Patent Application
20090325964
In one aspect, this invention relates to piperazine metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulators, and methods for their preparation. In a further aspect, the invention provides methods for using the mGluR5 negative allosteric modulators for treatment of diseases and disorders including schizophrenia, paranoia, depression, manic-depressive illness, anxiety (including panic disorders, social anxiety, obsessive compulsive disorders, generalized anxiety disorders, phobias), post-traumatic stress disorder, bipolar disorder, Asperger's syndrome, pervasive developmental disorders, gastrointestinal disorders such as gastroesophageal reflux disease, dyspepsia, irritable bowel syndrome, functional bloating, functional diarrhea, chronic constipation, functional disturbances of the biliary tract, migraine, chronic pain, fibromyalgia, neuropathic pain, post-herpatic neuropathic pain, addiction, Parkinson's disease, senile dementia, levadopa-induced dyskinesia, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, multiple sclerosis, Down Syndrome, fragile-X syndrome, autistic spectrum disorders, attention deficit hyperactivity disorder, stroke, ischemic injury, epilepsy, hypoglycemia and obesity.
The metabotropic glutamate 5 receptor (mGluR5) is a G-protein-coupled metabolic glutamate receptor that plays a role as a modulator of synaptic plasticity, ion channel activity, and excitotoxicity (Bach et al., Metabotropic Glutamate Receptor 5 Modulators and their Potential Therapeutic Applications, Department of Med. Chemistry, AstraZeneca R and D Moelndal, Moelndal, Sweden, Expert Opinion on Therapeutic Patents 2007, 17(4), 371-384 and references therein).
Recent evidence indicates that current mGluR5 negative allosteric modulators are not sufficiently selective, and cause off-target effects, such as inhibition of NMDA receptors. Thus, there exists an ongoing need for compounds that more selectively bind to mGluR5, and that are useful in repressing and/or treating disorders such as schizophrenia, paranoia, depression, manic-depressive illness and anxiety. This invention is directed to these, as well as other, important ends.
In one aspect, the invention provides compounds of Formula I:
wherein the constituent variables are as defined herein.
In another aspect, the invention provides pharmaceutical compositions containing a compound of the invention, and a pharmaceutically acceptable carrier.
In a further aspect, the invention provides methods for the treatment of a patient suffering from a chronic condition such as, schizophrenia, paranoia, manic-depressive illness, depression, or anxiety (including panic disorders, social anxiety, obsessive compulsive disorders, generalized anxiety disorders, phobias), post-traumatic stress disorder, bipolar disorder, Asperger's syndrome, pervasive developmental disorders, gastrointestinal disorders such as gastroesophageal reflux disease, dyspepsia, irritable bowel syndrome, functional bloating, functional diarrhea, chronic constipation, functional disturbances of the biliary tract, migraine, chronic pain, fibromyalgia, neuropathic pain, post-herpatic neuropathic pain, addiction, Parkinson's disease, senile dementia, levadopa-induced dyskinesia, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, multiple sclerosis, Down Syndrome, fragile-X syndrome, autistic spectrum disorders, attention deficit hyperactivity disorder, stroke, ischemic injury, epilepsy, hypoglycemia and obesity.
In yet another aspect, the invention provides methods for producing compounds of Formula I.
Other aspects of the present teachings are described further in the following detailed description.
In accordance with the invention, there are provided A compound of Formula I:
wherein:
R1 is each independently selected from H, C1-6 alkyl, halogen, OH, and OC1-6 alkyl;
R2 is selected from -(L1)a-(Y)c-(L2)b-Q3, -L3-Q4 and -L4-Q5;
L3 is C2-12 alkynyl optionally substituted with 1-3 substituents selected from OH and halogen;
L1 and L2 are each independently C1-3 alkyl;
L4 is C2-12 alkenyl optionally substituted with 1-3 substituents selected from OH and halogen;
n is 1 or 2
R4, R4a, R5, and R5a are each independently selected from H, (═O) and C1-6 alkyl; or R4 and one of R5a together can form a bridging methylene; or R5 can be together with the carbon to which it is attached —C(═O)
R6 is selected from H, CH3, -(L5)-(3- to 14-membered heterocycle), -(L5)-(5 to 14 membered heteroaromatic), (L5)-(3- to 10-membered cycloalkyl), (L5)-(C6-14 aryl) and -(L5)-C1-6 alkyl each of which except H can be optionally substituted with 1 to 3 substituents independently selected from H, C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl, CN, (5- to 14-membered heteroaromatic), NR1R1, SO2C1-6 alkyl, SO2, SO2NR1R1, C1-6alkylaryl, COC1-6 alkyl, and (3- to 14-membered heterocycle) optionally substituted with NO2.
L5 is selected from a bond, C1-3 alkyl, —C(═O)—, SO2, (3- to 6-membered heterocycle) and (5- to 14-membered heteroaromatic).
X1, X2 are independently CR3 or N;
each R3 is independently H, C1-6 alkyl, halogen, OH, OC1-6 alkyl, SO2, 3- to 14-membered heterocycle or 5- to 14-membered heteroaromatic, wherein each of C1-16 alkyl or OC1-6 alkyl can be optionally substituted with 1 to 3 substituents independently selected from halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl —NH2, —NH—(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl), cycloalkyl, NR1R1, or CN;
Z is CO;
Y is CR7R8, NR9, O, or S;
R7, R8, R9 are independently H, C1-6 alkyl, halogen, OH, or OC1-6 alkyl
a, b, c are independently 0 or 1; and
Q3 is C6-14 aryl, 5 to 14 membered heterocyclic, 5 to 14 membered heteroaromatic, or 4 to 9 membered carbocyclic; each of which can be optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl —NH2, —NH—(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl), OC1-6 haloalkyl, OC1-6 alkylaryl and CN;
Q4 is H, C6-14 aryl, 5 to 14 membered heterocyclic, 5 to 14 membered heteroaromatic, or 4 to 9 membered carbocyclic; each of which except H can be optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), —C(═O)C1-16 alkyl, NO2, C1-3 haloalkyl, —S—C1-6 alkyl —NH2, —NH—(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl), CO1-3haloalkyl, CO1-6alkylaryl and CN;
Q5 is C6-14 aryl, 5 to 14 membered heterocyclic, 5 to 14 membered heteroaromatic, or 4 to 9 membered carbocyclic; each of which can be optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl —NH2, —NH—(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl), CO1-3haloalkyl, CO1-6alkylaryl and CN.
In some embodiments of formula I, n is 1.
In some embodiments, R2 is -L3-Q4. In some embodiments, Z is CO. In some embodiments, R1, R4, R4a, R5, R5a, and R6 are each H. In some embodiments, R3 is H, methyl, methoxy or halogen.
In some embodiments, R2 is -L3-Q4, and Z is CO. In some such embodiments, R1, R4, R4a, R5, and R5a, are each H. In some further such embodiments, R1, R4, R4a, R5, and R5a, are each H; and R3 is H, methyl, methoxy or halogen. In some further such embodiments, Q4 is H. In some further such embodiments, Q4 is phenyl optionally substituted with 1 to 3 substituents independently selected from H, C1-6 alkyl, halogen, OH, and OC1-6 alkyl. In some further such embodiments, Q4 is 5 to 14 membered heterocyclic optionally substituted with 1 to 3 substituents independently selected from H, C1-6 alkyl, halogen, OH, and OC1-6 alkyl. In some further such embodiments, Q4 is 5 to 14 membered heteroaromatic optionally substituted with 1 to 3 substituents independently selected from H, C1-6 alkyl, halogen, OH, and OC1-6 alkyl.
In some embodiments R2 is -L3-Q4, Z is CO, and R6 is -(L5)-2-pyridyl, -(L5)-4-pyridyl, -(L5)-pyrazinyl, -(L5)-phenyl, -(L5)-(tetrazole-5-yl), pyrimidin-2-yl, -(4-phenyl)-pyrimidin-2-yl or -(L5)-1,2,5-diathiazole-3-yl, each of which can be optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl and CN. In some such embodiments, L5 is a bond.
In some embodiments of the compounds of Formula I, X1 and X2 are each independently CR3 or N.
In some embodiments of the compounds of Formula I, one of X1 and X2 is CR3, and the other of X1 and X2 is N. In some such embodiments, Z is CO. In some further such embodiments, Z is CO; R2 is -L3-Q4, and L3 is C2 alkynyl. In some further such embodiments, Z is CO; R2 is -L3-Q4, L3 is C2 alkynyl, and Q4 is phenyl optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl —NH2, —NH—(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl) and CN. In some such embodiments, R4, R4a, R5, and R5a, are each H. In some such embodiments, R6 is 5 to 14 membered heteroaromatic, each of which is optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl and CN.
In some embodiments of the compounds of Formula I, X1 and X2 are each independently CR3. In some such embodiments, R6 is H.
In some embodiments of the compounds of Formula I, X1 is CR3, X2 is CH, and R6 is H. In some such embodiments, Z is CO.
In some embodiments of the compounds of Formula I, X1 is CR3, X2 is CH, R6 is H, Z is CO and R1, R4, R4a, R5, and R5a, are each H.
In some embodiments of the compounds of formula I, X1 is CR3, X2 is CH, R6 is -(L5)-phenyl optionally substituted with halogen or C1-6 alkyl, wherein L5 is a bond, Z is CO and R4a and R5 form a bridging methylene, R2 is -L3-Q4, L3 is C2 alkynyl, and Q4 is 2-pyridyl or phenyl optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl —NH2, —NH—(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl) and CN. In some such further embodiments R3 is OC1-6 alkyl.
In some other embodiments of the compounds of formula I, R6 is H, CH3, -(L5)-2-pyridyl, -(L5)-4-pyridyl, -(L5)-pyrazinyl, -(L5)-phenyl, -(L5)-(3-14-membered heterocycle), -(L5)-(5- to 14-membered heteroaromatic), (L5)-cycloalkyl, (L5)-(3- to 10-membered cycloalkyl), (L5)-(C6-14 aryl) or -(L5)-C1-6 alkyl each of which except H can be optionally substituted with 1 to 3 substituents independently selected from H, C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl, CN, a 3- to 14-membered heterocycle or 5- to 14-membered heteroaromatic, NR1, SO2, SO2NR1R1 or C1-6 alkylaryl.
In other embodiments of the compounds of formula I, R6 is -(L5)-(3- to 14-membered heterocycle), -(L5)-(5 to 14 membered heteroaromatic) or (L5)-(C6-14 aryl), wherein L5 can be a bond, SO2
In some embodiments of the compounds of Formula I, X1 is CR3, X2 is CH, R6 is H, Z is CO, R1, R4, R4a, R5, and R5a, are each H, and R2 is -(L1)a-(Y)c-(L2)b-Q3 or -L4-Q5. In some such embodiments, Y is O. In some further such embodiments, Y is O, and Q3 and Q5 are each phenyl optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl —NH2, —NH—(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl) and CN. In some further such embodiments, R2 is —CH═CH—, —CH2—O— or —O—CH2—; Y is Q; and Q3 and Q5 are each phenyl optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-16 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl —NH2, —NH—(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl) and CN.
In some embodiments of the compounds of Formula I, Z is CH2. In some such embodiments, X1 and X2 are each CH.
In some embodiments of the compounds of Formula I, Z is CH2, X1 and X2 are each CH, and R6 is -(L5)-(5 to 14 membered heteroaromatic), optionally substituted with 1 to 3 substituents independently selected from H, C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl and CN.
In some embodiments of the compounds of Formula I, Z is CH2, X1 and X2 are each CH, and R2 is -L3-Q4; wherein Q4 is phenyl or 4 to 9 membered carbocyclic, each of which is optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl —NH2, —NH—(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl) and CN.
In some embodiments of the compounds of Formula I, Z is CH2, X1 and X2 are each CH, and R2 is -L3-Q4; wherein Q4 is phenyl or 4 to 9 membered carbocyclic, each of which is optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl —NH2, —NH—(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl) and CN; and R6 is -(L5)-(5 to 14 membered heteroaromatic), optionally substituted with 1 to 3 substituents independently selected from H, C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl and CN.
In some embodiments of the compounds of Formula I, Z is CH2, X1 and X2 are each CH, and R2 is -L3-Q4; wherein Q4 is phenyl or 4 to 9 membered carbocyclic, each of which is optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl —NH2, —NH—(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl) and CN; and R6 is (L5)-(C6-14 aryl), optionally substituted with 1 to 3 substituents independently selected from H, C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl and CN.
In some embodiments of the compounds of Formula I, Z is CH2, X1 and X2 are each CH, and R2 is -L3-Q4; wherein Q4 is phenyl, cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-6 alkyl, halogen, OH, OC1-6 alkyl and —NH2; and R6 is pyrid-2-yl. In some such embodiments, R1, R4, R4a, R5, and R5a, are each H, and L3 is C2-3 alkynyl.
In some embodiments of the compounds of Formula I, Z is SO2. In some such embodiments, X1 and X2 are each CH.
In some embodiments of the compounds of Formula I, Z is SO2, X1 and X2 are each CH, and R6 is -(L5)-(5 to 14 membered heteroaromatic), optionally substituted with 1 to 3 substituents independently selected from H, C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl and CN.
In some embodiments of the compounds of Formula I, Z is SO2, X1 and X2 are each CH, and R2 is -L3-Q4; wherein Q4 is phenyl or 4 to 9 membered carbocyclic, each of which is optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl and CN.
In some embodiments of the compounds of Formula I, Z is SO2, X1 and X2 are each CH, and R2 is -L3-Q4; wherein Q4 is phenyl or 4 to 9 membered carbocyclic, each of which is optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl and CN; and R6 is -(L5)-(5 to 14 membered heteroaromatic), optionally substituted with 1 to 3 substituents independently selected from H, C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl and CN.
In some embodiments of the compounds of Formula I, Z is SO2, X1 and X2 are each CH, and R2 is -L3-Q4; wherein Q4 is phenyl, cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-6 alkyl, halogen, OH, and OC1-6 alkyl; and R6 is pyrid-2-yl. In some such embodiments, R1, R4, R4a, R5, and R5a, are each H, and L3 is C2-3 alkynyl.
In some embodiments of the compounds of Formula I, R2 is -L3-Q4; Q4 is 5 to 14 membered heteroaromatic optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl —NH2, —NH—(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl) and CN; and R6 is -(L5)-(5 to 14 membered heteroaromatic) optionally substituted with 1 to 3 substituents independently selected from H, C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl and CN.
In some embodiments of the compounds of Formula I, R2 is -L3-Q4; Q4 is 5 to 14 membered heteroaromatic optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl —NH2, —NH—(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl) and CN; and R6 is -(L5)-(5 to 14 membered heteroaromatic) optionally substituted with 1 to 3 substituents independently selected from H, C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl and CN.
In some such embodiments, Q4 is pyridyl, preferably pyrid-2-yl, optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl —NH2, —NH—(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl) and CN.
In some further such embodiments, R6 is -(L5)-(pyridyl), preferably -(L5)-(pyrid-2-yl), optionally substituted with 1 to 3 substituents independently selected from H, C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl and CN.
In some further such embodiments, Z is CO. In some further such embodiments, X1 is CR3 and X2 is CH. In some further such embodiments, R1 is H. In some further such embodiments, R4, R4a, R5, and R5a are each H, and in some further such embodiments, R1 is H.
In some embodiments of the compounds of Formula I, one or more of the following conditions a-g exist:
(a) if R2 is -L3-Q4, L3 is C2 alkynyl, Q4 is cyclohexanol-1-yl, Z is CO, R1, R4, R4a, R5, and R5a, are each H, and X1 and X2 are each CH, then R6 is not 2-methoxyphenyl;
(b) if R2 is -L3-Q4, L3 is C2 alkynyl, Q4 is phenyl, Z is CO, R1, R4, R4a, R5, and R5a, are each H, and X1 and X2 are each CH, then R6 is not pyrimidin-2-yl;
(c) if R2 is -L3-Q4, L3 is C2 alkynyl, Q4 is phenyl, Z is CO, R1, R4, R4a, R5, and R5a, are each H, and X1 and X2 are each CH, then R6 is not 3-trifluoromethylphenyl;
(d) if R2 is -L3-Q4, L3 is C2 alkynyl, Q4 is phenyl, Z is CO, R1, R4, R4a, R5, and R5a, are each H, and X1 and X2 are each CH, then R6 is not 2-methoxyphenyl;
(e) if R2 is -L3-Q4, L3 is C2 alkynyl, Q4 is phenyl, Z is CO, R1, R4, R4a, R5, and R5a, are each H, and X1 and X2 are each CH, then R6 is not pyrid-2-yl;
(f) if R2 is -L3-Q4, L3 is C2 alkynyl, Q4 is phenyl, Z is CO, R1, R4, R4a, R5, and R5a, are each H, and X1 and X2 are each CH, then R6 is not 2-fluorophenyl;
(g) if R2 is -L3-Q4, L3 is C2 alkynyl, Q4 is cyclohexanol-1-yl, Z is CO, R1, R4, R4a, R5, and R5a, are each H, and X1 and X2 are each CH, then R6 is not 4-nitrophenyl.
In some embodiments of the compounds of Formula I, all of the foregoing conditions a-g exist. In some embodiments of the compounds of Formula I, none of the foregoing conditions a-g exist. In some embodiments of the compounds of Formula I, one or more, but less than all of the foregoing conditions a-g exist.
Prodrugs of the compounds of Formula I are also embraced by the present invention. The term “prodrug”, as used herein, means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of formula I. Various forms of prodrugs are known in the art, for example, as discussed in, for example, Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al. (ed.), “Design and Application of Prodrugs”, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991), Bundgaard, et al., Journal of Drug Deliver reviews, 8:1-38 (1992), Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975), each of which is incorporated by reference in its entirety.
The mGluR5 negative allosteric modulators disclosed herein are useful for treating diseases and disorders including schizophrenia, paranoia, depression, including manic-depressive illness, anxiety (including panic disorders, social anxiety, obsessive compulsive disorders, generalized anxiety disorders, phobias), post-traumatic stress disorder, bipolar disorder, Asperger's syndrome, pervasive developmental disorders, gastrointestinal disorders such as gastroesophageal reflux disease, dyspepsia, irritable bowel syndrome, functional bloating, functional diarrhea, chronic constipation, functional disturbances of the biliary tract, migraine, chronic pain, fibromyalgia, neuropathic pain, post-herpatic neuropathic pain, addiction, Parkinson's disease, senile dementia, levadopa-induced dyskinesia, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, multiple sclerosis, Down Syndrome, fragile-X syndrome, autistic spectrum disorders, attention deficit hyperactivity disorder, stroke, ischemic injury, epilepsy, hypoglycemia and obesity. Accordingly, in some embodiments, the invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of Formula I, or a pharmaceutically acceptable salt, hydrate or prodrug thereof. In further embodiments, the invention provides methods of treating a patient suffering from a chronic condition such as schizophrenia, paranoia, manic-depressive illness or anxiety, comprising providing a therapeutically effective amount of compound of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.
Some compounds of the present invention can contain an asymmetric atom (also referred as a chiral center), and some of the compounds can contain one or more asymmetric atoms or centers, which can thus give rise to optical isomers (enantiomers) and diastereomers (geometric isomers). The present invention includes such optical isomers and diastereomers, as well as, the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as, other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts, hydrates, solvates, metabolites and prodrugs thereof. Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, and include, but are not limited to, chiral chromatography, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. The present teachings also encompass cis and trans or E/Z isomers of compounds containing alkenyl moieties (e.g., alkenes and imines). It is also understood that this invention encompasses all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin-layer chromatography, and high-performance liquid chromatography.
Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.
Compounds of the invention can also include tautomeric forms, such as keto-enol tautomers. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
As used herein, the term “alkyl” as a group or part of a group is intended to denote hydrocarbon groups including straight chain, branched and cyclic saturated hydrocarbons. Alkyl groups can contain 1-20, or 1-12, or 1-6 carbon atoms. The term “lower alkyl” is intended to mean an alkyl group having up to 6 carbon atoms. Nonlimiting examples of straight chain and branched alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, and t-butyl), pentyl groups (e.g., n-pentyl, isopentyl, and neopentyl), hexyl groups, and the like.
The term “cycloalkyl” is intended to mean a monocyclic or bicyclic saturated hydrocarbon group having the indicated number of carbon atoms. For example, a C3-C8 cycloalkyl group would include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups, as well as polycyclic systems (e.g., containing fused, bridged, and/or spiro ring systems). Any suitable ring position of a cyclic alkyl group can be covalently linked to the defined chemical structure. Unless otherwise indicated, alkyl groups are unsubstituted. However, where indicated, alkyl groups may be substituted with one or more independently selected substituents as described herein.
As used herein, the term “alkenyl” as a group or part of a group is intended to denote an alkyl group that contains at least one carbon-carbon double bond. Alkenyl groups can contain 2-20, or 2-12, or 2-6 carbon atoms. The term “lower alkenyl” is intended to mean an alkenyl group having up to 6 carbon atoms. Nonlimiting examples of straight chain and branched alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, vinyl, allyl, 2-methyl-allyl, 4-but-3-enyl, 4-hex-5-enyl, 3-methyl-but-2-enyl, cyclohex-2-enyl, and the like. The one or more carbon-carbon double bonds can be internal (such as in 2-butene) or terminal (such as in 1-butene). Additionally, hydrocarbon alkenyl moieties may be mono or polyunsaturated, and may exist in the E or Z configurations. The compounds of this invention are meant to include all possible E and Z configurations. Alkenyl groups may be substituted with one or more independently selected substituents as described herein.
The term “cycloalkenyl” is intended to mean a cycloalkyl group that contains at least one carbon-carbon double bond. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, and the like. Alkenyl groups may be substituted with one or more independently selected substituents as described herein. Any suitable ring position of a cycloalkenyl group can be covalently linked to the defined chemical structure. Unless otherwise indicated, alkenyl groups are unsubstituted. However, where indicted, alkenyl groups may be substituted with one or more independently selected substituents as described herein.
As used herein, the term “alkynyl” is intended to denote an alkyl group that contains at least one carbon-carbon triple bond. Alkynyl groups can contain 2-20, or 2-12, or 2-6, or 2-3 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, pent-2-yne, ethynyl-cyclohexyl, and the like. The one or more carbon-carbon triple bonds can be internal (such as in 2-butyne) or terminal (such as in 1-butyne). Alkynyl groups may be substituted with one or more independently selected substituents as described herein.
As used herein, the term “aryl” as a group or part of a group refers to an aromatic monocyclic hydrocarbon ring system or a polycyclic ring system (e.g., bicyclic or tricyclic), e.g., of 6-14 carbon atoms where at least one of the rings present in the ring system is an aromatic hydrocarbon ring and any other aromatic rings present in the ring system include only hydrocarbons. Any suitable ring position of the aryl group can be covalently linked to the defined chemical structure. In some embodiments, an aryl group can have only aromatic carbocyclic rings e.g., phenyl, 1-naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl groups, and the like. In other embodiments, an aryl group can be a polycyclic ring system in which at least one aromatic carbocyclic ring is fused (i.e., having a bond in common with) to one or more cyclic alkyl or heterocyclic alkyl rings, provided that the group is attached to the remainder of the molecule through the aromatic portion thereof. Examples of such aryl groups include, among others, benzo derivatives of cyclopentane (i.e., an indanyl group, which is a 5,6-bicyclic cyclic alkyl/aromatic ring system), cyclohexane (i.e., a tetrahydronaphthyl group, which is a 6,6-bicyclic cyclic alkyl/aromatic ring system), imidazoline (i.e., a benzimidazolinyl group, which is a 5,6-bicyclic heterocyclic alkyl/aromatic ring system), and pyran (i.e., a chromenyl group, which is a 6,6-bicyclic heterocyclic alkyl/aromatic ring system). Other examples of aryl groups include, but are not limited to, benzodioxanyl, benzodioxolyl, chromanyl, indolinyl groups, and the like.
In some embodiments, an aryl group can be substituted with one or more (e.g., up to 4) independently selected substituents as described herein.
As used herein, the terms, “carbocyclyl”, “carbocycle” or “carbocyclic” refer to (1) a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms. In some embodiments (“C3-8 carbocyclyl”), a carbocyclyl group can have from 3 to 8 ring carbon atoms. In some embodiments (“C3-6 carbocyclyl”), a carbocyclyl group can have from 3 to 6 ring carbon atoms. Examples of such C3-6 carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and the like. Examples of such C3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl, cycloheptadienyl, cycloheptatrienyl, cyclooctyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl and the like. Examples of such C3-10 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as octahydro-1H-indenyl, decahydronaphthalenyl, spiro[4.5]decanyl and the like. As the foregoing examples illustrate, in some embodiments a carbocyclyl group can be monocyclic (“monocyclic carbocyclyl”) or bicyclic (e.g., containing a fused, bridged or spiro ring system), and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also refers to (2) a phenyl group; (3) an aryl group (as defined herein); and (4) a 5- or 6-membered heteroaryl group (as defined herein) fused to a monocyclic carbocyclyl group, where the point of attachment is on the carbocyclyl portion of the group. Examples of such carbocyclyl groups include 1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-2-yl, 1H-inden-1-yl, 5,6,7,8-tetrahydroquinolin-5-yl, 5,6,7,8-tetrahydroquinolin-7-yl, 4,5,6,7-tetrahydro-1H-indol-4-yl, 4,5,6,7-tetrahydro-1H-indol-6-yl, 4,5,6,7-tetrahydrobenzofuran-7-yl and the like.
The term “heterocyclic” or “heterocyclic group” or “heterocycle” is used herein to describe a 3-14 membered monocyclic or polycyclic, ring system having at least 1, and up to 4, ring heteroatoms independently selected from N, O and S. Heterocyclic groups can be saturated, partially unsaturated, or wholly unsaturated, but cannot be aromatic. When the heterocyclic ring contains nitrogen or sulfur atoms in the backbone of the ring, the nitrogen or sulfur atoms can be oxidized, for example, N-oxides, SO or SO2. Heterocyclic groups include, without limitation, oxygen-containing rings, nitrogen-containing rings, sulfur-containing rings, and mixed heteroatom-containing rings. Nonlimiting examples of heterocyclic groups include aziridinyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, dihydro-1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl.
The term “heteroaromatic” as used herein is intended to denote 3-14 membered monocyclic or polycyclic ring systems having at least one aromatic ring that contains at least 1, and up to 4, ring heteroatoms independently selected from N, O and S. Heteroaromatic groups can contain one or more non-aromatic rings fused to (i.e., sharing a bound in common with) the monocyclic or polycyclic heteroatom-containing ring described above, provided that the group is attached to the remainder of the molecule through the aromatic portion thereof. Thus, the term “heteroaromatic” includes groups such as 5,6,7,8-tetrahydroquinolin-2-yl groups. Further examples of heteroaromatic groups include furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, isoxazolyl, triazolyl, oxadiazolyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, benzothiophenyl, quinolinyl, isoquinolinyl, quinoxalinyl, and benzothiazolyl.
The term “optionally substituted” is used herein to refer to the optional substitution of one or more protons with a named substituent or substituents.
The term “alkoxy” as used herein refers to a group of formula —O-alkyl. Examples of alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy, octoxy, prop-2-oxy, but-2-oxy and methylprop-2-oxy.
The term “halogen” refers to Cl, Br, F, and I.
The term “haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen atom. Haloalkyl groups include perhaloalkyl groups, wherein all hydrogens of an alkyl group have been replaced with halogens (e.g., —CF3, —CF2CF3). The halogens can be the same (e.g., CHF2, —CF3) or different (e.g., CF2Cl). Haloalkyl groups can optionally be substituted with one or more substituents in addition to halogen. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups.
Methods of treating the diseases and syndromes listed herein are understood to involve administering to an individual in need of such treatment a therapeutically effective amount of a compound of the invention, or a salt, hydrate or solvate thereof, or a composition comprising one or more of the same. Accordingly, methods are provided in accordance with the invention for treating disorders involving the mGluR5 receptor, such as anxiety and depression diseases and/or disorders, including those specifically listed above, comprising the administration to a patient in need thereof a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof. Such methods comprise administering to the patient in need of such treatment a pharmaceutically or therapeutically effective amount of a compound of this invention. In the instances of combination therapies described herein, it will be understood the administration further includes a pharmaceutically or therapeutically effective amount of the second pharmaceutical agent in question. The second or additional pharmacological agents described herein may be administered in the doses and regimens known in the art.
As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that is effective to treat the condition of interest—i.e., the amount of active compound or pharmaceutical agent that is effective to elicit a biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following:
(1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomotology of the disease;
(2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomotology of the disease, condition or disorder (i.e., arresting or slowing further development of the pathology and/or symptomotology); and
(3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomotology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomotology).
When administered for the treatment or inhibition of a particular disease state or disorder, it is understood that the effective dosage may vary depending upon the particular compound utilized, the mode of administration, the condition, and severity thereof, of the condition being treated, as well as the various physical factors related to the individual being treated. Effective administration of the compounds (including the salts) and the compositions of the present invention may be given at an oral dose of from about 0.1 mg/day to about 1,000 mg/day. Preferably, administration will be from about 10 mg/day to about 600 mg/day, more preferably from about 50 mg/day to about 600 mg/day. The dosing regimen can be adjusted to provide the optimal therapeutic response, and the projected daily dosages are expected to vary with route of administration. Several divided doses can be delivered daily or a single daily dosage can be delivered. The dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
As used herein, the term “individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
Therapeutic doses of compounds or compositions of the invention can be administered in any manner useful in directing the active compounds herein to the recipient's bloodstream. For example, compounds and compositions of the invention can be delivered by a route such as oral, via implants, dermal, transdermal, intrabronchial, intranasal, parental (including intravenous, intraperitoneal, intraarticularly and subcutaneous injections), intraperitoneal, sublingual, intracranial, epidural, intratracheal, vaginal, rectal, topical, ocular (via eye drops) or by sustained release. Optionally, one or more of the compounds of Formula I can be mixed with other active agents.
When the compound is delivered orally, it can be sub-divided in a dose containing appropriate quantities of the active ingredient. The unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. The powders and tablets can contain up to 99% of the active ingredient.
The compounds of Formula I can be combined with one or more pharmaceutically acceptable carriers or excipients including, without limitation, solid and liquid carriers, which are compatible with the compounds of Formula I. Oral formulations containing the active compounds (including the salts, hydrates and solvates thereof) and the compositions of the present invention may comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. Such carriers can include adjuvants, syrups, elixirs, diluents, binders, lubricants, surfactants, granulating agents, disintegrating agents, emollients, solubilizers, suspending agents, fillers, glidants, compression aids, encapsulating materials, emulsifiers, buffers, preservatives, thickening agents, colors, viscosity regulators, stabilizers, osmoregulators, and combinations thereof. Optionally, one or more of the compounds of Formula I can be mixed with other active agents.
Adjuvants can include, without limitation, flavoring agents, sweeteners, coloring agents, preservatives, and supplemental antioxidants, which can include vitamin E, ascorbic acid, butylated hydroxytoluene (BHT) and butylated hydroxyanisole (NHA).
Elixirs and syrups can be prepared from acceptable sweeteners such as sugar, saccharine or a biological sweetener, a flavoring agent, and/or solvent.
Capsules and tablets may contain mixtures of the active compound(s) with inert fillers, diluents, binders, lubricants, granulating agents, disintegrating agents, emollients, surface modifying agents (including surfactants), suspending or stabilizing agents, and the like. Nonlimiting examples of diluents and fillers include materials in which the compound can be dispersed, dissolved, or incorporated, such as water, lower monovalent alcohols, polyhydric alcohols, and low molecular weight glycols and polyols, including, for example, propylene glycol, glycerol, butylenes glycol, 1,2,4-butanetriol, sorbitol esters, 1,2,6-hexanetriol, ethanol, isopropanol, butanediol, ethyl oleate, isopropyl myristate, ether propanol, ethoxylated ethers, propoxylated ethers, oils such as corn, peanut, fractionated coconut, arachis, sesame oils, dimethylsulfoxide (DMSO), dimethylformamide (DMF), waxes, dextrin, and combinations thereof. Examples of binders include, without limitation, cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidine, gelatin, gum Arabic, polyethylene glycol, starch, sugars such as, for example, sucrose kaolin, cellulose kaolin, and lactose. Nonlimiting examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, sorbitan esters, colloidal, silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, lauryl sulfates, and triethanolamine. Examples of lubricants include, without limitation, magnesium stearate, light anhydrous silicic acid, talc and sodium lauryl sulfate. Examples of granulating agents include, without limitation, silicon dioxide, microcrystalline cellulose, starch, calcium carbonate, pectin, crospovidone, and polyplasdone. Examples of disintegrating agents include, without limitation, pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), carboxymethylcellulose, hydroxypropylstarch, substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate, and calcium citrate. Examples of emollients include, without limitation, stearyl alcohol, mink oil, cetyl alcohol, oleyl alcohol, isopropyl laurate, polyethylene glycol, olive oil, petroleum jelly, palmitic acid, oleic acid, and myristyl myristate.
Useful tablet formulations may be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents as described above.
Oral formulations herein may utilize standard delay or time-release formulations to alter the absorption of the active compound(s). The oral formulation may also consist of administering the active ingredient in water or a fruit juice, containing appropriate solubilizers or emulsifiers as needed.
In some cases it may be desirable to administer the compounds (including the salts) and the compositions of the present invention directly to the airways in the form of an aerosol.
The compounds (including salts, hydrates and solvates) and the compositions of the present invention may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds (including the salts) and the compositions of the present invention can be prepared in water optionally mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to inhibit the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
For the purposes of this disclosure, transdermal administrations are understood to include all administrations across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administrations may be carried out using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).
Transdermal administration may be accomplished through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semi-permeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
In some embodiments, sustained delivery devices can be used, in order to avoid the necessity to take medications on a daily basis. The term “sustained delivery” is used herein to refer to delaying the release of an active agent, i.e., a compound of Formula I, until after placement in a delivery environment, followed by a sustained release of the agent at a later time. A number of sustained delivery devices are known in the art and include, for example, hydrogels (U.S. Pat. Nos. 5,266,325; 4,959,217; 5,292,515), osmotic pumps (U.S. Pat. Nos. 4,295,987 and 5,273,752 and European Pat. No. 314,206, among others; hydrophobic membrane materials, such as ethylenemethacrylate (EMA) and ethylenevinylacetate (EVA); bioresorbable polymer systems (International Patent Publication No. WO 98/44964 and U.S. Pat. Nos. 5,756,127 and 5,854,388); and other bioresorbable implant devises composed of, for example, polyesters, polyanhydrides, or lactic acid/glycolic acid copolymers (U.S. Pat. No. 5,817,343). For use in such sustained delivery devices, the compounds of the invention can be formulated as described herein.
Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin. Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, may also be used.
Additional numerous various excipients, dosage forms, dispersing agents and the like that are suitable for use in connection with the salt forms of the invention are known in the art and described in, for example, Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference in its entirety.
The compounds of Formula I have utility for the repression and/or treatment of disorders involving the mGluR5 receptor, such as anxiety and depression disorders. Examples of disorders or conditions which can be treated by the compounds, compositions and methods of this invention include anxiety and depression disorders. Anxiety disorders can include, for example, generalized anxiety disorder, panic disorder, PTSD, and social anxiety disorder. Depression disorders can include, for example, depression in cancer patients, depression in Parkinson's patients, post-myocardial infarction depression, depression in patients with human immunodeficiency virus (HIV), Subsyndromal Symptomatic depression, depression in infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, post partum depression, DSM-IV major depression, treatment-refractory major depression, severe depression, psychotic depression, post-stroke depression, neuropathic pain, manic depressive illness, including manic depressive illness with mixed episodes and manic depressive illness with depressive episodes, seasonal affective disorder, bipolar depression BP 1, bipolar depression BP II, or major depression with dysthymia.
Compounds of the invention can be prepared using the six general schemes outlined below, together with synthetic methods known in the synthetic organic arts or variations of these methods by one skilled in the art. See, Comprehensive Organic Synthesis, “Selectivity, Strategy & Efficiency in Modern Organic Chemistry”, ed., I. Fleming, Pergamon Press, New York (1991); Comprehensive Organic Chemistry, “The Synthesis and Reactions of Organic Compounds”, ed. J.F. Stoddard, Pergamon Press, New York (1979).
In some embodiments, compounds of the invention are produced in accordance with Scheme 1 below. Unless otherwise indicated, the constituent variables of the following Schemes are as defined above.
In accordance with Scheme 1, Sonagashira coupling of bromoaromatics with alkenes using Pd and catalytic CuI in TEA is used to produce the desired acetylenes (II) (Matsunaga, N. et al. Bioorg. Med. Chem. 2004, 12, 2251). Basic hydrolysis using NaOH in aqueous methanol produces acid (III). Reaction of the acid (III) with N-substituted piperazines using EDCl peptide coupling conditions (Rich, D. H. et al., Peptides (New York, 1979-1987) 1979, 1, 241-261) produced the target compounds (IV).
Accordingly, in some embodiments, the invention provides a method for preparing compound a compound of Formula IV:
comprising reacting a compound of Formula III:
with an N-substituted piperazine of Formula IIIa:
for a time and under conditions effective to form the compound of Formula IV;
wherein X1, X2, R6, R1 and Q4 are as defined above.
In some embodiments, compounds of the invention are produced in accordance with Scheme 2 below.
In this procedure, basic hydrolysis using NaOH in aqueous methanol produces an acid (V). The acid (V) is reacted with N-substituted piperazines using EDCl peptide coupling conditions (Rich, D. H. et al., Peptides (New York, 1979-1987) 1979, 1, 241-261) producing amides (VI). Sonagashira coupling of Bromoaromatics (VI) with Acetylenes using Pd(PPh3)2Cl2 in the presence of CuI and TEA under microwave conditions produced the desired target compounds (IV) (see WO 2005/123713). Accordingly, in some embodiments, processes are provided for preparing a compound of Formula IV comprising reacting a compound of Formula VI:
where the Rr, R6, X1, X2 and Z variables are as described above and X5 is halogen or bromine, with an acetylene of Formula Q4-CCH, in the presence of a palladium triphenylphosphine-containing catalyst for a time and under conditions effective to form a compound of Formula IV. In some embodiments, the palladium triphenylphosphine-containing catalyst is Pd(PPh3)2Cl2.
In further embodiments, compounds of the invention having the general Formula IX are produced in accordance with Scheme 3 below.
In accordance with Scheme 3, reaction of benzoic acids with N-substituted piperazines using EDCl peptide coupling conditions (Rich, D. H. et al., Peptides (New York, 1979-1987) 1979, 1, 241-261) produced amides (VIII). Subsequent alkylation of the phenol (VIII) with Cs2CO3 and the benzyl bromide derivatives produced the desired target compounds (IX). Accordingly, in some embodiments, processes are provided for preparing compounds of Formula IX:
wherein R3 is as defined above, R is C1-6 alkyl, halogen, OH, OC1-6 alkyl, —C(═O)O—(C1-6 alkyl), NO2, C1-3 haloalkyl, —S—C1-6 alkyl —NH2, —NH—(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl) or CN; and j is 0, 1, 2, or 3;
comprising reacting a compound of Formula VIII:
with a benzyl halide derivative of Formula VIIIa:
where X5 is halogen, for a time and under conditions effective to form the compound of Formula IX. In some embodiments, X5 is bromine.
In further embodiments, compounds of the invention having the general Formula XI are produced in accordance with Scheme 4 below.
In accordance with Scheme 4, acid chlorides are reacted with N-substituted piperazines using TEA in DCM producing an amide (X). Alkylation of the resulting benzyl chloride (X) with phenol derivatives and K2CO3 produced the desired target compounds (XI).
Accordingly, in some embodiments, processes are provided for preparing compounds of Formula XI:
comprising reacting a compound of Formula X:
with a phenol derivative of Formula Xa:
for a time and under conditions effective to form the compound of Formula XI; wherein the constituent variables are as defined above.
In further embodiments, compounds of the invention having the general Formula XII are produced in accordance with Scheme 5 below.
In accordance with Scheme 5, reaction of sulfonyl chlorides with N-substituted piperazines using TEA in DCM produced sulfonamides (XII). Sonagashira coupling of bromoaromatics (XII) with acetylenes using Pd(PPh3)2Cl2 in the presence of CuI and TEA under microwave conditions produced the desired target compounds (XIII) (see WO 2005/123713).
Accordingly, in some embodiments, processes are provided for preparing a compound of Formula XIII:
comprising reacting a compound of Formula XII:
wherein the constituent variables are as defined above, and X5 is halogen, with an acetylene of Formula Q4-CCH; in the presence of a palladium triphenylphosphine-containing catalyst for a time and under conditions effective to form the compounds of Formula XII. In some embodiments, the palladium triphenylphosphine-containing catalyst is Pd(PPh3)2Cl2.
In further embodiments, compounds of the invention having the general Formula XV are produced in accordance with Scheme 6 below.
In accordance with Scheme 6, reaction of benzyl bromides with N-substituted piperazines using DIEA in THF produced benzyl piperazines (XIV). Sonagashira coupling of bromoaromatics (XIV) with acetylenes using Pd (PPh3)2Cl2 in the presence of CuI and TEA under microwave conditions produced the desired product (XV) (see WO 2005/123713). Accordingly, in some embodiments, processes are provided for preparing compounds of Formula XV, wherein the constituent variables are as defined above, comprising reacting a compound of Formula XIV with an acetylene as shown in Scheme 6, in the presence of a palladium triphenylphosphine-containing catalyst, for example Pd(PPh3)2Cl2, for a time and under conditions effective to form the compound of Formula XV.
The following methods were used for the characterization of compounds appearing in the Examples below.
Standard LCMS Conditions for Compound Characterization:
Column: Thermo Aquasil C18, 50×2.1 mm, 5 μm
Mobile Phase A: 0.1% Formic Acid in water
Flow Rate: 0.800 mL/min
Column Temperature: 40° C.
Injection Volume: 5 mL
UV: monitor 215, 230, 254, 280, and 300 nm
Purity is reported at 254 nm unless otherwise noted.
Gradient Table:
MS Conditions: Instrument: Agilent MSD; Ionization Mode: API-ES; Gas Temperature: 350° C.; Drying Gas: 11.0 L/min.; Nebulizer Pressure: 55 psig; Polarity: 50% positive, 50% negative; VCap: 3000 V (positive), 2500 V (negative); Fragmentor: 80 (positive), 120 (negative); Mass Range: 100-1000 m/z; Threshold: 150; Step size: 0.15; Gain: 1; Peak width: 0.15 minutes.
Preparative reverse-phase HPLC(RP-HPLC): Compounds were in dissolved in 2 mL of 1:1 DMSO:MeCN, filtered through a 0.45 μm GMF, and purified on a Gilson HPLC, using a Phenomenex LUNA C18 column: 60 mm×21.2 mm I.D., 5 um particle size: with ACN/H2O (containing 0.2% TFA) gradient elution (95:5 H2O:MeCN to 10:90 H2O:MeCN; 8 minute run.
Compounds of the invention were prepared and analyzed to identify affinity at the rat mGluR5 receptor, based on their ability to displace [3H] labeled 2-methyl-6-(phenylethyl)-pyridine (“MPEP”; a mGluR5 selective negative allosteric modulator) from Hek-293 cell membranes expressing a rat mGluR5 receptor.
MGluR5 expressing HEK-293 cells were scraped off a plate, transferred to centrifuge tubes and washed twice by centrifugation (2000 rpm for 10 minutes, at 4° C.) in buffer (50 mM Tris pH 7.5). The resulting pellets were aliquoted and stored at minus 80° C. On the day of assay, the cells were thawed on ice and re-suspended in buffer. The binding assay was performed in a 96 well microtiter plate in a total volume of 250 μm. Non-specific binding was determined in the presence of 10 μM MPEP. The binding reaction included a final radioligand [3H]-MPEP concentration of 4 nM and 12-25 μg membrane protein per well. Following a 60 minute incubation at room temperature, the reaction was terminated by the addition of ice cold buffer and rapid filtration through a GF/B filter that had been presoaked for 30 minutes in 0.5% PEI. Compounds were initially tested in a single point assay to determine percent inhibition at 10 μM. Subsequently, Ki values were determined for compounds considered to be active.
Percent inhibition and Ki values were generated by GraphPad Prism and Excel Fit. IC50 values were calculated using GraphPad by fitting to a 1 or 2 site-binding model. Ki values were calculated from the apparent IC50 values using the Cheng-Prussof Equation (Biochem. Pharmacol. 22:3099-3108, 1973):
K
i
=IC
50/1+([L]/Kd)
where [L] is the concentration of free radioligand and Kd is the dissociation constant of radioligand for the receptor.
The following examples are provided to illustrate the production and activity of representative compounds of the present teachings and to illustrate their performance in a screening assay. One skilled in the art will appreciate that although specific reagents and conditions are outlined in the following examples, these reagents and conditions are not a limitation on the present teachings. In the following examples, chemical structures and names were produced using Chemdraw v 7.0.3. In any conflict between chemical nomenclature and structure, the structure should prevail.
1-(pyridin-2-yl)piperazine (13 mmol) was added to a solution of 3-bromo-4-methoxybenzoic acid (8.7 mmol) in DMF (100 mL) and DIEA (17.4 mmol). The solution was allowed to stir at room temperature for 10 minutes, and then HOBt (13 mmol) and 1-(3-(dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (WSCDI) (13 mmol) were added. The reaction was allowed to stir at room temperature for 16 hours, at which time Liquid Chromatography—Mass Spectrophotometry (LCMS) analysis indicated the reaction was complete. The solution was diluted with 100 mL ethyl acetate (EtOAc) and washed with 100 mL water. The organic layer was dried over MgSO4, and concentrated in vacuo. Purification via silica column chromatography (Hex:EtOAc as eluent) produced the intermediate compound (3-bromo-4-methoxyphenyl)(4-(pyridin-2-yl)piperazin-1-yl)methanone.
To a solution of (3-bromo-4-methoxyphenyl)(4-(pyridin-2-yl)piperazin-1-yl)methanone (0.15 mmol) and 3-ethynylanisole (0.23 mmol) in DMF (2 mL) in a microwave vial was added copper iodide (0.03 mmol) and TEA (0.45 mmol). Pd(PPh3)2Cl2 (0.03 mmol) was added to the resulting suspension, and the vial was purged with N2, capped, and microwaved for 10 minutes at 150° C. The solution was concentrated on a speedvac and purified via preparative HPLC (Gilson with NH4OH additive) to produce the title compound. LCMS Rt=1.84 min (MS=370).
Compounds 1-68, shown in Tables 1 and 1A below, were prepared using the procedure of Example 1 described above.
To ethyl 3-bromobenzoate (12.49 mmol), phenylacetylene (13.74 mmol), and bis(triphenylphosphine)palladium(II) dichloride (0.350 mmol) in TEA (40 ml) was added to copper(I) iodide (0.300 mmol). The reaction was flushed with N2, capped and stirred at 50° C. overnight. The reaction was cooled to room temperature, filtered through Celite, and the filtrate evaporated. The resultant residue was passed through short silica gel filtration in a fritted funnel (3:1 Hexanes:EtOAc) affording crude ethyl 3-(phenylethynyl)benzoate.
To the crude ethyl 3-(phenylethynyl)benzoate was added 10% aqueous NaOH (60 ml) and MeOH (30 ml). This reaction mixture was heated to 65° C. and stirred overnight. After the reaction was determined to be complete via Liquid Chromatography/Mass Spectrophotometer (LCMS), the organic solvent was evaporated. To the remaining solution was added water and EtOAC and then the phases were separated. The aqueous layer was acidified to pH 2 and extracted with EtOAc. The organic layer was dried, filtered and evaporated to afford 1.16 grams of 3-(phenylethynyl)benzoic acid, 42% over two steps.
1-(pyridin-2-yl)piperazine (0.051 ml, 0.337 mmol) was added to 3-(phenylethynyl)benzoic acid (50 mg, 0.225 mmol) in DMF (1 ml). This solution was stirred for 15 minutes at which time HOBt (51.7 mg, 0.337 mmol) and EDCl (64.7 mg, 0.337 mmol) were added, and the reaction was allowed to stir overnight. The reaction was then concentrated on a speedvac and purified via prep HPLC (Gilson with TFA additive) to afford 53.4 mg of 2-chloro-N-[3-(morpholin-4-ylcarbonyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-2-yl]benzamide as a white TFA salt. LCMS Rt=1.99 min (MS=368.2)
Compounds 69-149, shown in Tables 2 and 2A below, were prepared using the procedure of Example 2 described above.
To 1-(pyridin-2-yl)piperazine (5.18 mmol) and 3-hydroxybenzoic acid (5.18 mmol) was added 50 ml DMF. To this mixture was added HOBT (6.48 mmol), 1-(3-(dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (WSCDI) (6.48 mmol), followed by DIEA (10.37 mmol). The solution was stirred for 16 hours at which time LCMS indicated the reaction was complete. 200 mL Water and 150 mL EtOAc were added to the solution. The organic layer was collected, dried with Na2SO4, and concentrated in vacuo giving 0.83 g of (3-hydroxyphenyl)(4-(pyridin-2-yl)piperazin-1-yl)methanone compound as an off white solid that was triturated with Et2O. LCMS Rt=0.29 min (MS=284)
2 ml DMF was added to cesium carbonate (0.265 mmol) and (3-hydroxyphenyl)(4-(pyridin-2-yl)piperazin-1-yl)methanone (0.176 mmol). This mixture was heated to 35° C. for 30 minutes and (bromomethyl)benzene (0.194 mmol) was added to the mixture. The mixture was stirred for 16 hours at 35° C. The mixture was concentrated on a speedvac and purified via prep HPLC (Gilson with NH4OH additive) giving 30 mg of 1-[3-(benzyloxy)benzoyl]-4-pyridin-2-ylpiperazin. LCMS Rt=1.95 min (MS=374).
Compounds 150-163, shown in Tables 3 and 3A below, were prepared using the procedure of Example 3 described above.
3-(chloromethyl)benzoyl chloride (5.29 mmol) was added to a solution of 1-(pyridin-2-yl)piperazine (5.29 mmol) and TEA (5.29 mmol) in 50 mL DCM cooled to 0° C. The reaction was stirred at room temperature for 5 hours at which time LCMS indicated the reaction was complete. The reaction was washed with 100 mL water, 100 mL saturated NaHCO3, and 100 mL dilute HCl. The organic layer was dried with Na2SO4 and concentrated in vacuo producing 0.98 g (3-(chloromethyl)phenyl)(4-(pyridin-2-yl)piperazin-1-yl)methanone as a slightly yellow oily solid. LCMS Rt=0.61 min (MS=316).
A solution of potassium carbonate (0.277 mmol) and phenol (0.277 mmol) in DMF (1.5 ml) was prepared and stirred for 25 minutes. To this was added a solution of (3-(chloromethyl)phenyl)(4-(pyridin-2-yl)piperazin-1-yl)methanone (0.222 mmol) in DMF (1.5 ml). After stirring for 30 minutes at room temperature, the reaction was heated to 40° C. and stirred for 16 hours. The reaction was concentrated on a speedvac and purified via prep HPLC (Gilson with TFA additive) producing 37 mg of 1-[3-(phenoxymethyl)benzoyl]-4-pyridin-2-ylpiperazin. LCMS Rt=1.86 min (MS=374)
Compounds 164-171, shown in Tables 4 and 4A below, were prepared using the procedure of Example 4 described above.
To a solution of 1-(pyridin-2-yl)piperazine (6.21 mmol) and TEA (6.71 mmol) in 30 mL DCM was added dropwise a solution of 3-bromobenzene-1-sulfonyl chloride (6.21 mmol) in 10 mL DCM. The reaction was stirred at room temperature for 16 hours. The reaction was diluted with 20 mL DCM, washed with 30 mL water, 20 mL 5 percent (%) aq. K2CO3 solution, and brine. The organic layer was dried with MgSO4 and concentrated in vacuo producing 3-bromo-N-(2-(ethyl(pyridin-2-yl)amino)ethyl)-N-methylbenzenesulfonamide as a white solid used without further purification.
To a solution of 3-bromo-N-(2-(ethyl(pyridin-2-yl)amino)ethyl)-N-methylbenzenesulfonamide (0.13 mmol) and 3-hydroxyphenylacetylene (0.19 mmol) in DMF (2 mL) in a microwave vial was added copper iodide (0.026 mmol) and TEA (0.39 mmol). To the suspension was added Pd(PPh3)2Cl2 (0.026 mmol). The vial was purged with N2, capped, and microwaved for 10 minutes at 150° C. The product was concentrated on a speedvac and purified via prep HPLC (Gilson with TFA additive) to produce 3-({3-[(4-pyridin-2-ylpiperazin-1-yl)sulfonyl]phenyl}ethynyl)phenol. LCMS Rt=2.07 min (MS=420).
Compounds 172-176, shown in Table 5 below, were prepared using the procedure of Example 5 described above.
To a solution of 1-(pyridin-2-yl)piperazine (6.1 mmol) and DIEA (18.4 mmol) in 20 mL THF was added 1-bromo-3-(bromomethyl)benzene (7.4 mmol). The reaction was stirred at room temperature for 16 hours at which time LCMS indicated the reaction was complete. The reaction was diluted with 50 mL EtOAc and washed with 10 mL saturated NH4Cl, 10 mL water, and 50 mL brine. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification via silica column chromatography (Hex:EtOac as eluent) produced 1-(3-bromobenzyl)-4-(pyridin-2-yl)piperazine.
To a solution of 1-(3-bromobenzyl)-4-(pyridin-2-yl)piperazine (0.15 mmol) and 3-hydroxyphenylacetylene (0.23 mmol) in DMF (2 mL) was added copper iodide (0.03 mmol) and TEA (0.45 mmol). To the suspension was added Pd(PPh3)2Cl2 (0.03 mmol). The vial was purged with N2, capped, and microwaved for 10 minutes at 150° C. The reaction was concentrated on a speedvac and purified via prep HPLC (Gilson with TFA additive) producing 3-({3-[(4-pyridin-2-ylpiperazin-1-yl)methyl]phenyl}ethynyl)phenol. LCMS Rt=1.84 min (MS=370).
Compounds 177-181, shown in Table 6 below, were prepared using the procedure of Example 6 described above.
To a solution of (3-bromo-4-methoxyphenyl)(4-(pyridin-2-yl)piperazin-1-yl)methanone (0.2 mmol; as synthesized in Example 1) in NMP (1 mL) was added N,N dimethyl glycine (0.02 mmol), K2CO3 (0.4 mmol), styrene (0.3 mmol), and Pd(OAc)2 (0.02 mmol). The vial was purged with N2, capped, and heated to 130° C. for 18 hours. The reaction was concentrated on a speedvac and purified via prep HPLC (Gilson with TFA additive) to produce 1-{4-methoxy-3-[(E)-2-phenylvinyl]benzoyl}-4-pyridin-2-ylpiperazin. LCMS Rt=2.15 min (MS=400.2).
The properties of Compound 182 are shown in Tables 7 and 7A below.
Compounds 183-291, shown in Table 8 and 8A below, were prepared using the procedure of Example 2 described above.
To a solution of methyl 3-bromo-4-methoxybenzoate (5.0 g, 20.4 mmol) and 2-ethylnylpyridine (3.14 mL, 31.1 mmol) in toluene (100 mL) was added CuI (0.78 g, 3.9 mmol) and TEA (6.2 mL, 44.7 mmol). Pd(Ph3P)2Cl2 (2.9 g, 4.1 mmol) was then added to the resulting suspension. The vessel was purged with nitrogen and the reaction was stirred at 110° C. for 10 hours. The contents of the flask were then washed through a plug of silica gel with EtOAc and the resulting solution was concentrated at reduced pressure and purified by flash chromatography on silica (5% MeOH in DCM) to yield 4.1 g (75%) of product as a brown solid.
To a solution of methyl 4-methoxy-3-(pyridin-2-ylethynyl)benzoate (4.1 g, 15.3 mmol) in THF (150 mL), MeOH (20 mL), and H2O (40 mL) was added lithium hydroxide monohydrate (1.68 g, 40 mmol). The reaction was stirred at room temperature overnight and then concentrated at reduced pressure to an approximate volume of 40 mL. The remaining solution was diluted with an additional 50 mL of H2O, washed with Et2O (X2), and acidified to pH 4.0. The resulting precipitate was collected by suction filtration. The filtrate was saturated with solid NaCl and extracted with EtOAc (2×100 mL). The organic extracts were concentrated to yield a solid residue that was added to the collected precipitate and the combined solids were dried in a vacuum oven at 50° C. for 3 hours to yield 3.44 g (84%) of the carboxylic acid as a tan solid. No additional purification of the carboxylic acid was required.
To a stirred solution of 4-methoxy-3-(pyridin-2-ylethynyl)benzoic acid (1.50 g, 5.92 mmol) in DCM (45 mL) was added HOBT (1.45 g, 9.47 mmol) and EDC (1.70 g, 8.88 mmol). The resulting solution was stirred for 15 min, at which time tert-butyl piperazine-1-carboxylate (1.43 g, 7.70 mmol) and TEA (2.46 mL, 17.76 mmol) were added and the solution was stirred for 5 h. Upon completion, the solvent was removed under reduced pressure and the residue was purified via flash chromatography on silica gel (20:1 CH2Cl2/MeOH) to afford 2.02 g (81%) of the boc-piperazine as a light brown solid.
Acetyl chloride (186 mg, 2.38 mmol) was added in a dropwise fashion to a solution of tert-Butyl 4-(4-methoxy-3-(pyridin-2-ylethynyl)benzoyl)piperazine-1-carboxylate (1.00 g, 2.38 mmol) in MeOH (5 mL) cooled to 0° C. After 45 min, additional acetyl chloride (186 mg, 2.38 mmol) was added to the solution. The reaction solution solidified with quantitative formation of the piperazine hydrochloric acid salt as shown by LCMS. The product was filtered, washed with hexanes and was used without further purification or modification.
To a solution of (4-methoxy-3-(pyridin-2-ylethynyl)phenyl)(piperazin-1-yl)methanone hydrochloric acid salt (50 mg, 0.156 mmol) in isopropyl alcohol (0.40 mL) was added 4-amino-2-chloropyrimidine-5-carbonitrile (48 mg, 0.312 mmol) and TEA (0.065 mL). The vial was purged with nitrogen and the reaction solution was heated to 85° C. The reaction was stirred for 24 h, at which point the solvent was removed under reduced pressure and the residue was purified via flash chromatography on silica gel (5% MeOH in DCM) to afford 51 mg (74%) of the title compound as an off-white solid.
Compounds 292-306, shown in Table 9 and 9A below, were prepared using the procedure of Example 9 described above.
Methyl 3-iodo-4-methylbenzoate (5.52 g, 20 mmol), 2-ethylnylpyridine (3.2 mL, 31 mmol), and triethylamine (6.2 mL, 44.7 mmol) were dissolved in 100 mL of toluene and purged with nitrogen. Then CuI (0.78 g, 3.9 mmol) and Pd(Ph3P)2Cl2 (2.9 g, 4.1 mmol) were added and the resulting suspension was stirred at 100° C. for 6 hours. The reaction was concentrated at reduced pressure and purified by flash chromatography on silica (40:1 CH2Cl2/EtOAc) to yield 2.63 g (52%) of the product as a greenish solid.
Methyl 4-methyl-3-(pyridin-2-ylethynyl)benzoate (2.2 g, 8.7 mmol) was dissolved in a mixture of THF (75 mL), MeOH (25 mL), and H2O (25 mL) and treated with lithium hydroxide monohydrate (420 mg, 10 mmol). The reaction was stirred at room temperature overnight and then concentrated at reduced pressure. The remaining residue was diluted with 50 mL of H2O and acidified to pH 4.0 with 1N HCl. The resulting precipitate was collected by suction filtration. The collected precipitate was dried in a vacuum oven at 50° C. for 3 hours to yield 1.57 g (76%) of the carboxylic acid as a gray solid. No additional purification of the carboxylic acid was required.
4-Methyl-3-(pyridin-2-ylethynyl)benzoic acid (593 mg, 2.5 mmol), 3-(piperazin-1-yl)benzo[d]isoxazole (570 mg, 2.8 mmol), and triethylamine (1.05 mL, 7.5 mmol) are dissolved in 25 mL of CH2Cl2 and treated with EDCl (528 mg, 2.75 mmol) and HOBT (371 mg, 2.75 mmol). The reaction is stirred at room temperature overnight. The crude mixture is diluted EtOAc and washed with water and brine. The organic layer is dried over MgSO4, filtered, concentrated, and purified by flash chromatography on silica gel (CH2Cl2/EtOAc) to yield 887 mg (84%) of the product as an off white solid.
4-Methyl-3-(pyridin-2-y ethynyl)benzoic acid (47 mg, 0.2 mmol), 4-methoxy-2-(piperazin-1-yl)pyrimidine (49 mg, 0.25 mmol), and triethylamine (139 uL, 1.0 mmol) were dissolved in 3 mL of CH2Cl2 and treated with PyBOP (130 mg, 0.25 mmol). The reaction was stirred at room temperature overnight and directly purified by flash chromatography on silica gel (CH2Cl2/EtOAc) to yield 47 mg (57%) of the product as a white solid.
Compounds 308-311, shown in Table 11 and Table 11A below, were prepared using the procedure of Example 11 described above.
Methyl 3-bromo-4-fluorobenzoate (4.66 g, 20 mmol), 2-ethylnylpyridine (3.2 mL, 31 mmol), and triethylamine (6.2 mL, 44.7 mmol) were dissolved in 100 mL of toluene and purged with nitrogen. Then CuI (0.78 g, 3.9 mmol) and Pd(Ph3P)2Cl2 (2.9 g, 4.1 mmol) were added and the resulting suspension was stirred at 100° C. for 6 hours. The reaction was concentrated at reduced pressure and purified by flash chromatography on silica (40:1 CH2Cl2/EtOAc) to yield 2.0 g (39%) of the product as a brown solid.
Methyl 4-fluoro-3-(pyridin-2-ylethynyl)benzoate (1.7 g, 6.6 mmol) was dissolved in a mixture of THF (75 mL), MeOH (25 mL), and H2O (25 mL) and treated with lithium hydroxide monohydrate (420 mg, 10 mmol). The reaction was stirred at room temperature overnight and then concentrated at reduced pressure. The remaining residue was diluted with 50 mL of H2O and acidified to pH 4.0 with 1N HCl. The resulting precipitate was collected by suction filtration. The collected precipitate was dried in a vacuum oven at 50° C. for 3 hours to yield 1.24 g (78%) of the carboxylic acid as a tan solid. No additional purification of the carboxylic acid was required.
4-Fluoro-3-(pyridin-2-ylethynyl)benzoic acid (48 mg, 0.2 mmol), 2-(piperazin-1-yl)pyrimidine (38 uL, 0.25 mmol), and triethylamine (139 uL, 1.0 mmol) were dissolved in 3 mL of CH2Cl2 and treated with PyBOP (130 mg, 0.25 mmol). The reaction was stirred at room temperature overnight and directly purified by flash chromatography on silica gel (CH2Cl2/EtOAc) to yield 54 mg (70%) of the product as a pink solid.
Compounds 312-317, shown in Table 12 below, were prepared using the procedure of Example 12 described above.
Methyl 4-hydroxy-3-iodobenzoate (2.78 g, 10 mmol) was dissolved in 20 mL of DMF and treated with Cs2CO3 (6.5 g, 20 mmol) and ethyliodide (1.0 mL, 12 mmol). The resulting suspension was stirred at room temperature overnight. The reaction mixture was subsequently diluted with EtOAc and washed with water (×2) and brine. The organic layer was dried (MgSO4), filtered, and concentrated at reduced pressure to yield 3.0 g of a white solid. The crude material was used in the next step without additional purification.
Crude methyl 4-ethoxy-3-iodobenzoate (10 mmol), 2-ethylnylpyridine (1.6 mL, 15 mmol), and triethylamine (3.1 mL, 22 mmol) are dissolved in 50 mL of toluene and purged with nitrogen. Then CuI (390 mg, 2 mmol) and Pd(Ph3P)2Cl2 (1.45 g, 2 mmol) are added and the resulting suspension is stirred at 100° C. for 6 hours. The reaction is concentrated at reduced pressure and purified by flash chromatography on silica (40:1 CH2Cl2/EtOAc) to yield 1.25 g (44% for 2 steps) of the product as a white solid.
Methyl 4-ethoxy-3-(pyridin-2-ylethynyl)benzoate (1.1 g, 3.9 mmol) was dissolved in a mixture of THF (75 mL), MeOH (25 mL), and H2O (25 mL) and treated with lithium hydroxide monohydrate (420 mg, 10 mmol). The reaction was stirred at room temperature overnight and then concentrated at reduced pressure. The remaining residue was diluted with 50 mL of H2O and acidified to pH 4.0 with 1N HCl. The resulting precipitate was collected by suction filtration. The collected precipitate was dried in a vacuum oven at 50° C. for 3 hours to yield 857 mg (82%) of the carboxylic acid as an off-white solid. No additional purification of the carboxylic acid was required.
4-Ethoxy-3-(pyridin-2-ylethynyl)benzoic acid (53 mg, 0.2 mmol), 1-(pyridin-2-yl)piperazine (38 uL, 0.25 mmol), and triethylamine (139 uL, 1.0 mmol) were dissolved in 3 mL of CH2Cl2 and treated with PyBOP (130 mg, 0.25 mmol). The reaction was stirred at room temperature overnight and directly purified by flash chromatography on silica gel (CH2Cl2/EtOAc) to yield 59 mg (92%) of the product as a tan solid.
Compounds 318-322, shown in Table 13 below, were prepared using the procedure of Example 13 described above.
Methyl 4-hydroxy-3-iodobenzoate (2.78 g, 10 mmol) was dissolved in 20 mL of DMF and treated with Cs2CO3 (6.5 g, 20 mmol) and cyclopropylmethyl bromide (1.25 mL, 12 mmol). The resulting suspension was stirred at room temperature overnight. The reaction mixture was subsequently diluted with EtOAc and washed with water (×2) and brine. The organic layer was dried (MgSO4), filtered, and concentrated at reduced pressure to yield 3.3 g of a pale yellow oil. The crude material was used in the next step without additional purification.
Crude methyl 4-(cyclopropylmethoxy)-3-iodobenzoate (10 mmol), 2-ethylnylpyridine (1.6 mL, 15 mmol), and triethylamine (3.1 mL, 22 mmol) were dissolved in 50 mL of toluene and purged with nitrogen. Then CuI (390 mg, 2 mmol) and Pd(Ph3P)2Cl2 (1.45 g, 2 mmol) were added and the resulting suspension was stirred at 100° C. for 6 hours. The reaction was concentrated at reduced pressure and purified by flash chromatography on silica (CH2Cl2/EtOAc) to yield 1.52 g (50% for 2 steps) of the product as an oil.
Methyl 4-(cyclopropylmethoxy)-3-(pyridin-2-ylethynyl)benzoate (1.5 g, 4.9 mmol) was dissolved in a mixture of THF (75 mL), MeOH (25 mL), and H2O (25 mL) and treated with lithium hydroxide monohydrate (420 mg, 10 mmol). The reaction was stirred at room temperature overnight and then concentrated at reduced pressure. The remaining residue was diluted with 50 mL of H2O and acidified to pH 4.0 with 1N HCl. The resulting precipitate was collected by suction filtration. The collected precipitate was dried in a vacuum oven at 50° C. for 3 hours to yield 1.31 g (91%) of the carboxylic acid as a pale yellow solid. No additional purification of the carboxylic acid was required.
4-(Cyclopropylmethoxy)-3-(pyridin-2-ylethynyl)benzoic acid (59 mg, 0.2 mmol), 1-(pyridin-2-yl)piperazine (61 uL, 0.4 mmol), and triethylamine (84 uL, 0.6 mmol) were dissolved in 4 mL of CH2Cl2 and treated with HOBt (40 mg, 0.3 mmol) and EDC (58 mg, 0.3 mmol). The reaction was stirred at room temperature overnight and directly purified by flash chromatography on silica gel (CH2Cl2/EtOAc) to yield 79 mg (90%) of the product as a white solid.
Compounds 323-325, shown in Table 14, were prepared using the procedure of Example 13 described above.
Methyl 3-iodo-4-methoxybenzoate (6.0 g, 20.4 mmol), 2-ethylnylpyridine (3.14 mL, 31.1 mmol), and triethylamine (6.2 mL, 44.7 mmol) were dissolved in 100 mL of toluene and purged with nitrogen. Then CuI (0.78 g, 3.9 mmol) and Pd(Ph3P)2Cl2 (2.9 g, 4.1 mmol) were added and the resulting suspension was stirred at 100° C. for 6 hours. The reaction was concentrated at reduced pressure and purified by flash chromatography on silica (20:1 CH2Cl2/EtOAc) to yield 5.3 g (96%) of product as a brown solid.
Methyl 4-methoxy-3-(pyridin-2-ylethynyl)benzoate (5.3 g, 20 mmol) was dissolved in a mixture of THF (150 mL), MeOH (20 mL), and H2O (40 mL) and treated with lithium hydroxide monohydrate (1.68 g, 40 mmol). The reaction was stirred at room temperature overnight and then concentrated at reduced pressure to an approximate volume of 40 mL. The remaining solution was diluted with an additional 50 mL of H2O, washed with Et2O (×2), and acidified to pH 4.0. The resulting precipitate was collected by suction filtration. The filtrate was saturated with solid NaCl and extracted with EtOAc (2×100 mL). The organic extracts were concentrated to yield a solid residue that was added to the collected precipitate and the combined solids were dried in a vacuum oven at 50° C. for 3 hours to yield 4.65 g (93%) of the carboxylic acid as a tan solid. No additional purification of the carboxylic acid was required.
4-Methoxy-3-(pyridin-2-ylethynyl)benzoic acid (51 mg, 0.2 mmol), 1-(4-chlorophenyl)piperazin-2-one (74 mg, 0.3 mmol), and triethylamine (105 uL, 0.75 mmol) were dissolved in 3 mL of CH2Cl2 and treated with HOBt (34 mg, 0.25 mmol) and EDC (48 mg, 0.25 mmol). The reaction was stirred at room temperature overnight and directly purified by flash chromatography on silica gel (CH2Cl2/EtOAc) to yield 85 mg (95%) of the product as a white solid.
Compounds 326-330, shown in Table 15 below, were prepared using the procedure of Example 15 described above.
4-Methoxy-3-(pyridin-2-ylethynyl)benzoic acid (760 mg, 3.0 mmol), piperazin-2-one (455 mg, 4.5 mmol), and triethylamine (0.7 mL, 5 mmol) were dissolved in 30 mL of CH2Cl2 and treated with HOBt (608 mg, 4.5 mmol) and EDC (864 mg, 4.5 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with EtOAc and washed with water and brine. The organic layer was dried (Na2SO4), filtered, and purified by flash chromatography on silica gel (CH2Cl2/MeOH) to yield 469 mg (47%) of the product as a tan solid.
4-(4-Methoxy-3-(pyridin-2-ylethynyl)benzoyl)piperazin-2-one (50 mg, 0.15 mmol) was dissolved in 3 mL of DMF, cooled to −50° C., and treated with 400 uL of 0.5 M KHMDS in toluene (0.2 mmol). The reaction was stirred at −50° C. for 2 min. and treated with BnBr (42 uL, 0.35 mmol). The cold bath was removed and the reaction was warmed to room temperature. Upon reaching room temperature, the reaction was quenched with water, diluted with EtOAc, and washed with water and brine. The organic layer was dried (Na2SO4), filtered, and purified by flash chromatography on silica gel (CH2Cl2/EtOAc) to yield 30 mg (47%) of the product as an off white solid.
Compounds 331-334, shown in Table 16 below, were prepared using the procedure of Example 16 described above.
A solution of hydrogen peroxide (30% in water, 115 mL) in 15% aqueous NaOH was added slowly to a solution of 3-bromo-4-(trifluoromethoxy)benzaldehyde (25 g, 93 mmol) in methanol (115 mL) at 0° C. After the addition the reaction mixture was warmed up to room temperature and stirred for 4 hours. The reaction was monitored by TLC (10% MeOH in CH2Cl2). After the reaction was complete the reaction mixture was acidified with 5 N HCl to pH=1. The white solid formed was isolated by filtration, washed with water (2×), and then dried at 50° C. overnight to yield the title compound as a white solid (24.1 g, 91% yield).
HCl (concentrated, 20 mL) was added to a solution of 3-bromo-4-(trifluoromethoxy)benzoic acid (30 g, 105 mmol) in methanol (160 mL). The mixture was heated at 70° C. for 20 h. After the reaction is complete the reaction mixture was concentrated to give a semi-solid. This solid was stirred in hexane (250 mL) for 2 h. Unreacted solid was removed by filtration. The filtrate was evaporated to yield the title compound as an oil (28.1 g, 89% yield).
The title compound was prepared from methyl 3-bromo-4-(trifluoromethoxy)benzoate (step 2) in substantially the same manner as described in Example 3, step 3.
The title compound was prepared from methyl 4-(trifluoromethoxy)-3-(pyridin-2-ylethynyl)benzoate (step 3) in substantially the same manner as described in Example 3, step 4.
The title compound was prepared from 3-(pyridin-2-ylethynyl)-4-(trifluoro methoxy)benzoic acid (step 4) and 1-(pyridin-2-yl)piperazine in substantially the same manner as described in Example 3, step 5.
Compounds 335-340 were synthesized according to Example 17.
ylethynyl)- 4-(trifluoromethoxy) phenyl]carbonyl} piperazine
The title compound was prepared from methyl 3-bromo-4-methoxybenzoate and ethynyltrimethylsilane in substantially the same manner as described in Example 3, step 3.
A mixture of methyl 4-methoxy-3-((trimethylsilyl)ethynyl)benzoate (4.2 g, 16.0 mmol) and potassium carbonate (1.3 g, 9.6 mmol) in a mixed solvent of methanol and tetrahydrofuran (1:1; 20 mL) was stirred at room temperature for 2 h. After the reaction was complete the reaction mixture was dried with anhydrous Na2SO4, filtered and evaporated to yield the title compound as an oil (3.7 g, 64% yield).
The title compound was prepared from methyl 3-ethynyl-4-methoxybenzoate (step 2) in substantially the same manner as described in Example 3, step 4.
The title compound was prepared from 3-Ethynyl-4-methoxybenzoic acid (step 3) and 2-(piperazin-1-yl)pyrimidine in substantially the same manner as described in Example 3, step 5.
The title compound was prepared from methyl (3-ethynyl-4-methoxyphenyl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone (step 4) in substantially the same manner as described in Example 3, step 3.
Compounds 341-364 were synthesized according to Example 18.
A solution of 3-amino-4-(trifluoromethyl)benzoic acid (10 g, 48.8 mmol) and concentrated HCl (36%, 5.5 mL) in methanol (42 mL) was heated at 70° C. for 10 hours. After the reaction is complete, the reaction mixture was cooled down and concentrated in vacuo to afford methyl 3-amino-4-(trifluoromethyl)benzoate, HCl salt as a white solid (8.9 g, 34.8 mmol; 71% yield).
A solution of sodium nitrite (1.34 g 19.3 mmol) in water (7.0 mL) was added dropwise to a rapidly stirred suspension of methyl 3-amino-4-(trifluoromethyl)benzoate, HCl salt (4.5 g, 17.5 mmol) from step 1 in 6 N aqueous HCl (11 mL) at −5 to 0° C. over a period of five min. After the reaction was stirred at −5° C. for 30 min., a solution of potassium iodide (2.9 g, 17.5 mmol) in water (6.0 mL) and a small crystal of iodine were added slowly to the diazonium chloride formed in the reaction suspension. The resulting dark red solution was allowed to warm to room temperature and heated at 90° C. for one hour. The reaction mixture was extracted with ethyl acetate. The collected ethyl acetate extracts were washed with water. Separation and evaporation afforded methyl 3-iodo-4-(trifluoromethyl)benzoate as a dark brown solid (5.2 g, 15.8 mmol; 90% yield).
A mixture of methyl 3-iodo-4-(trifluoromethyl)benzoate (3 g, 9.1 mmol) from step 2,2-ethylnylpyridine (1.42 mL, 13.6 mmol), dichlorobistriphenylphosphine palladium(II) (1.28 g, 1.8 mmol), copper iodide (0.36 g, 1.82 mmol) and triethylamine (2.6 mL, 18.2 mmol) in toluene (46 mL) was stirred at 100° C. for six hours. The reaction mixture was monitored by LC-MS. After the reaction was complete, the reaction mixture was then allowed to cool down to room temperature. The reaction mixture was concentrated to yield a semi-solid residue. This residue was dissolved in ethyl acetate and the un-dissolved dark solid was removed by filtration. The ethyl acetate filtrate was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to provide a brown crude solid. This material was purified by flash chromatography on SiO2 (gradient elution using 0-3% MeOH in CH2Cl2) to yield the title compound as a brown solid (1.5 g, 4.9 mmol; 54% yield).
A 1.0 N solution of aqueous sodium hydroxide (7.3 mL, 7.3 mmol) was added to a solution of methyl 3-(pyridin-2-ylethynyl)-4-(trifluoromethyl)benzoate (1.1 g, 3.7 mmol) from step 3 in a mixed solvent of methanol and tetrahydrofuran (1:1; 20 mL) with stirring at room temperature. The reaction was complete in six hours. The reaction was acidified with 2.0 N aqueous HCl (3.7 mL, 7.3 mmol) to pH=1. The suspended mixture was filtered and evaporated to afford a light brown solid (1.5 g, 3.7 mmol; 100% yield) as a di-sodium chloride salt, which was used for the next reaction without any further purification.
Triethylamine (1.1 mL, 8.1 mmol) was added to a mixture of 3-(pyridin-2-ylethynyl)-4-(trifluoromethyl)benzoic acid (di-sodium chloride salt, 1.1 g, 2.7 mmol) from step 4, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol), 1-hydroxy-7-azabenzotriazole (0.44 mg, 3.2 mmol) and 3-(piperazin-1-yl)benzo[d]isoxazole (0.62 g, 3.0 mmol) in dichloromethane (20 mL) with stirring at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with a small amount of water. Solvents were removed and the residue was purified by flash chromatography on SiO2 (gradient elution using 40-60% EtOAc in hexane) to yield the title compound as a white solid (0.87 g, 67% yield).
Compounds 365-381 were synthesized according to Example 19.
A cold solution of difluoroiodomethane (5.0 g, 28.0 mmol) in DMF (15 mL) was added to a stirred suspension of potassium carbonate (5.2 g, 37.4 mmol) and methyl 4-hydroxy-3-iodobenzoate (5.4 g, 97%, 18.7 mmol) in DMF (65 mL) at 0° C. under an atmosphere of nitrogen. After the reaction was stirred at 0° C. for 30 min., the reaction mixture was stirred at room temperature for 2.5 hours. After the reaction was complete, solid material was removed by filtration and the filtrate was concentrated to yield a semi-solid residue. This residue was purified by flash chromatography on SiO2 (gradient elution using EtOAc/hexane 15/85) to yield the title compound as a white solid (5.0 g, 81% yield).
A mixture of methyl 4-(difluoromethoxy)-3-iodobenzoate (2 g, 6.1 mmol) from step 1,2-ethylnylpyridine (0.94 mL, 9.2 mmol), dichlorobistriphenylphosphine palladium(II) (0.86 g, 1.2 mmol), copper iodide (0.23 g, 1.2 mmol) and triethylamine (1.7 mL, 12.2 mmol) in toluene (30 mL) was stirred at 100° C. under an atmosphere of nitrogen for six hours. After the reaction was complete, the reaction mixture was concentrated to yield a semi-solid residue. This residue was purified by flash chromatography on SiO2 (gradient elution using EtOAc/hexane 20/80) to yield the title compound as a white solid (1.47 g, 80% yield).
A 1.0 N solution of aqueous sodium hydroxide (9.6 mL, 9.6 mmol) was added to a solution of methyl 4-(difluoromethoxy)-3-(pyridin-2-ylethynyl)benzoate (1.5 g, 4.8 mmol) from step 2 in a mixed solvent of methanol and tetrahydrofuran (1:1; 26 mL) with stirring at room temperature. The reaction was complete in three hours. The reaction was acidified with 2.0 N aqueous HCl (5.0 mL, 10.0 mmol) to pH=1. The suspended mixture was evaporated to afford a grey solid (1.84 g, 95% yield) containing two equivalents of sodium chloride, which was used for the next reaction without any further purification.
Triethylamine (0.48 mL, 3.5 mmol) was added to a mixture of 4-(difluoromethoxy)-3-(pyridin-2-ylethynyl)benzoic acid containing two equivalents of sodium chloride (700 mg, 1.72 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.43 g, 2.24 mmol), 1-hydroxy-7-azabenzotriazole (0.31 g, 2.24 mmol) and 2-(piperazin-1-yl)pyrazine (0.31 mL, 2.1 mmol) in dichloromethane (26 mL) with stirring at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with small amount of water. The solvents were removed and the residue was purified by flash chromatography on SiO2 (column diam: 60 mm; fraction size: 100 mL; gradient elution using 0-8% methanol in dichloromethane). Fractions 30-33 were combined and evaporated to give an oil, which was dissolved in methanol (20 mL). Aqueous HCl (2.0 N, 1.8 mL) was added to this methanol solution. The mixture was then stirred at room temperature for 20 min. Evaporation yielded a semi-solid, which was triturated with dichloromethane (3×) and dried in vacuo at 50° C. for 7 hours to afford the di-HCl product as a light green solid (0.81 g, 93% yield).
Compounds 382-385 were synthesized according to Example 20.
Methyl 3-bromo-4-chlorobenzoate (1.758 g, 7.089 mmol), 2-ethynyl pyridine (1.40 mL, 13.9 mmol), and triethylamine (2.20 mL, 15.8 mmol) were dissolved in 34 mL dry toluene. Nitrogen gas was bubbled through the mixture for 10 minutes, and then dichlorobis(triphenylphosphine)-palladium(II) (1.00 g, 1.42 mmol) and copper(I) iodide (0.268 g, 1.41 mmol) were added to the mixture. Nitrogen was bubbled through the mixture for another 5 minutes, and then the mixture was then heated to 100° C. for 6 hours. The mixture was cooled, and then filtered through a pad of Celite. The Celite pad was washed with ethyl acetate (2×) and then ˜5% methanol/methylene chloride (2×). The combined filtrate was evaporated and the residue was chromatographed on silica gel using a gradient elution of ethyl acetate in methylene chloride. Methyl 4-chloro-3-(pyridin-2-ylethynyl)benzoate is obtained (0.843 g, 3.11 mmol; 44% yield) as a light brown-gray solid.
Methyl 4-chloro-3-(pyridin-2-ylethynyl)benzoate (0.413 g, 1.52 mmol) was dissolved in 6 mL of methanol. Aqueous 2N NaOH (1.52 mL, 3.05 mmol) was added, and the mixture was stirred 24 hours at room temperature. Aqueous 2N HCl (1.52 mL, 3.05 mmol) was added, and the mixture was stirred 5 minutes at room temperature. The mixture was evaporated to dryness to afford 4-chloro-3-(pyridin-2-ylethynyl)benzoic acid (0.580 g) as a light gray solid containing 2 equivalents of sodium chloride. This material was used as is for subsequent reactions.
4-Chloro-3-(pyridin-2-ylethynyl)benzoic acid containing 2 equivalents of sodium chloride (0.040 g, 0.107 mmol) was dissolved in 0.8 mL dimethylformamide. N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDCl, 0.027 g, 0.141 mmol) was added, followed by 1-hydroxy-7-azabenzotriazole (HOAt, 0.019 g, 0.140 mmol) and then 1-(2-pyridyl)-piperazine (0.016 mL, 0.110 mmol). Triethylamine (0.045 mL, 0.323 mmol) was added, and the mixture was stirred overnight at room temperature. The mixture was then partitioned between ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The combined organic phase was pumped dry, and was purified by prep HPLC using a Gilson reversed-phase HPLC with TFA modified water and acetonitrile as eluant. The solid obtained from the fractions containing the desired product was taken up in 0.7 mL methanol, and 2N HCl (0.050 mL, 0.100 mmol) was added. The mixture was stirred at room temperature for 5 minutes, and was then pumped dry to afford the HCl salt of 1-[4-chloro-3-(pyridin-2-ylethynyl)benzoyl]-4-pyridin-2-ylpiperazin (0.026 g, 0.055 mmol; 51% yield) as a light greenish-white solid.
Compounds 386-396, shown in Table 21 below, were prepared using the procedure of Example 21 described above.
Variations, modifications, and other implementations of what is described herein will occur to those of ordinary skill in the art without departing from the spirit and the essential characteristics of the present teachings. Accordingly, the invention is intended to include all such modifications and implementations, and their equivalents.
Each reference cited in the present application, including books, patents, published applications, journal articles and other publications, is incorporated herein by reference in its entirety.
This application claims the benefit under 35 USC 119(e) of U.S. provisional application 61/055,671 filed on May 23, 2008, which is incorporated herein by reference in their entirety.
| Number | Date | Country | |
|---|---|---|---|
| 61055671 | May 2008 | US |
