to about 5%.
- system compositions comprise 0.01% to 50% of component A and 50 to 99.99% of component B.
- compositions for parenteral administration typically comprise A) 0.1 to 10% of the compounds of the present invention and B) 90 to 99.9% of a carrier comprising a) a diluent and m) a solvent.
- component a) comprises propylene glycol and m) comprises ethanol or ethyl oleate.
- compositions for oral administration can have various dosage forms.
- solid forms include tablets, capsules, granules, and bulk powders.
- These oral dosage forms comprise a safe and effective amount, usually at least about 5%, and more particularly from about 25% to about 50% of component A).
- the oral dosage compositions further comprise about 50 to about 95% of component B), and more particularly, from about 50 to about 75%.
- Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed. Tablets typically comprise component A, and component B a carrier comprising ingredients selected from the group consisting of a) diluents, b) lubricants, c) binders, d) disintegrants, e) colorants, f) flavors, g) sweeteners, k) glidants, and combinations thereof.
- Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose and cellulose.
- Specific binders include starch, gelatin, and sucrose.
- Specific disintegrants include alginic acid and croscarmelose.
- Specific lubricants include magnesium stearate, stearic acid, and talc.
- Specific colorants are the FD&C dyes, which can be added for appearance.
- Chewable tablets preferably contain g) sweeteners such as aspartame and saccharin, or f) flavors such as menthol, peppermint, fruit flavors, or a combination thereof.
- Capsules typically comprise component A, and a carrier comprising one or more a) diluents disclosed above in a capsule comprising gelatin.
- Granules typically comprise component A, and preferably further comprise k) glidants such as silicon dioxide to improve flow characteristics.
- Implants can be of the biodegradable or the non-biodegradable type. Implants may be prepared using any known biocompatible formulation.
- ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this invention. One skilled in the art would know how to select appropriate ingredients without undue experimentation.
- the solid compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that component A is released in the gastrointestinal tract in the vicinity of the desired application, or at various points and times to extend the desired action.
- the coatings typically comprise one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT® coatings (available from Rohm & Haas G.M.B.H. of Darmstadt, Germany), waxes and shellac.
- compositions for oral administration can also have liquid forms.
- suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like.
- Liquid orally administered compositions typically comprise component A and component B, namely, a carrier comprising ingredients selected from the group consisting of a) diluents, e) colorants, f) flavors, g) sweeteners, j) preservatives, m) solvents, n) suspending agents, and o) surfactants.
- Peroral liquid compositions preferably comprise one or more ingredients selected from the group consisting of e) colorants, f) flavors, and g) sweeteners.
- compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms.
- Such compositions typically comprise one or more of soluble filler substances such as a) diluents including sucrose, sorbitol and mannitol; and c) binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose.
- Such compositions may further comprise b) lubricants, e) colorants, f) flavors, g) sweeteners, h) antioxidants, and k) glidants.
- the compounds of the present invention are topically administered.
- Topical compositions that can be applied locally to the eye may be in any form known in the art, non-limiting Examples of which include solids, gelable drops, sprays, ointments, or a sustained or non-sustained release unit placed in the conjunctival cul-du-sac of the eye or another appropriate location.
- Topical compositions that can be applied locally to the skin may be in any form including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like.
- Topical compositions comprise: component A, the compounds described above, and component B, a carrier.
- the carrier of the topical composition preferably aids penetration of the compounds into the eye.
- Component B may further comprise one or more optional components.
- an effective amount of a compound according to the present invention will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of treatment, the nature of concurrent therapy, the route of administration, the particular pharmaceutically-acceptable carrier utilized, and like factors within the knowledge and expertise of the attending physician.
- an effective amount of the compounds of the present invention for systemic administration is from about 0.01 to about 1000 ⁇ g/kg body weight, preferably from about 0.1 to about 100 ⁇ g/kg per body weight, most preferably form about 1 to about 50 ⁇ g/kg body weight per day.
- the transdermal dosages will be designed to attain similar serum or plasma levels, based upon techniques known to those skilled in the art of pharmacokinetics and transdermal formulations.
- Plasma levels for systemic administration are expected to be in the range of 0.01 to 100 ng/mL, more preferably from 0.05 to 50 ng/mL and most preferably from 0.1 to 10 ng/mL. While these dosages are based upon a daily administration rate, the compounds of the present invention may also be administered at other intervals, such as twice per day, twice weekly, once weekly, or once a month. One of ordinary skill in the art would be able to calculate suitable effective amounts for other intervals of administration.
- the compounds of the present invention are useful in a method of reducing or decreasing intraocular pressure.
- the compounds of the present invention may be administered to a subject in need of treatment in an amount effective to reduce intraocular pressure.
- these compounds are useful in the treatment of glaucoma.
- the preferred route of administration for treating glaucoma is topically.
- each component in the topical composition depends on various factors.
- the amount of component A added to the topical composition is dependent on the IC 50 of component A, typically expressed in nanomolar (nM) units. For example, if the IC 50 of the medicament is 1 nM, the amount of component A will be from about 0.001 to about 0.3%. If the IC 50 of the medicament is 10 nM, the amount of component A) will be from about 0.01 to about 1%. If the IC 50 of the medicament is 100 nM, the amount of component A will be from about 0.1 to about 10%. If the IC 50 of the medicament is 1000 nM, the amount of component A will be 1 to 100%, preferably 5% to 50%. If the amount of component A is outside the ranges specified above (i.e., lower), efficacy of the treatment may be reduced.
- One skilled in the art understands how to calculate and understand an IC 50 .
- the remainder of the composition, up to 100%, is component B.
- the amount of the carrier employed in conjunction with component A is sufficient to provide a practical quantity of composition for administration per unit dose of the medicament.
- Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).
- Component B may comprise a single ingredient or a combination of two or more ingredients.
- component B comprises a topical carrier.
- Suitable topical carriers comprise one or more ingredients selected from the group consisting of phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More particularly, carriers for skin applications include propylene glycol, dimethyl isosorbide, and water, and even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols and symmetrical alcohols.
- the carrier of the topical composition may further comprise one or more ingredients selected from the group consisting of q) emollients, r) propellants, s) solvents, t) humectants, u) thickeners, v) powders, w) fragrances, x) pigments, and y) preservatives.
- Ingredient q) is an emollient.
- the amount of ingredient q) in a skin-based topical composition is typically about 5 to about 95%.
- Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glyco
- Ingredient r) is a propellant.
- the amount of ingredient r) in the topical composition is typically about 0 to about 95%.
- Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof.
- Ingredient s) is a solvent.
- the amount of ingredient s) in the topical composition is typically about 0 to about 95%.
- Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof.
- Specific solvents include ethyl alcohol and homotopic alcohols.
- Ingredient t) is a humectant.
- the amount of ingredient t) in the topical composition is typically 0 to 95%.
- Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof.
- Specific humectants include glycerin.
- Ingredient u) is a thickener.
- the amount of ingredient u) in the topical composition is typically about 0 to about 95%.
- Ingredient v) is a powder.
- the amount of ingredient v) in the topical composition is typically 0 to 95%.
- Suitable powders include beta-cyclodextrins, hydroxypropyl cyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically-modified magnesium aluminum silicate, organically-modified Montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof.
- specific powders include beta-cyclodextrin, hydroxypropyl cyclodextrin, and sodium polyacrylate.
- sodium polyacrylate may be used.
- Ingredient w) is a fragrance.
- the amount of ingredient w) in the topical composition is typically about 0 to about 0.5%, particularly, about 0.001 to about 0.1%.
- a fragrance is not typically used.
- Ingredient x) is a pigment.
- Suitable pigments for skin applications include inorganic pigments, organic lake pigments, pearlescent pigments, and mixtures thereof.
- Inorganic pigments useful in this invention include those selected from the group consisting of rutile or anatase titanium dioxide, coded in the Color Index under the reference CI 77,891; black, yellow, red and brown iron oxides, coded under references CI 77,499, 77,492 and, 77,491; manganese violet (CI 77,742); ultramarine blue (CI 77,007); chromium oxide (CI 77,288); chromium hydrate (CI 77,289); and ferric blue (CI 77,510) and mixtures thereof.
- the organic pigments and lakes useful in this invention include those selected from the group consisting of D&C Red No. 19 (CI 45,170), D&C Red No. 9 (CI 15,585), D&C Red No. 21 (CI 45,380), D&C Orange No. 4 (CI 15,510), D&C Orange No. 5 (CI 45,370), D&C Red No. 27 (CI 45,410), D&C Red No. 13 (CI 15,630), D&C Red No. 7 (CI 15,850), D&C Red No. 6 (CI 15,850), D&C Yellow No. 5 (CI 19,140), D&C Red No. 36 (CI 12,085), D&C Orange No. 10 (CI 45,425), D&C Yellow No. 6 (CI 15,985), D&C Red No. 30 (CI 73,360), D&C Red No. 3 (CI 45,430), the dye or lakes based on Cochineal Carmine (CI 75,570) and mixtures thereof.
- D&C Red No. 19 CI 45,170
- the pearlescent pigments useful in this invention include those selected from the group consisting of the white pearlescent pigments such as mica coated with titanium oxide, bismuth oxychloride, colored pearlescent pigments such as titanium mica with iron oxides, titanium mica with ferric blue, chromium oxide and the like, titanium mica with an organic pigment of the above-mentioned type as well as those based on bismuth oxychloride and mixtures thereof.
- the amount of pigment in the topical composition is typically about 0 to about 10%. For ocular applications a pigment is generally not used.
- topical pharmaceutical compositions for ocular administration are prepared typically comprising component A and B (a carrier), such as purified water, and one or more ingredients selected from the group consisting of y) sugars or sugar alcohols such as dextrans, particularly mannitol and dextran 70, z) cellulose or a derivative thereof, aa) a salt, bb) disodium EDTA (Edetate disodium), and cc) a pH adjusting additive.
- a carrier such as purified water
- y sugars or sugar alcohols
- dextrans particularly mannitol and dextran 70, z
- cellulose or a derivative thereof aa salt
- bb) disodium EDTA (Edetate disodium) a pH adjusting additive
- Examples of z) cellulose derivatives suitable for use in the topical pharmaceutical composition for ocular administration include sodium carboxymethylcellulose, ethylcellulose, methylcellulose, and hydroxypropyl-methylcellulose, particularly, hydroxypropyl-methylcellulose.
- Examples of aa) salts suitable for use in the topical pharmaceutical composition for ocular administration include mono-, di- and trisodium phosphate, sodium chloride, potassium chloride, and combinations thereof.
- pH adjusting additives examples include HCl or NaOH in amounts sufficient to adjust the pH of the topical pharmaceutical composition for ocular administration to 5.0-7.5.
- Component A may be included in kits comprising component A, a systemic or topical composition described above, or both; and information, instructions, or both that use of the kit will provide treatment for cosmetic and medical conditions in mammals (particularly humans).
- the information and instructions may be in the form of words, pictures, or both, and the like.
- the kit may comprise the medicament, a composition, or both; and information, instructions, or both, regarding methods of application of medicament, or of composition, preferably with the benefit of treating or preventing cosmetic and medical conditions in mammals (e.g., humans).
- HPLC purification when appropriate, was performed by redissolving the compound in a small volume of DMSO and filtering through a 0.45 micron (nylon disc) syringe filter. The solution was then purified using, for example, a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C 8 column. A typical initial eluting mixture of 40-80% MeOH:H 2 O was selected as appropriate for the target compound. This initial gradient was maintained for 0.5 minutes then increased to 100% MeOH:0% H 2 O over 5 minutes. 100% MeOH was maintained for 2 more minutes before re-equilibration back to the initial starting gradient. A typical total run time was 8 minutes. The resulting fractions were analyzed, combined as appropriate, and then evaporated to provide purified material.
- Proton magnetic resonance CH NMR Proton magnetic resonance CH NMR spectra were recorded on either a Varian INOVA 600 MHz ( 1 H) NMR spectrometer, Varian INOVA 500 MHz ( 1 H) NMR spectrometer, Varian Mercury 300 MHz ( 1 H) NMR spectrometer, or a Varian Mercury 200 MHz ( 1 H) NMR spectrometer. All spectra were determined in the solvents indicated. Although chemical shifts are reported in ppm downfield of tetramethylsilane, they are referenced to the residual proton peak of the respective solvent peak for 1 H NMR. Interproton coupling constants are reported in Hertz (Hz).
- the settings for the MS probe were a cone voltage at 38 mV and a desolvation temperature at 250° C. Any variations in these methods are noted below.
- Example 45 Preparation of methyl 3-(1,3-dioxoisoindolin-2-yl)-2-(thiophen-3-yl)propanoate (E45).
- Example 48 Preparation of tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(thiophen-3-yl)propylcarbamate (E48).
- Topical pharmaceutical compositions for lowering intraocular pressure are prepared by conventional methods and formulated as follows:
- a compound according to this invention is used as the beta amino acid isoquinolyl amide.
- the composition When the composition is topically administered to the eyes once daily, the above composition decreases intraocular pressure in a subject suffering from glaucoma.
- Example 183 is repeated using 3-amino-N-(isoquinolin-6-yl)-3-(thiophen-3-yl)propanamide dihydrochloride (E6) according to this invention.
- E6 3-amino-N-(isoquinolin-6-yl)-3-(thiophen-3-yl)propanamide dihydrochloride
- Example 183 is repeated using a gamma amino acid isoquinolyl amide according to this invention. When administered as a drop twice per day, the above composition decreases intraocular pressure.
- Example 183 is repeated using a benzamide according to this invention.
- the above composition substantially decreases allergic symptoms and relieves dry eye syndrome.
- Example 183 is repeated using 3-(dimethylamino)-N-(isoquinolin-6-yl)-2-(thiophen-3-yl)propanamide dihydrochloride (E44) according to this invention.
- E44 3-(dimethylamino)-N-(isoquinolin-6-yl)-2-(thiophen-3-yl)propanamide dihydrochloride
- Example 183 is repeated using 3-amino-N-(5-chloroisoquinolin-6-yl)-2-(thiophen-3-yl)propanamide dihydrochloride according to this invention.
- the above composition decreases intraocular pressure and serves as a neuroprotective agent.
- Example 183 is repeated using 3-amino-N-(isoquinolin-6-yl)-2-(thiophen-3-yl)propanamide dihydrochloride (E49) according to this invention.
- E49 3-amino-N-(isoquinolin-6-yl)-2-(thiophen-3-yl)propanamide dihydrochloride
- Example 183 is repeated using 4-(2-(dimethylamino)-2-(thiophen-3-yl) acetamido)benzamide (E115) according to this invention.
- the above composition decreases ocular pressure, allergic symptoms and relieves dry eye syndrome.
- the anterior section of porcine eyes was harvested within 4 hours post-mortem.
- the iris and ciliary body were removed and trabecular meshwork cells were harvested by blunt dissection.
- Finely minced trabecular meshwork tissue was plated into collagen-coated 6-well plates in Medium-199 containing 20% fetal bovine serum (FBS). After two passages at confluence, cells were transferred to low-glucose DMEM containing 10% FBS. Cells were used between passage 3 and passage 8.
- FBS fetal bovine serum
- Cells were plated into fibronectin-coated, glass multiwell plates the day before compound testing under standard culture conditions. Compounds were added to cells in the presence of 1% FBS-containing DMEM and 1% DMSO. When compounds were incubated with the cells for the duration determined to be optimal, the media and compound is removed and cells fixed for 20 minutes in 3% methanol-free paraformaldehyde. Cells were rinsed twice with phosphate buffered saline (PBS) and cells are permeabilized with 0.5% Triton X-100 for two minutes. Following an additional two washes with PBS, F-actin was stained with Alexa-fluor 488-labelled phalloidin and nuclei are stained with DAPI.
- PBS phosphate buffered saline
- Y-27632 is a rho-kinase inhibitor known to result in the depolymerization of F-actin in these cells.
- Pharmacological activity for glaucoma can be demonstrated using assays designed to test the ability of the subject compounds to decrease intraocular pressure. Examples of such assays are described in the following reference, incorporated herein by reference: C. Liljebris, G. Selen, B. Resul, J. Sternschantz, and U.hacksell, “Derivatives of 17-phenyl-18,19,20-trinorprostaglandin F 2 ⁇ , Isopropyl Ester: Potential Anti-glaucoma Agents”, Journal of Medicinal Chemistry 1995, 38 (2): 289-304.
Abstract
Description
- This application is a continuation of U.S. patent application Ser. No. 16/730,085, filed Dec. 30, 2019, which is a continuation of U.S. patent application Ser. No. 16/712,186, filed Dec. 12, 2019, now U.S. Pat. No. 10,882,840, issued Jan. 5, 2021, which is a continuation of U.S. patent application Ser. No. 16/138,837, filed Sep. 21, 2018, now U.S. Pat. No. 10,532,993, issued Jan. 14, 2020, which is a continuation of U.S. patent application Ser. No. 15/844,399, filed Dec. 15, 2017, now U.S. Pat. No. 10,112,920, issued Oct. 30, 2018, which is a continuation of U.S. patent application Ser. No. 15/341,545, filed Nov. 2, 2016, now U.S. Pat. No. 9,884,840, issued Feb. 6, 2018, which is a continuation of U.S. patent application Ser. No. 14/790,376, filed Jul. 2, 2015, now U.S. Pat. No. 9,512,101, issued Dec. 6, 2016, which is a continuation of U.S. patent application Ser. No. 14/273,895, filed May 9, 2014, now U.S. patent application No. 9,096,569, issued Aug. 4, 2015, which is a continuation of U.S. patent application Ser. No. 13/442,263, filed Apr. 9, 2012, now U.S. patent application No. 8,759,388, issued Jun. 24, 2014, which is a divisional of U.S. patent application Ser. No. 12/180,259, filed Jul. 25, 2008, now U.S. Pat. No. 8,450,344, issued May 28, 2013, each of which are incorporated herein by reference in their entireties.
- The present invention relates to beta and gamma-amino isoquinoline amide compounds and substituted benzamide compounds that affect the function of kinases in a cell and that are useful as therapeutic agents or with therapeutic agents. In particular, these compounds are useful in the treatment of eye diseases such as glaucoma, for the treatment of cardiovascular diseases, and for diseases characterized by abnormal growth, such as cancers.
- A variety of hormones, neurotransmitters and biologically active substances control, regulate or adjust the functions of living bodies via specific receptors located in cell membranes. Many of these receptors mediate the transmission of intracellular signals by activating guanine nucleotide-binding proteins (G proteins) to which the receptor is coupled. Such receptors are generically referred to as G-protein coupled receptors (GPCRs) and include, among others, α-adrenergic receptors, β-adrenergic receptors, opioid receptors, cannabinoid receptors and prostaglandin receptors. The biological effects of activating these receptors is not direct but is mediated by a host of intracellular proteins. The importance of these secondary proteins has only recently been recognized and investigated as intervention points in disease states. One of the most important classes of these downstream effectors is the “kinase” class.
- The various kinases thus play important roles in the regulation of various physiological functions. For example, kinases have been implicated in a number of disease states, including, but not limited to: cardiac indications such as angina pectoris, essential hypertension, myocardial infarction, supraventricular and ventricular arrhythmias, congestive heart failure, atherosclerosis, renal failure, diabetes, respiratory indications such as asthma, chronic bronchitis, bronchospasm, emphysema, airway obstruction, upper respiratory indications such as rhinitis, seasonal allergies, inflammatory disease, inflammation in response to injury, rheumatoid arthritis. The importance of p38 MAPK inhibitors in particular as new drugs for rheumatoid arthritis is reflected by the large number of compounds that has been developed over the last years Westra and P.C. Limburg Mini-Reviews in Medicinal Chemistry Volume 6, Number 8, August 2006). Other conditions include chronic inflammatory bowel disease, glaucoma, hypergastrinemia, gastrointestinal indications such as acid/peptic disorder, erosive esophagitis, gastrointestinal hypersecretion, mastocytosis, gastrointestinal reflux, peptic ulcer, Zollinger-Ellison syndrome, pain, obesity, bulimia nervosa, depression, obsessive-compulsive disorder, organ malformations (e.g., cardiac malformations), neurodegenerative diseases such as Parkinson's Disease and Alzheimer's Disease, multiple sclerosis, Epstein-Barr infection and cancer (Nature Reviews Drug Discovery 2002, 1: 493-502). In other disease states, the role of kinases is only now becoming clear. The retina is a complex tissue composed of multiple interconnected cell layers, highly specialized for transforming light and color into electrical signals that are perceived by the brain. Damage or death of the primary light-sensing cells, the photoreceptors, results in devastating effects on vision. Despite the identification of numerous mutations that cause inherited retinal degenerations, the cellular and molecular mechanisms leading from the primary mutations to photoreceptor apoptosis are not well understood, but may involve the wnt pathway (AS Hackam “The Wnt Signaling Pathway in Retinal Degeneration” IUBMB Life Volume 57, Number 6/June 2005).
- The success of the tyrosine-kinase inhibitor STI571 (Gleevec) in the treatment of chronic myelogenous leukaemia (Nature Reviews Drug Discovery 2003, 2: 296-313) has spurred considerable efforts to develop other kinase inhibitors for the treatment of a wide range of other cancers (Nature Reviews Cancer 2003, 3: 650-665). The balance between the initiation and the inactivation of intracellular signals determines the intensity and duration of the response of the receptors to stimuli such as agonists. When desensitization occurs, the mediation or regulation of the physiological function mediated or regulated by the G proteins to which the receptors are coupled is reduced or prevented. For example, when agonists are administered to treat a disease or condition by activation of certain receptors, the receptors relatively quickly become desensitized from the action of the GRKs such that agonist administration may no longer result in therapeutic activation of the appropriate receptors. At that point, administration of the agonist no longer enables sufficient or effective control of or influence on the disease or condition intended to be treated.
- In view of the role that kinases have in many disease states, there is an urgent and continuing need for small molecule ligands which inhibit or modulate the activity of kinases. Without wishing to be bound by theory, it is thought that modulation of the activity of kinases by the compounds of the present invention is responsible for their beneficial effects.
- In a first aspect of the invention, a compound is provided according to Formula I:
- wherein R1 and R2 are, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl or C1-C4 carboxyl; or R1 and R2 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms, or R1 and R3 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms; and
wherein one of R3 and R4 is an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and the other of R3 and R4 is hydrogen or C1-C4 alkyl, the stereocenters being either ‘R’ or ‘S’ in configuration independently; and
wherein X1 and X2 are, independently, hydrogen, hydroxyl, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, nitro, cyano, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl or C1-C4 carboxyl. - In a second aspect of the invention, a compound is provided according to Formula II:
- wherein R1 and R2 are, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl or C1-C4 carboxyl; or R1 and R2 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms; or R1 and R3 combine to form a heterocycloalkyl ring of at least 5 and at least 8 member atoms; and
wherein one of R3, R4 and R5 is an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and the other two of R3, R4 and R5 are, independently, hydrogen or C1-C4 alkyl, the stereocenters being either ‘R’ or ‘S’ in configuration independently; and
wherein X1 and X2 are, independently, hydrogen, hydroxyl, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, nitro, cyano, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl or C1-C4 carboxyl. - In a third aspect of the invention, a compound is provided according to Formula III:
- wherein R1, R2 and R4 are, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl or C1-C4 carboxyl; or R1 and R2 combine to form an alkyl or heteroalkyl ring of at least 5 and at most 8 member atoms, or R1 and R3 combine to form an alkyl or heteroalkyl ring of at least 5 and at most 8 member atoms; and
wherein one of the R3 groups is an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and the other R3 groups are, independently, hydrogen or C1-C4 alkyl, the stereocenters being either ‘R’ or ‘S’ in configuration independently; and
wherein n is 1 to 4; and
wherein, X1 and X2 are, independently, hydrogen, hydroxyl, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, nitro, cyano, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl or C1-C4 carboxyl. - In another aspect of the invention, a composition is provided, comprising a compound according to Formula I, II, or III as described above, and a carrier.
- In yet a further aspect of the invention, a method of treating a disease is provided, comprising administering to a subject in need of treatment effective amount of a compound according to Formula I, II, or III as described above, wherein the disease is selected from the group consisting of eye disease, bone disorder, obesity, heart disease, hepatic disease, renal disease, pancreatitis, cancer, myocardial infarct, gastric disturbance, hypertension, fertility control, disorders of hair growth, nasal congestion, neurogenic bladder disorder, gastrointestinal disorder, and dermatological disorder.
- In another aspect of the invention, a method of modulating kinase activity is provided, comprising contacting a cell with a compound according to the Formula I, II or III in an amount effective to modulate kinase activity
- Publications and patents are referred to throughout this disclosure. All U.S. Patents cited herein are hereby incorporated by reference. All percentages, ratios, and proportions used herein are percent by weight unless otherwise specified.
- Beta- and gamma-amino isoquinolines and benzamides are provided.
- “Alkyl” refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups. “Alkyl” may be exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl and the like. Alkyl groups may be substituted or unsubstituted. More than one substituent may be present. Substituents may also be themselves substituted. When substituted, the substituent group is preferably but not limited to C1-C4 alkyl, aryl, heteroaryl, amino, imino, cyano, halogen, alkoxy or hydroxyl. “C1-C4 alkyl” refers to alkyl groups containing one to four carbon atoms.
- “Alkenyl” refers to an unsaturated aliphatic hydrocarbon moiety including straight chain and branched chain groups. Alkenyl moieties must contain at least one alkene. “Alkenyl” may be exemplified by groups such as ethenyl, n-propenyl, isopropenyl, n-butenyl and the like. Alkenyl groups may be substituted or unsubstituted. More than one substituent may be present. When substituted, the substituent group is preferably alkyl, halogen or alkoxy. Substitutients may also be themselves substituted. Substituents can be placed on the alkene itself and also on the adjacent member atoms or the alkynyl moiety. “C2-C4 alkenyl” refers to alkenyl groups containing two to four carbon atoms.
- “Alkynyl” refers to an unsaturated aliphatic hydrocarbon moiety including straight chain and branched chain groups. Alkynyl moieties must contain at least one alkyne. “Alkynyl” may be exemplified by groups such as ethynyl, propynyl, n-butynyl and the like. Alkynyl groups may be substituted or unsubstituted. More than one substituent may be present. When substituted, the substituent group is preferably alkyl, amino, cyano, halogen, alkoxyl or hydroxyl. Substituents may also be themselves substituted. Substituents are not on the alkyne itself but on the adjacent member atoms of the alkynyl moiety. “C2-C4 alkynyl” refers to alkynyl groups containing two to four carbon atoms.
- “Acyl” or “carbonyl” refers to the group —C(O)R wherein R is alkyl; alkenyl; alkynyl, aryl, heteroaryl, carbocyclic, heterocarbocyclic; C1-C4 alkyl aryl or C1-C4 alkyl heteroaryl. C1-C4 alkylcarbonyl refers to a group wherein the carbonyl moiety is preceded by an alkyl chain of 1-4 carbon atoms.
- “Alkoxy” refers to the group —O—R wherein R is acyl, alkyl alkenyl, alkyl alkynyl, aryl, carbocyclic; heterocarbocyclic; heteroaryl, C1-C4 alkyl aryl or C1-C4 alkyl heteroaryl.
- “Amino” refers to the group —NR′R′ wherein each R′ is, independently, hydrogen, amino, hydroxyl, alkoxyl, alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, C1-C4 alkyl aryl or C1-C4 alkyl heteroaryl. The two R′ groups may themselves be linked to form a ring. The R′ groups may themselves be further substituted, in which case the group also known as guanidinyl is specifically contemplated under the term ‘amino”.
- “Aryl” refers to an aromatic carbocyclic group. “Aryl” may be exemplified by phenyl. The aryl group may be substituted or unsubstituted. More than one substituent may be present. Substituents may also be themselves substituted. When substituted, the substituent group is preferably but not limited to heteroaryl; acyl, carboxyl, carbonylamino, nitro, amino, cyano, halogen, or hydroxyl.
- “Carboxyl” refers to the group —C(═O)O—C1-C4 alkyl.
- “Carbonyl” refers to the group —C(O)R wherein each R is, independently, hydrogen, alkyl, aryl, cycloalkyl; heterocycloalkyl; heteroaryl, C1-C4 alkyl aryl or C1-C4 alkyl heteroaryl.
- “Carbonylamino” refers to the group —C(O)NR′R′ wherein each R′ is, independently, hydrogen, alkyl, aryl, cycloalkyl; heterocycloalkyl; heteroaryl, C1-C4 alkyl aryl or C1-C4 alkyl heteroaryl. The two R′ groups may themselves be linked to form a ring.
- “C1-C4 alkyl aryl” refers to C1-C4 alkyl groups having an aryl substituent such that the aryl substituent is bonded through an alkyl group. “C1-C4 alkyl aryl” may be exemplified by benzyl.
- “C1-C4 alkyl heteroaryl” refers to C1-C4 alkyl groups having a heteroaryl substituent such that the heteroaryl substituent is bonded through an alkyl group.
- “Carbocyclic group” or “cycloalkyl” means a monovalent saturated or unsaturated hydrocarbon ring. Carbocyclic groups are monocyclic, or are fused, spiro, or bridged bicyclic ring systems. Monocyclic carbocyclic groups contain 3 to 10 carbon atoms, preferably 4 to 7 carbon atoms, and more preferably 5 to 6 carbon atoms in the ring. Bicyclic carbocyclic groups contain 8 to 12 carbon atoms, preferably 9 to 10 carbon atoms in the ring. Carbocyclic groups may be substituted or unsubstituted. More than one substituent may be present. Substituents may also be themselves substituted. Preferred carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and cycloheptyl. More preferred carbocyclic groups include cyclopropyl and cyclobutyl. The most preferred carbocyclic group is cyclopropyl. Carbocyclic groups are not aromatic.
- “Halogen” refers to fluoro, chloro, bromo or iodo moieties. Preferably, the halogen is fluoro, chloro, or bromo.
- “Heteroaryl” or “heteroaromatic” refers to a monocyclic or bicyclic aromatic carbocyclic radical having one or more heteroatoms in the carbocyclic ring. Heteroaryl may be substituted or unsubstituted. More than one substituent may be present. When substituted, the substituents may themselves be substituted. Preferred but non limiting substituents are aryl, C1-C4 alkylaryl, amino, halogen, hydroxy, cyano, nitro, carboxyl, carbonylamino, or C1-C4 alkyl. Preferred heteroaromatic groups include tetrazoyl, triazolyl, thienyl, thiazolyl, purinyl, pyrimidyl, pyridyl, and furanyl. More preferred heteroaromatic groups include benzothiofuranyl; thienyl, furanyl, tetrazoyl, triazolyl, and pyridyl.
- “Heteroatom” means an atom other than carbon in the ring of a heterocyclic group or a heteroaromatic group or the chain of a heterogeneous group. Preferably, heteroatoms are selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Groups containing more than one heteroatom may contain different heteroatoms.
- “Heterocarbocyclic group” or “heterocycloalkyl” or “heterocyclic” means a monovalent saturated or unsaturated hydrocarbon ring containing at least one heteroatom. Heterocarbocyclic groups are monocyclic, or are fused, spiro, or bridged bicyclic ring systems. Monocyclic heterocarbocyclic groups contain 3 to 10 carbon atoms, preferably 4 to 7 carbon atoms, and more preferably 5 to 6 carbon atoms in the ring. Bicyclic heterocarbocyclic groups contain 8 to 12 carbon atoms, preferably 9 to 10 carbon atoms in the ring. Heterocarbocyclic groups may be substituted or unsubstituted. More than one substituent may be present. Substituents may also be themselves substituted. Preferred heterocarbocyclic groups include epoxy, tetrahydrofuranyl, azacyclopentyl, azacyclohexyl, piperidyl, and homopiperidyl. More preferred heterocarbocyclic groups include piperidyl, and homopiperidyl. The most preferred heterocarbocyclic group is piperidyl. Heterocarbocyclic groups are not aromatic.
- “Hydroxy” or “hydroxyl” means a chemical entity that consists of —OH. Alcohols contain hydroxy groups. Hydroxy groups may be free or protected. An alternative name for hydroxy is hydroxyl.
- “Linker” means a linear chain of n member atoms where n is an integer of from 1 to 4.
- “Member atom” means a carbon, nitrogen, oxygen or sulfur atom. Member atoms may be substituted up to their normal valence. If substitution is not specified the substituents required for valency are hydrogen.
- “Ring” means a collection of member atoms that are cyclic. Rings may be carbocyclic, aromatic, or heterocyclic or heteroaromatic, and may be substituted or unsubstituted, and may be saturated or unsaturated. More than one substituent may be present. Ring junctions with the main chain may be fused or spirocyclic. Rings may be monocyclic or bicyclic. Rings contain at least 3 member atoms and at most 10 member atoms. Monocyclic rings may contain 3 to 7 member atoms and bicyclic rings may contain from 8 to 12 member atoms. Bicyclic rings themselves may be fused or spirocyclic.
- “Thioalkyl” refers to the group —S— alkyl.
- “Sulfonyl” refers to the —S(O)2R′ group wherein R′ is alkoxy, alkyl, aryl, carbocyclic, heterocarbocyclic; heteroaryl, C1-C4 alkyl aryl or C1-C4 alkyl heteroaryl.
- “Sulfonylamino” refers to the —S(O)2NR′R′ group wherein each R′ is independently alkyl, aryl, heteroaryl, C1-C4 alkyl aryl or C1-C4 alkyl heteroaryl.
- “Pharmaceutically acceptable carrier” means a carrier that is useful for the preparation of a pharmaceutical composition that is: generally compatible with the other ingredients of the composition, not deleterious to the recipient, and neither biologically nor otherwise undesirable. “A pharmaceutically acceptable carrier” includes both one and more than one carrier. Embodiments include carriers for topical, ocular, parenteral, intravenous, intraperitoneal intramuscular, sublingual, nasal and oral administration. “Pharmaceutically acceptable carrier” also includes agents for preparation of aqueous dispersions and sterile powders for injection or dispersions.
- “Excipient” as used herein includes physiologically compatible additives useful in preparation of a pharmaceutical composition. Examples of pharmaceutically acceptable carriers and excipients can for example be found in Remington Pharmaceutical Science, 16th Ed.
- “Therapeutically effective amount” as used herein refers to a dosage of the compounds or compositions effective for influencing, reducing or inhibiting the activity of or preventing activation of a kinase. This term as used herein may also refer to an amount effective at bringing about a desired in vivo effect in an animal, preferably, a human, such as reduction in intraocular pressure.
- “Administering” as used herein refers to administration of the compounds as needed to achieve the desired effect.
- “Eye disease” as used herein includes, but is not limited to, glaucoma, allergy, cancers of the eye, neurodegenerative diseases of the eye, and dry eye.
- The term “disease or condition associated with kinase activity” is used to mean a disease or condition treatable, in whole or in part, by inhibition of one or more kinases.
- The term “controlling the disease or condition” is used to mean changing the activity of one or more kinases to affect the disease or condition.
- The term “contacting a cell” is used to mean contacting a cell in vitro or in vivo (i.e. in a subject, such as a mammal, including humans, rabbits, cats and dogs).
- The beta-amino isoquinoline amide compounds may be represented by Formula I:
- wherein R1 and R2 are, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl or C1-C4 carboxyl; or R1 and R2 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms, or R1 and R3 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms; and
wherein one of R3 and R4 is an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and the other of R3 and R4 is hydrogen or C1-C4 alkyl, the stereocenters being either ‘R’ or ‘S’ in configuration independently,
wherein X1 and X2 are, independently, hydrogen, hydroxyl, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, nitro, cyano, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl or C1-C4 carboxyl. - In a preferred embodiment of Formula I, R1 and R2 are methyl groups or hydrogens, R4 is an aryl or heteroaryl group and R3 and X2 are hydrogen. In another preferred embodiment of Formula I, R1 is a cycloalkyl group, and R2 is hydrogen and R3 are methyl and X1 is a hydroxyl group.
- The gamma-amino isoquinoline amide compounds may be represented by Formula II:
- wherein R1 and R2 are, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl or C1-C4 carboxyl; or R1 and R2 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms; and
wherein one of R3, R4 and R5 is an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and the other two of R3, R4 and R5 are, independently, hydrogen or C1-C4 alkyl, the stereocenters being either ‘R’ or ‘S’ in configuration independently; and
wherein X1 and X2 are, independently, hydrogen, hydroxyl, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, nitro, cyano, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl or C1-C4 carboxyl. - In a preferred embodiment of Formula II, R1 and R2 are methyl groups or hydrogens, R4 is an aryl or heteroaryl group and R3 and X2 are hydrogen. In another preferred embodiment of Formula II, R1 is a cycloalkyl group, and R2 is a hydrogen and R3 are methyl and X1 is a hydroxyl group.
- The benzamide compounds may be represented by Formula III:
- wherein R1, R2 and R4 are, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl or C1-C4 carboxyl; or R1 and R2 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms, or R1 and R3 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms; and
wherein one of the R3 groups is an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and the other R3 groups are, independently, hydrogen or C1-C4 alkyl, the stereocenters being either ‘R’ or ‘S’ in configuration independently; and
wherein n is 1 to 4; and
wherein X1 and X2 are, independently, hydrogen, hydroxyl, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, nitro, cyano, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl or C1-C4 carboxyl. - In a preferred embodiment of Formula III, R1 and R2 are methyl groups or hydrogens, R3 is an aryl or heteroaryl group and R4 and X2 are hydrogen. In another preferred embodiment of Formula III, R1 is a cycloalkyl group, and R2 is a hydrogen and R3 are methyl and X1 is a fluoride or a hydrogen.
- In one embodiment of Formula III, n is 1 to 3. Alternatively, n is 2.
- The beta or gamma-amino isoquinoline amide or substituted benzamide compounds may be synthesized by the general Schemes 1-7 set forth below:
- According to Scheme 1, the selected acid (S1) is reduced with an appropriate agent such as borane then activated as the tosylate to form the desired intermediate (S2). The tosylate (S2) is reacted with the sodium cyanide in DMSO to generate the nitrile (S3) directly which is then hydrolyzed with sodium hydroxide to form the one-carbon longer amino acid (S4). Following this scheme, alpha amino acids are transformed into beta amino acids and beta amino acids are turned into gamma, and gamma to delta in turn.
- According to Scheme 2, the selected acid (S4) is activated with an appropriate agent such as EDC then coupled to a 6-aminoisoquinoline (S5) using standard coupling procedures to form the desired intermediate (S6). The amine (S6) is reacted with the HCl in methylene chloride to generate the amide (S7) directly. When an alkyl group is desired to be added, (S6) is subjected to reductive amination conditions to generate the N,N-disubstituted compounds of type (S8).
- Benzamidines are synthesized using the procedures outlined in Scheme 2, but substituting the para-amino benzamide of choice for the amino isoquinoline, as shown in Scheme 3.
- The benzamide compounds may be synthesized by the general Schemes 6-7 set forth below:
- According to Scheme 6, the appropriate acid is converted to its acid chloride with oxalyl chloride then reacted with ammonia gas or another amine to give the amide. The nitro group is reduced to the aniline with hydrogen or another reducing agent. The aniline is coupled with an appropriate acid using standard coupling procedures such as EDC and DMAP in pyridine.
- An alternative synthetic route is outlined in Scheme 7:
- According to Scheme 7, the aniline is coupled with an appropriate acid using standard coupling procedures such as EDC and DMAP in pyridine. The ester is then converted to the corresponding primary amide using formamide and NaOMe in DMF or to a substituted amide by heating with the appropriate amine in a solvent such as MeOH.
- The abbreviations used in the synthetic schemes shown have the following meanings: Boc2O means di-tert-butyl-dicarbonate, DMAP means dimethyl aminopyridine, DMSO means dimethyl sulfoxide, HATU means 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, LDA means lithium diisopropyl amide, DMF is dimethylformamide, THF is tetrahydrofuran, and EDC means N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride.
- The compounds of the above Formulae and compositions including them have kinase inhibitory activity and are thus useful in modulating the action of kinases, and in treatment and/or prevention of diseases or conditions influenced by kinases. The above Formulae and compositions may be used to modulate (e.g., influence or inhibit) the action of kinases either in a cell in vitro or in a cell in a living body in vivo. Specifically, in one embodiment, a method is provided of inhibiting the action of a kinase comprising applying to a medium such as an assay medium or contacting with a cell either in a cell in vitro or in a cell in a living body in vivo an effective inhibitory amount of a compound according to Formulae I or II or III. In a preferred embodiment, the kinase inhibited is a rho kinase.
- Compounds according to Formulae I or II or III are used in methods of inhibiting kinases in a cell, a tissue or a subject such as a human comprising contacting the cell with an amount of one or more of the compounds of the present invention effective to inhibit the kinase. In one embodiment, the compounds are administered in a pharmaceutically acceptable composition, such as in or with a pharmaceutically acceptable carrier.
- In another embodiment, the compounds of the present invention are used in methods for modulating the action of a kinase in a cell comprising contacting the cell with amount of one or more compounds according to Formulae I or II or III effective to modulate the action of a kinase in a cell. In one embodiment, the compounds of the present invention are administered in a pharmaceutically acceptable composition, such as in or with a pharmaceutically acceptable carrier.
- Treatment or prevention of diseases or conditions for which the compounds of the present invention may be useful includes any of the diseases or conditions associated with kinase activity or diseases or conditions affected by kinases. Examples of these types of diseases include retinal degradation, glaucoma, cardiovascular diseases and cancer.
- In some embodiments, the compounds of the present invention will be administered in conjunction with one or more additional therapeutic agents. Suitable additional therapeutic agents include, but are not limited to, beta blockers, alpha-agonists, carbonic anhydrase inhibitors, prostaglandin-like compounds, miotic or cholinergic agents, or epinephrine compounds.
- Beta blockers. These reduce the production of aqueous humor. Examples include levobunolol (Betagan), timolol (Betimol, Timoptic), betaxolol (Betoptic) and metipranolol (OptiPranolol).
- Alpha-agonists. These reduce the production of aqueous humor and increase drainage. Examples include apraclonidine (Iopidine) and brimonidine (Alphagan).
- Carbonic anhydrase inhibitors. These also reduce the production of aqueous humor. Examples include dorzolamide (Trusopt) and brinzolamide (Azopt).
- Prostaglandin-like compounds. These eyedrops increase the outflow of aqueous humor. Examples include latanoprost (Xalatan), bimatoprost (Lumigan) and travoprost (Travatan).
- Miotic or cholinergic agents. These also increase the outflow of aqueous humor. Examples include pilocarpine (Isopto Carpine, Pilopine) and carbachol (Isopto Carbachol).
- Epinephrine compounds. These compounds, such as dipivefrin (Propine), also increase the outflow of aqueous humor.
- The additional therapeutic agent or agents can be administered simultaneously or sequentially with the compounds of the present invention. Sequential administration includes administration before or after the compounds of the present invention. In some embodiments, the additional therapeutic agent or agents can be administered in the same composition as the compounds of the present invention. In other embodiments, there can be an interval of time between administration of the additional therapeutic agent and the compounds of the present invention.
- In some embodiments, the administration of an additional therapeutic agent with a compound of the present invention will enable lower doses of the other therapeutic agents to be administered for a longer period of time.
- Compounds of the present invention may be obtained in the form of various salts or solvates. As the salts, physiologically acceptable salts or salts available as raw materials are used.
- Compositions may include one or more of the isoforms of the compounds of the present invention. When racemates exists, each enantiomer or diastereomer may be separately used, or they may be combined in any proportion. Where tautomers exist all possible tautomers are specifically contemplated.
- Pharmaceutical compositions for use in accordance with the present invention may be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients. Thus, the compounds and their physiologically acceptable salts and solvates may be formulated for administration by, for example, solid dosing, eyedrop, in a topical oil-based formulation, injection, inhalation (either through the mouth or the nose), implants, or oral, buccal, parenteral or rectal administration. Techniques and formulations may generally be found in “Remington's Pharmaceutical Sciences”, (Meade Publishing Co., Easton, Pa.).
- The route by which the compounds of the present invention (component A) will be administered and the form of the composition will dictate the type of carrier (component B) to be used. The composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral) or topical administration (e.g., local application on the skin, ocular, liposome delivery systems, or iontophoresis).
- Carriers for systemic administration typically comprise at least one of a) diluents, b) lubricants, c) binders, d) disintegrants, e) colorants, f) flavors, g) sweeteners, h) antioxidants, j) preservatives, k) glidants, m) solvents, n) suspending agents, o) wetting agents, p) surfactants, combinations thereof, and others. All carriers are optional in the systemic compositions.
- Ingredient a) is a diluent. Suitable diluents for solid dosage forms include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitol; and sorbitol. The amount of ingredient a) in the systemic or topical composition is typically about 50 to about 90%.
- Ingredient b) is a lubricant. Suitable lubricants for solid dosage forms are exemplified by solid lubricants including silica, talc, stearic acid and its magnesium salts and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma. The amount of ingredient b) in the systemic or topical composition is typically about 5 to about 10%.
- Ingredient c) is a binder. Suitable binders for solid dosage forms include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of ingredient c) in the systemic composition is typically about 5 to about 50%, and in ocular solid dosing forms up to 99%.
- Ingredient d) is a disintegrant. Suitable disintegrants for solid dosage forms include agar, alginic acid and the sodium salt thereof, effervescent mixtures, croscarmelose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of ingredient d) in the systemic or topical composition is typically about 0.1 to about 10%.
- Ingredient e) for solid dosage forms is a colorant such as an FD&C dye. When used, the amount of ingredient e) in the systemic or topical composition is typically about 0.005 to about 0.1%.
- Ingredient 0 for solid dosage forms is a flavor such as menthol, peppermint, and fruit flavors. The amount of ingredient 0, when used, in the systemic or topical composition is typically about 0.1 to about 1.0%.
- Ingredient g) for solid dosage forms is a sweetener such as aspartame and saccharin. The amount of ingredient g) in the systemic or topical composition is typically about 0.001 to about 1%.
- Ingredient h) is an antioxidant such as butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), and vitamin E. The amount of ingredient h) in the systemic or topical composition is typically about 0.1 to about 5%.
- Ingredient j) is a preservative such as benzalkonium chloride, methyl paraben and sodium benzoate. The amount of ingredient j) in the systemic or topical composition is typically about 0.01 to about 5%.
- Ingredient k) for solid dosage forms is a glidant such as silicon dioxide. The amount of ingredient k) in the systemic or topical composition is typically about 1 to about 5%.
- Ingredient m) is a solvent, such as water, isotonic saline, ethyl oleate, glycerine, hydroxylated castor oils, alcohols such as ethanol, and phosphate buffer solutions. The amount of ingredient m) in the systemic or topical composition is typically from about 0 to about 100%.
- Ingredient n) is a suspending agent. Suitable suspending agents include AVICEL® RC-591 (from FMC Corporation of Philadelphia, Pa.) and sodium alginate. The amount of ingredient n) in the systemic or topical composition is typically about 1 to about 8%.
- Ingredient o) is a surfactant such as lecithin, Polysorbate 80, and sodium lauryl sulfate, and the TWEENS® from Atlas Powder Company of Wilmington, Del.
- Suitable surfactants include those disclosed in the C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp. 587-592; Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of ingredient o) in the systemic or topical composition is typically about 0.1% to about 5%.
- Although the amounts of components A and B in the systemic compositions will vary depending on the type of systemic composition prepared, the specific derivative selected for component A and the ingredients of component B, in general, system compositions comprise 0.01% to 50% of component A and 50 to 99.99% of component B.
- Compositions for parenteral administration typically comprise A) 0.1 to 10% of the compounds of the present invention and B) 90 to 99.9% of a carrier comprising a) a diluent and m) a solvent. In one embodiment, component a) comprises propylene glycol and m) comprises ethanol or ethyl oleate.
- Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms comprise a safe and effective amount, usually at least about 5%, and more particularly from about 25% to about 50% of component A). The oral dosage compositions further comprise about 50 to about 95% of component B), and more particularly, from about 50 to about 75%.
- Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed. Tablets typically comprise component A, and component B a carrier comprising ingredients selected from the group consisting of a) diluents, b) lubricants, c) binders, d) disintegrants, e) colorants, f) flavors, g) sweeteners, k) glidants, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmelose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are the FD&C dyes, which can be added for appearance. Chewable tablets preferably contain g) sweeteners such as aspartame and saccharin, or f) flavors such as menthol, peppermint, fruit flavors, or a combination thereof.
- Capsules (including implants, time release and sustained release formulations) typically comprise component A, and a carrier comprising one or more a) diluents disclosed above in a capsule comprising gelatin. Granules typically comprise component A, and preferably further comprise k) glidants such as silicon dioxide to improve flow characteristics. Implants can be of the biodegradable or the non-biodegradable type. Implants may be prepared using any known biocompatible formulation.
- The selection of ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this invention. One skilled in the art would know how to select appropriate ingredients without undue experimentation.
- The solid compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that component A is released in the gastrointestinal tract in the vicinity of the desired application, or at various points and times to extend the desired action. The coatings typically comprise one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT® coatings (available from Rohm & Haas G.M.B.H. of Darmstadt, Germany), waxes and shellac.
- Compositions for oral administration can also have liquid forms. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid orally administered compositions typically comprise component A and component B, namely, a carrier comprising ingredients selected from the group consisting of a) diluents, e) colorants, f) flavors, g) sweeteners, j) preservatives, m) solvents, n) suspending agents, and o) surfactants. Peroral liquid compositions preferably comprise one or more ingredients selected from the group consisting of e) colorants, f) flavors, and g) sweeteners.
- Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as a) diluents including sucrose, sorbitol and mannitol; and c) binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Such compositions may further comprise b) lubricants, e) colorants, f) flavors, g) sweeteners, h) antioxidants, and k) glidants.
- In one embodiment of the invention, the compounds of the present invention are topically administered. Topical compositions that can be applied locally to the eye may be in any form known in the art, non-limiting Examples of which include solids, gelable drops, sprays, ointments, or a sustained or non-sustained release unit placed in the conjunctival cul-du-sac of the eye or another appropriate location.
- Topical compositions that can be applied locally to the skin may be in any form including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. Topical compositions comprise: component A, the compounds described above, and component B, a carrier. The carrier of the topical composition preferably aids penetration of the compounds into the eye. Component B may further comprise one or more optional components.
- An effective amount of a compound according to the present invention will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of treatment, the nature of concurrent therapy, the route of administration, the particular pharmaceutically-acceptable carrier utilized, and like factors within the knowledge and expertise of the attending physician. For example, an effective amount of the compounds of the present invention for systemic administration is from about 0.01 to about 1000 μg/kg body weight, preferably from about 0.1 to about 100 μg/kg per body weight, most preferably form about 1 to about 50 μg/kg body weight per day. The transdermal dosages will be designed to attain similar serum or plasma levels, based upon techniques known to those skilled in the art of pharmacokinetics and transdermal formulations. Plasma levels for systemic administration are expected to be in the range of 0.01 to 100 ng/mL, more preferably from 0.05 to 50 ng/mL and most preferably from 0.1 to 10 ng/mL. While these dosages are based upon a daily administration rate, the compounds of the present invention may also be administered at other intervals, such as twice per day, twice weekly, once weekly, or once a month. One of ordinary skill in the art would be able to calculate suitable effective amounts for other intervals of administration.
- The compounds of the present invention are useful in a method of reducing or decreasing intraocular pressure. The compounds of the present invention may be administered to a subject in need of treatment in an amount effective to reduce intraocular pressure. Thus, these compounds are useful in the treatment of glaucoma. The preferred route of administration for treating glaucoma is topically.
- The exact amounts of each component in the topical composition depend on various factors. The amount of component A added to the topical composition is dependent on the IC50 of component A, typically expressed in nanomolar (nM) units. For example, if the IC50 of the medicament is 1 nM, the amount of component A will be from about 0.001 to about 0.3%. If the IC50 of the medicament is 10 nM, the amount of component A) will be from about 0.01 to about 1%. If the IC50 of the medicament is 100 nM, the amount of component A will be from about 0.1 to about 10%. If the IC50 of the medicament is 1000 nM, the amount of component A will be 1 to 100%, preferably 5% to 50%. If the amount of component A is outside the ranges specified above (i.e., lower), efficacy of the treatment may be reduced. One skilled in the art understands how to calculate and understand an IC50. The remainder of the composition, up to 100%, is component B.
- The amount of the carrier employed in conjunction with component A is sufficient to provide a practical quantity of composition for administration per unit dose of the medicament. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).
- Component B may comprise a single ingredient or a combination of two or more ingredients. In the topical compositions, component B comprises a topical carrier. Suitable topical carriers comprise one or more ingredients selected from the group consisting of phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More particularly, carriers for skin applications include propylene glycol, dimethyl isosorbide, and water, and even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols and symmetrical alcohols.
- The carrier of the topical composition may further comprise one or more ingredients selected from the group consisting of q) emollients, r) propellants, s) solvents, t) humectants, u) thickeners, v) powders, w) fragrances, x) pigments, and y) preservatives.
- Ingredient q) is an emollient. The amount of ingredient q) in a skin-based topical composition is typically about 5 to about 95%. Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for skin include stearyl alcohol and poly dimethylsiloxane.
- Ingredient r) is a propellant. The amount of ingredient r) in the topical composition is typically about 0 to about 95%. Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof.
- Ingredient s) is a solvent. The amount of ingredient s) in the topical composition is typically about 0 to about 95%. Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols.
- Ingredient t) is a humectant. The amount of ingredient t) in the topical composition is typically 0 to 95%. Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin.
- Ingredient u) is a thickener. The amount of ingredient u) in the topical composition is typically about 0 to about 95%.
- Ingredient v) is a powder. The amount of ingredient v) in the topical composition is typically 0 to 95%. Suitable powders include beta-cyclodextrins, hydroxypropyl cyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically-modified magnesium aluminum silicate, organically-modified Montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof. For ocular applications, specific powders include beta-cyclodextrin, hydroxypropyl cyclodextrin, and sodium polyacrylate. For gel dosing ocular formulations, sodium polyacrylate may be used.
- Ingredient w) is a fragrance. The amount of ingredient w) in the topical composition is typically about 0 to about 0.5%, particularly, about 0.001 to about 0.1%. For ocular applications a fragrance is not typically used.
- Ingredient x) is a pigment. Suitable pigments for skin applications include inorganic pigments, organic lake pigments, pearlescent pigments, and mixtures thereof. Inorganic pigments useful in this invention include those selected from the group consisting of rutile or anatase titanium dioxide, coded in the Color Index under the reference CI 77,891; black, yellow, red and brown iron oxides, coded under references CI 77,499, 77,492 and, 77,491; manganese violet (CI 77,742); ultramarine blue (CI 77,007); chromium oxide (CI 77,288); chromium hydrate (CI 77,289); and ferric blue (CI 77,510) and mixtures thereof.
- The organic pigments and lakes useful in this invention include those selected from the group consisting of D&C Red No. 19 (CI 45,170), D&C Red No. 9 (CI 15,585), D&C Red No. 21 (CI 45,380), D&C Orange No. 4 (CI 15,510), D&C Orange No. 5 (CI 45,370), D&C Red No. 27 (CI 45,410), D&C Red No. 13 (CI 15,630), D&C Red No. 7 (CI 15,850), D&C Red No. 6 (CI 15,850), D&C Yellow No. 5 (CI 19,140), D&C Red No. 36 (CI 12,085), D&C Orange No. 10 (CI 45,425), D&C Yellow No. 6 (CI 15,985), D&C Red No. 30 (CI 73,360), D&C Red No. 3 (CI 45,430), the dye or lakes based on Cochineal Carmine (CI 75,570) and mixtures thereof.
- The pearlescent pigments useful in this invention include those selected from the group consisting of the white pearlescent pigments such as mica coated with titanium oxide, bismuth oxychloride, colored pearlescent pigments such as titanium mica with iron oxides, titanium mica with ferric blue, chromium oxide and the like, titanium mica with an organic pigment of the above-mentioned type as well as those based on bismuth oxychloride and mixtures thereof. The amount of pigment in the topical composition is typically about 0 to about 10%. For ocular applications a pigment is generally not used.
- In a particularly preferred embodiment of the invention, topical pharmaceutical compositions for ocular administration are prepared typically comprising component A and B (a carrier), such as purified water, and one or more ingredients selected from the group consisting of y) sugars or sugar alcohols such as dextrans, particularly mannitol and dextran 70, z) cellulose or a derivative thereof, aa) a salt, bb) disodium EDTA (Edetate disodium), and cc) a pH adjusting additive.
- Examples of z) cellulose derivatives suitable for use in the topical pharmaceutical composition for ocular administration include sodium carboxymethylcellulose, ethylcellulose, methylcellulose, and hydroxypropyl-methylcellulose, particularly, hydroxypropyl-methylcellulose.
- Examples of aa) salts suitable for use in the topical pharmaceutical composition for ocular administration include mono-, di- and trisodium phosphate, sodium chloride, potassium chloride, and combinations thereof.
- Examples of cc) pH adjusting additives include HCl or NaOH in amounts sufficient to adjust the pH of the topical pharmaceutical composition for ocular administration to 5.0-7.5.
- Component A may be included in kits comprising component A, a systemic or topical composition described above, or both; and information, instructions, or both that use of the kit will provide treatment for cosmetic and medical conditions in mammals (particularly humans). The information and instructions may be in the form of words, pictures, or both, and the like. In addition or in the alternative, the kit may comprise the medicament, a composition, or both; and information, instructions, or both, regarding methods of application of medicament, or of composition, preferably with the benefit of treating or preventing cosmetic and medical conditions in mammals (e.g., humans).
- The invention will be further explained by the following illustrative Examples that are to be considered to be non-limiting.
- Specific procedures for the preparation of beta and gamma-amino isoquinoline amide compounds and substituted benzamide compounds are described in the following Examples.
- All temperatures are in degrees Centigrade. Reagents and starting materials were purchased from commercial sources or prepared following published literature procedures.
- Unless otherwise noted, HPLC purification, when appropriate, was performed by redissolving the compound in a small volume of DMSO and filtering through a 0.45 micron (nylon disc) syringe filter. The solution was then purified using, for example, a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C8 column. A typical initial eluting mixture of 40-80% MeOH:H2O was selected as appropriate for the target compound. This initial gradient was maintained for 0.5 minutes then increased to 100% MeOH:0% H2O over 5 minutes. 100% MeOH was maintained for 2 more minutes before re-equilibration back to the initial starting gradient. A typical total run time was 8 minutes. The resulting fractions were analyzed, combined as appropriate, and then evaporated to provide purified material.
- Proton magnetic resonance CH NMR) spectra were recorded on either a Varian INOVA 600 MHz (1H) NMR spectrometer, Varian INOVA 500 MHz (1H) NMR spectrometer, Varian Mercury 300 MHz (1H) NMR spectrometer, or a Varian Mercury 200 MHz (1H) NMR spectrometer. All spectra were determined in the solvents indicated. Although chemical shifts are reported in ppm downfield of tetramethylsilane, they are referenced to the residual proton peak of the respective solvent peak for 1H NMR. Interproton coupling constants are reported in Hertz (Hz).
- Analytical LCMS spectra were obtained using a Waters ZQ MS ESI instrument with an Alliance 2695 HPLC and a 2487 dual wavelength UV detector. Spectra were analyzed at 254 and 230 nm. Samples were passed through a Waters Symmetry C18 4.6×75 mm 3.5μ column with or without a guard column (3.9×20 mm 5μ). Gradients were run with mobile phase A: 0.1% formic acid in H2O and mobile phase B: ACN with a flow rate of 0.8 mL/min. Two gradients will illustrate:
-
Gradient A Gradient B Time A % B % Time A % B % 0.00 80.0 20.0 0.00 80.0 20.0 1.00 80.0 20.0 1.00 80.0 20.0 6.00 25.0 75.0 6.00 25.0 75.0 7.00 5.0 95.0 7.00 5.0 95.0 8.00 5.0 95.0 8.00 5.0 95.0 9.00 80.0 20.0 9.00 80.0 20.0 12.00 80.0 20.0 12.00 80.0 20.0 - The settings for the MS probe were a cone voltage at 38 mV and a desolvation temperature at 250° C. Any variations in these methods are noted below.
- The following preparations illustrate procedures for the preparation of intermediates and methods for the preparation of a beta or gamma-amino isoquinoline amide derivative or substituted benzamide derivatives.
- Example 1. Preparation of tert-butyl 2-hydroxy-1-(thiophen-3-yl)ethylcarbamate (E1).
- To (±)-2-(tert-butoxycarbonylamino)-2-(thiophen-3-yl)acetic acid in THF at 0° C. was added BH3-THF dropwise. The solution was allowed to warm to room temperature and stirred for an additional 2 hours. The solution was cooled to 0° C., quenched with AcOH (10%)/MeOH and evaporated. Column chromatography (SiO2, EtOAc) gave pure tert-butyl 2-hydroxy-1-(thiophen-3-yl)ethylcarbamate (E1).
- Example 2. Preparation of 2-(tert-butoxycarbonylamino)-2-(thiophen-3-yl)ethyl 4-methylbenzenesulfonate (E2).
- To tert-butyl 2-hydroxy-1-(thiophen-3-yl)ethylcarbamate (E1) in CH2C12 was added NEt3, DMAP, and TsCl. The solution was stirred at room temperature for 3 hours and then poured into NH4C1 (sat) and extracted with EtOAc, dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 30% EtOAc/Hexanes) gave pure 2-(tert-butoxycarbonylamino)-2-(thiophen-3-yl)ethyl 4-methylbenzenesulfonate (E2).
- Example 3. Preparation of tert-butyl 2-cyano-1-(thiophen-3-yl)ethylcarbamate (E3).
- To 2-(tert-butoxycarbonylamino)-2-(thiophen-3-yl)ethyl 4-methylbenzenesulfonate (E2) in DMSO was added NaCN, and the solution was heated to 90° C. for 2 hours. The reaction was cooled, poured into NaCl (sat), and extracted with EtOAc. The organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 25% EtOAc/Hexanes) gave pure tert-butyl 2-cyano-1-(thiophen-3-yl)ethylcarbamate (E3).
- Example 4. Preparation of 3-(tert-butoxycarbonylamino)-3-(thiophen-3-yl)propanoic acid (E4).
- To tert-butyl 2-cyano-1-(thiophen-3-yl)ethylcarbamate (E3) in EtOH was added NaOH (2M), and the solution was heated to 90° C. for 4 hours. The reaction was cooled, acidified with HCl, and extracted with EtOAc. The organics were dried (Na2SO4) and evaporated to give pure 3-(tert-butyoxcarbonylamino)-3-(thiophen-3-yl)propanoic acid (E4).
- Example 5. Preparation of tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-1-(thiophen-3-yl)propylcarbamate (E5).
- To 3-(tert-butyoxcarbonylamino)-3-(thiophen-3-yl)propanoic acid (E4) in pyridine was added EDC, DMAP, and 6-aminoisoquinoline. The solution was stirred for 10 hours at room temperature. The mixture was poured into NaHCO3(sat) and extracted with EtOAc, dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 5% MeOH/CH2C12) gave pure tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-1-(thiophen-3-yl)propylcarbamate (E5).
- Example 6. Preparation of 3-amino-N-(isoquinolin-6-yl)-3-(thiophen-3-yl)propanamide dihydrochloride (E6).
- To tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-1-(thiophen-3-yl)propylcarbamate (E5) in CH2C12 was added HCl (4N in dioxane), and the solution was stirred for 8 hours. The solvents were evaporated to give 3-amino-N-(isoquinolin-6-yl)-3-(thiophen-3-yl)propanamide dihydrochloride (E6).
- Examples 7-40.
- Using commercially available compounds and largely the procedures set forth in Examples 1-6 and substituting the appropriate starting materials, the compounds 7-11, 13-16, 18-21, and 25 were made, and compounds 12, 17, 22-24, and 26-40 can be made.
-
Example X R3 R2 R1 7 H (S)-C6H5 H H 8 H (R)-C6H5 H H 9 OH (S)-C6H5 H H 10 OH (R)-C6H5 H H 11 OH (S)-C6H5 Me Me 12 H (S)-C6H5 Me H 13 H (±)-o-chloro-C6H4 H H 14 OH (±)-o-chloro-C6H4 H H 15 H (±)-p-fluoro-C6H4 H H 16 OH (±)-p-fluoro-C6H4 H H 17 H (±)-p-fluoro-C6H4 Me H 18 H (S)-3-thienyl H H 19 OH (S)-3-thienyl H H 20 H (S)-3-thienyl Me Me 21 OH (S)-3-thienyl Me Me 22 H (R)-3-thienyl Me Me 23 OH (R)-3-thienyl Me Me 24 OH (S)-3-thienyl Me H 25 H (S)-2-thienyl Me Me 26 H (R)-2-thienyl Me Me 27 H 3-furyl H H 28 OH 2-furyl Me Me 29 OH 3,5-difluoroC6H3 Me H 30 H m-CH3 H H 31 H 2-pyridyl H H 32 OH 4-pyridyl Me Me 33 H Benzyl H H 34 H Cyclohexyl Me Me 35 H Cyclopropyl H H 36 OH Methyl cyclohexyl Me H 37 H 4-fluorobenzyl H H 38 H 2-thiazole Me Me 39 OH 2-oxazole H Me 40 H 3-piperdyl Me Me - Example 41. Preparation of methyl 2-(thiophen-3-yl)acetate (E41).
- To 2-(thiophen-3-yl)acetic acid in MeOH at 0° C. was added TMS-CH2N2. The solution was stirred for 3 hours then quenched with a few drops of AcOH. The solvents were evaporated. Column chromatography (SiO2, 3-15% EtOAc/Hex) gave pure methyl 2-(thiophen-3-yl)acetate (E41).
- Example 42. Preparation of methyl 3-(dimethylamino)-2-(thiophen-3-yl)propanoate (E42).
- To methyl 2-(thiophen-3-yl)acetate (E41) in THF cooled to −78° C. was added LiHMDS, and the solution stirred at −78° C. for 30 min. Then N,N-Dimethylmethyleneiminium iodide was added directly and the solution was allowed to warm to 0° C. The mixture was poured into NaHCO3(sat), extracted with EtOAc, dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 5% MeOH/CH2C12) gave pure methyl 3-(dimethylamino)-2-(thiophen-3-yl)propanoate (E42).
- Example 43. Preparation of 3-(dimethylamino)-2-(thiophen-3-yl)propanoic acid (E43).
- To methyl 3-(dimethylamino)-2-(thiophen-3-yl)propanoate (E42) in THF/H2O/MeOH was added LiOH*H2O, and the solution was stirred for 12 hours. AcOH was added and the solvents were evaporated. Column chromatography (SiO2, 10-15% 2M NH3— MeOH/EtOH) gave pure 3-(dimethylamino)-2-(thiophen-3-yl)propanoic acid (E43).
- Example 44. Preparation of 3-(dimethylamino)-N-(isoquinolin-6-yl)-2-(thiophen-3-yl)propanamide dihydrochloride (E44).
- To 3-(dimethylamino)-2-(thiophen-3-yl)propanoic acid (E43) in pyridine was added EDC, DMAP, and 6-aminoisoquinoline. The solution was stirred overnight at room temperature. The mixture was poured into NaHCO3(sat) and extracted with EtOAc. The organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 5-20% MeOH/CH2C12) gave pure 3-(dimethylamino)-N-(isoquinolin-6-yl)-2-(thiophen-3-yl)propanamide. The pure compound was taken up in CH2C12 and HCl was added. The solvents were evaporated to give pure 3-(dimethylamino)-N-(isoquinolin-6-yl)-2-(thiophen-3-yl)propanamide dihydrochloride (E44).
- Example 45. Preparation of methyl 3-(1,3-dioxoisoindolin-2-yl)-2-(thiophen-3-yl)propanoate (E45).
- To pure methyl 2-(thiophen-3-yl)acetate (E41) in THF cooled to −78° C. was added LiHMDS, and the solution stirred at −78° C. for 30 min. Then N-(bromomethyl)phthalimide was added directly, and the solution was allowed to warm to 0° C. The mixture was poured into NaHCO3(sat), extracted with EtOAc, dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2,0-40% EtOAc/Hex) gave pure methyl 3-(1,3-dioxoisoindolin-2-yl)-2-(thiophen-3-yl)propanoate (E45).
- Example 46. Preparation of 3-amino-2-(thiophen-3-yl)propanoic acid hydrochloride (E46).
- To methyl 3-(1,3-dioxoisoindolin-2-yl)-2-(thiophen-3-yl)propanoate (E45) was added 6 N HCl, and the solution was refluxed for 4 hours. The solvents were evaporated to give 3-amino-2-(thiophen-3-yl)propanoic acid (E46).
- Example 47. Preparation of 3-(tert-butoxycarbonylamino)-2-(thiophen-3-yl)propanoic acid (E47).
- To Boc2O in dioxane at 0° C. was added a cooled solution (0° C.) of 3-amino-2-(thiophen-3-yl)propanoic acid hydrochloride (E46) in 1 N NaOH. The solution was stirred at 0° C. for 30 min, then at room temperature for 4 hours. The mixture was acidified with HCl and extracted with EtOAc and NH4C1 (sat). The organics were dried (Na2SO4), filtered, and evaporated to give pure 3-(tert-butoxycarbonylamino)-2-(thiophen-3-yl)propanoic acid (E47).
- Example 48. Preparation of tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(thiophen-3-yl)propylcarbamate (E48).
- To 3-(tert-butoxycarbonylamino)-2-(thiophen-3-yl)propanoic acid (E47) in pyridine was added EDC, DMAP, and 6-aminoisoquinoline. The solution was stirred overnight at room temperature. The mixture was poured into NaHCO3(sat) and extracted with EtOAc. The organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 3% MeOH/CH2Cl2) gave pure tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(thiophen-3-yl) propylcarbamate (E48).
- Example 49. Preparation of 3-amino-N-(isoquinolin-6-yl)-2-(thiophen-3-yl)propanamide dihydrochloride (E49).
- Examples 50-72.
- To tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(thiophen-3-yl)propylcarbamate (E48) in CH2C12 was added HCl (4N in dioxane), and the solution was stirred for 8-10 hours. The solvents were evaporated to give pure 3-amino-N-(isoquinolin-6-yl)-2-(thiophen-3-yl)propanamide dihydrochloride (E49).
- Using commercially available compounds and largely the procedures set forth in Examples 41-49 and substituting the appropriate starting materials, the compounds 50 and 52-54 were made, and compounds 51 and 55-72 can be made.
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Example X R4 R2 R1 50 OH (±)-3-thienyl Me Me 51 OH (±)-3-thienyl H H 52 H C6H5 H H 53 H C6H5 Me Me 54 OH C6H5 H H 55 OH C6H5 Me Me 56 H (±)-2-thienyl H H 57 OH (±)-2-thienyl Me Me 58 H (R)-C6H5 H H 59 H (S)-C6H5 H H 60 OH p-fluoro-C6H4 Me Me 61 H p-fluoro-C6H4 benzyl H 62 H Benzyl Me H 63 H p-fluoro benzyl Me H 64 OH 3-pyridyl H H 65 H 4-pyridyl Me Me 66 OH 3-furyl H H 67 H cyclopropyl Me Me 68 H cyclopentyl Me Me 69 OH cyclohexyl H H 70 H 3-benzo[b]thiophene Me Me 71 H H H 72 OH 2-oxazole H H - Example 73. Preparation of a gamma amino acid version. (E73)
- To (±)-2-(tert-butoxycarbonylamino)-2-(thiophen-3-yl)propanoic acid (E4) in THF at 0° C. is added BH3-THF dropwise. The solution is allowed to warm to room temperature and stirred for an additional 2 hours. The solution is cooled to 0° C., quenched with AcOH (10%)/MeOH, and evaporated. Column chromatography (SiO2, EtOAc) gives pure tert-butyl 3-hydroxy-1-(thiophen-3-yl)propylcarbamate (E73A).
- Preparation of 3-(tert-butoxycarbonylamino)-3-(thiophen-3-yl)propyl 4-methylbenzenesulfonate (E73B).
- To tert-butyl 2-hydroxy-1-(thiophen-3-yl)ethylcarbamate (E73A) in CH2C12 is added NEt3, DMAP, and TsCl. The solution is stirred at room temperature for 3 hours and then poured into NH4C1 (sat) and extracted with EtOAc, dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 30% EtOAc/Hexanes) gives pure 3-(tert-butoxycarbonylamino)-3-(thiophen-3-yl) propyl 4-methylbenzenesulfonate (E73B).
- Preparation of tert-butyl 3-cyano-1-(thiophen-3-yl)propylcarbamate (E73C).
- To 3-(tert-butoxycarbonylamino)-3-(thiophen-3-yl)propyl 4-methylbenzenesulfonate (E73B) in DMSO is added NaCN, and the solution is heated to 90° C. for 2 hours. The reaction is cooled, poured into NaCl (sat), and extracted with EtOAc. The organics are dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 25% EtOAc/Hexanes) gives pure tert-butyl 2-cyano-1-(thiophen-3-yl)ethylcarbamate (E73C).
- Preparation of 3-(tert-butyoxcarbonylamino)-3-(thiophen-3-yl)propanoic acid (E73D).
- To tert-butyl 3-cyano-1-(thiophen-3-yl)propylcarbamate (E3) in EtOH is added NaOH (2M) and the solution is heated to 90° C. for 4 hours. The reaction is cooled, acidified with HCl, and extracted with EtOAc. The organics are dried (Na2SO4) and evaporated to give pure 4-(tert-butyoxcarbonylamino)-4-(thiophen-3-yl)butanoic acid (E73D).
- Preparation of tert-butyl 4-(isoquinolin-6-ylamino)-4-oxo-1-(thiophen-3-yl)butylcarbamate (E73E).
- To 4-(tert-butyoxcarbonylamino)-4-(thiophen-3-yl)butanoic acid (E73D) in pyridine is added EDC, DMAP and 6-aminoisoquinoline and the solution is stirred for 10 hours at room temperature. The mixture is poured into NaHCO3(sat) and extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, 5% MeOH/CH2C12) gives pure tert-butyl 4-(isoquinolin-6-ylamino)-4-oxo-1-(thiophen-3-yl)butylcarbamate (E73E).
- Preparation of 4-amino-N-(isoquinolin-6-yl)-4-(thiophen-3-yl)butanamide dihydrochloride (E73).
- To tert-butyl 4-(isoquinolin-6-ylamino)-4-oxo-1-(thiophen-3-yl)butylcarbamate (E73E) in CH2C12 is added HCl (4N in dioxane), and the solution is stirred for 8 hours. The solvents are evaporated to give 4-amino-N-(isoquinolin-6-yl)-4-(thiophen-3-yl)butanamide dihydrochloride (E73).
- Examples 74-93.
- Using the general procedure shown for Example 73, the following compounds 74-93 can be synthesized from the corresponding 6-aminoisoquinoline.
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Example X R5 R4 R3 R2 R1 74 H C6H5 H H H H 75 OH C6H5 H H H H 76 H (S)-C6H5 H H H H 77 OH (R)-C6H5 H H H H 78 OH (S)-C6H5 H H H H 79 H (S)-C6H5 H H CH3 CH3 80 H p-fluoro- H H H H C6H4 81 H p-fluoro- H H CH3 H C6H4 82 OH cyclopropyl H H CH3 H 83 H 3-thienyl H H H H 84 H (S)-3- H H H H thienyl 85 OH cyclohexyl H H CH3 CH3 86 H H C6H5 H H 87 H H C6H5 CH3 H 88 H C6H5 H H CH2C6H5 H 89 H H p-fluoro- H H H C6H4 90 OH H CH2C6H5 H CH3 H 91 H H 3-thienyl H CH3 H 92 OH H 2-thienyl H CH3 CH3 93 H H p-chloro H H H benzyl - Examples 94-110.
- Using largely the procedure set forth in Example 73 and substituting the appropriate starting materials, the compounds 94-110 can be made.
- Example 111. Preparation of 2-methyl-4-nitrobenzamide (E111).
- To 2-methyl-4-nitrobenzoic acid suspended in CH2C12 under Ar was added DMF then oxalyl chloride. The reaction was stirred at room temperature 1.5 hours then the solvent was evaporated. The residue was dissolved in THF and ammonia gas was bubbled through the reaction for 15 minutes. The solvent was evaporated and the residue partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The extracts were dried (MgSO4), filtered and evaporated. Column chromatography (SiO2,0-100% EtOAc/Hex) gave pure 2-methyl-4-nitrobenzamide (E111).
- Example 112. Preparation of 4-amino-2-methylbenzamide (E112).
- 2-methyl-4-nitrobenzamide (E111) was dissolved in EtOH under Ar and 10% Pd/C added. The reaction was pump-purged with H2 and left stirring at room temperature overnight. The catalyst was removed by filtration and the reaction concentrated to give pure 4-amino-2-methylbenzamide (E112).
- Example 113. Preparation of 4-(2-(dimethylamino)-2-(thiophen-3-yl)acetamido)-2-methylbenzamide (E113).
- To 2-(dimethylamino)-2-(thiophen-3-yl)acetic acid in pyridine was added EDC, DMAP and 4-amino-2-methylbenzamide (E112) and the solution was stirred for 10 hours at room temperature. The mixture was poured into NaHCO3(sat) and extracted with EtOAc. The extracts were dried (MgSO4), filtered and evaporated. Column chromatography (SiO2,0-100% EtOAc/Hex) gave pure 4-(2-(dimethylamino)-2-(thiophen-3-yl)acetamido)-2-methylbenzamide (E113).
- Example 114. Preparation of methyl 4-(2-(dimethylamino)-2-(thiophen-3-yl)acetamido)benzoate (E114).
- To 2-(dimethylamino)-2-(thiophen-3-yl)acetic acid in pyridine was added EDC, DMAP and 4-aminobenzoate and the solution was stirred for 10 hours at room temperature. The mixture was poured into NaHCO3(sat) and extracted with EtOAc. The extracts were dried (MgSO4), filtered and evaporated. Column chromatography (SiO2,0-100% EtOAc/Hex) gave pure methyl 4-(2-(dimethylamino)-2-(thiophen-3-yl)acetamido)benzoate (E114).
- Example 115. Preparation of 4-(2-(dimethylamino)-2-(thiophen-3-yl)acetamido) benzamide (E115).
- Methyl 4-(2-(dimethylamino)-2-(thiophen-3-yl)acetamido)benzoate (E114) and formamide dissolved in DMF under Ar were heated to 100° C. The NaOMe was then added and the reaction heated for 2 hours. The reaction was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The extracts were dried (MgSO4), filtered and evaporated. Column chromatography (SiO2,0-100% EtOAc/Hex) gave pure 4-(2-(dimethylamino)-2-(thiophen-3-yl)acetamido)benzamide (E115).
- Examples 116-122.
- Using commercially available compounds and largely the procedures set forth in Examples 111-115 and substituting the appropriate starting materials, the compounds 116-122 were made:
- Examples 123-133.
- Using commercially available compounds and largely the procedures set forth in Examples 111-115 and substituting the appropriate starting materials, the compounds 125 and 127 were made, and compounds 123-124, 126, and 128-133 can be made.
- Examples 134-180.
- Using commercially available compounds and largely the procedures set forth in Examples 111-115 and substituting the appropriate starting materials, the compounds 134-180 can be made:
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Ex- ample R1 R2 R3 R4 R5 R6 134 H H 3-thienyl Cl Cl H 135 H H 3-thienyl H H H 136 H H 3-thienyl F F H 137 H H C6H6 H H H 138 CH3 CH3 C6H6 H H H 139 CH3 CH3 C6H6 F Cl H 140 CH3 CH3 cyclohexyl H H H 141 CH3 CH3 —CH(CH3)2 H H H 142 CH3 CH3 3-thienyl CF3 H H 143 CH3 CH3 3-thienyl OCF3 H H 144 CH3 CH3 3-thienyl CN H H 145 CH3 CH3 2-pyridyl H H H 146 CH3 CH3 3-pyridyl H H H 147 CH3 CH3 4-pyridyl H H H 148 CH3 CH3 2-thienyl H H H 149 H CH3 3-thienyl H H H 150 CH3 CH3 3-thienyl NO2 H H Ex- ample R1 R2 R3 R4 R5 R6 R7 151 H H 3-thienyl H H H H 152 CH3 CH3 3-thienyl H H H H 153 H H H 3-thienyl H H H 154 CH3 CH3 H 3-thienyl H H H 155 CH3 CH3 3-thienyl H F H H 156 CH3 CH3 3-thienyl H H F H 157 CH3 CH3 3-thienyl H H H F 158 CH3 CH3 H 3-thienyl CH3 H H 159 CH3 CH3 H 3-thienyl H CH3 H 160 CH3 CH3 H 3-thienyl H H CH3 161 CH3 CH3 C6H5 H H H H 162 H H cyclohexyl H H H H 163 CH3 H —CH(CH3)2 H H H H 164 CH3 CH3 H C6H6 H H H 165 CH3 H H cyclohexyl H H H 166 H H H —CH(CH3)2 H H H 167 CH3 CH3 —C≡C—C6H5 H H H H 168 CH3 CH3 3-thienyl H Cl Cl H Ex- ample R1 R2 R3 R4 R5 R6 R7 169 H H 3-thienyl H H H H 170 CH3 CH3 3-thienyl H H H H 171 H H H 3-thienyl H H H 172 CH3 CH3 H 3-thienyl H H H 173 CH3 CH3 H H 3- H H thienyl 174 CH3 CH3 H H 3- F H thienyl 175 H H cyclohexyl H H H F 176 H H H —CH(CH3)2 H H H 177 H H H H C6H5 CH3 H 178 CH3 CH3 H cyclopropyl H H CH3 179 CH3 CH3 C6H5 H H H H 180 H H H 4-pyridyl H H H - Example 181.
- Using commercially available compounds and largely the procedures set forth in Examples 1-6 and substituting the appropriate starting materials, the compounds 181-195 were made.
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Example X R1 R2 R3 181 H (S)-C6H5 Me Me 182 H (R)-3-theinyl H H 183 OH (R)-3-thienyl H H 184 H (S)-2-thienyl H H 185 OH (S)-2-thienyl H H 186 OH (S)-2-thienyl Me Me 187 H (R)-CH2-3-thienyl H H 188 H (S)-CH2-2-thienyl H H 189 H (S)-2-furyl H H 190 H (S)-3-pyridyl H H 191 H (S)-2-methoxy-5-pyridyl H H - Example 182.
- Using commercially available compounds and largely the procedures set forth in Examples 41-49 and substituting the appropriate starting materials, the compounds 196-202 were made.
- Example 183.
- Topical pharmaceutical compositions for lowering intraocular pressure are prepared by conventional methods and formulated as follows:
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Ingredient Amount (wt %) beta amino acid isoquinolyl amide 0.50 Dextran 70 0.1 Hydroxy propyl methylcellulose 0.3 Sodium Chloride 0.77 Potassium chloride 0.12 Disodium EDTA 0.05 Benzalkonium chloride 0.01 HCl and/or NaOH pH 5.5-6.5 Purified water q.s. to 100% - A compound according to this invention is used as the beta amino acid isoquinolyl amide. When the composition is topically administered to the eyes once daily, the above composition decreases intraocular pressure in a subject suffering from glaucoma.
- Example 184.
- Example 183 is repeated using 3-amino-N-(isoquinolin-6-yl)-3-(thiophen-3-yl)propanamide dihydrochloride (E6) according to this invention. When administered as a drop 2 times per day, the above composition decreases intraocular pressure and serves as a neuroprotective agent.
- Example 185.
- Example 183 is repeated using a gamma amino acid isoquinolyl amide according to this invention. When administered as a drop twice per day, the above composition decreases intraocular pressure.
- Example 186.
- Example 183 is repeated using a benzamide according to this invention. When administered as a drop twice per day, the above composition substantially decreases allergic symptoms and relieves dry eye syndrome.
- Example 187.
- Example 183 is repeated using 3-(dimethylamino)-N-(isoquinolin-6-yl)-2-(thiophen-3-yl)propanamide dihydrochloride (E44) according to this invention. When administered as a drop as needed, the above composition decreases hyperemia, redness and ocular irritation.
- Example 188.
- Example 183 is repeated using 3-amino-N-(5-chloroisoquinolin-6-yl)-2-(thiophen-3-yl)propanamide dihydrochloride according to this invention. When administered as a drop 4 times per day, the above composition decreases intraocular pressure and serves as a neuroprotective agent.
- Example 189.
- Example 183 is repeated using 3-amino-N-(isoquinolin-6-yl)-2-(thiophen-3-yl)propanamide dihydrochloride (E49) according to this invention. When administered as a drop twice per day, the above composition decreases intraocular pressure.
- Example 190.
- Example 183 is repeated using 4-(2-(dimethylamino)-2-(thiophen-3-yl) acetamido)benzamide (E115) according to this invention. When administered as a drop twice per day, the above composition decreases ocular pressure, allergic symptoms and relieves dry eye syndrome.
- Reference Example One. The Cell-Based Porcine Trabecular Meshwork (PTM) Assay.
- The anterior section of porcine eyes was harvested within 4 hours post-mortem. The iris and ciliary body were removed and trabecular meshwork cells were harvested by blunt dissection. Finely minced trabecular meshwork tissue was plated into collagen-coated 6-well plates in Medium-199 containing 20% fetal bovine serum (FBS). After two passages at confluence, cells were transferred to low-glucose DMEM containing 10% FBS. Cells were used between passage 3 and passage 8.
- Cells were plated into fibronectin-coated, glass multiwell plates the day before compound testing under standard culture conditions. Compounds were added to cells in the presence of 1% FBS-containing DMEM and 1% DMSO. When compounds were incubated with the cells for the duration determined to be optimal, the media and compound is removed and cells fixed for 20 minutes in 3% methanol-free paraformaldehyde. Cells were rinsed twice with phosphate buffered saline (PBS) and cells are permeabilized with 0.5% Triton X-100 for two minutes. Following an additional two washes with PBS, F-actin was stained with Alexa-fluor 488-labelled phalloidin and nuclei are stained with DAPI.
- Data was reduced to the mean straight actin-fiber length and normalized to DMSO-treated control cells (100%) and 50 μM Y-27632 (0%). Y-27632 is a rho-kinase inhibitor known to result in the depolymerization of F-actin in these cells.
- Reference Example Two. Pharmacological Activity for Glaucoma Assay.
- Pharmacological activity for glaucoma can be demonstrated using assays designed to test the ability of the subject compounds to decrease intraocular pressure. Examples of such assays are described in the following reference, incorporated herein by reference: C. Liljebris, G. Selen, B. Resul, J. Sternschantz, and U. Hacksell, “Derivatives of 17-phenyl-18,19,20-trinorprostaglandin F2α, Isopropyl Ester: Potential Anti-glaucoma Agents”, Journal of Medicinal Chemistry 1995, 38 (2): 289-304.
- While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention.
Claims (48)
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11590123B2 (en) | 2016-08-31 | 2023-02-28 | Aerie Pharmaceuticals, Inc. | Ophthalmic compositions |
US11618748B2 (en) | 2009-05-01 | 2023-04-04 | Aerie Pharmaceuticals, Inc. | Dual mechanism inhibitors for the treatment of disease |
US11891376B2 (en) | 2018-09-14 | 2024-02-06 | Aerie Pharmaceuticals, Inc. | Aryl cyclopropyl-amino-isoquinolinyl amide compounds |
Families Citing this family (59)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9512125B2 (en) * | 2004-11-19 | 2016-12-06 | The Regents Of The University Of California | Substituted pyrazolo[3.4-D] pyrimidines as anti-inflammatory agents |
WO2007008926A1 (en) * | 2005-07-11 | 2007-01-18 | Aerie Pharmaceuticals, Inc. | Isoquinoline compounds |
NZ571182A (en) | 2006-04-04 | 2010-09-30 | Univ California | Pyrazolo[3,4-d]pyrimidines |
EP2526948A1 (en) | 2006-09-20 | 2012-11-28 | Aerie Pharmaceuticals, Inc. | RHO kinase inhibitors |
US8455513B2 (en) * | 2007-01-10 | 2013-06-04 | Aerie Pharmaceuticals, Inc. | 6-aminoisoquinoline compounds |
GB2467670B (en) * | 2007-10-04 | 2012-08-01 | Intellikine Inc | Chemical entities and therapeutic uses thereof |
US8193182B2 (en) | 2008-01-04 | 2012-06-05 | Intellikine, Inc. | Substituted isoquinolin-1(2H)-ones, and methods of use thereof |
SG187425A1 (en) | 2008-01-04 | 2013-02-28 | Intellikine Llc | Certain chemical entities, compositions and methods |
US8455514B2 (en) * | 2008-01-17 | 2013-06-04 | Aerie Pharmaceuticals, Inc. | 6-and 7-amino isoquinoline compounds and methods for making and using the same |
WO2009114874A2 (en) | 2008-03-14 | 2009-09-17 | Intellikine, Inc. | Benzothiazole kinase inhibitors and methods of use |
JP5547099B2 (en) * | 2008-03-14 | 2014-07-09 | インテリカイン, エルエルシー | Kinase inhibitors and methods of use |
CA2730106A1 (en) | 2008-07-08 | 2010-01-14 | Intellikine, Inc. | Kinase inhibitors and methods of use |
WO2010006072A2 (en) * | 2008-07-08 | 2010-01-14 | The Regents Of The University Of California | Mtor modulators and uses thereof |
US8450344B2 (en) | 2008-07-25 | 2013-05-28 | Aerie Pharmaceuticals, Inc. | Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds |
WO2010036380A1 (en) | 2008-09-26 | 2010-04-01 | Intellikine, Inc. | Heterocyclic kinase inhibitors |
EP2358720B1 (en) | 2008-10-16 | 2016-03-02 | The Regents of The University of California | Fused ring heteroaryl kinase inhibitors |
US8476282B2 (en) * | 2008-11-03 | 2013-07-02 | Intellikine Llc | Benzoxazole kinase inhibitors and methods of use |
JP5789252B2 (en) | 2009-05-07 | 2015-10-07 | インテリカイン, エルエルシー | Heterocyclic compounds and uses thereof |
US8980899B2 (en) | 2009-10-16 | 2015-03-17 | The Regents Of The University Of California | Methods of inhibiting Ire1 |
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US8901133B2 (en) | 2010-11-10 | 2014-12-02 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
PE20141303A1 (en) | 2011-01-10 | 2014-10-01 | Infinity Pharmaceuticals Inc | PROCEDURE FOR PREPARING ISOQUINOLINONES AND SOLID FORMS OF ISOQUINOLINONES |
CA2828483A1 (en) | 2011-02-23 | 2012-11-01 | Intellikine, Llc | Combination of kinase inhibitors and uses thereof |
CA2842190A1 (en) | 2011-07-19 | 2013-01-24 | Infinity Pharmaceuticals Inc. | Heterocyclic compounds and uses thereof |
JP6027610B2 (en) | 2011-07-19 | 2016-11-16 | インフィニティー ファーマシューティカルズ, インコーポレイテッド | Heterocyclic compounds and uses thereof |
US8785470B2 (en) | 2011-08-29 | 2014-07-22 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
CA2846496C (en) | 2011-09-02 | 2020-07-14 | The Regents Of The University Of California | Substituted pyrazolo[3,4-d]pyrimidines and uses thereof |
WO2013104829A1 (en) * | 2012-01-13 | 2013-07-18 | Medeia Therapeutics Ltd | Novel arylamide derivatives having antiandrogenic properties |
US8940742B2 (en) | 2012-04-10 | 2015-01-27 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
US8828998B2 (en) | 2012-06-25 | 2014-09-09 | Infinity Pharmaceuticals, Inc. | Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors |
JP2015532287A (en) | 2012-09-26 | 2015-11-09 | ザ・リージエンツ・オブ・ザ・ユニバーシテイー・オブ・カリフオルニア | IRE1 regulation |
CA2905830C (en) | 2013-03-12 | 2022-01-18 | Curegenix Inc. | Quinazoline and naphthyridine derivatives useful in the treatment of cancer |
US9481667B2 (en) | 2013-03-15 | 2016-11-01 | Infinity Pharmaceuticals, Inc. | Salts and solid forms of isoquinolinones and composition comprising and methods of using the same |
WO2014144781A1 (en) | 2013-03-15 | 2014-09-18 | Aerie Pharmaceuticals, Inc. | Combination therapy |
WO2015051241A1 (en) | 2013-10-04 | 2015-04-09 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
PE20160685A1 (en) | 2013-10-04 | 2016-07-23 | Infinity Pharmaceuticals Inc | HETEROCYCLIC COMPOUNDS AND USES OF THEM |
DE202014010806U1 (en) | 2013-10-29 | 2016-09-20 | Mary Kay Inc. | Cosmetic compositions |
JP6701088B2 (en) | 2014-03-19 | 2020-05-27 | インフィニティー ファーマシューティカルズ, インコーポレイテッド | Heterocyclic compounds for use in the treatment of PI3K-gamma mediated disorders |
WO2015160975A2 (en) | 2014-04-16 | 2015-10-22 | Infinity Pharmaceuticals, Inc. | Combination therapies |
EA201790434A1 (en) | 2014-08-22 | 2017-07-31 | Окленд Юнисервисиз Лимитед | CHANNEL MODULATORS |
WO2016053289A1 (en) * | 2014-09-30 | 2016-04-07 | Avon Products, Inc. | Topical compositions and methods for skin lightening |
US9708348B2 (en) | 2014-10-03 | 2017-07-18 | Infinity Pharmaceuticals, Inc. | Trisubstituted bicyclic heterocyclic compounds with kinase activities and uses thereof |
EP3313396B1 (en) * | 2015-06-26 | 2021-12-15 | The Regents of The University of Michigan | G protein-coupled receptor kinase inhibitors and methods for use of the same |
CA2998469A1 (en) | 2015-09-14 | 2017-03-23 | Infinity Pharmaceuticals, Inc. | Solid forms of isoquinolinones, and process of making, composition comprising, and methods of using the same |
US9643927B1 (en) | 2015-11-17 | 2017-05-09 | Aerie Pharmaceuticals, Inc. | Process for the preparation of kinase inhibitors and intermediates thereof |
CN108601355B (en) | 2015-11-17 | 2021-03-30 | 爱瑞制药公司 | Process for preparing kinase inhibitors and intermediates thereof |
US10759806B2 (en) | 2016-03-17 | 2020-09-01 | Infinity Pharmaceuticals, Inc. | Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as PI3K kinase inhibitors |
WO2017214269A1 (en) | 2016-06-08 | 2017-12-14 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
MX2018016227A (en) | 2016-06-24 | 2019-07-08 | Infinity Pharmaceuticals Inc | Combination therapies. |
WO2018034702A1 (en) * | 2016-08-19 | 2018-02-22 | Aerie Pharmaceuticals, Inc. | Beta-amino-isoquinolinyl amide compounds |
WO2018183911A1 (en) | 2017-03-31 | 2018-10-04 | Aerie Pharmaceuticals, Inc. | Aryl cyclopropyl-amino-isoquinolinyl amide compounds |
MX2019013561A (en) * | 2017-05-19 | 2022-02-09 | Nflection Therapeutics Inc | Pyrrolopyridine-aniline compounds for treatment of dermal disorders. |
CN107441045B (en) | 2017-07-21 | 2018-10-19 | 广州源生医药科技有限公司 | Liposomal formulation and preparation method thereof for delivering Wnt signal path inhibitor |
JP7416700B2 (en) | 2017-11-14 | 2024-01-17 | ザ スキーペンズ アイ リサーチ インスティチュート インコーポレイテッド | Methods of RUNX1 inhibition for the treatment of conditions associated with proliferative vitreoretinopathy and epithelial-mesenchymal transition |
EP3765449A4 (en) * | 2018-03-14 | 2022-03-30 | Aerie Pharmaceuticals, Inc. | Amino-benzoisothiazole and amino-benzoisothiadiazole amide compounds |
KR20200142022A (en) * | 2018-03-30 | 2020-12-21 | 에어리 파마슈티컬즈, 인코포레이티드 | Monovalent-(acid) salts of 6-aminoisoquinoline and uses thereof |
EP3843845A4 (en) | 2018-08-29 | 2022-05-11 | University Of Massachusetts | Inhibition of protein kinases to treat friedreich ataxia |
WO2020047496A1 (en) * | 2018-08-31 | 2020-03-05 | Aerie Pharmaceuticals, Inc. | Isoquinoline-steroid conjugates and uses thereof |
CA3167785A1 (en) * | 2020-02-25 | 2021-09-02 | Tes Pharma S.R.L. | Heterocyclic compounds for modulating nr2f6 |
Family Cites Families (152)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2623228C3 (en) * | 1976-05-24 | 1981-09-10 | Ludwig Merckle Kg Chem. Pharm. Fabrik, 7902 Blaubeuren | N-acyl-substituted benzamides, processes for their preparation and pharmaceuticals containing such benzamides |
JPS5587771A (en) | 1978-12-27 | 1980-07-02 | Teikoku Hormone Mfg Co Ltd | 1-phenylisoquinoline derivative |
US4456757A (en) | 1981-03-20 | 1984-06-26 | Asahi Kasei Kogyo Kabushiki Kaisha | Isoquinolinesulfonyl derivatives and process for the preparation thereof |
JPS5993054A (en) | 1982-11-18 | 1984-05-29 | Asahi Chem Ind Co Ltd | Isoquinolinesulfonic acid amide derivative |
JPS6153252A (en) * | 1984-08-24 | 1986-03-17 | Hokuriku Seiyaku Co Ltd | P-aminosalicylic acid derivative |
DK8386A (en) | 1986-01-15 | 1987-07-09 | Tpo Pharmachim | NEW N-SUBSTITUTED 1-BENZYL-2-CARBAMOYLTETRAHYDROISOQUINOLINES AND PROCEDURES FOR THE PREPARATION OF THE SAME |
US4911928A (en) * | 1987-03-13 | 1990-03-27 | Micro-Pak, Inc. | Paucilamellar lipid vesicles |
US5591887A (en) | 1987-04-30 | 1997-01-07 | R-Tech Ueno, Ltd. | Prostaglandins of the F series |
JPH01139528A (en) * | 1987-11-24 | 1989-06-01 | Showa Denko Kk | Antiulcerative |
ATE101342T1 (en) | 1988-09-06 | 1994-02-15 | Kabi Pharmacia Ab | PROSTAGLAND INDIVIDUALS FOR THE TREATMENT OF GREEN STAR OR OCULAR HYPERTENSION. |
EP0389995B1 (en) | 1989-03-28 | 1995-05-31 | Nisshin Flour Milling Co., Ltd. | Isoquinoline derivatives for the treatment of glaucoma or ocular hypertension |
KR920008026A (en) | 1990-10-24 | 1992-05-27 | 오노 화아마슈티칼 캄파니 리미팃드 | Isoquinolinone derivatives or nontoxic acid addition salts thereof or hydrates thereof, methods for preparing the same, and pharmaceutical compositions comprising the same |
WO1993018028A1 (en) | 1992-03-12 | 1993-09-16 | Smithkline Beecham Plc | Indole derivatives as 5ht1c antagonists |
US5972991A (en) | 1992-09-21 | 1999-10-26 | Allergan | Cyclopentane heptan(ene) oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents |
DE4332168A1 (en) * | 1993-02-22 | 1995-03-23 | Thomae Gmbh Dr K | Cyclic derivatives, pharmaceutical compositions containing these compounds and process for their preparation |
US5510383A (en) | 1993-08-03 | 1996-04-23 | Alcon Laboratories, Inc. | Use of cloprostenol, fluprostenol and their salts and esters to treat glaucoma and ocular hypertension |
US6124344A (en) | 1993-12-28 | 2000-09-26 | Allergan Sales, Inc. | Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents |
US5462968A (en) | 1994-01-19 | 1995-10-31 | Allergan, Inc. | EP2 -receptor agonists as agents for lowering intraocular pressure |
US5698733A (en) | 1994-09-30 | 1997-12-16 | Alcon Laboratories, Inc. | Use of 9-deoxy prostaglandin derivatives to treat glaucoma |
WO1998021180A1 (en) | 1995-06-07 | 1998-05-22 | Alcon Laboratories, Inc. | Conformationally rigid aryl- or heteroaryl prostaglandins for use in glaucoma therapy |
US5814660A (en) | 1995-12-22 | 1998-09-29 | Alcon Laboratories, Inc. | 9-oxa prostaglandin analogs as ocular hypotensives |
ES2225897T3 (en) | 1995-12-22 | 2005-03-16 | Alcon Laboratories, Inc. | ANALOGS OF TETRAHYDROFURAN REPLACED PROSTAGLANDINAS AS OCULAR HYPOTENSORS. |
US5866602A (en) | 1995-12-22 | 1999-02-02 | Alcon Laboratories, Inc. | Keto-substituted tetrahydrofuran analogs of prostaglandins as ocular hypotensives |
US6586425B2 (en) * | 1996-02-21 | 2003-07-01 | Wisconsin Alumni Research Foundation | Cytoskeletal active agents for glaucoma therapy |
US5798380A (en) * | 1996-02-21 | 1998-08-25 | Wisconsin Alumni Research Foundation | Cytoskeletal active agents for glaucoma therapy |
WO1998012175A1 (en) | 1996-09-17 | 1998-03-26 | Asahi Glass Company Ltd. | Fluorinated prostaglandin derivatives and medicines |
DE69705421T2 (en) | 1996-11-12 | 2002-05-16 | Alcon Lab Inc | 15-FLUORO-PROSTAGLANDINE AS AN EYE PRESSURING AGENT |
US6353014B1 (en) | 1996-11-12 | 2002-03-05 | Alcon Laboratories, Inc. | 15-ketal postaglandins for the treatment of glaucoma or ocular hypertension |
WO1998020880A2 (en) | 1996-11-12 | 1998-05-22 | Alcon Laboratories, Inc. | 11-halo prostaglandins for the treatment of glaucoma or ocular hypertension |
US6235779B1 (en) | 1996-11-12 | 2001-05-22 | Alcon Laboratories, Inc. | Use of cis-Δ4 analogs of prostaglandins as ocular hypotensives |
WO1998039293A2 (en) | 1997-03-07 | 1998-09-11 | Alcon Laboratories, Inc. | 13-thia prostaglandins for use in glaucoma therapy |
AU725677B2 (en) | 1997-05-09 | 2000-10-19 | Mount Sinai School Of Medicine Of The City University Of New York, The | 8-iso-prostaglandins for glaucoma therapy |
US5891646A (en) * | 1997-06-05 | 1999-04-06 | Duke University | Methods of assaying receptor activity and constructs useful in such methods |
SE9702706D0 (en) | 1997-07-11 | 1997-07-11 | Pharmacia & Upjohn Ab | Prostaglandin derivatives devoid of side effects for the treatment of glaucoma |
WO2000077027A2 (en) | 1999-06-14 | 2000-12-21 | Tularik Limited | Serine protease inhibitors |
IL134840A0 (en) | 1997-09-09 | 2001-05-20 | Procter & Gamble | Aromatic c16-c20-substituted tetrahydro prostaglandins useful as fp agonists |
IL134792A0 (en) | 1997-09-09 | 2001-04-30 | Procter & Gamble | Aromatic c16-c20-substituted tetrahydro prostaglandins useful as fp agonists |
ATE270660T1 (en) | 1997-09-09 | 2004-07-15 | Univ Duke | AROMATIC C16-C20-SUBSTITUTED TETRAHYDRO-PROSTAGLANDINS USABLE LIKE FP AGONISTS |
US5877211A (en) | 1997-11-21 | 1999-03-02 | Allergan | EP2 receptor agonists as neuroprotective agents for the eye |
AU1709699A (en) | 1997-12-22 | 1999-07-12 | Alcon Laboratories, Inc. | 13-oxa prostaglandins for the treatment of glaucoma and ocular hypertension |
CN1146423C (en) | 1998-07-14 | 2004-04-21 | 阿尔康实验室公司 | Prostaglandin product |
TWI249520B (en) | 1998-07-15 | 2006-02-21 | Ono Pharmaceutical Co | 5-Thia-omega-substituted phenyl prostaglandin E derivatives, method for producing the same and medicines containing the same as the active ingredient |
US6720175B1 (en) * | 1998-08-18 | 2004-04-13 | The Johns Hopkins University School Of Medicine | Nucleic acid molecule encoding homer 1B protein |
US20020065296A1 (en) | 1999-01-13 | 2002-05-30 | Bayer Corporation | Heteroaryl ureas containing nitrogen hetero-atoms as p38 kinase inhibitors |
CA2374793A1 (en) | 1999-05-24 | 2000-11-30 | Penglie Zhang | Inhibitors of factor xa |
EP1249233B9 (en) | 1999-11-26 | 2009-08-05 | Shionogi & Co., Ltd. | Npyy5 antagonists |
HUP0203973A3 (en) | 1999-12-28 | 2004-07-28 | Eisai Co Ltd | Heterocyclic compounds having sulfonamide groups, pharmaceutical compositions containing them and their use |
YU54202A (en) | 2000-01-18 | 2006-01-16 | Agouron Pharmaceuticals Inc. | Indazole compounds,pharmaceutical compositions,and methods for mediating or inhibiting cell proliferation |
HN2001000008A (en) | 2000-01-21 | 2003-12-11 | Inc Agouron Pharmaceuticals | AMIDA COMPOSITE AND PHARMACEUTICAL COMPOSITIONS TO INHIBIT PROTEINKINASES, AND THE INSTRUCTIONS FOR USE |
JP4039856B2 (en) * | 2000-02-03 | 2008-01-30 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Integrin expression inhibitor |
US6410566B1 (en) * | 2000-05-16 | 2002-06-25 | Teijin Limited | Cyclic amine derivatives and their use as drugs |
US6908741B1 (en) * | 2000-05-30 | 2005-06-21 | Transtech Pharma, Inc. | Methods to identify compounds that modulate RAGE |
US6323228B1 (en) | 2000-09-15 | 2001-11-27 | Abbott Laboratories | 3-substituted indole angiogenesis inhibitors |
US7312358B2 (en) | 2000-10-17 | 2007-12-25 | Laboratoires Serono Sa | Pharmaceutically active sulfanilide derivatives |
US7163800B2 (en) * | 2000-11-03 | 2007-01-16 | Molecular Devices Corporation | Methods of screening compositions for G protein-coupled receptor desensitization inhibitory activity |
CA2440037C (en) * | 2001-03-05 | 2010-02-16 | Transtech Pharma, Inc. | Benzimidazole derivatives for modulating the rage receptor |
JP4366936B2 (en) | 2001-04-20 | 2009-11-18 | バイエル コーポレイション | Inhibition of RAF kinase using quinolyl, isoquinolyl or pyridylurea |
US6956035B2 (en) * | 2001-08-31 | 2005-10-18 | Inotek Pharmaceuticals Corporation | Isoquinoline derivatives and methods of use thereof |
AU2003202263A1 (en) * | 2002-01-10 | 2003-07-30 | Bayer Healthcare Ag | Roh-kinase inhibitors |
TW200306819A (en) | 2002-01-25 | 2003-12-01 | Vertex Pharma | Indazole compounds useful as protein kinase inhibitors |
AR038420A1 (en) | 2002-02-15 | 2005-01-12 | Glaxo Group Ltd | AMIDA COMPOSITE, PROCEDURE FOR THE PREPARATION OF THE SAME, ITS USE FOR THE MANUFACTURE OF A MEDICINAL PRODUCT AND PHARMACEUTICAL COMPOSITION THAT INCLUDES IT |
US20040180889A1 (en) | 2002-03-01 | 2004-09-16 | Pintex Pharmaceuticals, Inc. | Pin1-modulating compounds and methods of use thereof |
DK1482931T3 (en) * | 2002-03-05 | 2011-12-19 | Transtech Pharma Inc | Mono- and bicyclic azole derivatives that inhibit the interaction of ligands with RAGE |
GB0206876D0 (en) | 2002-03-22 | 2002-05-01 | Merck Sharp & Dohme | Therapeutic agents |
US7645878B2 (en) | 2002-03-22 | 2010-01-12 | Bayer Healthcare Llc | Process for preparing quinazoline Rho-kinase inhibitors and intermediates thereof |
JP2005525814A (en) * | 2002-05-13 | 2005-09-02 | ノラック バイオサイエンシズ インコーポレイテッド | Constitutively translocated cell lines |
EP1541151B1 (en) | 2002-08-29 | 2012-02-22 | Santen Pharmaceutical Co., Ltd. | REMEDY FOR GLAUCOMA COMPRISING Rho KINASE INHIBITOR AND PROSTAGLANDINS |
CA2496891A1 (en) * | 2002-08-30 | 2004-03-18 | Anges Mg, Inc. | Novel actin-related cytoskeletal protein lacs |
JPWO2004024717A1 (en) | 2002-09-12 | 2006-01-05 | 麒麟麦酒株式会社 | Isoquinoline derivative having kinase inhibitory activity and medicament containing the same |
AU2003285952A1 (en) | 2002-10-21 | 2004-05-13 | Irm Llc | Pyrrolidones with anti-hiv activity |
US7557129B2 (en) | 2003-02-28 | 2009-07-07 | Bayer Healthcare Llc | Cyanopyridine derivatives useful in the treatment of cancer and other disorders |
PT1632477T (en) * | 2003-06-12 | 2017-04-04 | Astellas Pharma Inc | Benzamide derivative or salt thereof |
WO2005020921A2 (en) | 2003-08-29 | 2005-03-10 | Exelixis, Inc. | C-kit modulators and methods of use |
US20070123561A1 (en) * | 2003-10-06 | 2007-05-31 | Dennis Lee | Preparation of 1,7-disubstituted azabensimidazoles as kinase inhibitors |
JP2007008816A (en) | 2003-10-15 | 2007-01-18 | Ube Ind Ltd | New isoquinoline derivative |
CA2542609C (en) * | 2003-10-15 | 2013-06-04 | Ube Industries, Ltd. | Novel indazole derivatives |
DE10348023A1 (en) | 2003-10-15 | 2005-05-19 | Imtm Gmbh | New alanyl aminopeptidase inhibitors for the functional manipulation of different cells and for the treatment of immunological, inflammatory, neuronal and other diseases |
SE0400284D0 (en) * | 2004-02-10 | 2004-02-10 | Astrazeneca Ab | Novel compounds |
JP2005227441A (en) | 2004-02-12 | 2005-08-25 | Konica Minolta Medical & Graphic Inc | Photothermographic imaging material |
US7592357B2 (en) * | 2004-02-20 | 2009-09-22 | Smithkline Beecham Corporation | Compounds |
US20080096238A1 (en) * | 2004-03-30 | 2008-04-24 | Alcon, Inc. | High throughput assay for human rho kinase activity with enhanced signal-to-noise ratio |
DE102004017438A1 (en) * | 2004-04-08 | 2005-11-03 | Bayer Healthcare Ag | Hetaryloxy-substituted phenylaminopyrimidines |
US7453002B2 (en) * | 2004-06-15 | 2008-11-18 | Bristol-Myers Squibb Company | Five-membered heterocycles useful as serine protease inhibitors |
WO2006009889A1 (en) * | 2004-06-17 | 2006-01-26 | Smithkline Beecham Corporation | Novel inhibitors of rho-kinases |
ES2535364T3 (en) | 2004-06-18 | 2015-05-08 | Tobii Ab | Eye control of computer equipment |
PT1786785E (en) | 2004-08-26 | 2010-05-21 | Pfizer | Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors |
WO2006041119A1 (en) | 2004-10-13 | 2006-04-20 | Eisai R & D Management Co., Ltd. | Hydrazide derivatives |
UY29198A1 (en) | 2004-11-09 | 2006-05-31 | Cancer Rec Tech Ltd | SUBSTITUTED DERIVATIVES OF QUINAZOLINONA AND REPLACED DERIVATIVES OF QUINAZOLINA-2, 4-DIONA, COMPOSITIONS CONTAINING THEM, PREPARATION PROCEDURES AND APPLICATIONS |
GB0425026D0 (en) | 2004-11-12 | 2004-12-15 | Biofocus Discovery Ltd | Compounds which bind to the active site of protein kinase enzymes |
WO2006062982A2 (en) | 2004-12-07 | 2006-06-15 | Locus Pharmaceuticals, Inc. | Urea inhibitors of map kinases |
WO2007076360A1 (en) | 2005-12-22 | 2007-07-05 | Alcon Research, Ltd. | (indazol-5-yl)-pyrazines and (1,3-dihydro-indol-2-one)- pyrazines for treating rho kinase-mediated diseases and conditions |
EP1833832A1 (en) | 2004-12-31 | 2007-09-19 | GPC Biotech AG | Napthyridine compounds as rock inhibitors |
EP1856053A1 (en) | 2005-01-14 | 2007-11-21 | Millennium Pharmaceuticals, Inc. | Cinnamide and hydrocinnamide derivatives with raf-kinase inhibitory activity |
KR20090028846A (en) | 2005-01-28 | 2009-03-19 | 아이알엠 엘엘씨 | Phenyl-substituted pyrrolidones |
EP1851197A2 (en) * | 2005-02-09 | 2007-11-07 | Microbia, Inc. | Phenylazetidinone derivatives |
RU2007140957A (en) * | 2005-05-25 | 2009-06-27 | Вайет (Us) | METHODS FOR SYNTHESIS OF 6-ALKYLAMINOCHINOLINE DERIVATIVES |
SE529058C2 (en) | 2005-07-08 | 2007-04-17 | Plasma Surgical Invest Ltd | Plasma generating device, plasma surgical device, use of a plasma surgical device and method for forming a plasma |
WO2007008942A2 (en) | 2005-07-11 | 2007-01-18 | Aerie Pharmaceuticals, Inc. | Phenylamino-acetic acid [1-(pyridin-4-yl)-methylidene]-hydrazide derivatives and related compounds as modulators of g protein-coupled receptor kinases for the treatment of eye diseases |
WO2007008926A1 (en) | 2005-07-11 | 2007-01-18 | Aerie Pharmaceuticals, Inc. | Isoquinoline compounds |
US7381635B2 (en) * | 2005-07-18 | 2008-06-03 | International Business Machines Corporation | Method and structure for reduction of soft error rates in integrated circuits |
ATE551059T1 (en) * | 2005-10-26 | 2012-04-15 | Asahi Kasei Pharma Corp | FASUDIL IN COMBINATION WITH BOSENTAN FOR THE TREATMENT OF PULMONARY ARTERIAL HYPERTENSION |
TW200738682A (en) | 2005-12-08 | 2007-10-16 | Organon Nv | Isoquinoline derivatives |
AR057252A1 (en) * | 2005-12-27 | 2007-11-21 | Alcon Mfg Ltd | INHIBITION OF RHO KINASE MEDIATED BY ARNI FOR THE TREATMENT OF EYE DISORDERS |
EP1968940B1 (en) | 2005-12-30 | 2014-04-02 | Novartis AG | 3 , 5-substitued piperidine compounds as renin inhibitors |
US8012966B2 (en) | 2006-01-27 | 2011-09-06 | Shanghai Hengrui Pharmaceutical Co., Ltd. | Pyrrolo [3,2-c] pyridine-4-one 2-indolinone protein kinase inhibitors |
JP5476559B2 (en) | 2006-02-10 | 2014-04-23 | 国立大学法人九州大学 | Novel substrate polypeptide of phosphorylase |
AU2007221049A1 (en) | 2006-02-28 | 2007-09-07 | Amgen Inc. | Cinnoline and quinazoline derivates as phosphodiesterase 10 inhibitors |
JP2007246466A (en) | 2006-03-17 | 2007-09-27 | Osaka Univ | Neurological function reconstruction method using rho kinase inhibitor on transplantation of olfactory mucosa for damage of central nerve |
WO2007142323A1 (en) | 2006-06-08 | 2007-12-13 | Ube Industries, Ltd. | Novel indazole derivative having spiro ring structure in side chain |
WO2008036459A2 (en) | 2006-07-20 | 2008-03-27 | Borchardt Allen J | Inhibitors of rho kinase |
US20080021026A1 (en) * | 2006-07-20 | 2008-01-24 | Mehmet Kahraman | Benzothiophene inhibitors of rho kinase |
CN101495117B (en) | 2006-07-31 | 2012-08-15 | 千寿制药株式会社 | Aqueous liquid preparation containing amide compound |
EP2526948A1 (en) | 2006-09-20 | 2012-11-28 | Aerie Pharmaceuticals, Inc. | RHO kinase inhibitors |
WO2008054599A2 (en) | 2006-09-27 | 2008-05-08 | Surface Logix, Inc. | Rho kinase inhibitors |
US20110039893A1 (en) | 2006-10-11 | 2011-02-17 | Takeda Pharmaceutical Company Limited | Gsk-3beta inhibitor |
US8949825B1 (en) | 2006-10-17 | 2015-02-03 | Manageiq, Inc. | Enforcement of compliance policies in managed virtual systems |
WO2008049000A2 (en) | 2006-10-18 | 2008-04-24 | United Therapeutics Corporation | Combination therapy for pulmonary arterial hypertension |
WO2008049919A2 (en) | 2006-10-26 | 2008-05-02 | Devgen N.V. | Rho kinase inhibitors |
US8071779B2 (en) | 2006-12-18 | 2011-12-06 | Inspire Pharmaceuticals, Inc. | Cytoskeletal active rho kinase inhibitor compounds, composition and use |
WO2008079945A2 (en) | 2006-12-20 | 2008-07-03 | University Of South Florida | Rock inhibitors and uses thereof |
AR064420A1 (en) * | 2006-12-21 | 2009-04-01 | Alcon Mfg Ltd | OPHTHALMIC PHARMACEUTICAL COMPOSITIONS THAT INCLUDE AN EFFECTIVE AMOUNT OF ANALOGS OF 6-AMINOIMIDAZO [1,2B] PIRIDAZINAS, USEFUL FOR THE TREATMENT OF GLAUCOMA AND / OR CONTROL THE NORMAL OR ELEVATED INTRAOCULAR PRESSURE (IOP). |
DK2132194T3 (en) | 2006-12-27 | 2011-06-27 | Sanofi Aventis | Substituted isoquinolines and their use as Rho kinase inhibitors |
PT2125744E (en) | 2006-12-27 | 2011-07-01 | Sanofi Aventis | Cycloalkylamine substituted isoquinolone and isoquinolinone derivatives |
CN101616909B (en) | 2006-12-27 | 2013-09-11 | 塞诺菲-安万特股份有限公司 | Substituted isoquinoline and isoquinolinone derivatives as inhibitors of rho-kinase |
CA2673920C (en) | 2006-12-27 | 2015-03-24 | Sanofi-Aventis | Cycloalkylamine substituted isoquinoline derivatives |
KR101474228B1 (en) | 2006-12-27 | 2014-12-18 | 사노피 | Cycloalkylamine substituted isoquinolone derivatives |
CA2673918C (en) * | 2006-12-27 | 2015-02-17 | Sanofi-Aventis | Substituted isoquinoline and isoquinolinone derivatives |
PT2102164E (en) | 2006-12-27 | 2011-01-21 | Sanofi Aventis | Cycloalkylamine substituted isoquinoline and isoquinolinone derivatives |
US8455513B2 (en) * | 2007-01-10 | 2013-06-04 | Aerie Pharmaceuticals, Inc. | 6-aminoisoquinoline compounds |
JP2010523689A (en) | 2007-04-10 | 2010-07-15 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Glucocorticoid mimetics, process for producing the same, pharmaceutical composition and use thereof |
US8618097B2 (en) | 2007-07-05 | 2013-12-31 | Array Biopharma, Inc. | Pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
NZ585980A (en) | 2007-11-16 | 2012-04-27 | Vertex Pharma | Isoquinoline modulators of atp-binding cassette transporters |
US8455514B2 (en) | 2008-01-17 | 2013-06-04 | Aerie Pharmaceuticals, Inc. | 6-and 7-amino isoquinoline compounds and methods for making and using the same |
US8450344B2 (en) | 2008-07-25 | 2013-05-28 | Aerie Pharmaceuticals, Inc. | Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds |
WO2010019910A1 (en) | 2008-08-15 | 2010-02-18 | N30 Pharmaceuticals, Llc | Novel pyrrole inhibitors of s-nitrosoglutathione reductase as therapeutic agents |
EP2424842B1 (en) * | 2009-05-01 | 2015-10-28 | Aerie Pharmaceuticals, Inc. | Dual mechanism inhibitors for the treatment of disease |
DK2444395T3 (en) | 2009-06-19 | 2016-03-14 | Western Therapeutics Inst Inc D | substituted isoquinoline |
WO2011085351A2 (en) | 2010-01-11 | 2011-07-14 | The Johns Hopkins University | Method of treating kcnq related disorders |
US20130296363A1 (en) | 2010-09-01 | 2013-11-07 | Ambit Biosciences Corporation | Quinoline and isoquinoline derivatives for use as jak modulators |
US20120264681A1 (en) | 2010-11-08 | 2012-10-18 | Healor Ltd. | Buffered ophthalmic compositions and methods of use thereof |
TW201906614A (en) | 2011-02-04 | 2019-02-16 | 日商興和股份有限公司 | Eye drops for the prevention or treatment of glaucoma or ocular hypertension |
EP2671883A1 (en) | 2012-06-05 | 2013-12-11 | Bioprojet | New 6,11-dihydro-5H-benzo[d]imidazo[1,2-a]azepines derivatives as histamine H4 receptor ligands |
RU2015106915A (en) | 2012-08-01 | 2016-09-20 | Мерк Шарп И Доум Корп. | Α7 NICOTINE ACETYLCHOLINE RECEPTOR MODULATORS AND THEIR APPLICATION |
WO2014144781A1 (en) | 2013-03-15 | 2014-09-18 | Aerie Pharmaceuticals, Inc. | Combination therapy |
US20160016951A1 (en) | 2014-07-17 | 2016-01-21 | Merck Patent Gmbh | Novel naphthyridines and isoquinolines and their use as cdk8/19 inhibitors |
WO2016123627A1 (en) | 2015-01-30 | 2016-08-04 | Vanderbilt University | Isoquiniline and napthalene-substituted compounds as mglur4 allosteric potentiators, compounds, and methods of treating neurological dysfunction |
US9770466B2 (en) | 2015-07-02 | 2017-09-26 | Veloce Biopharma, Llc | Ophthalmic composition and methods of use |
US9643927B1 (en) | 2015-11-17 | 2017-05-09 | Aerie Pharmaceuticals, Inc. | Process for the preparation of kinase inhibitors and intermediates thereof |
WO2018034702A1 (en) | 2016-08-19 | 2018-02-22 | Aerie Pharmaceuticals, Inc. | Beta-amino-isoquinolinyl amide compounds |
KR102568082B1 (en) | 2016-08-31 | 2023-08-17 | 에어리 파마슈티컬즈, 인코포레이티드 | ophthalmic composition |
WO2018183911A1 (en) | 2017-03-31 | 2018-10-04 | Aerie Pharmaceuticals, Inc. | Aryl cyclopropyl-amino-isoquinolinyl amide compounds |
KR20200142022A (en) | 2018-03-30 | 2020-12-21 | 에어리 파마슈티컬즈, 인코포레이티드 | Monovalent-(acid) salts of 6-aminoisoquinoline and uses thereof |
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US11590123B2 (en) | 2016-08-31 | 2023-02-28 | Aerie Pharmaceuticals, Inc. | Ophthalmic compositions |
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