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  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D231/38—Nitrogen atoms
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  • A61P35/00—Antineoplastic agents
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  • A61P37/00—Drugs for immunological or allergic disorders
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D231/38—Nitrogen atoms
  • C07D231/40—Acylated on said nitrogen atom
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing alicyclic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

• the subject invention relates to pyrazole derivatives, pharmaceutical compositions comprising such derivatives and methods of using such derivatives to treat abnormal cell growth and certain diseases and conditions of the central nervous system.
• the compounds of the present invention act as inhibitors of cyciin-dependent protein kinase enzymes cdk5 (cyciin-dependent protein kinase 5) and cdk2 (cyciin-dependent protein kinase 2).
• the compounds of the present invention also are inhibitors of the enzyme GSK-3 (glygocen synthase kinase-3) enzyme.
• cdk5 serine/threonine kinase cdk5 along with its cofactor p25 (or the longer cofactor, p35) has been linked to neurodegenerative disorders, and inhibitors of cdk5/p25 (or cdk5/p35) are therefore useful for the treatment of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, stroke, or Huntington's disease.
• Treatment of such neurodegenerative disorders using cdk5 inhibitors is supported by the finding that cdk5 is involved in the phosphorylation of tau protein (J. Biochem, 117, 741-749 (1995)).
• cdk5 also phosphorylates Dopamine and Cyclic AMP-Regulated Phosphorprotein (DARPP-32) at threonine 75 and is thus indicated in having a role in dopaminergic neurotransmission (Nature, 402, 669-671 (1999)).
• DARPP-32 Cyclic AMP-Regulated Phosphorprotein
• the serine/threonine kinase cdk2 is essential for normal cell cycling and plays a critical role in disorders arising from abnormal cell cycling, a common characteristic of many oncological disorders. Inhibitors of cdk2 are therefore useful for the treatment of various types of cancer and other diseases or conditions related to abnormal cell growth (Meijer, et al., Properties and Potential-applications of Chemical Inhibitors of Cyciin-dependent Kinsases, Pharmacology & therapeutics, 82 (2-3), 279-284 (1999); Sausville, et al., Cyciin-dependent Kinases: Initial Approaches to Exploit a Novel Therapeutic Target, Pharmacology & therapeutics 82 (2-3) 285-292 (1999)).
• GSK-3 is a serine/threonine protein kinase. It is one of several protein kinases which phosphorylate glycogen synthase (Embi, et al., Eur. J. Biochem. 107:519-527 (1980); Hemmings, et al., Eur. J. Biochem. 119:443-451 (1982)). GSK-3 exists in two isoforms, and ⁇ , in vertebrates, reported as having a monomeric structure of 49kD and 47kD respectively. Both isoforms phosphorylate muscle glycogen synthase (Cross, et al., Biochemical Journal 303: 21-26 (1994)).
• GSK-3 has been implicated in numerous different disease states and conditions. For example, Chen, et al, Diabetes 43: 1234-1241 (1994) have suggested that an increase in GSK-3 activity can be important in Type 2 diabetes. Increased GSK-3 expression in diabetic muscle is also though to contribute to the impaired glycogen synthase activity and skeletal muscle insulin resistance present in Type 2 diabetes (Nikoulina, et al., Diabetes 49: 263-271 (2000)). Also, a higher activity of a type 1 protein phosphatase measured in immotile sperm was attributed to higher GSK-3 activity and was indicated as responsible for holding the sperm motility in check (Vijayaraghavan, et al. Biology of Reproduction 54: 709-718 (1996)).
• GSK-3 activity has also been associated with Alzheimer's disease and mood disorders such as bipolar disorder (WO 97/41854).
• GSK-3 has furthermore been implicated in hair loss, schizophrenia, and neurodegeneration, including both chronic neurodegenerative diseases (such as Alzheimer's, supra) and neurotrauma, for example stroke, traumatic brain injury, and spinal cord trauma.
• R 1 is a straight chain or branched (C.
• R 4 is a straight chain or a branched (C r C 8 )alkyl, a straight chain or a branched (C 2 - C 8 )alkenyl, a straight chain or branched (C 2 -C 8 alkynyl), (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )cycloalkenyl, (3-8 membered) heterocycloalkyl, (C 5 -C 11 )bicycloalkyl, (C C ⁇ bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C 6 -C 14 )aryl, or (5-14 membered) heteroaryl; and wherein R 4 is optionally substituted with from one to three
• Amino-substituted pyrazoles can exist as mixtures of tautomeric isomers in equilibrium with one another.
• the present invention includes all such tautomers of compounds of formula 1, and references herein to compounds of formula 1, unless otherwise indicated, encompass also the tautomers of compounds of formula 1.
• Compounds of formula 1 of the invention are inhibitors of serine/threonine kinases, especially cyciin-dependent kinases such as cdk ⁇ and cdk2, and are useful for the treatment of neurodegenerative disorders and other CNS disorders, and of abnormal cell growth, including cancer.
• the compounds of formula 1 are particularly useful in inhibiting cdk5.
• the compounds of formula 1 are also useful as inhibitors of GSK-3.
• alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, and t-butyl.
• alkenyl as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon double bond wherein alkyl is as defined above. Examples of alkenyl include, but are not limited to, ethenyl and propenyi.
• alkynyl as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above.
• alkynyl groups include, but are not limited to, ethynyl and 2-propynyl.
• cycloalkyl includes non- aromatic saturated cyclic alkyl moieties wherein alkyl is as defined above.
• examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
• Bicycloalkyl groups are non-aromatic saturated carbocyclic groups consisting of two rings, wherein said rings share one or two carbon atoms.
• bicycloalkyl groups include spiro groups and fused ring groups.
• bicycloalkyl groups include, but are not limited to, bicyclo-[3.1.0]- hexyl, norbornyl, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[4.3]octyl, and spiro[4.2]heptyl.
• Cycloalkenyl and “bicycloalkenyl” refer to non-aromatic carbocyclic cycloalkyl and bicycloalkyl moieties as defined above, except comprising one or more carbon-carbon double bonds connecting carbon ring members (an “endocyclic” double bond) and/or one or more carbon-carbon double bonds connecting a carbon ring member and an adjacent non-ring carbon (an “exocyclic” double bond).
• Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl and cyclobutenyl, and a non-limiting example of a bicycloalkenyl group is norbornenyl.
• Cycloalkyl, cycloalkenyl, bicycloalkyl, and bicycloalkenyl groups also include groups that are substituted with one or more oxo moieties. Examples of such groups with oxo moieties are oxocyclopentyl, oxocyclobutyl, oxocyclopentenyl, and norcamphoryl.
• aryl includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl, naphthyl, indenyl, and fluorenyl.
• heterocyclic refers to non-aromatic cyclic groups containing one or more heteroatoms, prefereabiy from one to four heteroatoms, each selected from O, S and N.
• Heterobicycloalkyl are non-aromatic two- ringed cyclic groups, wherein said rings share one or two atoms, and wherein at least one of the rings contains a heteroatom (O, S, or N).
• Heterobicycloalkyl groups for purposes of the present invention, and unless otherwise indicated, include spiro groups and fused ring groups.
• each ring in the heterobicycloalkyl contains up to four heteroatoms (i.e. from zero to four heteroatoms, provided that at least one ring contains at least one heteroatom).
• the heterocyclic groups of this invention can also include ring systems substituted with one or more oxo moieties.
• non-aromatic heterocyclic groups are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, 1 ,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholino, thiomorpholino, thioxanyl, pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3- dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]
• Heteroaryl refers to aromatic groups containing one or more heteroatoms (O, S, or N), preferably from one to four heteroatoms.
• a multicyclic group containing one or more heteroatoms wherein at least one ring of the group is aromatic is a "heteroaryl” group.
• the heteroaryl groups of this invention can also include ring systems substituted with one or more oxo moieties.
• heteroaryl groups are pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,
• a group derived from pyrrole may be pyrrol- 1-yl (N-attached) or pyrrol-3-yl (C-attached).
• the terms referring to the groups also encompass all possible tautomers.
• R 3 is -(CR 10 R 11 ) n -, and n is zero.
• R 3 is -(CR 10 R 1 ) n -, n is zero, and R 4 is (C 6 -C 14 )aryl or (5-14 membered) heteroaryl, each optionally substituted as recited above.
• a compound of formula 1 wherein R 1 is optionally substituted (C 3 -C 8 )cycloalkyl or optionally substituted bicycloalkyl.
• R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or norbornyl, each optionally substituted as recited above (i.e.
• a compound of formula 1 wherein R 1 is optionally substituted straight chain or branched (C.,-C B )alkyl or optionally substituted straight chain or branched (C 2 -C 8 )alkenyl.
• compounds of formula 1 are provided, but wherein R 2 is hydrogen.
• R 2 is hydrogen, and R 1 is as subdefined in the preceding paragraphs.
• this invention provides a compound of formula 1 wherein R 4 is (C 6 -C 14 )aryl or (5-14 membered) heteroaryl, each optionally substituted.
• R 4 is optionally substituted phenyl or optionally substituted pyridyl.
• R 4 is naphthyl, quinolyl, or isoquinolyl, each optionally substituted.
• R 4 is napthyl, quinolyl, or isoquinolyl, and is unsubstituted.
• R 4 is pyrimidinyl, pyrazinyl, or pyridazyl, and in each case R 4 is optionally substituted.
• R 4 is pyrimidinyl, pyrazinyl, or pyridazyl, and R 4 is unsubstituted.
• Examples of preferred compounds of formula 1 are: (5-cyclobutyl-2H-pyrazol-3-yl)-(3-trifluoromethoxy-phenyl)-amine;
• 6-chloro-pyridine-2-carboxylic acid (c/s-3-[5-(2-naphthalen-1 -yl-acetylamino)-2H- pyrazol-3-yl]-cyclobutyl ⁇ -amide; quinoline-2-carboxylic acid ⁇ c/s-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol-3-yl]- cyclobutyl ⁇ -amide; pyrazine-2-carboxylic acid ⁇ c/s-3-[5-(2-naphthalen-1 -yl-acetylamino)-2H-pyrazol-3-yl]- cyclobutyl ⁇ -amide;
• 6-methyl-pyridine-2-carboxylic acid (3- ⁇ 5-[2-(4-methoxy-phenyl)-acetylamino]-2H- pyrazol-3-yl ⁇ -cyclobutyl)-annide; 6-methyl-pyridine-2-carboxylic acid (3- ⁇ 5-[2-(4-chloro-phenyl)-acetylamino]-2H- pyrazol-3-yl ⁇ -cyclobutyl)-amide; and pharmaceutically acceptable salts of said compounds.
• Salts of compounds of formula 1 can be obtained by forming salts with any acidic or basic group present on a compound of formula 1.
• Examples of pharmaceutically acceptable salts of the compounds of formula 1 are the salts of hydrochloric acid, p-toluenesulfonic acid, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, maleic acid, di-p-toluoyl tartaric acid, acetic acid, sulfuric acid, hydroiodic acid, mandelic acid, sodium, potassium, magnesium, calcium, and lithium.
• the compounds of formula 1 may have optical centers and therefore may occur in different enantiomeric and other stereoisomeric configurations.
• the invention includes all enantiomers, diastereomers, and other stereoisomers of such compounds of formula 1, as well as racemic and other mixtures thereof.
• the subject invention also includes isotopically-labeled compounds, which are identical to those recited in formula 1, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as 3 H, 11 C, 14 C, 18 F, 123 l and 125 l.
• Compounds of the present invention and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
• Isotopically-labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. 11 C and 18 F isotopes are particularly useful in PET (positron emission tomography), and 1 5 l isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging.
• Isotopically labeled compounds of formula 1 of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
• This invention also includes compounds of the formula
• n 1
• This invention also provides a pharmaceutical composition for treating a disease or condition comprising abnormal cell growth in a mammal, including a human, comprising a compound of formula 1 in an amount effective in inhibiting abnormal cell growth, and a pharmaceutically acceptable carrier.
• This invention also provides a pharmaceutical composition for treating a disease or condition comprising abnormal cell growth in a mammal, including a human, comprising a compound of formula 1 in an amount effective to inhibit cdk2 activity, and a pharmaceutically acceptable carrier.
• This invention also provides a method for treating a disease or condition comprising abnormal cell growth in a mammal, including a human, comprising administering to the mammal a compound of formula 1 in an amount effective in inhibiting abnormal cell growth.
• This invention also provides a method for treating a diseases or condition comprising abnormal cell growth in a mammal, including a human, comprising administering to the mammal a compound of formula 1 in an amount effective to inhibit cdk2 activity.
• the disease or condition comprising abnormal cell growth is in one embodiment cancer.
• the cancer may be a carcinoma, for example carcinoma of the bladder, breast, colon, kidney, liver, lung, for example small cell lung cancer, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, or skin, for example squamous cell carcinoma; a hematopoietic tumor of lymphoid lineage, for example leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, or Burkett's lymphoma; a hematopoietic tumor of myeloid lineage, for example acute and chronic myelogenous leukemias, myelodysplastic syndrome, or promyelocytic leukemia; a tumor
• the disease or condition comprising abnormal cell growth is benign.
• diseases and conditions include benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, fungal infection, and endotoxic shock.
• This invention also provides a pharmaceutical composition for treating a neurodegenerative disease or condition in a mammal, including a human, comprising a compound of formula 1 in an amount effective in treating said disease or condition, and a pharmaceutically acceptable carrier.
• This invention also provides a pharmaceutical composition for treating a neurodegenerative disease or condition in a mammal, including a human, comprising a compound of formula 1 in an amount effective in inhibiting cdk5 activity, and a pharmaceutically acceptable carrier.
• This invention also provides a method for treating a neurodegnerative disease or condition in a mammal, including a human, comprising administering to the mammal a compound of formula 1 in an amount effective in inhibiting cdk5 activity.
• This invention also provides a method for treating a neurodegenerative disease or condition in a mammal, including a human, comprising administering to the mammal a compound of formula 1 in an amount effective in treating said disease or condition.
• the neurodegenerative disease or condition which is treated is selected from Huntington's disease, stroke, spinal cord trauma, traumatic brain injury, multiinfarct dementia, epilepsy, amyotrophic lateral sclerosis, pain, viral induced dementia for example AIDS induced dementia, neurodegeneration associated with bacterial infection, migraine, hypoglycemia, urinary incontinece, brain ischemia, multiple sclerosis, Alzheimer's disease, senile dementia of the Alzheimer's type, mild cognitive impairment, age- related cognitive decline, emesis, corticobasal degeneration, dementia pugilistica, Down's syndrome, myoto ⁇ ic dystrophy, Niemann-Pick disease, Pick's disease, prion disease with tangles, progessive supranuclear palsy, lower lateral sclerosis, and subacute sclerosing panencephalistis.
• Huntington's disease Huntington's disease
• stroke spinal cord trauma
• traumatic brain injury traumatic brain injury
• multiinfarct dementia
• This invention also provides a pharmaceutical composition for treating a disease or condition the treatment of which can be effected or facilitated by altering dopamine mediated neurotransmission in a mammal, including a human, comprising a compound of formula 1 in an amount effective in treating said disease or condition and a pharmaceutically acceptable carrier.
• This invention also provides a pharmaceutical composition for treating a disease or condition the treatment of which can be effected or facilitated by altering dopamine mediated neurotransmission in a mammal, including a human, comprising a compound of formula 1 in an amount effective to inhibit cdk ⁇ and a pharmaceutically acceptable carrier.
• This invention also provides a method for treating a disease or condition the treatment of which can be effected or facilitated by altering dopamine mediated neurotransmission in a mammal, including a human, comprising administering to the mammal a compound of formula 1 in an amount effective in inhibiting cdk ⁇ activity.
• This invention also provides a method for treating a disease or condition the treatment of which can be effected or facilitated by altering dopamine mediated neurotransmission in a mammal, including a human, comprising administering to the mammal a compound of formula 1 in an amount effective in treating said disease or condition.
• the disease or condition the treatment of which can be effected or facilitated by altering dopamine mediated neurotransmission is selected from Parkinson's disease; schizophrenia; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; delusional disorder; substance- induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, ***e, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; personality disorder of the schizoid type; drug addiction, including narcotic (e.g.
• a major depressive episode a manic or mixed mood episode, a hypomanic mood episode, a depressive episode with atypical features or with melancholic features or catatonic features, a mood episode with postpartum onset; post-stroke depression, major depressive disorder, dysthymic disorder, minor depressive disorder, premenstrual dysphoric disorder, post-psychotic depressive disorder of schizophrenia, a major depressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia, a bipolar disorder, for example bipolar I disorder, bipolar II disorder, cyclothymic disorder; anxiety; attention deficit and hyperactivity disorder; and attention deficit disorder.
• This invention also provides a pharmaceutical composition for treating a disease or condition the treatment of which can be effected or facilitated by decreasing cdk5 activity in a mammal, including a human, which composition comprises a compound of formula 1 in an amount effective in inhibiting cdk ⁇ activity and a pharmaceutically acceptable carrier.
• This invention also provides a method for treating a disease or condition the treatment of which can be effected or facilitated by decreasing cdk5 activity in a mammal, including a human, which method comprises administering to the mammal a compound of formula 1 in an amount effective in inhibiting cdk ⁇ activity.
• the compounds of formula 1 have activity in inhibiting GSK- 3.
• the compounds of formula 1 therefore can be expected to be useful in treating diseases and conditions the treatment of which can be effected or facilitated by inhibition of GSK-3.
• Diseases and conditions the treatment of which can be effected or facilitated by inhibiting GSK-3 include neurodegenerative diseases and conditions.
• Neurodegenerative diseases and conditions are discussed above and include, but are not limited to, for example Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke, cerebral ischemia, AIDS-related dementia, neurodegeneration associated with bacterial infection, multiinfarct dementia, traumatic brain injury, and spinal cord trauma. Therefore, compounds of formula 1 are effective in treating neurodegenerative diseases and conditions based on both cdk5 activity and GSK-3 activity.
• GSK-3 diseases and conditions the treatment of which can be effected or facilitated by inhibiting GSK-3 include psychotic disorders and conditions, for example schizophrenia, schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, ***e, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type.
• the treatment of such diseases and conditions can also be effected or facilitated by altering dopamine mediated neurotransmission. Therefore, compounds of formula 1 are effective in treating such disorders and conditions based on both cdk ⁇ activity and GSK-3 activity.
• disorders and conditions the treatment of which can be effected or facilitated by inhibiting GSK-3 include mood disorders and mood episodes, for example a major depressive episode, a manic or mixed mood episode, a hypomanic mood episode, a depressive episode with atypical features or with melancholic features or catatonic features, a mood episode with postpartum onset; post-stroke depression, major depressive disorder, dysthymic disorder, minor depressive disorder, premenstrual dysphoric disorder, post-psychotic depressive disorder of schizophrenia, a major depressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia, a bipolar disorder, for example bipolar I disorder, bipolar II disorder, and cyclothymic disorder.
• a major depressive episode for example a manic or mixed mood episode, a hypomanic mood episode, a depressive episode with atypical features or with melancholic features or catatonic features, a mood episode with postpartum onset
• post-stroke depression major depressive disorder, dysthymic disorder
• GSK-3 disorders and conditions the treatment of which can be effected or facilitated by inhibiting GSK-3 are male fertility and sperm motility; diabetes mellitus; impaired glucose 0 tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesity; myogenesis and frailty, for example age-related decline in physical performance; acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, bed rest, limb immobilization, or major thoracic, abdominal, and/or orthopedic surgery; sepsis; spinal cord injury; hair loss, hair thinning, and balding; immunodeficiency; and cancer.
• the present invention also provides a pharmaceutical composition for treating in a mammal, including a human, a disease or condition selected from male fertility and sperm motility; diabetes mellitus; impaired glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesity; myogenesis and frailty, for example age-related decline in physical performance; acute sarcopenia, for example 0 muscle atrophy and/or cachexia associated with burns, bed rest, limb immobilization, or major thoracic, abdominal, and/or orthopedic surgery; sepsis; hair loss, hair thinning, and balding; and immunodeficiency; which composition comprises a pharmaceutically acceptable carrier and an amount of a compound of formula 1 effective in treating said disease or condition.
• a disease or condition selected from male fertility and sperm motility; diabetes mellitus; impaired glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesity; myogenesis and frailt
• the present invention further provides a pharmaceutical composition for treating in a ⁇ mammal, including a human, a disease or condition selected from male fertility and sperm motility; diabetes mellitus; impaired glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesity; myogenesis and frailty, for example age-related decline in physical performance; acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, bed rest, limb immobilization, or major thoracic, 0 abdominal, and/or orthopedic surgery; sepsis; hair loss, hair thinning, and balding; and immunodeficiency; which composition comprises a pharmaceutically acceptable carrier and an amount of a compound of formula 1 effective in inhibiting GSK-3.
• a disease or condition selected from male fertility and sperm motility
• diabetes mellitus impaired glucose tolerance
• metabolic syndrome or syndrome X polycystic ovary syndrome
• adipogenesis and obesity myogenesis and fra
• the present invention also provides a method for treating in a mammal, including a human, a disease or condition selected from male fertility and sperm motility; diabetes ⁇ mellitus; impaired glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesity; myogenesis and frailty, for example age-related decline in physical performance; acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, bed rest, limb immobilization, or major thoracic, abdominal, and/or orthopedic surgery; sepsis; hair loss, hair thinning, and balding; and immunodeficiency; which method comprises administering to said mammal an amount of a compound of formula 1 ⁇ effective in treating said disease or condition.
• a disease or condition selected from male fertility and sperm motility
• diabetes ⁇ mellitus impaired glucose tolerance
• metabolic syndrome or syndrome X polycystic ovary syndrome
• adipogenesis and obesity myogenesis and
• the present invention also provides a method for treating in a mammal, including a human, a disease or condition selected from male fertility and sperm motility; diabetes mellitus; impaired glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesity; myogenesis and frailty, for example age-related decline 0 in physical performance; acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, bed rest, limb immobilization, or major thoracic, abdominal, and/or orthopedic surgery; sepsis; hair loss, hair thinning, and balding; and immunodeficiency; which method comprises administering to said mammal an amount of a compound of formula 1 effective in inhibiting GSK-3.
• the present invention further provides a method for inhibiting GSK-3 in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula 1 effective in inhibiting GSK-3.
• the present invention further provides a pharmaceutical composition for treating in a mammal, including a human, a disorder selected from Alzheimer's disease, mild cognitive 0 impairment, and age-related cognitive decline comprising a compound of formula 1 and a COX-II inhibitor together in an amount effective in treating said disorder, and a pharmaceutically acceptable carrier.
• This invention also provides a method for treating in a mammal, including a human, a disorder selected from Alzheimer's disease, mild cognitive impariment, and age-related ⁇ cognitive decline which method comprises administering to said mammal a compound of formula 1 and a COX-II inhibitor, wherein the combined amounts of the compound of formula 1 and the COX-II inhibitor are effective in treating said disorder.
• the compound of formula 1 and the COX-II inhibitor can be administered to the mammal at the same time and/or separately.
• the compound of formula 1 and the COX-II inhibitor can be administered in a single 0 composition or in separate compositions.
• a compound of formula 1 of the invention can be administered or formulated into a pharmaceutical composition with one or more anti-depressants or anxiolytic compounds for treatment or prevention of depression and/or anxiety.
• this invention also provides a pharmaceutical composition for treating depression or anxiety in a mammal, including a human, comprising a compound of formula 1 and an NK-1 receptor antagonist together in an amount effective in treating depression or anxiety, and a pharmaceutically acceptable carrier.
• This invention further provides a method for treating depression or anxiety in a mammal, including a human, which method comprises administering to said mammal a 5 compound of formula 1 and an NK-1 receptor antagonist, wherein the combined amounts of the compound of formula 1 and the NK-1 receptor antagonist are effective in treating depression or anxiety.
• the compound of formula 1 and the NK-1 receptor antagonist can be administered to the mammal at the same time and/or at different times. Moreover, the may be administered together in a single pharmaceutical composition or in separate compositions.
• This invention also provides a pharmaceutical composition for treating depression or anxiety in a mammal, including a human, comprising a compound of formula 1 and a ⁇ HT 1D receptor antagonist together in an amount effective in treating depression or anxiety, and a pharmaceutically acceptable carrier.
• This invention further provides a method for treating depression or anxiety in a ⁇ mammal, including a human, which method comprises administering to said mammal a compound of formula 1 and a 5HT 1D receptor antagonist, wherein the combined amounts of the compound of formula 1 and the 5HT 1D receptor antagonist are effective in treating depression or anxiety.
• the compound of formula 1 and the 5HT 1D receptor antagonist can be administered to the mammal at the same time and/or at different times. Moreover, they may 0 be administered together in a single pharmaceutical composition or in separate compositions.
• This invention also provides a pharmaceutical composition for treating depression or anxiety in a mammal, including a human, comprising a compound of formula 1 and a SSRI together in an amount effective in treating depression or anxiety, and a pharmaceutically acceptable carrier.
• This invention further provides a method for treating depression or anxiety in a mammal, including a human, which method comprises administering to said mammal a compound of formula 1 and a SSRI, wherein the combined amounts of the compound of formula 1 and the SSRI are effective in treating depression or anxiety.
• the compound of formula 1 and the SSRI can be administered to the mammal at the same time and/or at 0 different times. Moreover, they may be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.
• This invention also provides a pharmaceutical composition for treating schizophrenia in a mammal, including a human, comprising a compound of formula 1 and an antipsychotic selected from ziprasidone, olanzapine, risperidone, L-74 ⁇ 870, sonepiprazole, RP 62203, NGD ⁇ 941 , balaperidone, flesinoxan, and gepirone, together in an amount effective in treating schizophrenia, and a pharmaceutically acceptable carrier.
• an antipsychotic selected from ziprasidone, olanzapine, risperidone, L-74 ⁇ 870, sonepiprazole, RP 62203, NGD ⁇ 941 , balaperidone, flesinoxan, and gepirone
• This invention further provides a method for treating schizophrenia in a mammal, including a human, which method comprises administering to said mammal a compound of formula 1 and an antipsychotic selected from ziprasidone, olanzapine, risperidone, L-74 ⁇ 870, sonepiprazole, RP 62203, NGD 941 , balaperidone, flesinoxan, and gepirone, wherein the combined amounts of the compound of formula 1 and the antipsychotic are effective in treating schizophrenia.
• the compound of formula 1 and the antipsychotic can be administered to the mammal at the same time and/or at different times. Moreover, they may be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.
• This invention also provides a pharmaceutical composition for treating a disorder selected from Alzheimer's disease, mild cognitive impairment, and age-related cognitive decline in a mammal, including a human, comprising a compound of formula 1 and an acetylcholinesterase inhibitor together in an amount effective in treating said disorder, and a pharmaceutically acceptable carrier.
• This invention further provides a method for treating in a mammal, including a human, a disorder selected from Alzheimer's disease, mild cognitive impairment, and age-related cognitive decline, which method comprises administering to said mammal a compound of formula 1 and an acetylcholinesterase inhibitor, wherein the combined amounts of the compound of formula 1 and the acetylcholinesterase inhibitor are effective in treating said disorder.
• the compound of formula 1 and the acetylcholinesterase inhibitor can be administered to the mammal at the same time and/or at different times. Moreover, they may be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.
• This invention also provides a pharmaceutical composition for treating a disease or condition selected from stroke, spinal cord trauma, traumatic brain injury, multiinfarct dementia, epilepsy, pain, Alzheimer's disease, and senile dementia comprising a compound of formula 1 and TPA (tissue plasminogen activator, for example ACTIVASE) together in an amount effective in treating said disorder, and a pharmaceutically acceptable carrier.
• a disease or condition selected from stroke, spinal cord trauma, traumatic brain injury, multiinfarct dementia, epilepsy, pain, Alzheimer's disease, and senile dementia
• TPA tissue plasminogen activator, for example ACTIVASE
• This invention further provides a method for treating in a mammal, including a human, a disease or condition selected from stroke, spinal cord trauma, traumatic brain injury, multiinfarct dementia, epilepsy, pain, Alzheimer's disease, and senile dementia, which method comprises administering to said mammal a compound of formula 1 and TPA, wherein the combined amounts of the compound of formula 1 and the TPA are effective in treating said disease or condition.
• the compound of formula 1 and the TPA can be administered to the mammal at the same time and/or at different times. Moreover, they may be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.
• This invention also provides a pharmaceutical composition for treating a disease or condition selected from stroke, spinal cord trauma, traumatic brain injury, multiinfarct dementia, epilepsy, pain, Alzheimer's disease, and senile dementia in a mammal, including a human, comprising a compound of formula 1 and NIF (neutrophil inhibitory factor) together in an amount effective in treating said disorder, and a pharmaceutically acceptable carrier.
• a disease or condition selected from stroke, spinal cord trauma, traumatic brain injury, multiinfarct dementia, epilepsy, pain, Alzheimer's disease, and senile dementia in a mammal, including a human, comprising a compound of formula 1 and NIF (neutrophil inhibitory factor) together in an amount effective in treating said disorder, and a pharmaceutically acceptable carrier.
• NIF neurotrophil inhibitory factor
• This invention further provides a method for treating in a mammal, including a human, a ⁇ disease or condition selected from stroke, spinal cord trauma, traumatic brain injury, multiinfarct dementia, epilepsy, pain, Alzheimer's disease, and senile dementia, which method comprises administering to said mammal a compound of formula 1 and NIF, wherein the combined amounts of the compound of formula 1 and the NIF are effective in treating said disease or condition.
• the compound of formula 1 and the NIF can be administered to the mammal at the 0 same time and/or at different times. Moreover, they may be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.
• This invention also provides a pharmaceutical composition for treating a disease or condition selected from Huntington's disease, stroke, spinal cord trauma, traumatic brain injury, multiinfarct dementia, epilepsy, amyotrophic lateral sclerosis, pain, viral induced ⁇ dementia for example AIDS induced dementia, migraine, hypoglycemia, urinary incontinece, brain ischemia, multiple sclerosis, Alzheimer's disease, senile dementia of the Alzheimer's type, mild cognitive impairment, age-related cognitive decline, emesis, corticobasal degeneration, dementia pugilistica, Down's syndrome, myotonic dystrophy, Niemann-Pick disease, Pick's disease, prion disease with tangles, progessive supranuclear palsy, lower 0 lateral sclerosis, and subacute sclerosing panencephalistis in a mammal, including a human, comprising a compound of formula 1 and an NMDA receptor antagonist together in an amount effective in treating said disorder, and
• This invention further provides a method for treating in a mammal, including a human, a disease or condition selected from Huntington's disease, stroke, spinal cord trauma, ⁇ traumatic brain injury, multiinfarct dementia, epilepsy, amyotrophic lateral sclerosis, pain, viral induced dementia for example AIDS induced dementia, migraine, hypoglycemia, urinary incontinece, brain ischemia, multiple sclerosis, Alzheimer's disease, senile dementia of the Alzheimer's type, mild cognitive impairment, age-related cognitive decline, emesis, corticobasal degeneration, dementia pugilistica, Down's syndrome, myotonic dystrophy, 0 Niemann-Pick disease, Pick's disease, prion disease with tangles, progessive supranuclear palsy, lower lateral sclerosis, and subacute sclerosing panencephalistis, which method comprises administering to said mammal a compound of formula 1 and an NMDA receptor antagonist, wherein the
• This invention also provides a pharmaceutical composition for treating a disease or condition selected from stroke, spinal cord trauma, traumatic brain injury, multiinfarct
• dementia 5 dementia, epilepsy, pain, Alzheimer's disease, and senile dementia in a mammal, including a human, comprising a compound of formula 1 and a potassium channel modulator together in an amount effective in treating said disorder, and a pharmaceutically acceptable carrier.
• This invention further provides a method for treating in a mammal, including a human, a disease or condition selected from stroke, spinal cord trauma, traumatic brain injury, 0 multiinfarct dementia, epilepsy, pain, Alzheimer's disease, and senile dementia, which method comprises administering to said mammal a compound of formula 1 and a potassium channel modulator, wherein the combined amounts of the compound of formula 1 and the potassium channel modulator are effective in treating said disease or condition.
• the compound of formula 1 and the potassium channel modulator can be administered to the mammal at the 5 same time and/or at different times. Moreover, they may be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.
• treatment refers to reversing, alleviating, or inhibiting the progress of the disease or condition to which such term applies, or one or more symptoms of such disease or condition.
• these terms also encompass, 0 depending on the condition of the patient, preventing the onset of a disease or condition or of symptoms associated with a disease or condition, including reducing the severity of a disease or condition or symptoms associated therewith prior to affliction with said disease or condition.
• Such prevention or reduction prior to affliction refers to administration of the compound of the invention to a subject that is not at the time of administration afflicted with the disease or ⁇ condition.
• Preventing also encompasses preventing the recurrence of a disease or condition or of symptoms associated therewith.
• Abnormal cell growth refers to cell growth, either malignant (e.g. as in cancer) or benign, that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition).
• benign proliferative diseases are psoriasis, benign prostatic 0 hypertrophy, human papilloma virus (HPV), and restinosis.
• Neurodegenerative diseases and conditions refers to diseases and conditions having associated therewith degeneration of neurons. Conditions and diseases that are neurodegenerative in nature are generally known to those of ordinary skill in the art. ⁇ References herein to diseases and conditions "the treatment of which can be effected or facilitated by altering dopamine mediated neurotransmission” mean a disease or condition that is caused at least in part by dopamine neurotransmission, or a disease or condition that result in abnormal dopamine neurotransmission, thus contributing to symptoms or manifestations of the disease condition.
• references herein to diseases and conditions "the treatment of which can be effected or ⁇ facilitated by decreasing cdk ⁇ activity" mean a disease or condition that is caused at least in part by cdk ⁇ activity, or a disease or condition that results in abnormal cdk ⁇ activity that contributes to symptoms or manifestations of the disease or condition.
• an “amount effective to inhibit cdk ⁇ ” as used herein refers to an amount of a compound sufficient to bind to the enzyme cdk ⁇ with the effect of decreasing cdk ⁇ activity.
• An “amount effective to inhibit cdk2 activity” as used herein refers to an amount of a compound sufficient to bind to the enzyme cdk2 with the effect of decreasing cdk2 activity.
• reaction inert solvent refers to a solvent system in which the components do not interact with starting materials, reagents, or intermediates of 0 products in a manner which adversely affects the yield of the desired product.
• any of the following synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981 ; and T. W. ⁇ Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, Inc., 1999.
• a preferred alkyl cyano ⁇ acetate is ethyl cyano acetate.
• Hydrolysis and decarboxylation of 3a to 3 may be accomplished by exposing 3a to water in a reaction inert solvent, preferably dimethylsulfoxide, at a temperature from about 21 °C to 200 °C, preferably from about 100 °C to 118 °C.
• Reaction of 3 in a reaction inert solvent, such as a lower alcohol in the presence of a hydrazine at a reaction temperature of from about 0 °C to about 150 °C, where a temperature of from about 70 °C to about 8 ⁇ °C is preferred, affords the corresponding product 4.
• the ⁇ hydrazine used may be anhydrous hydrazine or a hydrate form of hydrazine, or N-alkyl- hydrazine or N-acyl-hydrazine.
• Coupling of 4 with an aryl halide or heteroaryl halide to obtain an intermediate of formula 5, wherein R 3 is -(CR 10 R 11 ) 0 - (a bond) can be accomplished by reaction of 4 in a 0 reaction inert solvent, preferably toluene, at a reaction temperature of from about 21 °C to about 1 ⁇ 0 °C, preferably at about 100 °C to about 110 °C, in the presence of a palladium catalyst, a base, preferably cesium carbonate or sodium or potassium tert-butoxide, a ligand, where preferred ligands are 2,2'-bis(diphenylphosphino)-1 ,1 '-binaphythyl, 2- (dicyclohexylphosphino)biphenyl, and 2-(di-tert-butylphosphino)biphenyl, and in the presence ⁇ of the appropriate aryl halide or heteroaryl halide, where
• the metal catalyst may be a palladium species, for example palladium chloride, palladium acetate, dichlorobis(acetonitrile)palladium, or derivatives thereof, wherein palladium acetate is preferred.
• Removal of the protecting group from 5 can be accomplished by reaction of 5 in a reaction inert solvent, preferably 0 methylene chloride or no solvent, in the presence of an acid, wherein trifluoro acetic acid is preferred, at a reaction temperature from about 20 °C to about 100 °C, preferably from about 6 ⁇ °C to about 7 ⁇ °C, to yield 1a, wherein R 3 represents a bond and R 4 is as defined above for compounds of formula 1.
• a reaction inert solvent preferably methylene chloride, pyridine, tetrahydrofuran, or die
• the activated carboxylic acid derivative can be prepared from the carboxylic acid and known activating reagents such as polymer supported coupling agents or coupling agents such as, for instance, dicyclohexyl carbodiimide, carbonyl diimidazole, tripropylphosphonic anhydride, alkyl chioroformate, bis(2-oxo-3-oxazolidinyl)phosphinic 5 chloride, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, or any other such standard literature reagents.
• activating reagents such as polymer supported coupling agents or coupling agents such as, for instance, dicyclohexyl carbodiimide, carbonyl diimidazole, tripropylphosphonic anhydride, alkyl chioroformate, bis(2-oxo-3-oxazolidinyl)phosphinic 5 chloride, benzotriazol-1-y
• Removal of the protecting group on 6 may be accomplished by reaction 6 in a reaction inert solvent, wherein methylene chloride or no solvent is preferred, in the presence of an acid, wherein trifluoro acetic acid is preferred, at a reaction temperature from about 20 °C to about 100 °C, preferably from about 6 ⁇ °C to about 7 ⁇ °C.
• R 3 is -(CR 10 R 11 ) (1 . 3) -
• a reaction inert solvent preferably toluene, tetrahydrofuran or methanol
• reaction temperature from about 0 °C to about 110 °C, preferably about 21 °C
• preferred reducing reagents are sodium triacetoxyborohydride, sodium cyanoborohydride, and lithium aluminum hydride to afford an intermediate of formula 6 wherein R 3 is -(CR 10 R 1 ) ⁇ 1 . 3) -.
• Scheme 2 illustrates an alternative method suitable for preparing compounds of formula 1.
• the method depicted in Scheme 2 is preferred when R 4 is an electron deficient aryl moiety, such as 4-nitrophenyl, or an electron deficient heteroaryl moiety.
• hindered amine bases include lithium diisopropyl amide, potassium bis(trimethylsilyl) amide, lithium bis(trimethylsilyl) amide, and other such standard literature reagents.
• a reaction inert solvent a preferred solvent being a lower alcohol
• an acid preferably acetic acid
• a reaction temperature of from about 21 °C to about 100 °C, preferably from about 7 ⁇ °C to about 85 °C, and in the presence of hydrazine, affords a compound of the formula 1a, wherein R 3 is a bond and R 4 is aryl or heteroaryl.
• Deprotection of the oxo moiety R 5 can be accomplished using well-known conditions, which appear in the literature. For example, treating compound 10a in a reaction inert solvent, preferably a lower ketone for example acetone, in the presence of an acid, preferably hydrogen chloride, p-toluenesulfonic acid monohydrate, or pyridinium p-toluenesulfonate, at a ⁇ temperature of from about room temperature to about 80 °C, preferably about 7 ⁇ °C, affords 10b, wherein R 5 is an oxo (carbonyl) moiety, R 1 is as defined above, R 3 is a bond, and R 4 is aryl or heteroaryl.
• a reaction inert solvent preferably a lower ketone for example acetone
• an acid preferably hydrogen chloride, p-toluenesulfonic acid monohydrate, or pyridinium p-toluenesulfonate
• Reduction of the oxo moiety to obtain an alocohol can be accomplished using well established chemistry.
• the oxo moiety of 10b can be reacted with an 0 amine, either primary or secondary, wherein the preferred amine is an alkyl amine for example 4-methoxy-benzyl-amine, in a reaction inert solvent, preferably toluene or tetrahydrofuran, at a reaction temperature from about 21 °C to about 1 ⁇ 0 °C, preferably at about 70 °C to about 110 °C.
• the reaction is cooled to a temperature of about 21 °C to about ⁇ O °C and a reducing reagent is ⁇ added, where preferred reducing reagents are sodium triacetoxyborohydride, sodium cyanoborohydride and lithium aluminum hydride, to afford 10c, wherein R is as defined above, R 3 is a bond, R 4 is aryl or heteroaryl, and R 5 is -NR 7 R 8 .
• the activated carboxylic acid derivative is prepared from the carboxylic acid and known activating reagents such as polymer supported coupling agents or alternatively dicyclohexyl carbodiimide, carbonyl diimidazole, tripropylphosphonic anhydride, alkyl chloroformate, bis(2- ⁇ oxo-3-oxazolidinyl)phosphinic chloride, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, or any other such standard literature reagents, in the presence of a trialkyl amine base, such as triethyl amine or diisopropylethyl amine, wherein tripropylphosphonic anhydride and triethylamine are a preferred combination.
• activating reagents such as polymer supported coupling agents or alternatively dicyclohexyl carbodiimide, carbonyl diimidazole, tripropylphosphonic anhydr
• Removal of the protecting group on 10b, 10c, or 10d may be accomplished by reaction in a reaction inert solvent, wherein methylene chloride or no solvent is preferred, in the presence of an acid, preferably trifluoro acetic acid, at a reaction temperature from about 20 °C to about 100 °C, preferably from about 6 ⁇ °C to about 75 °C, to yield the corresponding compounds of formula 1 , for example 1c, as depicted in Scheme 2.
• Scheme 3 illustrates an alternative method suitable for the preparation of compounds of formula 1.
• a base such as triethylamine, diisopropylethylamine, pyridine, or 2,6-lutidine
• Intermediate 7c wherein R 3 is -(CR 10 R 11 ) (1 . 3) - can be prepared from intermediate 4a by reaction of 4a with an oxo moiety (aldehyde or ketone) in a reaction inert solvent, preferably toluene, tetrahydrofuran or methanol at a reaction temperature from about 0 °C to about 110 °C, preferably about 21 °C, in the presence of a reducing reagent, where preferred reducing 0 reagents are sodium triacetoxyborohydride, sodium cyanoborohydride, and lithium aluminum hydride to afford an intermediate of formula 6a wherein R 3 is -(CR 10 R 11 ) (1 . 3) -.
• a reaction inert solvent preferably toluene, tetrahydrofuran or methanol
• R 5 in 5a and 6a is a protected oxo (carbonyl) moiety (specifically acetal or ketal)
• removal of the protecting group can first be accomplished using well-known conditions, which appear in the literature.
• 12 and 15 can be reacted with an amine, primary or secondary, wherein the preferred amines are alkyl amine for example 4-methoxy-benzyl-amine, in a reaction inert solvent, preferably toluene or tetrahydrofuran, at a reaction temperature from about 21 °C to about 1 ⁇ 0 °C, preferably at about 70 °C to about 110 °C.
• a reaction inert solvent preferably toluene or tetrahydrofuran
• the reaction can be cooled to a temperature of about 21 °C to about ⁇ O °C, and a reducing reagent is added.
• Preferred reducing reagents are sodium triacetoxyborohydride, sodium cyanoborohydride and lithium aluminum hydride.
• the activated carboxylic acid can be prepared as described above.
• a base such as triethylamine, diisopropylethylamine, pyridine, or 2,6-lutidine
• R 7 diisopropylethylamine and chloroformates are a preferred combination
• Schemes 4 and ⁇ illustrate a preferred method for the preparation of compounds of the formula 1 , wherein R 1 is optionally substituted with OR 7 or R 7 .
• Preparation of the intermediates 12 and 15 can be accomplished as described in the description of Scheme 3.
• R 3 in intermediate 12 is a bond
• R s is an oxo (carbonyl) moiety.
• R 5 being -OR 7 .
• R 1 is hydroxylated and substituted with R 7 , for example ( ⁇ -(3-hydroxy, 3-phenyl-cyclobutyl)-2-(Prot)-pyrazol-3-yl)-naphthalen-2-yl-amine.
• an inert 0 solvent such as methylene chloride, chloroform, or 1 ,2-dichloroethane, or preferably no solvent
• an acid preferably trifluoroacetic acid
• silane where tri
• the metal catalyst may be conveniently suspended on an inert solid support such as charcoal, in a solvent such as ethyl acetate, tetrahydrofuran, dioxane, or a mixture thereof.
• a base such as triethylamine, 0 diisopropylethylamine, pyridine, or 2,6-lutidine
• Removal of the protecting group of 22, 27, or a derivative of 19 or 24 can be accomplished by reaction in a reaction inert solvent, preferably methylene chloride, ⁇ chloroform, 1 ,2-dichloroethane, or no solvent, in the presence of an acid, where trifluoroacetic acid is preferred, at a reaction temperature from about 20 °C to about 100 °C, preferably from about 6 ⁇ °C to about 7 ⁇ °C, affording a compound of formula 1i, 1k, or other compound of formula 1.
• a reaction inert solvent preferably methylene chloride, ⁇ chloroform, 1 ,2-dichloroethane, or no solvent
• an acid where trifluoroacetic acid is preferred
• compounds of formula 1 as described herein wherein R 2 is other than hydrogen can be prepared by transformations of the compounds of formula 1 herein wherein R 2 is hydrogen using methods that are well known in the art.
• compounds of formula 1 wherein R 2 is F can be prepared by treating compounds of formula 17, 6a, or 14 with N-fluorobenzenesulfonimide in a reaction of inert solvent, wherein toluene, dioxane, or xylenes are preferred, from about room temperature to about 150°C, preferably from about 100°C to about 120°C to obtain the corresponding intermediates wherein R 2 is F.
• Removal of the protecting group from these intermediates may be accomplished by reaction in a reaction of inert solvent, wherein methylene chloride or no solvent are preferred, in the presence of an acid, wherein trifluoro acetic acid is preferred, at a reaction temperature from about 20°C to about 100°C, preferably from about 65°C to about 7 ⁇ °C, thus affording compounds of formula 1 wherein R 2 is F.
• Pharmaceutically acceptable salts of a compound of formula 1 can be prepared in a conventional manner by treating a solution or suspension of the corresponding free base or acid with one chemical equivalent of a pharmaceutically acceptable acid or base. Conventional concentration or crystallization techniques can be employed to isolate the salts.
• suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic acids such as methanesulfonic, benzene sulfonic, p- toluenesulfonic, and related acids.
• Illustrative bases are sodium, potassium, and calcium.
• a compound of this invention may be administered alone or in combination with ⁇ pharmaceutically acceptable carriers, in either single or multiple doses.
• Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
• the pharmaceutical compositions formed by combining a compound of formula 1 or a pharmaceutically acceptable salt thereof can then be readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like.
• These 0 pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
• tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch, methylcellulose, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, ⁇ gelatin and acacia.
• binding agents such as polyvinylpyrrolidone, sucrose, ⁇ gelatin and acacia.
• lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes.
• Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols.
• the essential active ingredient therein 0 may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.
• solutions containing a compound of this invention or a pharmaceutically acceptable salt thereof in sesame or peanut oil, aqueous propylene glycol, or ⁇ in sterile aqueous solution may be employed.
• aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
• sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
• a compound of formula 1 or a pharmaceutically acceptable salt thereof can be administered orally, transdermally (e.g., through the use of a patch), parenterally (e.g. intravenously), rectally, or topically.
• the daily dosage for treating a neurodegenerative disease or condition or a disease or condition the treatment of which can be effected or facilitated by altering dopamine mediated neurotransmission will generally range from about 0.0001 to about 10.0 mg/kg body weight of the patient to be treated.
• the daily dosage for treating cancer or disease or condition involving abnormal cell growth of a benign nature will generally range from about 0.0001 to about ⁇ OO mg/kg body weight of the patient to be treated.
• a compound of the formula 1 or a pharmaceutically acceptable salt thereof can be administered for treatment of a neurodegenerative disorder to an adult human of average weight (about 70kg) in a dose ranging from about 0.01 mg up to about 1000 mg per day, preferably from about 0.1 to about 500 mg per day, in single or divided (i.e., multiple) portions. Variations based on the aforementioned dosage ranges may be made by a physician of ordinary skill taking into account known considerations such as the weight, age, and condition of the person being treated, the severity of the affliction, and the particular route of administration chosen.
• the compounds of formula 1 and their pharmaceutically acceptable salts can furthermore also be administered or formulated into a pharmaceutical composition with an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, and antiproliferative agents, which amounts are together effective in inhibiting abnormal cell growth.
• Anti-angiogenesis agents such as MMP-2 (matrix-metalloproteinase 2) inhibitors,
• MMP-9 matrix-metalloproteinase 9 inhibitors
• COX-II cyclooxygenase II
• MMP-9 matrix-metalloproteinase 9 inhibitors
• COX-II cyclooxygenase II
• MMP-9 matrix-metalloproteinase 9 inhibitors
• COX-II cyclooxygenase II inhibitors
• Examples of useful COX-II inhibitors include CELEBREXTM (celecoxib), valdecoxib, and rofecoxib.
• Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), European Patent Application No. 97304971.1 (filed July 8, 1997), European Patent Application No.
• PCT/IB98/01113 (filed July 21 , 1998), European Patent Application No. 99302232.1 (filed March ⁇ 26, 1999), Great Britain patent application number 9912961.1 (filed June 3, 1999), United States Provisional Application No. 60/148,464 (filed August 12, 1999), United States Patent 5,863,949 (issued January 26, 1999), United States Patent 6,861,610 (issued January 19, 1999), and European Patent Publication 780,386 (published June 2 ⁇ , 1997), all of which are incorporated herein in their entireties by reference.
• Preferred MMP-2 and MMP-9 inhibitors are those that 0 have little or no activity inhibiting MMP-1.
• MMP- 2 and/or MMP-9 are those that selectively inhibit MMP- 2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e. MMP-1 , MMP-3, MMP-4, MMP- ⁇ , MMP-6, MMP-7, MMP-8, MMP-10, MMP-11 , MMP-12, and MMP-13).
• MMP-1 , MMP-3, MMP-4, MMP- ⁇ , MMP-6, MMP-7, MMP-8, MMP-10, MMP-11 , MMP-12, and MMP-13 are those that selectively inhibit MMP- 2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e. MMP-1 , MMP-3, MMP-4, MMP- ⁇ , MMP-6, MMP-7, MMP-8, MMP-10, MMP-11 , MMP-12, and MMP-13).
• MMP inhibitors useful in the present invention are AG-3340, RO 32-3 ⁇ , RS 13-0830, and the compounds recited in the following list: ⁇ 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1 -hydroxycarbamoyl-cyclopentyl)- aminoj-propionic acid;
• anti-angiogenesis agents including other COX-II inhibitors and other MMP inhibitors, can also be used in the present invention.
• the effective amount of a COX-II inhibitor in combination with a compound of formula 1 can generally be determined by a person of ordinary skill.
• a proposed daily effective dose range 0 for a COX-II inhibitor in combination with a cdk5 inhibitor is from about 0.1 to about 2 ⁇ mg/kg body weight.
• the effective daily amount of the compound of formula 1 generally will be between about 0.0001 to about 10 mg/kg body weight. In some instances the amount of COX-II inhibitor and/or the compound of formula 1 in the combination may be less than would be required on an individual basis to achieve the same desired effect in inhibiting abnormal cell growth.
• a compound of formula 1 can also be used with signal transduction inhibitors, such as agents that can inhibit EGFR (epidermal growth factor receptor) responses, such as EGFR antibodies, EGF antibodies, and molecules that are EGFR inhibitors; VEGF (vascular endothelial growth factor) inhibitors; and erbB2 receptor inhibitors, such as organic molecules or antibodies that bind to the erbB2 receptor, for example, HERCEPTINTM (Genentech, Inc. of 0 South San Francisco, California, USA).
• signal transduction inhibitors such as agents that can inhibit EGFR (epidermal growth factor receptor) responses, such as EGFR antibodies, EGF antibodies, and molecules that are EGFR inhibitors; VEGF (vascular endothelial growth factor) inhibitors; and erbB2 receptor inhibitors, such as organic molecules or antibodies that bind to the erbB2 receptor, for example, HERCEPTINTM (Genentech, Inc. of 0 South San Francisco, California, USA).
• HERCEPTINTM Genetech
• EGFR inhibitors are described in, for example in WO 96/19970 (published July 27, 1995), WO 98/14451 (published April 9, 1998), WO 98/02434 (published January 22, 1998), and United States Patent 5,747,498 (issued May 5, 1998), and such substances can be used in the ⁇ present invention as described herein.
• EGFR-inhibiting agents include, but are not limited to, the monoclonal antibodies C22 ⁇ and anti-EGFR 22Mab (ImClone Systems Incorporated of New York, New York, USA), the compounds ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX-447 (Medarex Inc.
• VEGF inhibitors for example SU-5416 and SU-6668 (Sugen Inc. of South San Francisco).
• VEGF inhibitors are described in, for example in WO 99/24440 (published May 20, 1999), PCT 5 International Application PCT/IB99/00797 (filed May 3, 1999) " ; in WO 95/21613 (published
• VEGF inhibitors useful in the present invention are IM862 (Cytran Inc. of Kirkland, Washington, USA); anti-VEGF monoclonal antibody of Genentech, Inc. of South San 0 Francisco, California; and angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colorado) and Chiron (Emeryville, California). These and other VEGF inhibitors can be used in the present invention as described herein.
• ErbB2 receptor inhibitors such as GW-282974 (Glaxo Wellcome pic), and the monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Texas, USA) ⁇ and 2B-1 (Chiron), can also be combined with a compound of formula 1 , for example those indicated in WO 98/02434 (published January 22, 1998), WO 99/36146 (published July 15, 1999), WO 99/35132 (published July 15, 1999), WO 98/02437 (published January 22, 1998), WO 97/13760 (published April 17, 1997), WO 96/19970 (published July 27, 1996), United States Patent 5,687,468 (issued December 24, 1996), and United States Patent 6,877,306 (issued 0 March 2, 1999), which are all hereby incorporated herein in their entireties by reference.
• ErbB2 receptor inhibitors useful in the present invention are also described in United States Provisional Application No. 60/117,341 , filed January 27, 1999, and in United States Provisional Application No. 60/117,346, filed January 27, 1999, both of which are incorporated in their entireties herein by reference.
• the erbB2 receptor inhibitor compounds and substance described in the 5 aforementioned PCT applications, U.S. patents, and U.S. provisional applications, as well as other compounds and substances that inhibit the erbB2 receptor, can be used with a compound of formula 1 , in accordance with the present invention.
• a compound of formula 1 can also be used with other agents useful in treating abnormal cell growth or cancer, including, but not limited to, agents capable of enhancing 0 antitumor immune responses, such as CTLA4 (cytotoxic lymphocite antigen 4) antibodies, and other agents capable of blocking CTLA4; and anti-proliferative agents such as farnesyl protein transferase inhibitors.
• CTLA4 cytotoxic lymphocite antigen 4
• anti-proliferative agents such as farnesyl protein transferase inhibitors.
• Specific CTLA4 antibodies that can be used in the present invention include those described in United States Provisional Application 60/113,647 (filed December 23, 1998) which is incorporated by reference in its entirety, however other CTLA4 antibodies 6 can be used in the present invention.
• Th e compounds of formula 1 can also be administered in a method for inhibiting abnormal cell growth in a mammal in combination with radiation therapy. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. The administration
• Compounds of formula 1 can also be administered in combination with a COX-II inhibitor for treating Alzheimer's disease, mild cognitive impairment, or age-related cognitive decline.
• COX-II inhibitors useful in this aspect of the invention are provided above, wherein use of a COX-II inhibitor in combination with a compound of formula 1 for treatment of abnormal cell growth is described.
• the effective amount of a COX-II inhibitor in combination with a compound of formula 1 can generally be determined by a person of ordinary skill.
• a proposed effective daily dose range for a COX-II inhibitor in combination with a compound of formula 1 is from about 0.1 to about 26 mg/kg body weight.
• the daily effective amount of the compound of formula 1 generally will be between about 0.0001 to about 10 mg/kg body weight. In some instances the amount of COX-II inhibitor and/or the amount of the compound of formula 1 in the combination may be less than would be required on an individual basis to achieve the same desired effect in treating Alzheimer's disease, mild cognitive impairment, or age-related cognitive decline.
• NK-1 receptor antagonists can also be administered in combination with an NK-1 receptor antagonist for treatment of depression or anxiety.
• An NK-1 receptor antagonist as recited herein, is a substance that is able to antagonize NK-1 receptors, thereby inhibiting tachykinin-mediated responses, such as responses mediated by substance P.
• Various NK-1 receptor antagonists are known in the art, and any such NK-1 receptor antagonist can be utilized in the present invention as described above in combination with a compound of formula 1.
• NK-1 receptor antagonists are described in, for example, United States Patent 5,716,965 (issued February 10, 1998); United States Patent 5,852,038 (issued December 22, 1998); WO 90/05729 (International Publication Date May 31 , 1990); United States Patent 5,807,867 (issued September 15, 1998); United States Patent 5,886,009 (issued March 23, 1999); United States Patent 5,939,433 (issued August 17, 1999); United States Patent 5,773,450 (issued June 30, 1998); United States Patent 5,744,480 (issued April 28, 1998); United States Patent 5,232,929 (issued August 3, 1993); United Stated Patent 5,332,817 (issued July 26, 1994); United States Patent 5,122,525 (issued June 16, 1992), United States Patent 5,843,966 (issued December 1 , 1998); United States Patent 5,703,240 (issued December 30, 1997); United States Patent 5,719,147 (issued February 17, 1998); and United States Patent 5,637,699 (issued June 10, 1997).
• the effective amount of an NK-1 receptor antagonist in combination with a compound of formula 1 can generally be determined by a person of ordinary skill.
• a proposed effective daily dose range for an NK-1 receptor antagonist in combination with a compound of formula 1 is from about 0.07 to about 21 mg/kg body weight.
• the effective amount of the compound of formula 1 will be between about 0.0001 to about 10 mg/kg body weight.
• the amount of NK-1 receptor antagonist and/or the amount of the compound of formula 1 in the combination may be less than would be required on an individual basis to achieve the same desired effect in treating depression or anxiety.
• the subject invention also provides combining a compound of formula 1 with a 5HT 1D receptor antagonist for treatment of depression or anxiety.
• a 5HT 1D receptor antagonist as recited herein, is a substance that antagonizes the 5HT 1D subtype of serotonin receptor. Any such substance can be used in the present invention as described above in combination with a compound of formula 1. Substances having 5HT 1D receptor antagonizing activity can be determined by those of ordinary skill in the art.
• 5HT 1D receptor antagonists are described in WO 98/14433 (International Publication Date April 9, 1998); WO 97/36867 (International Publication Date October 9, 1997); WO 94/21619 (International Publication Date September 29, 1994); United States Patent 5,610,350 (issued April 23, 1996); United States Patent 5,358,948 (issued October 25, 1994); and GB 2276162 A (published September 21 , 1994).
• These 5HT 1D receptor antagonists, as well as others, can be used in the present invention.
• the aforementioned published patent applications and patents are incorporated herein by reference in their entireties.
• the effective amount of a 5HT1 D receptor antagonist in combination with a compound of formula 1 can generally be determined by a person of ordinary skill.
• a proposed effective daily dose range for a 5HT1 D receptor antagonist in combination with a compound of formula 1 is from about 0.01 to about 40 mg/kg body weight.
• the effective daily amount of the compound of formula 1 generally will be between about 0.0001 to about 10 mg/kg body weight. In some instances the amount of 5HT1 D receptor antagonist and/or the amount of compound of formula 1 in the combination may be less than would be required on an individual basis to achieve the same desired effect in treating depression or anxiety.
• This invention also provides a pharmaceutical composition and method for treating depression or anxiety in a mammal comprising a compound of formula 1 and a SSRI.
• SSRIs that can be combined in a method or pharmaceutical composition with compounds of formula 1 and their pharmaceutically acceptable salts include, but are not limited to, fluoxetine, paroxetine, sertraline, and fluvoxamine.
• Other SSRIs may be combined or administered in combination with a compound of formula 1 or a pharmaceutically acceptable salt thereof.
• Other antidepressants and/or anxiolytic agents with which a compound of formula 1 may be combined or administered include WELLBUTRIN, SERZONE and EFFEXOR.
• the effective amount of a SSRI in combination with a compound of formula 1 can generally be determined by a person of ordinary skill.
• a proposed effective daily dose range for a SSRI in combination with a compound of formula 1 is from about 0.01 to about 500 mg/kg body weight.
• the effective daily amount of the compound of formula 1 generally will be between about 0.0001 to about 10 mg/kg body weight. In some instances the amount of SSRI and/or the amount of the compound of formula 1 in the combination may be less than would be required on an individual basis to achieve the same desired effect in treating depression or anxiety.
• a compound of formula 1 can also be combined with one or more antipsychotic agents, for example a dopaminergic agent, for the treatment of diseases or conditions the treatment of which can be effected or facilitated by altering dopamine neurotransmission, such as schizophrenia.
• antipsychotics with which a compound of the invention can be combined include ziprasidone (5-(2-(4-(1 ,2- benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1 ,3-dihydro-2H-indol-2-one; U.S. Patent 4,831 ,031 and U.S.
• Patent 5,312,925 olanzapine (2-methyl-4-(4-methyl-1-piperazinyl-10H- thieno (2,3b) (1 ,5)benzodiazepine; U.S Patent 4,115,574 and U.S. Patent 5,229,382); risperidone (3-[2-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]6,7,8,9-tetrahydro-2- methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one; U.S.
• Patent 4,804,663 L-745870 (3-(4-(4- chlorophenyl)piperazin-1-yl)methyl-1 H-pyrrolo(2,3-b)pyridine; U.S. Patent 5,432,177); sonepiprazole (S-4-(4-(2-(isochroman-1-yl)ethyl)piperazin-1-yl)benzenesulfonamide; U.S.
• Patent 5,877,317 discloses RP 62203 (fananserin; 2-(3-(4-(4-fluorophenyl)-1- piperazinyl)propyl)naphtho(1 ,8-c,d)isothiazole-1 ,1 -dioxide; U.S. Patent 5,021 ,420); NGD 941 (U.S. Patent 5,633,376 and U.S.
• Patent 5,428,165 balaperidone ((1 ⁇ ,5 ⁇ ,6 ⁇ )-3-(2-(6-(4- fluorophenyl)-3-azabicyclo(3.2.0)hept-3-yl)ethyl)-2,4(1 H,3H)-quinazolinedione; U.S. Patent 6,475,105); flesinoxan ((+)-4-fluoro-N-[2-[4-5-(2-hydroxymethyl-1 ,4-benzodioxanyl)]-1- piperazinyl]ethyl]benzamide; U.S.
• Patent 4,833,142 gepirone (4,4-dimethyl-1-(4-(4-(2- pyrimidinyl)-1-piperazinyl)butyl)-2,6-piperidinedione; U.S. Patent 4,423,049).
• the patents recited above in this paragraph are each incorporated herein by reference in their entireties.
• the effective daily amount of the compound of formula 1 will typically be between about 0.0001 to about 10 mg/kg body weight.
• the amount of any of the aforementioned antipsychotic agents contemplated for use in combination with a compound of formula 1 is generally the amount known in the art to be useful for treating psychotic conditions.
• the amount of the antipsychotic and/or the amount of the compound of formula 1 in the combination may be less than would be required on an individual basis to achieve the same desired effect in treating depression or anxiety. It is furthermore to be understood that the present invention also encompasses combining a compound of formula 1 with antipsychotic or dopaminergic other than those in the aforementioned list.
• a proposed amount for sonepiprazole in the above-described combination with a compound of formula 1, is from about 0.006 to about 60 mg/kg body weight of the patient per day.
• a proposed amount of RP 62203 in such combination is from about 0.20 to about 6 mg/kg body weight of the patient per day.
• a proposed amount of NGD 941 in such combination is from about 0.1 to about 140 mg/kg of body weight per day.
• a proposed amount of balaperidone in such combination is from about 1 to about 100 mg/kg body weight per day.
• a proposed amount of flesinoxan in such combination is from about 0.02 to about 1.6 mg/kg body weight per day.
• a proposed amount for gepirone in such combination is from about .01 to about 2 mg/kg body weight per day.
• a proposed amount of L-746870 in such combination is from about 0.01 to about 250 mg/kg body weight per day, preferably from about 0.05 to about 100 mg/kg body weight per day.
• a proposed amount of risperidone in such combination is from about O.O ⁇ to about 60 mg/kg body weight per day.
• a proposed amount of olanzapine in such combination is from about 0.0006 to about 0.6 mg/kg body weight per day.
• a proposed amount of ziprasidone in such combination is from about O.O ⁇ to about 10 mg/kg body weight per day.
• the amount of each specific ingredient in the combination may be less than would be required on an individual basis to achieve the same desired effect in treating a psychotic condition.
• This invention also provides a pharmaceutical composition and method for treating Alzheimer's disease, mild cognitive impairment, or age-related cognitive decline comprising a compound of formula 1 and an acetylcholinesterase inhibitor.
• Acetylcholinesterase inhibitors are known in the art, and any such acetylcholinesterase inhibitor can be used in the above- described pharmaceutical composition or method.
• Examples of acetylcholinesterase inhibitors that can be used in this invention are ARICEPT (donepezil; U.S. Patent 4,895,841 ); EXELON (rivastigmine ((S)-[N-ethyl-3-[1-(dimethylamino)ethyl]phenyl carbamate); U.S.
• Patent 5,603,176 and U.S. Patent 4,948,807 ; metrifonate ((2,2,2-trichloro-1-hydroxyethyl)phosphonic acid dimethyl ester; U.S. Patent 2,701 ,225 and U.S. Patent 4,950,658); galantamine (U.S. Patent 4,663,318); physostigmine (Forest, USA); tacrine (1 ,2,3,4-tetrahydro-9-acridinamine; U.S.
• Patent 4,816,456 huperzine A (5R-(5 ,9 ⁇ ,11 E))-5-amino-11-ethylidene- ⁇ ,6,9,10- tetrahydro-7-methyl- ⁇ ,9-methaneocycloocta(b)pyridin-2-(1 H)-one); and icopezil (5,7-dihydro-3- (2-(1-(phenylmethyl)-4-piperidinyl)ethyl)-6H-pyrroio(3,2-f)-1 ,2-benzisoxazol-6-one; U.S. Patent 6,760,642 and WO 92/17475).
• the patents and patent applications recited above in this paragraph are herein incorporated by reference in their entireties.
• the effective amount of an acetylcholinesterase inhibitor in combination with a compound of formula 1 can generally be determined by a person of ordinary skill.
• a proposed effective daily dose range for an acetylcholinesterase inhibitor in combination with a compound of formula 1 is from about 0.01 to about 10 mg/kg body weight.
• the effective daily amount of the compound of formula 1 generally will be between about 0.0001 to about 10 mg/kg body weight.
• the amount of acetylcholinesterase inhibitor and/or the amount of the compound of formula 1 in the combination may be less than would be required on an individual basis to achieve the same desired effect in treating Alzheimer's disease, mild cognitive impairment, or age-related cognitive decline.
• the present invention also provides for combining a compound of formula 1 with neuroprotectants, for example NMDA receptor antagonists, for treatment of Huntington's disease, stroke, spinal cord trauma, traumatic brain injury, multiinfarct dementia, epilepsy, amyotrophic lateral sclerosis, pain, viral induced dementia for example AIDS induced dementia, migraine, hypoglycemia, urinary incontinece, brain ischemia, multiple sclerosis, Alzheimer's disease, senile dementia of the Alzheimer's type, mild cognitive impairment, age- related cognitive decline, emesis, corticobasal degeneration, dementia pugilistica, Down's syndrome, myotonic dystrophy, Niemann-Pick disease, Pick's disease, prion disease with tangles, progessive supranuclear palsy, lower lateral sclerosis, or subacute sclerosing panencephalistis.
• neuroprotectants for example NMDA receptor antagonists
• NMDA receptor antagonists examples include (1 S,2S)-1 -(4-hydroxyphenyi)-2-(4-hydroxy-4-phenylpiperidin-1 -yl)-1 - propanol (U.S. Patent 5,272,160), eliprodil (U.S. Patent 4,690,931), and gavestenel (U.S. Patent 5,373,018).
• Other NMDA receptor antagonists which can also be used in the present invention, are described in U.S. Patent 6,373,018; U.S. Patent 4,690,931; U.S. Patent 6,272,160; U.S. Patent 5,186,343; U.S. Patent 5,356,905; U.S.
• the aforementioned patents and patent applications are each hereby incorporated by reference in their entireties.
• the effective daily amount of the compound of formula 1 in the combination with an NMDA receptor antagonist generally will be between about 0.0001 to about 10 mg/kg body weight.
• the amount of the NMDA receptor antagonist contemplated for use in combination with a compound of formula 1 for treatment of any of the aforementioned disorders, for example Alzheimer's disease is generally within the range of from about 0.02 mg/kg/day to about 10 mg/kg/day.
• the amount of the NMDA antagonist and/or the amount of the compound of formula 1 in the combination may be less than would be required on an individual basis to achieve the same desired effect in treating said disorders.
• the subject invention also provides for combining a compound of formula 1 with certain substances capable of treating a stroke or traumatic brain injury, such as TPA, NIF, or potassium channel modulators, for example BMS-204352.
• TPA traumatic brain injury
• NIF neurodegenerative disorders
• BMS-204352 potassium channel modulators
• Such combinations are useful for treating neurodegenerative disorders such as stroke, spinal cord trauma, traumatic brain injury, multiinfarct dementia, epilepsy, pain, Alzheimer's disease, and senile dementia, for example.
• the effective amounts of the compound of the invention and of the other agent can generally be determined by those of ordinary skill in the art, based on the effective amounts for the compounds described herein and those known or described for the other agent known in the art, for example the amounts described in the above-recited patents and patent application incorporated herein.
• the formulations and routes of administration for such therapies and compositions can be based on the information described herein for compositions and therapies comprising a compound of the invention as the sole active agent and on information provided for the other agent in combination therewith.
• a specific compound of formula 1 can be determined to inhibit cdk2, cdk5, or GSK-3 using biological assays known to those of ordinary skill in the art, for example the assays described below.
• Enzyme activities can be assayed as the incorporation of [33P] from the gamma phosphate of [33P]ATP (Amersham, cat. no. AH-9968) into biotinylated peptide substrate PKTPKKAKKL
• reactions are carried out in a buffer containing ⁇ OmM Tris- HCI, pH 8.0; 10mM MgCI2, 0.1 mM Na3V04, and 1mM DTT.
• the final concentration of ATP is about O. ⁇ uM (final specific radioactivity of 4uCi/nmol), and the final concentration of substrate 0.7 ⁇ uM.
• Reactions initiated by the addition of either cdk ⁇ and activator protein p25 or cdk2 and activator cyclin E, may be carried out at room temperature for about 60 minutes. Reactions are stopped by addition of 0.6 volume of buffer containing (final concentrations): 2.5mM EDTA, 0.05%Triton-X 100, 100uM ATP, and 1.25 mg/ml streptavidin coated SPA beads (Amersham cat. no. RPNQ0007). Radioactivity associated with the beads is quantified by scintillation counting.
• a cell-free assay can be carried out in general by incubating GSK-3 with a peptide substrate, radiolabeled ATP (such as, for example, ⁇ 33 P- or ⁇ 32 -P-ATP, both available from Amersham, Arlington Heights, Illinois), magnesium ions, and the compound to be assayed. The mixture is incubated for a period of time to allow incorporation of radiolabeld phosphate into the peptide substrate by GSK-3 activity.
• radiolabeled ATP such as, for example, ⁇ 33 P- or ⁇ 32 -P-ATP, both available from Amersham, Arlington Heights, Illinois
• the reaction mixture is washed to remove unreacted radiolabeled ATP, typically after first transferring all or a portion of the enzyme reaction mixture to a well that contains a uniform amount of a ligand that is capable of binding to the peptide substrate.
• the amount of 33 P or 32 P remaining in each well after washing is then quantified to determine the amount of radiolabeled phosphate incorporated into the peptide substrate. Inhibition is observed as a reduction, relative to a control, in the incorporation of radiolabeled phosphate into the peptide substrate.
• An example of a suitable GSK-3 peptide substrate for an assay is the SGSG-linked CREB peptide sequence, derived from the CREB DNA binding protein, described in Wang, et al., Anal.
• Purified GSK-3 for an assay may, for example, be obtained from cells transfected with a human GSK-3 ⁇ expression plasmid as described in, for example Stambolic, et al., Current Biology 6:1664-68 (1996).
• WO 99/65897; Wang, et al., and Stambolic, et al. are incorporated in their entireties herein by reference.
• GSK-3 assay Another example of a GSK-3 assay, similar to the one described in the preceding paragraph is as follows: Enzyme activities are assayed as the incorporation of [33P] from gamma phosphate of [33P]ATP (Amersham, cat. No. AH-9968) into biotinylated peptide substrate PKTPKKAKKL. Reactions are carried out in a buffer containing 50mM Tris-HCI, pH 8.0; 10mM MgCI 2 , 0.1 mM Na 3 V0 4 , and 1 mM DTT. The final concentration of ATP is 0.5 ⁇ M (final specific radioactivity of 4 ⁇ Ci/nmol), and the final concentration of substrate is 0.75 ⁇ M.
• Reactions initiated by the addition of enzyme, are carried out at room temperature for about 60 minutes. Reactions are stopped by addition of 0.6 volume of buffer containing (final concentrations): 2.5mM EDTA, 0.05%Triton-X 100, 100 ⁇ M ATP, and 1.25 mg/ml streptavidin coated SPA beads (Amersham cat. No. RPNQ0007). Radioactivity associated with the beads is quantified by scintillation counting.
• TFA indicates “trifluoroacetic acid”
• THF indicates “tetrahydrofuran”
• MPLC indicates “medium pressure liquid chromatography”
• TLC indicates
• the title compound was prepared according to the method for Example 1 , using 5 analogous reactants.
• the title compound was prepared according to the method for Example 1 , using analogous reactants.
• the title compound was prepared according to the method for Example 1 , using 0 analogous reactants.
• the title compound was prepared according to the method for Example 1 , using analogous reactants.
• Example 7 (3-Bromo-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine The title compound was prepared according to the method for Example 1 , using analogous reactants. HNMR (400MHz, CDCI 3 ), ⁇ 1.82-1.99 (m, 2H), 2.06-2.17 (m, 2H), 2.21-2.29 (m, 2H),
• the title compound was prepared according to the method for Example 1 , using analogous reactants.
• Example 9 (2-Chloro-4-nitro-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine
• the title compound was prepared according to the method for Example 1 , using analogous reactants.
• Example 10 (3,5-Bis-trifluoromethyl-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)- amine
• the title compound was prepared according to the method for Example 1 , using analogous reactants.
• the title compound was prepared according to the method for Example 1 , using analogous reactants.
• Example 13 (2-Bromo-phenyl)-(5-cyclobutyl-2H-pyrazol-3-yl)-amine 0
• the title compound was prepared according to the method for Example 1 , using analogous reactants.
• Example 14 (5-Cyclobutyl-2H-pyrazol-3-yl)-(3,5-dichloro-phenyl)-amine The title compound was prepared according to the method for Example 1 , using analogous reactants.
• the reaction was allowed to slowly warm to rt over 20 hr. The reaction was then cooled to 0
• This material was purified by vacuum distillation (95-106 °C, 2-3 mm) to give the title compound in a quantitative yield and as a colorless oil.
• the title compound was prepared according to the method for Preparation 1.1 , using analogous reactants.
• Procedure B Cesium carbonate (296mg, 0.454mmol) was flame dried in a reaction flask and 3.9ml of dry toluene was then transferred followed by 200mg (0.778mmol) of 5- ⁇ Cyclobutyl-2-(4-methoxy-benzyl)-2H-pyrazol-3-ylamine (Preparation 1.3). The resulting mixture was stirred at rt for 10min followed by the additions of 2-chloro-6-methoxy pyridine (93.2mg, 0.648mmol), 2-(dicyclohexylphosphino)-biphenyl (11.7mg, 0.0334mmol) and palladium acetate (3.6mg, 0.0162mmol). Refluxing under nitrogen overnight took the reaction to completion. Filtration through Celite, concentration of the filtrate, and chromatography as in 0 procedure A yielded the title compound of Preparation 1.4 (120mg, 51 % yield) as a solid.
• Example 17 (5-Cyclobu tyl-2H-pyrazol-3-yl)-(3-trif luoromethyl-phenyl)-amine The title compound was made according to the method for Example 1 ⁇ , using analogous reactants.
• the title compound was made according to the method for Example 15, using analogous reactants.
• the title compound was made according to the method for Example 15, using ⁇ analogous reactants.
• the title compound was made according to the method for Example 15, using analogous reactants.
• the title compound was made according to the method for Example 15, using ⁇ analogous reactants.
• Example 25 (5-Cyclobutyl-2H-pyrazol-3-yl)-(6-methoxy-pyridin-2-yl)-amine 0
• the title compound was made according to the method for Example 15, using analogous reactants.
• Example 26 3-7rans-[5-(3-trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]- cyclopentanone ⁇
• the title compound was prepared according to the method for Preparation 3.4, using hydrazine instead of 4-methoxy-benzyl-hydrazine (see synthesis of Preparation 3.3, supra).
• a racemate comprising cis:trans isomers of [5-(3-Benzylamino-cyclopentyl)-1 H- pyrazol-3-yl]-(3-trifluoromethyl-phenyl)-amine was prepared according to the method for
• the title compound was prepared according to the method for preparation 3.6, using the title compound of Example 26 instead of the title compound of Preparation 3.4.
• Analytical separation of the four isomers of the title compound was accomplished using the following conditions: Column: Chiralcel OD, ⁇ cm x 10cm. Mobile phase: 96/5 heptane/EtOH containing 0.025% DEA as a modifier. Flow rate: 76 mL/min. The sample was loaded using 1:1 Methylene chloride/mobile phase. The retention times for the four isomers were 30 min, 37 min, 45min, and 60 min, respectively.
• the title compound was prepared according to the method for Example 30, using analogous reactants.
• Example 32 Pyridine-2-carboxylic acid ⁇ 3-[5-(3-trifluoromethyl-phenylamino)-2H- pyrazol-3-yl]-cyclopentyl ⁇ -amide
• the title compound was prepared according to the method for Example 30, using analogous reactants.
• the title compound was prepared according to the method for Example 30, using analogous reactants.
• the title compound was prepared according to the method for Example 30, using analogous reactants.
• the title compound was prepared according to the method for Example 30, using analogous reactants.
• Example 38 N- ⁇ 3-[5-(3-Trifluoromethyl-phenylamino)-2H-pyrazol-3-yl]- cyclopentyl ⁇ -propionamide
• the title compound was prepared according to the method for Example 30, using analogous reactants.
• the title compound was prepared according to the method for Example 30, using analogous reactants.
• the title compound was prepared according to the method for Preparation 3.5, using the title compound of Preparation 4.4 as a reactant instead of the title compound of 0 Preparation 3.4.
• the title compound was prepared according to the method for Preparation 4.6, using analogous reactants.
• the title compound was synthesized by the method for Example 30, using analogous reactants.
• Example 43 N- 3-[5-(2-Naphthalen-1 -yl-acetylamino)-1 H-pyrazol-3-yl]- cyclopentyl ⁇ -benzamide
• the title compound was synthesized by the method for Example 30, using analogous reactants.
• Example 54 4-Methoxy-N- ⁇ c/s-3-[5-(2-naphthalen-1-yl-acetylamino)-2H-pyrazol- 3-yl]-cyclobutyl ⁇ -benzamide ⁇ R f 0.35 (5% MeOH/ CH 2 CI 2 ).
• 1 HNMR 400MHz, CD 3 OD), ⁇ 2.17-2.26 (m, 2H), 2.68-
• Example 62 N- ⁇ 5-[(1 R)-(Benzothiazol-2-yloxy)-ethyl]-1 H-pyrazol-3-yl ⁇ -2- naphthalen-1 -yl-acetamide
• the title compound was synthesized according to the method for Example 60, using analogous reactants.
• the title compound was synthesized according to the method for Example 60, using analogous reactants.
• Example 65-71 The title compounds of the following Examples 65-71 were synthesized as in Example 64, including synthesis of Preparations 7.1 and 7.2, using an analogous starting ketone:

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