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WO1999051600A1 - DERIVES AMINOALKYLE SUBSTITUES DE 9H-PYRIDINO [2,3-b]INDOLE ET 9H-PYRIMIDINO [4,5-b]INDOLE - Google Patents

DERIVES AMINOALKYLE SUBSTITUES DE 9H-PYRIDINO [2,3-b]INDOLE ET 9H-PYRIMIDINO [4,5-b]INDOLE Download PDF

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WO1999051600A1
WO1999051600A1 PCT/US1999/007254 US9907254W WO9951600A1 WO 1999051600 A1 WO1999051600 A1 WO 1999051600A1 US 9907254 W US9907254 W US 9907254W WO 9951600 A1 WO9951600 A1 WO 9951600A1
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Prior art keywords
methyl
indole
trimethylphenyl
amino
pyridino
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PCT/US1999/007254
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Raymond F. Horvath
James W. Darrow
George D. Maynard
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Neurogen Corporation
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Priority to CA002326606A priority Critical patent/CA2326606A1/fr
Priority to AU34645/99A priority patent/AU3464599A/en
Priority to JP2000542321A priority patent/JP2002510688A/ja
Priority to EP99916294A priority patent/EP1068207A1/fr
Publication of WO1999051600A1 publication Critical patent/WO1999051600A1/fr

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Definitions

  • the present invention relates to aminoalkyl substituted 9H-pyridino [2, 3-b] indole and 9H-pyrimidino [4 , 5-b] indole derivatives which selectively bind to corticotropin-releasing factor (CRF]_) receptors and to mammalian neuropeptide Y (NPY ] _) receptors. It further relates to pharmaceutical compositions containing such compounds and the use of such compounds in treating physiological disorders induced or facilitated by CRF or those associated with an excess of neuropeptide Y.
  • CRF corticotropin-releasing factor
  • Corticotropin releasing factor (herein referred to a ⁇ CRF) , a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC) derived peptide secretion from the anterior pituitary gland [J. Rivier et al . , Proc . Na t . Acad . Sci . (USA) 80:4851 (1983); . Vale et al . , Science 213:1394 (1981)].
  • POMC proopiomelanocortin
  • CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders.
  • CRF cerebral spinal fluid
  • CRF produces anxiogenic effects in animals and interactions between benzodiazepine /
  • CRF cardiovascular or heart-related diseases such as hypertension, tachycardia and congestive heart failure, stroke and osteoporosis.
  • CRF has also been implicated in premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus and colonic hypersensitivity associated with psychopathological disturbance and stress.
  • Neuropeptide Y a peptide first isolated in 1982, is widely distributed in the central and peripheral neurons and is responsible for a multitude of biological effects in the brain and the periphery.
  • Various animal studies have shown that activation of neuropeptide NPYi receptors is related to vasoconstriction, Wahlestedt et al . , Regul . Peptides, 13_: 307- 318 (1986), McCauley and Westfall, J. Pharmacol . Exp . Ther. 261: 863-868 (1992), and Grundemar et al . , Br. J. Pharmacol .
  • This invention provides novel compounds of Formula I which interact with CRF ⁇ receptors and NPY ⁇ receptors. It further relates to the use of such compounds, pharmaceutical compositions comprising these compounds, and methods useful for the treatment of psychiatric and affective disorders and neurological diseases, including major depression, headaches, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy, as well as treatment of immunological, cardiovascular or heart-related diseases, hypertension, feeding disorders, diabetes, dislipidemia, colonic hypersensitivity associated with psychopathological disturbance, and stress. It further relates to the use of such compounds in treating physiological disorders induced or facilitated by CRF or those associated with an excess of neuropeptide Y.
  • this invention provides aminoalkyl substituted 9H-pyridino [2 , 3- b] indole and 9H-pyrimidino [4 , 5-b] indole derivatives of Formula
  • CRF ⁇ mammalian neuropeptide Y receptors and/or to mammalian neuropeptide Y (NPY ] _) receptors.
  • Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl , hydroxy, amino, lower alkylamino, lower dialkylamino, carboxamido, N-lower alkyl carboxamido, N,N-lower dialkyl carboxamido, Ci-C ⁇ alkyl, Ci-C ⁇ alkoxy, with the proviso that at least one of the positions ortho or para to the point of attachment of Ar to the tricyclic ring system is substituted;
  • R is hydrogen, halogen, trifluoromethyl , C ⁇ -C6 alkyl, or (C ⁇
  • 3 3 W is N or C-R where R is hydrogen or C ⁇ -C6 alkyl
  • V and V are CH2 , CO, CS, SO2 or CH(C_-C6 alkyl), with
  • Y and Y independently represent a bond or C]_-C6 alkylene
  • A is NR R wherein R and R are independently hydrogen, a lower alkyl group which optionally forms
  • R and R cannot both be alkanoyl or alkylsulfonyl
  • N 1 wherein e and f are independently 1, 2 or 3 and the sum of e and f is at least 3;
  • R is hydrogen or C ⁇ Cg alkyl
  • R is hydrogen or C ⁇ -C6 alkyl; C ⁇ -C ⁇ arylalkyl or C -C6 heteroarylalkyl , where aryl is phenyl, and heteroaryl is 2-, 3-, or 4- pyridyl, 2-, 4- or 5-pyrimidinyl , 1-, 2- or 4- imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5- thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4- triazolyl, 2-pyrazinyl, or 1-, 2- or 5- tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl , hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substitu
  • G is oxygen or sulfur and R is hydrogen, trifluoromethyl or C ⁇ -C6 alkyl
  • heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5- pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5- oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4- pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-,
  • 2- or 5-tetrazolyl each of which is optionally mono- or disubstituted with halogen, trifluoromethyl , amino, C ⁇ -C6 alkyl, C ⁇ -C6 alkoxy, with the proviso that tetrazolyl can have at most one substituent ;
  • Z is carbon or nitrogen; where when Z 2 is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3,
  • R is carboxamido, or (Crj-C6 alkylene) -G -R
  • G is NH, NH(C ⁇ -C6 alkyl) and R is hydrogen, C ⁇ -Cg alkyl, C ⁇ -C6 arylalkyl or C ⁇ -C6 heteroarylalkyl, where aryl is phenyl , and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5- pyrimidinyl, 1-, 2- or 4-imidazolyl , 2-, 4-, or 5- oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4- pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl , hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent
  • N-ring represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl , each of which is optionally substituted with amino, trifluoromethyl, carboxamido, or (C ⁇ -C6
  • R is hydrogen, C ⁇ -Cg alkyl, C ⁇ -C6 arylalkyl or C ⁇ -C6 heteroarylalkyl , where aryl is phenyl, and heteroaryl is 2-, 3-, or 4- pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4- imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5- thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4- triazolyl, 2-pyrazinyl, or 1-, 2- or 5- tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl
  • the compounds of Formula I are antagonists at the CRFx receptor and are useful in the diagnosis and treatment of stress related disorders such as post traumatic stress disorder (PTSD) as well as depression, headache and anxiety.
  • stress related disorders such as post traumatic stress disorder (PTSD) as well as depression, headache and anxiety.
  • psychiatric and affective disorders and neurological diseases including major depression, headaches, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy, as well as treatment of immunological, cardiovascular or heart - related diseases, hypertension, feeding disorders, diabetes, dislipidemia, colonic hypersensitivity associated with psychopathological disturbance, and stress.
  • Such methods involve administration to a mammal of an effective amount of a compound of the invention.
  • the compounds of Formula I are also neuropeptide Y ] _ receptor antagonists, and, therefore, are also of value in the treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of neuropeptide Y.
  • the compounds of Formula I have different chemical structures which affect their selectivity towards either the CRFx or the
  • NPYx receptors NPYx receptors
  • Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, carboxamido, N-lower alkyl carboxamido, N,N-lower dialkyl carboxamido, C ⁇ -C6 alkyl, C ⁇ -C6 alkoxy, with the proviso that at least one of the positions ortho or para to the point of attachment of Ar to the tricyclic ring system is substituted;
  • R is hydrogen, halogen, trifluoromethyl, C ⁇ -Cg alkyl, or (C ⁇
  • W is N or C-R where R is hydrogen or C ⁇ -C6 alkyl
  • V and V are CH2 , CO, CS, SO2 or CH(C ⁇ -C6 alkyl), with
  • Y and Y independently represent a bond or C ⁇ -C ⁇ alkylene
  • R and R are independently hydrogen, a lower alkyl group which optionally forms
  • heterocycloalkyl group with Y C ⁇ -C6 arylalkyl or C ⁇ -Cg heteroarylalkyl , where aryl is phenyl, and heteroaryl is 2-, 3-, or 4- pyridyl, 2-, 4- or 5-pyrimidinyl , 1-, 2- or 4- imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5- thiazolyl , 1- , 3- or 4-pyrazolyl, 1-, 3- or 4- triazolyl, 2-pyrazinyl, or 1-, 2- or 5- tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or hetero
  • R and R cannot both be alkanoyl or alkylsulfonyl
  • N 1 wherein e and f are independently 1, 2 or 3 and the sum of e and f is at least 3;
  • R is hydrogen or C ⁇ C g alkyl
  • C ⁇ -C6 arylalkyl or C ⁇ -C6 heteroarylalkyl where aryl is phenyl , and heteroaryl is 2-, 3-, or 4- pyridyl, 2-, 4- or 5-pyrimidinyl , 1-, 2- or 4- imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5- thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4- triazolyl, 2-pyrazinyl, or 1-, 2- or 5- tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring;
  • G is oxygen or sulfur and R is hydrogen, trifluoromethyl or C ⁇ -C6 alkyl
  • heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5- pyrimidinyl, 1-, 2- or 4-imidazolyl , 2-, 4-, or 5- oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4- pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-,
  • Z is C ⁇ -C6 alkyl
  • R is carboxamido, or (C0-C6 alkylene) -G -R
  • G is NH, NH(C ⁇ -C6 alkyl) and R is hydrogen, C_,_-C6 alkyl, C ⁇ -C6 arylalkyl or C ⁇ -C6 heteroarylalkyl, where aryl is phenyl , and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5- pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5- oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4- pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent
  • N-ring represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with amino, trifluoromethyl, carboxamido, or (C ⁇ -C6
  • R is hydrogen, C ⁇ -Cg alkyl, C ⁇ -C6 arylalkyl or C ⁇ -C6 heteroarylalkyl , where aryl is phenyl, and heteroaryl is 2-, 3-, or 4- pyridyl , 2-, 4- or 5-pyrimidinyl , 1-, 2- or 4- imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5- thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4- triazolyl, 2-pyrazinyl, or 1-, 2- or 5- tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloal
  • ⁇ 16- Preferred compounds of Formula I include those of Formula
  • each R a is C ⁇ Cg alkyl;
  • R b is hydrogen or methyl;
  • R- L is C ⁇ Cg alkyl;
  • R s is Ci-Cg alkyl, (C 3 -C 5 ) cycloalkyl (C 1 -C 3 ) alkyl, (C 1 -C 3 ) alkoxy (C - C 3 ) alkyl, or (C 3 -C 5 ) cycloalkyl ;
  • t is 1, 2 or 3;
  • R x is hydrogen, C ⁇ Cg alkyl, phenyl (C ⁇ Cg) alkyl where phenyl is optionally mono- or disubstituted independently with Ci-C 6 alkyl, C ⁇ Cg alkoxy, halogen, or hydroxy; and R y is hydrogen, C ⁇ -C 6 alkyl, (C 3 -C 6 ) cycloalkyl ; or
  • NR x R y represents pyrrolidinyl, N- (Ci-C 6 ) alkylpyrrolidin-2-yl , piperidinyl, morpholinyl, or N- (C ⁇ -C 6 ) alkylpiperazinyl .
  • Preferred compounds of Formula IA include those where R s is Ci-Cg alkyl or cyclopropylmethyl. Other preferred compounds of Formula IA include those where R s is cyclopropyl (Ci-C 3 ) alkyl . Still other preferred compounds of Formula IA include those where R x and R y independently represent hydrogen or Ci-C 2 alkyl. More preferred compounds of IA include those where R s is cyclopropyl (C 1 -C 3 ) alkyl, R x and R y independently represent hydrogen or C x -C 2 alkyl; and each R a is methyl. Particularly preferred compounds of IA are those W is nitrogen.
  • each R a is C 1 -C 6 alkyl ; Ri is Ci-Cg alkyl ; R s is Ci-Cg alkyl , cyclopropyl (Ci-C 3 ) alkyl or (Ci ⁇ C 3 ) alkoxy ( C x -
  • R x is hydrogen, Ci-C 6 alkyl , phenyl (C ⁇ Cg) alkyl where phenyl is optionally mono- or disubstituted independently with C ⁇ -C 6 alkyl , Ci-C 6 alkoxy, halogen, or hydroxy; and R y is hydrogen, Ci-C 3 alkyl , (C 3 -C 6 ) cycloalkyl ; or
  • NR x R y represents pyrrolidinyl , N- (Ci-C 3 ) alkylpyrrolidin-2 -yl , piperidinyl , morpholinyl , or N- (C ⁇ Cg) alkylpiperazinyl .
  • Preferred compounds of Formula IB include those where R s is Ci-Cg alkyl or cyclopropylmethyl. Other preferred compounds of Formula IB include those where R s is cyclopropyl (Ci-C 3 ) alkyl . Yet other preferred compounds of Formula IB include those where t is 1 and R x and R y independently represent hydrogen or C ⁇ -C 2 alkyl . More preferred compounds of Formula IB include those where R s is cyclopropyl (Ci-C 3 ) alkyl , t is 1 and R x and R y independently represent hydrogen or Ci-C 2 alkyl.
  • Particularly preferred compounds of IB are those where each R a is methyl, R s is cyclopropyl (Ci-C 3 ) alkyl , t is 1 and R x and R y independently represent hydrogen or Ci-C 2 alkyl.
  • Highly preferred compounds of Formula IB are those where W is nitrogen.
  • Other preferred compounds of Formula I include those of Formula IC:
  • each R a is C ⁇ -C 6 alkyl
  • Ri Ci-Cg alkyl ; t is 1 or 2 ;
  • Preferred compounds of Formula IC include those wherein R 1 is Ci-C 2 alkyl and W is nitrogen. Other preferred compounds of IC are those where each R a is methyl and W is nitrogen.
  • each R a independently represents Ci.C 6 alkyl
  • R is hydrogen, halogen, trifluoromethyl , C -C6 alkyl, or (C ⁇
  • V and V are CH2 , CO, CS, SO2 or CH(C ⁇ -C6 alkyl), with
  • Y and Y independently represent a bond or C ⁇ -C6 alkylene
  • 1 4 5 , 4 5 A is NR R wherein R and R are independently hydrogen, a lower alkyl group which optionally forms
  • C ⁇ -C6 arylalkyl or C ⁇ -C6 heteroarylalkyl where aryl is phenyl, and heteroaryl is 2-, 3-, or 4- pyridyl, 2-, 4- or 5-pyrimidinyl , 1-, 2- or 4- imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5- thiazolyl, 1- , 3- or 4-pyrazolyl, 1-, 3- or 4- triazolyl, 2-pyrazinyl, or 1-, 2- or 5- tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents
  • -20- can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring; lower alkanoyl, lower alkylsulfonyl, with the proviso
  • R and R cannot both be alkanoyl or alkylsulfonyl
  • N 1 wherein e and f are independently 1, 2 or 3 and the sum of e and f is at least 3;
  • R is hydrogen or Ci-C 6 alkyl
  • C ⁇ -C6 arylalkyl or C ⁇ -C ⁇ heteroarylalkyl where aryl is phenyl, and heteroaryl is 2-, 3-, or 4- pyridyl, 2-, 4- or 5-pyrimidinyl , 1-, 2- or 4- imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5- thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4- triazolyl, 2-pyrazinyl, or 1-, 2- or 5- tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl , hydroxy, amino, lower alkylamino, lower dialkylamino, lower
  • G is oxygen or sulfur and R is hydrogen, trifluoromethyl or C ⁇ -C6 alkyl
  • heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5- pyrimidinyl, 1-, 2- or 4-imidazolyl , 2-, 4-, or 5- oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4- pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono- or disubstituted with halogen, trifluoromethyl , amino, C ⁇ -C6 alkyl, C -C6 alkoxy, with the proviso that tetrazolyl can have at most one substituent ;
  • Z is C ⁇ -C6 alkyl
  • V , Y and A are as defined above;
  • Z is carbon or nitrogen
  • R is carboxamido, or (C0-C6 alkylene) -G -R
  • G is NH, NH(C ⁇ -C6 alkyl) and R is hydrogen, C ⁇ -C6 alkyl, C ⁇ -C6 arylalkyl or C ⁇ -C6 heteroarylalkyl, where aryl s phenyl, and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5- pyrimidinyl, 1-, 2- or 4-imidazolyl , 2-, 4-, or 5- oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4- pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substitu
  • N-ring represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with amino, trifluoromethyl , carboxamido, or (C ⁇ -C6
  • R is hydrogen, C ⁇ -C6 alkyl, C ⁇ -C ⁇
  • aryl is phenyl, and heteroaryl is 2-, 3-, or 4- pyridyl, 2-, 4- or 5-pyrimidinyl , 1-, 2- or 4- imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5- thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4- triazolyl, 2-pyrazinyl, or 1-, 2- or 5- tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring.
  • Preferred compounds of Formula II are those where V 1 and
  • V 2 represent methylene; Y 1 is a bond; A 1 represents pyrrolidinyl, morpholinyl; piperazinyl, mono- or di-Ci-C 6 alkyl, C ⁇ -C6 arylalkyl or C ⁇ -C6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5- pyrimidinyl, 1-, 2- or 4-imidazolyl , 2-, 4-, or 5-oxazolyl, 2-,
  • Y 2 represents a bond or methylene; and A 2 represents C ⁇ C g alkyl or Ci-C 8 alkoxymethyl .
  • each R a independently represents C ⁇ C g alkyl
  • R is hydrogen, halogen, trifluoromethyl , C ⁇ -C6 alkyl, or (C ⁇
  • V and V are CH2, CO, CS, SO2 or CH(C ⁇ -C6 alkyl), with
  • Y and Y independently represent a bond or C -C ⁇ alkylene
  • A is NR R wherein R and R are independently hydrogen, a lower alkyl group which optionally forms
  • heterocycloalkyl group with Y C ⁇ -C6 arylalkyl or C ⁇ -C6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-, 3-, or 4- pyridyl, 2-, 4- or 5-pyrimidinyl , 1-, 2- or 4- imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5- thiazolyl, 1- , 3- or 4-pyrazolyl, 1-, 3- or 4-
  • R and R cannot both be alkanoyl or alkylsulfonyl
  • R is hydrogen or C ⁇ C g alkyl
  • CONH2 CO[N(C ⁇ -C6 alkyl )R ] wherein R is hydrogen or C ⁇ -C6 alkyl; C ⁇ -C6 arylalkyl or C ⁇ -C6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-, 3-, or 4- pyridyl, 2-, 4- or 5-pyrimidinyl , 1-, 2- or 4-
  • A is hydrogen, C ⁇ -Cg alkyl, (C ⁇ -Cg alkylene) -G -R
  • G is oxygen or sulfur and R is hydrogen, trifluoromethyl or C ⁇ -Cg alkyl
  • heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5- pyrimidinyl, 1-, 2- or 4 -imidazolyl, 2-, 4-, or 5- oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4- pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-,
  • 2- or 5-tetrazolyl each of which is optionally mono- or disubstituted with halogen, trifluoromethyl , amino, C ⁇ -Cg alkyl, C ⁇ -Cg alkoxy, with the proviso that tetrazolyl can have at most one substituent ;
  • Z is C ⁇ -Cg alkyl
  • V , Y and A are as defined above;
  • Z is carbon or nitrogen; where when Z 2 is CH, n is 0, 1, 2 or 3 - and p is 1, 2, or 3,
  • R is carboxamido, or (Cn-Cg alkylene) -G -R
  • G is NH, NH(C ⁇ -Cg alkyl) and R is hydrogen, C ⁇ -Cg alkyl, C ⁇ -Cg arylalkyl or C ⁇ -Cg heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5- pyrimidinyl, 1-, 2- or 4 -imidazolyl, 2-, 4-, or 5- oxazolyl, 2-, 4-, or 5 -thiazolyl, 1-, 3- or 4- pyrazolyl, 1-, 3- or 4 -triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl , each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the provis
  • N-ring represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with amino, trifluoromethyl, carboxamido, or (C ⁇ -Cg
  • R is hydrogen, C ⁇ -Cg alkyl, C ⁇ -Cg arylalkyl or C ⁇ -Cg heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-, 3-, or 4- pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4- imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5- thiazolyl, 1-, 3- or 4 -pyrazolyl, 1-, 3- or 4- triazolyl, 2-pyrazinyl, or 1-, 2- or 5- tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl,
  • Preferred compounds of Formula III are those where V 1 and V 2 represent methylene; Y 1 is a bond; A 1 represents pyrrolidinyl, morpholinyl; piperazinyl, mono- or di-Ci-C 6 alkyl, C ⁇ -Cg arylalkyl or C ⁇ -Cg heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-, 3-, or 4 -pyridyl, 2-, 4- or 5- pyrimidinyl, 1-, 2- or 4 - imidazolyl , 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4- triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl , each of
  • Preferred compounds of the invention include: 4- (N- (2-N' ,N' -Dimethylaminoethyl) -N-ethyl) amino-2 -methyl - 9- (4-bromo-2 , 6-dimethylphenyl) -9H-pyrimidino [4 , 5-b] indole
  • the compounds of Formula I may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms.
  • These compounds can be, for example, racemates or optically active forms.
  • the single enantiomers, i.e., optically active forms can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such
  • Representative compounds of the present invention include, but are not limited to the compounds in Table I and their pharmaceutically acceptable acid addition salts.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt, particularly a pharmaceutically acceptable addition salt may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds .
  • Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC- (CH 2 )n-COOH where n is 0-4, and the like.
  • acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC- (CH 2 )n-COOH where n is 0-4, and the like.
  • the present invention also encompasses the acylated prodrugs of the compounds of Formula I.
  • acylated prodrugs of the compounds of Formula I Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I .
  • alkyl straight or branched chain alkyl groups having 1-6 carbon atoms optionally forming a 3 to 6 atoms carbocycle, such as, for example, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, 2-pentyl, i'sopentyl, neopentyl,
  • Co-Cg alkylene is meant a direct bond or a C ⁇ -Cg alkylene group, optionally forming a 3 to 6 atoms carbocycle, such as methylene, ethylidene, propylidene, butylidene, pentylidene, cyclopentylidene, hexylidene, cyclohexylidene.
  • alkoxy straight or branched chain alkoxy groups having 1-6 carbon atoms optionally forming a 3 to 6 atoms carbocycle, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, cyclopropylmethoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentoxy, neopentoxy, cyclopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, cyclohexoxy.
  • alkanoyl straight or branched chain alkanoyl groups having 1-6 carbon atoms optionally forming a 3 to 6 atom carbocycle, such as, for example, acetyl, propionyl, isopropionyl, cyclopropionyl, butanoyl, pentanoyl, cyclopentanoyl, hexanoyl, cyclhexanoyl .
  • the " ⁇ -position" of the alkanoyl groups herein is the terminal carbon atom.
  • CONH represents an amide functional group, i.e., O
  • heterocycle or “heterocycloalkyl” means a monocyclic or bicyclic hydrocarbon group which in which one or more of the ring carbon atoms has been replaced with a heteroatom, e.g., oxygen, sulfur or nitrogen. Such groups preferably have 4 to 10 carbon atoms and 1 to 4 heteroatoms .
  • halogen in the present invention is meant fluorine, bromine, chlorine, and iodine.
  • the compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier.
  • One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients.
  • compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an i-nert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an i-nert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters
  • aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachid oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending age-.c and one or more preservatives.
  • a dispersing or wetting agent suspending age-.c and one or more preservatives.
  • Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachid oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation
  • emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1, 3-butanediol .
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono-or diglycerides .
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of general Formula I may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • Compounds of general Formula I may be administered parenterally in a sterile medium.
  • the drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
  • adjuvants such as
  • Dosage levels of the order of from about 0. l ⁇ mg to about 140Umg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5Umg to about 7Ug per patient per day) .
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • Dosage unit forms will generally contain between from about l ⁇ mg to about 500Umg of an active ingredient.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • THF refers to tetrahydrofuran.
  • LDA refers to lithium diisopropylamide and DDQ refers to 2 , 3-dichloro-5 , 6-
  • Example 1 A. 2 -Amino-4 ,5,6, 7 -tetrahydro-1 -phenyl -lH-indole-3- carbonitrile
  • Example IA To the product of Example IA (535 g) dissolved in dichloroethane (4 L) are added 2-methoxypropene (550 mL) and p- toluenesulfonic acid monohydrate (3.6 g) . The mixture is refluxed for 1 hour then the solvent is removed by distillation. The residue is dissolved in THF (3 L) and cooled to 0°C. To this solution, under an atmosphere of nitrogen gas, is added LDA (2.0M, 1.2 L) at a rate to keep the reaction's internal temperature below 10°C. After 3 hours the reaction is neutralized with aqueous HCl. The aqueous layer is extracted with ethyl acetate and combined with the THF layer.
  • 2-methoxypropene 550 mL
  • p- toluenesulfonic acid monohydrate 3.6 g
  • the mixture is refluxed for 1 hour then the solvent is removed by distillation.
  • the residue is dissolved in THF (3 L) and
  • Example IB The product of Example IB (600 g) is dissolved in decahydronaphthalene (4 L) and heated to distill off low boiling impurities that are present. The solution is cooled to ambient temperature and charged with 10% Palladium on Carbon
  • a steel bomb containing the product from Example IE (61 g) , pyrrolidine (60 mL) and N-methylpyrrolidinone (250 mL) is sealed and heated to 120°C for 5 hours.
  • the mixture is poured into water and extracted with ethyl acetate.
  • the organic layer is washed with water, dried over sodium sulfate, filtered and concentrated.
  • the product is purified by flash chromatography. First 100% ethyl acetate is used to elute impurities followed by 10% methanol in dichloromethane to elute the desired product. Obtain 60 g of compound that crystallizes on standing.
  • the sulfate salt of the amine is formed by adding concentrated sulfuric acid (2.44 mL) to amine (21.4 g) dissolved in ethanol (50 mL) . Isopropanol (200 mL) is added to the ethanol solution at reflux. Crystals of sulfate that form on cooling are collected by filtration and washed with cold isopropanol: MS (free base) 467 (M+H).
  • Example 2 The following compounds are prepared essentially according to the procedures set forth above in Example 1. a) 4- (N- (2-N' ,N' -Dimethylaminoethyl) -N-propyl) amino-2- methyl-9- (2,4, 6 -trimethylphenyl) -9H-pyridino [2, 3-b] indole: MS 429 (M+H) . (Compound 2)
  • Example 9 The following compounds are prepared essentially according to the procedure set forth in Example 8.
  • Example 11 The following compounds are prepared essentially according to the procedure set forth in Example 10. a) 4- (N- (2-Pyrrolidinoethyl) -N- cyclopropyloxomethyl) amino-2 -methyl -9- (2,4, 6-trimethylphenyl) - 9H-pyridino [2,3-b] indole: MS 481 (M+H). (Compound 69)
  • Example 13 The following compounds are prepared essentially according to the procedure of Example 12. a) 4- (N- (2 -N' ,N' -Dimethylamino-2 -oxoethyl ) -N-2 - methoxyethyl) amino-2 -methyl -9- (2,4, 6 -trimethylphenyl) -9H- pyridino [2, 3-b] indole: MS 459 (M+H). (Compound 72)
  • Example 16 The following compounds are prepared essentially according to the procedures set forth above in Example 15.
  • Example 17 A. 2 -Amino- 1 -phenyl -1H- indole-3 -carbonitrile
  • Example 12B The compound from Example 12B (2.2 g) is refluxed in phosphoryl chloride (30 mL) for 3 hours. The excess phosphoryl chloride is removed under reduced pressure and the residue is partitioned between aqueous potassium carbonate and dichloromethane. The aqueous is extracted with more dichloromethane. The combined extracts are dried over sodium sulfate, filtered and concentrated to give a tan colored solid: MS 336 (M+H) .
  • Example 18 The following compounds are prepared essentially according to the procedure of Example 17.
  • Example 19 The pharmaceutical utility of compounds of this invention is indicated by the following assays for human CRF1 and NPYI receptor activity. Assay for CRF Receptor Binding Activity
  • CRF receptor binding is performed using a modified version of the assay described by Grigoriadis and De Souza (Methods in Neurosci ences, Vol. 5, 1991) .
  • Membrane pellets containing CRF receptors are re-suspended in 50mM Tris buffer pH 7.7 containing 10 mM MgCl2 and 2 mM EDTA and centrifuged for 10 minutes at 48000g. Membranes are washed again and brought to a
  • binding buffer Tris buffer above with 0.1 % BSA, 15 mM bacitracin and 0.01 mg/mL aprotinin
  • 100 mL of the membrane preparation is added to 96 well microtube plates containing 100 mL of 1 25I-CRF (SA 2200 Ci/mmol, final concentration of 100 pM) and 50 mL of drug. Binding is carried out at room temperature for 2 hours. Plates are then harvested on a Brandel 96 well cell harvester and filters are counted for gamma emissions on a Wallac 1205 Betaplate liquid scintillation counter. Non specific binding is defined by 1 mM cold CRF.
  • I 50 values are calculated with the non-linear curve fitting program RS/1 (BBN Software Products Corp., Cambridge, MA) .
  • the binding affinity for the compounds of Formula I expressed as IC50 value generally ranges from about 0.5 nanomolar to about 10 micromolar.
  • the binding activity of the compounds of formula I to the human CRF receptor can be measured as follows : Assay for Human CRF Receptor Binding Activity in IMR32 cells
  • IMR-32 human neuroblastoma cells are grown to 80% confluence in EMEM containing Earle's Balanced Salts and 2 mM 1 -glutamine with 10% FBS, 25 mM HEPES, 1 mM Sodium Pyruvate, and nonessential amino acids. At this time, flasks of cells are treated with 2.5 ⁇ M 5-bromo-2 ' -deoxyuridine (Br-dU) for 10 days. Media is changed every 3-4 days across the 10 day period. Cells are harvested using No-Zyme (JRH Biosciences) and rinsed with PBS. For membrane preparation, cells are homogenized in wash buffer (50 mM Tris HCl, 10 mM
  • -81- is performed using assay buffer (50 mM Tris HCl, 10 mM MgCl 2 , 2 mM EGTA, pH 7.4 , 0.1% BSA, 0.1 mM bacitrac (22.0mg/l00 mL) ) , 150 ⁇ g protein/tube, and [ 125 I] Sauvagine (NEN; 100 pM for competition analysis and 10 pM-1 nM for saturation analysis) to yield a final volume of 200 ⁇ L.
  • Nonspecific binding is defined using 2 ⁇ M r/h CRF or 9-41 alpha-helical CRF. Cells are incubated for 2 hours at room temperature.
  • the assay is terminated by rapid vacuum filtration (Tomtec: Deepwell 3) through GFC filters presoaked in 1% PEI using ice-cold 50 mM Tris HCl and dry thoroughly by air.
  • Specific Binding 70-80%; Kd (nM) : 0.30 nM; Bmax (fmole/mg protein): 40-50.
  • IC50 values are calculated with the non-linear curve fitting program RS/l (BBN Software Products Corp., Cambridge, MA) .
  • the binding affinities for the compounds of Formula I towards the 0RF ⁇ receptor are expressed as IC50 values and are less than 10 micromolar.
  • Compounds are assayed for activity using the following method: Baculovirus-infected Sf9 cells expressing recombinant human NPY Yl receptors are harvested at 42-48 hours at which time batches of 500 mL of cell suspension are pellete ⁇ by centrifugation.
  • Each pellet is re-suspended 30 mL of lysis buffer (10 mM HEPES, 250 mM sucrose, 0.5 ⁇ g/mL leupeptin, 2 ⁇ g/mL Aprotonm, 200 ⁇ M PMSF and 2.5 mM EDTA, pH 7.4 and gently homogenized by 50 strokes using a dounce homogenizer
  • the homogenate is centrifuged at 4°C for 10 minutes at 536 x g to pellet the nuclei.
  • the supernatant is collected into a fresh tube and centrifuged twice in the same buffer at 48,000 x g for 40 minutes.
  • the final pellet is subsequently re-suspe ⁇ e ⁇ 10 L of PBS containing 5 mM EDTA by dounce homogenization and stored m aliquots at -80°C.
  • NPY [ 125I] NPY (porcine) for saturation analysis.
  • GTP is added at a final concentration of 100 ⁇ M.
  • Cold displacers are added at concentrations ranging from 10 - ⁇ 2 M to 10 6 M to yield a final volume of 0.250 mL.
  • Nonspecific binding is determined in the presence of 1 ⁇ M NPY (human) and accounts for less than 10% of total binding.
  • the reaction is terminated by rapid vacuum filtration. Samples are filtered over presoaked GF/C Whatman filters (1.0% polyethyleneimine for 2 hours) and rinsed 2 times with 5 mL cold binding buffer lacking BSA. Remaining bound radioactivity is measured by gamma counting. To estimate the Bmax, Kd and Ki , the results of binding experiments are analyzed using SigmaPlot software (Jandel) .
  • the binding affinities for the compounds of Formula I towards the NPY]_ receptor are expressed as IC50 values and are less than 10 micromolar.

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Abstract

L'invention concerne des composés de la formule (I) dans laquelle Ar, R1, W et X sont des substituants tels que définis dans la présente invention, ces composés étant: (1) des antagonistes de récepteurs de CRF¿1? et étant donc utiles pour le diagnostic et le traitement de troubles liés au stress tels que le syndrome de stress post-traumatique (PTSD), ainsi que la dépression, les céphalées et l'anxiété; et (2) des antagonistes de récepteurs de neuropeptide Y1, ces composés étant donc utiles pour le traitement de plusieurs troubles cliniques caractérisés par la présence d'un excès de neuropeptide Y.
PCT/US1999/007254 1998-04-02 1999-04-01 DERIVES AMINOALKYLE SUBSTITUES DE 9H-PYRIDINO [2,3-b]INDOLE ET 9H-PYRIMIDINO [4,5-b]INDOLE WO1999051600A1 (fr)

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CA002326606A CA2326606A1 (fr) 1998-04-02 1999-04-01 Derives aminoalkyle substitues de 9h-pyridino [2,3-b]indole et 9h-pyrimidino [4,5-b]indole
AU34645/99A AU3464599A (en) 1998-04-02 1999-04-01 Aminoalkyl substituted 9h-pyridino(2,3-b)indole and 9h-pyrimidino(4,5-b)indole derivatives
JP2000542321A JP2002510688A (ja) 1998-04-02 1999-04-01 アミノアルキル置換９Ｈ−ピリジノ［２，３−ｂ］インドールおよび９Ｈ−ピリミジノ［４，５−ｂ］インドール誘導体
EP99916294A EP1068207A1 (fr) 1998-04-02 1999-04-01 DERIVES AMINOALKYLE SUBSTITUES DE 9H-PYRIDINO 2,3-b]INDOLE ET 9H-PYRIMIDINO 4,5-b]INDOLE

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US8045198P 1998-04-02 1998-04-02
US60/080,451 1998-04-02

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WO1999051600A1 true WO1999051600A1 (fr) 1999-10-14

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WO2000066585A1 (fr) * 1999-04-30 2000-11-09 Neurogen Corporation Derives 9h-pyrimido[4,5-b]indoles: ligands specifiques de crf1
WO2004002986A2 (fr) 2002-06-28 2004-01-08 Banyu Pharmaceutical Co., Ltd. Nouveaux dérivés de benzimidazole
WO2005028438A1 (fr) 2003-09-22 2005-03-31 Banyu Pharmaceutical Co., Ltd. Nouveau derive de piperidine
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EP1097709A3 (fr) * 1999-10-29 2005-12-21 Pfizer Products Inc. Usilisation d' antagonistes du facteur de libération de la corticotropine pour le traitement du syndrome X
WO2006001511A1 (fr) * 2004-06-25 2006-01-05 Taisho Pharmaceutical Co., Ltd. Dérivés de pyrrolopyrimidine et de pyrrolopyridine substitués par un groupe amino cyclique servant d'antagonistes du crf
US7030123B2 (en) 2000-05-31 2006-04-18 Astrazeneca Ab Indole derivatives with vascular damaging activity
US7125906B2 (en) 2002-04-03 2006-10-24 Astrazeneca Ab Indole derivatives having anti-angiogenetic activity
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WO2007049798A1 (fr) 2005-10-27 2007-05-03 Banyu Pharmaceutical Co., Ltd. Nouveau derive de benzoxathiine
WO2007055418A1 (fr) 2005-11-10 2007-05-18 Banyu Pharmaceutical Co., Ltd. Derive spiro aza-substitue
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US7408064B2 (en) 2001-09-11 2008-08-05 Astrazeneca Ab Carbazole derivatives and their use as NPY5 receptor antagonists
WO2008120653A1 (fr) 2007-04-02 2008-10-09 Banyu Pharmaceutical Co., Ltd. Dérivé d'indoledione
US7557111B2 (en) 2004-01-06 2009-07-07 Taisho Pharmaceutical Co., Ltd. Substituted thieno[3,2-d]pyrimidines as CRF receptor antagonists
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WO2009154132A1 (fr) 2008-06-19 2009-12-23 萬有製薬株式会社 Dérivé de spirodiamine-diarylcétoxime
WO2010013595A1 (fr) 2008-07-30 2010-02-04 萬有製薬株式会社 Dérivé de cycloalkylamine à noyaux fusionnés à (5 chaînons)-(5 chaînons) ou (5 chaînons)–(6 chaînons)
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
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EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
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EP2330125A2 (fr) 2005-08-11 2011-06-08 Amylin Pharmaceuticals, Inc. Polypeptides hybrides ayant des propriétés sélectionnables
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
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US6284766B1 (en) 1999-04-30 2001-09-04 Neurogen Corporation 9H-pyrimido [4,5-b] indole derivatives: CRF1 specific ligands
EP1097709A3 (fr) * 1999-10-29 2005-12-21 Pfizer Products Inc. Usilisation d' antagonistes du facteur de libération de la corticotropine pour le traitement du syndrome X
US7332492B2 (en) 2000-05-05 2008-02-19 Astrazeneca Ab Amino substituted dibenzothiophene derivatives for the treatment of disorders mediated by NP Y5 receptor
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US7408064B2 (en) 2001-09-11 2008-08-05 Astrazeneca Ab Carbazole derivatives and their use as NPY5 receptor antagonists
US7125906B2 (en) 2002-04-03 2006-10-24 Astrazeneca Ab Indole derivatives having anti-angiogenetic activity
WO2004002986A2 (fr) 2002-06-28 2004-01-08 Banyu Pharmaceutical Co., Ltd. Nouveaux dérivés de benzimidazole
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US7557111B2 (en) 2004-01-06 2009-07-07 Taisho Pharmaceutical Co., Ltd. Substituted thieno[3,2-d]pyrimidines as CRF receptor antagonists
US8106194B2 (en) 2004-01-06 2012-01-31 Taisho Pharmaceutical Co., Ltd. Pyrrolopyrimidine and pyrrolotriazine derivatives
EP2088154A1 (fr) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Procédés et compositions pour le traitement de troubles gastro-intestinaux
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EP1953160A1 (fr) * 2004-06-25 2008-08-06 Taisho Pharmaceutical Co., Ltd Pyrrolopyrimidine et dérivés de pyrrolopyrimidine substitués par un groupe aminé cyclique comme les antagonistes CRF
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US7951811B2 (en) 2004-06-25 2011-05-31 Taisho Pharmaceutical Co., Ltd. Pyrrolo[2,3-D]pyrimidine derivatives substituted with a cyclic amino group
WO2006001511A1 (fr) * 2004-06-25 2006-01-05 Taisho Pharmaceutical Co., Ltd. Dérivés de pyrrolopyrimidine et de pyrrolopyridine substitués par un groupe amino cyclique servant d'antagonistes du crf
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US11254644B2 (en) 2014-08-29 2022-02-22 Tes Pharma S.R.L. Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase
WO2016030534A1 (fr) 2014-08-29 2016-03-03 Tes Pharma S.R.L. Inhibiteurs de la semialdéhyde décarboxylase de l'acide alpha-amino-bêta-carboxymuconique
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WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
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US12186317B2 (en) 2018-11-20 2025-01-07 Tes Pharma S.R.L. Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase
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EP1068207A1 (fr) 2001-01-17

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