WO2001058871A1 - Piperidyl carboxylic acids as integrin antagonists - Google Patents

Piperidyl carboxylic acids as integrin antagonists Download PDF

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WO2001058871A1
WO2001058871A1 PCT/EP2001/001491 EP0101491W WO0158871A1 WO 2001058871 A1 WO2001058871 A1 WO 2001058871A1 EP 0101491 W EP0101491 W EP 0101491W WO 0158871 A1 WO0158871 A1 WO 0158871A1
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alkyl
cio
cycloalkyl
substituted
group
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PCT/EP2001/001491
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French (fr)
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Rüdiger Fischer
Thomas Lehmann
Gerhard Müller
Gerhard Hessler
Masaomi Tajimi
Karl Ziegelbauer
Hiromi Okigami
Haruki Hasegawa
Hiroshi Komura
Manami Mizoguchi
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Bayer Aktiengesellschaft
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Priority to AU2001231730A priority Critical patent/AU2001231730A1/en
Publication of WO2001058871A1 publication Critical patent/WO2001058871A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds of formula (I),
  • compositions as integrin antagonists especially as ⁇ 4 ⁇ j and/or ⁇ 4 ⁇ and/or ⁇ 9 ⁇ integrin antagonists and in particular for the production of pharmaceutical compositions suitable for the inhibition or the pre- vention of cell adhesion and cell-adhesion mediated disorders.
  • integrin antagonists especially as ⁇ 4 ⁇ j and/or ⁇ 4 ⁇ and/or ⁇ 9 ⁇ integrin antagonists and in particular for the production of pharmaceutical compositions suitable for the inhibition or the pre- vention of cell adhesion and cell-adhesion mediated disorders.
  • COPD chronic obstructive pulmonary disease
  • allergies diabetes
  • inflammatory bowel disease multiple sclerosis
  • myocardial ischemia myocardial ischemia
  • rheumatoid arthritis transplant rejection and other inflammatory, autoimmune and immune disorders.
  • vascular cell adhesion molecules arrest circulating leukocytes, thereby serving as the first step in their recruitment to infected or inflamed tissue sites. Subsequently, the leukocytes reaching the extravascular space interact with connective tissue cells such as fibroblasts as well as extracellular matrix proteins such as fibronectin, laminin, and collagen. Adhesion molecules on the leukocytes and on the vascular endothelium are hence essential to leukocyte migration and attractive therapeutic targets for intervention in many inflammatory disorders.
  • Leukocyte recruitment to sites of inflammation occurs in a stepwise fashion beginning with leukocyte tethering to the endothelial cells lining the blood vessels.
  • NCAM-1 is a member of immunoglobulin (Ig) superfamily and is one of the key regulators of leukocyte trafficking to sites of inflammation.
  • Ig immunoglobulin
  • NCAM-1 along with intracellular adhesion molecule 1 (ICAM-1) and E-selectin, is expressed on inflamed endothelium activated by such cytokines as interleucin 1 (IL-1) and tumor necrosis factor ⁇ (T ⁇ F- ⁇ ), as well as by lipopolysaccharide (LPS), via nuclear factor KB ( ⁇ F- KB) dependent pathway.
  • IL-1 interleucin 1
  • T ⁇ F- ⁇ tumor necrosis factor ⁇
  • LPS lipopolysaccharide
  • ⁇ F- KB nuclear factor KB
  • NCAM-1 may be involved in numerous physiological and pathological processes including myogenesis, hematopoiesis, inflammatory reactions, and the development of autoimmune disorders. Integrins NLA-4 and ⁇ 4 ⁇ 7 both function as leukocyte receptors for NCAM-1.
  • the integrin ⁇ 4 ⁇ t is a heterodimeric protein expressed in substantial levels on all circulating leukocytes except mature neutrophils. It regulates cell migration into tissues during inflammatory responses and normal lymphocyte trafficking.
  • NLA-4 binds to different primary sequence determinants, such as a QEDSP motif of NCAM- 1 and a ILDNP sequence of the major cell type-specific adhesion site of the alternatively spliced type III connecting segment domain (CS-1) of fibronectin.
  • the compounds of the present invention can also be used as ⁇ 4 ⁇ or ⁇ 9 ⁇ t integrin antagonists.
  • An object of the present invention is to provide new, alternative, piperidyl carboxylic acids or cyclic analogs derived integrin antagonists for the treatment of inflammatory, autoimmune and immune diseases.
  • the present invention therefore relates to compounds of the general formula (I):
  • R 1 and R 2 form a 4- to 8-membered saturated or unsaturated cyclic residue, which can contain 0 to 1 nitrogen atoms and 0 to 2 heteroatoms selected independently from the group S and O,
  • cyclic residue formed by R and R can be armulated with a 4- to 8-membered saturated, unsaturated or aromatic cyclic residue, which can contain 0 to 2 heteroatoms selected independently from the group N, S and O,
  • cyclic residue formed by R 1 and R 2 and/or a ring armulated to the cyclic residue formed by R 1 and R 2 can optionally be independently substituted by 0 to 2 substituents -R 1"1 ⁇ 1"2 -R ⁇ -Z, wherein
  • R represents a bond, -O-, -S-, NR 1"4 , d - C ⁇ 0 alkyl, C 2 - C ⁇ 0 alkenyl, C 2 - do alkynyl, C 6 or do aryl, C 3 -C 7 cycloalkyl, a 4- 9-membered saturated or unsaturated heterocyclic residue containing up to 3 heteroatoms selected from the group oxygen, nitrogen or sulfur, wherein
  • R 1"1 can optionally be substituted by 1 to 2 substituents selected from the group R 1"4 , wherein R 1"4 represents hydrogen, d - do alkyl, C 2 - do alkenyl, C 2 - C 10 alkynyl, C 6 or do aryl, C 3 -C 7 cycloalkyl or a 4-9- membered saturated or unsaturated heterocyclic residue containing up to 3 heteroatoms selected from the group oxygen, nitrogen or sulfur, wherein
  • R 1"4 can optionally be substituted by 1 to 3 substituents selected from the group Ci - C 4 alkyl, d - C 4 alkyloxy, phenyl, C - C 6 cycloalkyl, halogen, nitro, cyano, oxo, R 1"2 represents a bond, -O-, -S-, NR 1"5 , d - C 10 alkyl, C 2 - C 10 alkenyl, C 2 - Cio alkynyl, wherein
  • R 1"2 can optionally be substituted by Ci - do alkyl, C 2 - Cio alkenyl, C 2 - Cio alkynyl or R 1"5 , wherein
  • R 1"5 represents hydrogen, Ci - do alkyl, C 2 - do alkenyl,
  • R 1"5 can optionally be substituted by 1 to 3 substituents 15 selected from the group d - C 4 alkyl, Ci - C 4 alkyloxy, phenyl, C 3 - C 6 cycloalkyl, halogen, nitro, cyano, oxo,
  • R 1"3 represents a bond, Ci - Cio alkyl, C 2 - Cio alkenyl, C 2 - Cio alkynyl, wherein
  • R can optionally be substituted by Ci - Cio alkyl, C 2 - Cio alkenyl, C 2 - Cio alkynyl or R 1"6 , wherein
  • R 1"6 represents hydrogen, Ci - Cio alkyl, C 2 - Cio alkenyl, 25 C 2 - Cio alkynyl, C 6 or Cio aryl, C 3 -C 7 cycloalkyl or a
  • R 1"6 can optionally be substituted by 1 to 3 substituents selected from the group Ci - C 4 alkyl, Ci - C 4 alkyloxy, phenyl, C 3 - C 6 cycloalkyl, halogen, nitro, cyano, oxo,
  • R 2 - 2 is hydrogen, -C(O)R 2 - 4 or - ⁇ 0 2 ZA , Ci - C 4 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, C 3 - C 6 cycloalkyl, C 6 or Cio aryl, wherein
  • R 2"2 can optionally be substituted by 1 to 3 substituents selected from the group halogen, nitro, cyano, oxo, wherein
  • R 2"4 is Ci - C 4 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 - C 6 cycloalkyl, C 6 or Cio aryl, wherein
  • R 2"4 can optionally be substituted by 1 to 3 substituents selected from the group halogen, nitro, cyano, oxo,
  • R “ and R " are identical or different and represent hydrogen, Ci - C 4 alkyl, C 2 - C 6 alkenyl, C 2 - C 6 alkynyl, C 3 - C 6 cycloalkyl, C 6 or Cio aryl, wherein R 2" ' and R 2"3 can optionally be substituted by 1 to 3 substituents selected from the group Ci - C 4 alkyl, Ci - C 4 alkyloxy, halogen, nitro, cyano,
  • cyclic residue formed by R and R and/or a ring annulated to the cyclic residue formed by R 1 and R 2 can optionally be substituted by 0 to 2 substituents R " , halogen, nitro, amino, cyano and oxo, wherein
  • R 1"8 can independently be selected from the group of Ci - C 4 alkyl, Ci - C 4 alkyloxy, phenyl, C 3 - C 6 cycloalkyl, and wherein
  • R 1"8 can be substituted by 0-5 halogen atoms
  • R 3 represents hydrogen, Ci - Cio alkyl, C 2 - Cio alkenyl, C 2 - Cio alkynyl, C 6 or Cio aryl, C 3 -C 7 cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
  • C 3 - C 7 cycloalkyl C 6 or Cio aryl, C - C heteroaryl or a heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
  • R 3"1 represents Ci - C 4 alkyl, trifluoromethyl, trifluoromethoxy, -OR 3"2 ,
  • R 3"2 represents hydrogen, Ci - C 4 alkyl, C 3 - C 6 cycloalkyl, C 6 or 5 Cio aryl which can optionally be substituted by 1 substituent selected from the group Ci - C 4 alkyl, Ci - C 4 alkyloxy, phenyl, C 3 - C 6 cycloalkyl, halogen, nitro, cyano, and wherein
  • R 3"3 and R 3"4 are identical or different and represent hydrogen, Ci - C 4 10 alkyl, C 3 - C 6 cycloalkyl, C 6 or Cio aryl,
  • R " and R together form a 4-7-membered ring, which includes the 15 nitrogen atom to which R 3"3 and R 3"4 are bonded and which contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur and which contains up to 2 double bonds,
  • R 4 represents hydrogen, Ci - Cio alkyl, C 2 - Cio alkenyl, C 2 - Cio alkynyl,
  • R 4"1 represents Ci - C alkyl, trifluoromethyl, trifluoromethoxy
  • R 4"2 represents hydrogen, Ci - C 4 alkyl, C - C 6 cycloalkyl, C 6 or
  • Cio aryl which can optionally be substituted by 1 substituent selected from the group Ci - C 4 alkyl, Ci - C 4 alkyloxy, phenyl, C 3 -C 6 cycloalkyl, halogen, nitro, cyano, and wherein
  • R 4*3 and R 4"4 are identical or different and represent hydrogen, C alkyl, C 3 - C 6 cycloalkyl, C 6 or Cio aryl,
  • R 4"3 and R 4"4 together form a 4-7-membered ring, which includes the nitrogen atom to which R 4"3 and R 4"4 are bonded and which contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur and which contains up to 2 double bonds,
  • R 5 represents hydrogen, Ci - Cio alkyl, C 2 - Cio alkenyl, C 2 - Cio alkynyl, C 6 or Cio aryl, C 3 -C 7 cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
  • R 5"1 represents Ci - C 4 alkyl, trifluoromethyl, trifluoromethoxy, 10 -OR 5"2 , -SR 5"2 , -NR 5 3 R 5"4 , -C(O)R 5"2 , S(O)R 5"2 , -SO 2 R 5"2 ,
  • R 5"2 represents hydrogen, Cj - C 4 alkyl, C 3 - C 6 cycloalkyl,
  • Cio aryl which can optionally be substituted by 1 substituent selected from the group Ci - C 4 alkyl,
  • R 5"3 and R 5"4 are identical or different and represent hydrogen, Ci - C 4 alkyl, C 3 - C 6 cycloalkyl, C 6 or do aryl,
  • R 5"3 and R 5"4 together form a 4-7-membered ring, which includes the nitrogen atom to which R 5"3 and R 5"4 are bonded and which contains up to 2 additional hetero-
  • R 6 represents phenyl or a 5- to 6-membered aromatic heterocyclic residue containing up to 3 heteroatoms independently selected from the group of oxygen, nitrogen or sulfur, 5 which can optionally be annulated with a 5- to 8-membered saturated or unsaturated cyclic residue containing up to 2 heteroatoms independently selected from the group oxygen, nitrogen or sulfur,
  • Ci - Cio alkyl C 2 - Cio alkenyl, C 2 - Cio alkynyl, C 6 or Cio aryl, C 3 -C 7 cycloalkyl or a 4-9- membered saturated or unsaturated heterocyclic residue containing up to 3 heteroatoms independently selected from the group oxygen,
  • R 6"1 represents Ci - C 4 alkyl, trifluoromethyl, trifluoromethoxy
  • R 6"2 represents hydrogen, Ci - C alkyl, C 3 - C 6 cycloalkyl,
  • Cio aryl C 6 or Cio aryl, or a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 3 heteroatoms selected from the group oxygen, nitrogen or sulfur,
  • R 6"5 represents Ci - C 4 alkyl, trifluoromethyl, trifluoro- 5 methoxy, -OR 6"6 , -SR 6"6 , -NR 6"7 R 6"8 , wherein
  • R 6"6 represents hydrogen, Ci - C 4 alkyl, C 3 - C 6 cycloalkyl,
  • Cio aryl which can optionally be substituted by 1 to 3 substituents selected from the group Ci - C 4 alkyl,
  • R 6"7 and R 6"8 are identical or different and represent hydrogen, 15 Ci - C alkyl, C 3 - C 6 cycloalkyl, C 6 or Cio aryl or a 4-
  • R 6"7 and R 6"8 together form a 4-7-membered ring, which contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur and which contains
  • R 6"3 and R 6"4 are identical or different and represent hydrogen, bond, Ci - C 4 alkyl, C 3 - C 6 cycloalkyl, C 6 or Cjo aryl or a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from
  • R 6"9 represents hydrogen, Ci - C 4 alkyl, C 3 - C 6 cycloalkyl,
  • R 6"10 and R 6"11 are identical or different and represent hydrogen, Ci - C 4 alkyl, C 3 - C 6 cycloalkyl, C 6 or Cio aryl or 25 a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
  • substituents 30 selected from the group Ci - C 4 alkyl, Ci - C 4 alkyloxy, phenyl, benzyl, C 3 -C 6 cycloalkyl, hydroxy, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,
  • R 6"9 and R 6"10 together form a 4-7-membered ring, which contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur and which contains up to 2 double bonds, which can optionally be sub-
  • R 6"2 and R 6"3 and/or R 6"3 and R 6"4 together form a 4-7- membered ring, which includes the nitrogen atom to which R 6"3 , R 6"3 and R 6"4 are bonded and which con-
  • 20 tains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur and which contains up to 2 double bonds, which can optionally be substituted by 1 to 2 substituents selected from the group d - C 4 alkyl, d - C 4 alkyloxy, phenyl, benzyl, C 3 -C 6 cyclo-
  • R 3 and R 4 or R and R together form a 4-7-membered saturated or unsaturated ring containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur, which can optionally be substituted by 1 to 2 substituents selected from the group Ci - C 4 alkyl, phenyl, benzyl,
  • A represents -C(O)-, -C(O)-C(O)-, -SO-, -SO 2 -, -P(O)R A 1 -, -PO 2 -, 2- pyrimidyl, 4-pyrimidyl, 2-pyridyl, 2-imidazolyl, 4-imidazolyl, 2- benzimidazolyl or a ring selected from the following group:
  • ring systems can optionally be substituted by d - C 4 alkyl, Ci - C 4 alkoxy, halogen, nitro, amino, cyano, wherein
  • R A 1 can be selected from the group of d - C 4 alkyl, d - C 4 alkoxy, X represents a bond, -CR X 1 R X"2 -, oxygen or -NR X"3 , wherein
  • R X I , R x"2 , R x"3 can be independently selected from the group bond, hydrogen, Ci - C 4 alkyl, C 2 - C 4 alkenyl, C 2 - C 4 alkynyl,
  • R 6 together with R 6 form a 4-7-membered ring, which includes the nitro- gen atom to which R 6 and R X 1 or R x"2 or R x"3 can be attached and which can contain up to 2 additional heteroatoms independently selected from the group oxygen, nitrogen or sulfur and containing up to 2 double bonds, which can optionally be substituted by 1 to 2 substituents selected from the group Ci - C 4 alkyl, phenyl, benzyl, C 3 -C 7 cycloalkyl, d - C 4 alkyloxy, halogen, nitro, cyano, oxo,
  • Y represents bond, -C(O)-, -S(O)-, -SO 2 -, -O-, -S-, -CR Y 1 R Y"2 -, or -NR Y"3 , wherein R ⁇ _1 , R ⁇ "2 , R ⁇ "3 can be independently selected from the group bond, hydrogen, Ci - C 4 alkyl, C 2 - C 4 alkenyl, C 2 - C 4 alk- ynyl,
  • R D" ' can be independently selected from the group bond, hydrogen, Ci - C 4 alkyl, C 2 - C 4 alkenyl, C 2 - C 4 alkynyl, and can optionally be substituted by 1 to 2 substituents independently selected from the group Ci - C 4 alkyl, phenyl, benzyl, C 3 - C cycloalkyl, Ci - C 4 alkyloxy, halogen, nitro, cyano, oxo,
  • the present invention relates to compounds according to the general formula (I), wherein
  • R 1 and R 2 form a 4- to 8-membered saturated or unsaturated cyclic residue
  • cyclic residue formed by R 1 and R 2 can be annulated with a 5- to 7-membered saturated, unsaturated or aromatic cyclic residue, which can contain 0 to 2 heteroatoms selected independently from the group N, S and O,
  • cyclic residue formed by R 1 and R 2 and/or a ring annulated to the cyclic residue formed by R 1 and R 2 can optionally be independently substituted by 1 to 2 substituents -R M -R' "2 -R 1 3 -Z, wherein
  • R 1"1 represents a bond, -O-, -S-, NR 1"4 , Ci - Cio alkyl, C 2 - Cio alkenyl,
  • R 1"1 can optionally be substituted by 1 to 2 substituents selected from the group R 1"4 , wherein R represents hydrogen, Ci - Cio alkyl, C 2 - Cio alkenyl, C 2 - Cio alkynyl, C 6 or Cio aryl, C 3 -C 7 cycloalkyl or a 4-9- membered saturated or unsaturated heterocyclic residue containing up to 3 heteroatoms selected from the group oxygen, nitrogen or sulfur, wherein
  • R 1"4 can optionally be substituted by 1 to 3 substituents selected from the group Ci - C 4 alkyl, Ci - C 4 alkyloxy, phenyl, C 3 - C 6 cycloalkyl, halo- gen, nitro, cyano, oxo,
  • R 1"2 represents a bond, -O-, -S-, NR 1"5 , Ci - Cio alkyl, C 2 - C 10 alkenyl,
  • R , 1- " 2 can optionally be substituted by Ci - Cio alkyl, C 2 - Cio alkenyl,
  • R 1"5 represents hydrogen, Ci - Cio alkyl, C 2 - Cio alkenyl, C 2 - Cio alkynyl,
  • R 1"5 can optionally be substituted by 1 to 3 substituents selected from the group Ci - C 4 alkyl, Ci - C 4 alkyloxy, phenyl, C 3 - C 6 cycloalkyl, halogen, nitro, cyano, oxo,
  • R 1"3 represents a bond, Ci - Cio alkyl, C 2 - Cio alkenyl, C 2 - Cio alkynyl, wherein
  • R 1"3 can optionally be substituted by Ci - do alkyl, C 2 - do alkenyl,
  • R 1"7 represents hydrogen, d - Cio alkyl, C 2 - Cio alkenyl, C 2 - Cio alkynyl, C 6 or do aryl, C 3 - C 7 cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 3 heteroatoms selected from the group oxygen, nitrogen or sulfur, wherein
  • R 1"7 can optionally be substituted by 1 to 3 substituents selected from the group d - C 4 alkyl, Ci - C 4 alkyloxy, phenyl, C 3 - C 6 cycloalkyl, halogen, nitro, cyano, oxo,
  • R 2"2 is hydrogen, -C(O)R z"4 or -SO 2 R 2"4 , Ci - C 4 alkyl, C 3 - C 6 cycloalkyl, C 6 or Cio aryl, wherein
  • R 2"2 can optionally be substituted by 1 to 3 substituents selected from the group halogen, nitro, cyano, oxo, wherein
  • R 2"4 is Ci - C alkyl, C 3 - C 6 cycloalkyl, C 6 or Cio aryl, wherein
  • R 2"4 can optionally be substituted by 1 to 3 substituents selected from the group halogen, nitro, cyano, oxo,
  • R 2"1 and R 2"3 are identical or different and represent hydrogen, Ci - C 4 alkyl,
  • cyclic residue formed by R and R and/or a ring annulated to the cyclic residue formed by R 1 and R 2 can optionally be substituted by 0 to 2 substituents R 1"8 , halogen, nitro, amino, cyano and oxo, wherein
  • R 1"8 can independently be selected from the group of Ci - C alkyl, Ci - C 4 alkyloxy, phenyl, C 3 - C 6 cycloalkyl, and wherein
  • R 1"8 can be substituted by 0-5 halogen atoms
  • R , 3 represents hydrogen, Ci - Cio alkyl, C 6 or Cio aryl, C 3 - C 7 cycloalkyl or a 4- 9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
  • R " represents Ci - C 4 alkyl, trifluoromethyl, trifluoromethoxy, -OR “ , -NR “ R , -CO2R “ , halogen, cyano, nitro or oxo, wherein
  • R " represents hydrogen, Ci - C 4 alkyl, C 3 - C O cycloalkyl, C 6 or Cio aryl and wherein R 3"3 and R 3"4 are identical or different and represent hydrogen, Ci - C 4 alkyl, C 3 - C 6 cycloalkyl, C 6 or Cio aryl,
  • R 3"3 and R 3"4 together form a 4-7-membered ring, which includes the nitrogen atom to which R 3"3 and R 3"4 are bonded and which contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur,
  • Ci - Cio alkyl represents hydrogen, Ci - Cio alkyl, C 6 or Cio aryl, C 3 - C 7 cycloalkyl or a 4- 9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
  • R 4"1 represents Ci - C 4 alkyl, trifluoromethyl, trifluoromethoxy, -OR 4"2 , -NR 4"3 R 4"4 , -CO 2 R 4"2 , halogen, cyano, nitro or oxo,wherein
  • R 4" represents hydrogen, Ci - C alkyl, C 3 - C 6 cycloalkyl, C 6 or
  • R 4"3 and R 4A are identical or different and represent hydrogen, C M alkyl, C 3 -C 6 cycloalkyl, C 6 or Cio aryl, or
  • R 4"3 and R 4 ⁇ together form a 4-7-membered ring, which includes the nitrogen atom to which R 4"3 and R 4"4 are bonded and which contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur,
  • R »5 represents hydrogen, Ci - Cio alkyl
  • R 5"1 represents Ci - C 4 alkyl, trifluoromethyl, trifluoromethoxy, -OR 5"2 , -NR 5"3 R 5"4 , -CO 2 R 5"2 , halogen, cyano, nitro or oxo, wherein
  • R 5"2 represents hydrogen, Ci - C 4 alkyl, C 3 - C 6 cycloalkyl, C 6 or Cio aryl and wherein
  • R 5"3 and R 5"4 are identical or different and represent hydrogen, Ci - C 4 alkyl, C 3 - C 6 cycloalkyl, C 6 or Cio aryl,
  • R 5"3 and R together form a 4-7-membered ring, which includes the nitrogen atom to which R 5"3 and R 5"4 are bonded and which contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur, represents phenyl or a 6-membered aromatic heterocyclic residue containing up to 2 nitrogen atoms,
  • R 6"1 represents -C(O)NR 6"2 R 6"3 , -NR 6"3 C(O)R 6"2 , -SO 2 NR 6"2 R 6"3 , NR 6 3 SO 2 R 6"2 , -NR 6"3 C(O)NR 6"2 R 6"4 , -NR 6 3 C(O)OR 6"2 ,
  • R 6"2 represents C 6 or a 5 -6-membered unsaturated heterocyclic residue containing up to 3 heteroatoms selected from the group oxygen, nitrogen or sulfur,
  • R 6"5 represents Ci - C 4 alkyl, trifluoromethyl, trifluoromethoxy, -OR 6"6 , -SR 6"6 , -NR 6"7 R 6"8 , wherein
  • R 6"6 represents hydrogen, Cj - C alkyl, and wherein
  • Ci - C 4 alkyl C 3 - C 6 cycloalkyl
  • R 6"7 and R 6"8 together form a 5 -6-membered ring, which contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur and wherein
  • R 6"3 and R 6"4 are identical or different and represent hydrogen, bond,
  • R 3 and R 4 together form a 4-7-membered saturated ring containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur, which can optionally be substituted by 1 to 2 substituents selected from the group
  • A represents -C(O)-, -SO 2 -,
  • X represents a bond, -CR x l R x"2 -, oxygen or -NR X"3 , wherein
  • R x_1 , R x"2 , R X"3 can be independently selected from the group bond, hydrogen, Ci - C 4 alkyl,
  • Y represents bond, -C(O)-, -SO 2 -, -O-, -CR Y"1 R Y"2 -, or -NR Y"3 , wherein
  • R Y 1 , R ⁇ "2 , R ⁇ "3 can be independently selected from the group bond, hydrogen, Ci - C 4 alkyl,
  • R D represents N, or CR D 1 , wherein R D 1 can be independently selected from the group bond, hydrogen, Ci - C 4 alkyl,
  • the present invention relates to compounds according to the general formula (I), wherein
  • R 1 and R 2 form a 5- or 6-membered saturated cyclic residue, which can contain 1 nitrogen atom,
  • R 1"1 represents a bond or Ci - C 2 alkyl, wherein
  • R 1"1 can optionally be substituted by one C 6 aryl
  • R 1"2 represents a bond
  • R 1"3 represents a bond
  • Z represents -C(O)OR z-i , or 5-tetrazolyl
  • R 2"1 represents hydrogen, or C 2 alkyl
  • R 1"8 is Ci alkyl, and wherein
  • R 1"8 is substituted by 3 fluorine atoms
  • R 3 represents isobutyl
  • R 4 and R 5 represent hydrogen
  • R 6 represents
  • A represents -C(O)-
  • X represents -CH2-
  • Y represents -C(O)-
  • the present invention relates to compounds according to the general formula (I), wherein R 1 and R 2 form a piperidine ring.
  • the present invention relates to compounds according to the general formula (I), wherein R and R form a pyrrolidine ring.
  • the present invention relates to compounds according to the general formula (I), wherein R 6 represents
  • the present invention relates to compounds according to the general formula (I), wherein R 6 represents
  • the present invention relates to compounds according to the general formula (I), wherein wherein the compound is selected from the following group:
  • the invention relates to the use of a compound according general formula (I) in the manufacture of a medicament for the treatment of a condition mediated by integrins and pharmaceutical compositions, comprising compounds according general formula (I) and a pharmaceutically acceptable carrier.
  • alkyl stands for a straight-chain or branched alkyl residue, such as methyl, ethyl, n-propyl, iso-propyl, n-pentyl.
  • Ci - Cio alkyl is preferred.
  • Alkenyl and alkinyl stand for straight-chain or branched residues containing one or more double or triple bonds, e.g. vinyl, allyl, isopropinyl, ethinyl. Preferred is Ci - Cio alkenyl or alkinyl.
  • Cycloalkyl stands for a cyclic alkyl group such as cyclopropyl, cyclobutyl, cyclo- pentyl, cyclohexyl or cycleheptyl. Preferred is C 3 - C cycloalkyl.
  • Halogen in the context of the present invention stands for fluorine, chlorine, bromine or iodine. If not specified otherwise, chlorine or fluorine are preferred.
  • Heteroaryl stands for a monocyclic heteroaromatic system containing 4 to 9 ring atoms, which can be attached via a carbon atom or eventually via a nitrogen atom within the ring, for example, furan-2-yl, furan-3-yl, pyrrol- 1-yl, pyrrol-2-yl, pyrrol-3- yl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl or pyridazinyl.
  • a saturated or unsaturated heterocyclic residue stands for a heterocyclic system containing 4 to 9 ring atoms, which can contain one or more double bonds and which can be attached via a ring carbon atom or eventually via a nitrogen atom, e.g. tetra- hydrofur-2-yl, pyrrolidine-1-yl, piperidine-1-yl, piperidine-1-yl, morpholine-1-yl, 1 ,4-diazepine- 1 -yl or 1 ,4-dihydropyrine- 1 -yl.
  • heteroatom stands for O, S, N or P.
  • Annulated describes 1,1- or 1,2-fused ring systems, e.g. spiro systems or systems with a [0] -bridge. If not stated otherwise, substituents described for the "parent" ring system (the ring to which the annulated ring is attached) can also be present on the annulated ring.
  • the compounds of the present invention show good integrin antagonistic activity. They are therefore suitable especially as ⁇ 4 ⁇ and/or ⁇ 4 ⁇ 7 and/or ⁇ 9 ⁇ integrin antagonists and in particular for the production of pharmaceutical compositions for the inhibition or the prevention of cell adhesion and cell-adhesion mediated disorders. Examples are the treatment and the prophylaxis of athero- sclerosis, asthma, chronic obstructive pulmonary disease (COPD), allergies, diabetes, inflammatory bowel disease, multiple sclerosis, myocardial ischemia, rheumatoid arthritis, transplant rejection and other inflammatory, autoimmune and immune disorders.
  • COPD chronic obstructive pulmonary disease
  • integrin antagonists of the invention are useful not only for treatment of the physiological conditions discussed above, but are also useful in such activities as purification of integrins and testing for activity.
  • the compounds according to the invention can exhibit non-systemic or systemic activity, wherein the latter is preferred.
  • the active compounds can be administered, among other things, orally or parenterally, wherein oral administration is preferred.
  • parenteral administration forms of administration to the mucous membranes (i.e. buccal, lingual, sublingual, rectal, nasal, pulmonary, conjunctival or intravaginal) or into the interior of the body are particularly suitable.
  • Administration can be carried out by avoiding abso ⁇ tion (i.e. intracardiac, intra-arterial, intravenous, intraspinal or intralumbar administration) or by including abso ⁇ tion (i.e. intracutaneous, subcutaneous, percutaneous, intramuscular or intraperitoneal administration).
  • abso ⁇ tion i.e. intracardiac, intra-arterial, intravenous, intraspinal or intralumbar administration
  • abso ⁇ tion i.e. intracutaneous, subcutaneous, percutaneous, intramuscular or intraperitoneal administration.
  • the active compounds can be administered per se or in administration forms.
  • Suitable administration forms for oral administration are, inter alia, normal and enteric-coated tablets, capsules, coated tablets, pills, granules, pellets, powders, solid and liquid aerosols, syrups, emulsions, suspensions and solutions.
  • Suitable administration forms for parenteral administration are injection and infusion solutions.
  • the active compound can be present in the administration forms in concentrations of from 0.001 - 100 % by weight; preferably the concentration of the active compound should be 0.5 - 90% by weight, i.e. quantities which are sufficient to allow the specified range of dosage.
  • the active compounds can be converted in the known manner into the above- mentioned administration forms using inert non-toxic pharmaceutically suitable auxiliaries, such as for example excipients, solvents, vehicles, emulsifiers and/or dis- persants.
  • auxiliaries such as for example excipients, solvents, vehicles, emulsifiers and/or dis- persants.
  • auxiliaries can be mentioned as examples: water, solid excipients such as ground natural or synthetic minerals (e.g. talcum or silicates), sugar (e.g. lactose), non-toxic organic solvents such as paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethanol, glycerol), glycols (e.g. polyethylene glycol), emulsifying agents, dispersants (e.g. polyvinylpyrrolidone) and lubricants (e.g. magnesium sulphate).
  • ground natural or synthetic minerals e.g. talcum or silicates
  • sugar e.g. lactose
  • non-toxic organic solvents such as paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethanol, glycerol), glycols (e.g. polyethylene glycol), emulsifying agents, dispersants (e.g. polyvinylpyrrolidone) and
  • tablets can of course also contain additives such as sodium citrate as well as additives such as starch, gelatin and the like.
  • Flavour enhancers or colorants can also be added to aqueous preparations for oral administration.
  • parenteral administration it has generally proven advantageous to administer quantities of about 0.001 to 100 mg/kg, preferably about 0.01 to 1 mg/kg of body weight.
  • the quantity is about 0.01 to 100 mg/kg, preferably about 0.1 to 10 mg/kg of body weight.
  • Suitable pharmaceutically acceptable salts of the compounds of the present invention that contain an acidic moiety include addition salts formed with organic or inorganic bases.
  • the salt forming ion derived from such bases can be metal ions, e.g., alumi- num, alkali metal ions, such as sodium of potassium, alkaline earth metal ions such as calcium or magnesium, or an amine salt ion, of which a number are known for this pu ⁇ ose.
  • Examples include ammonium salts, arylalkylamines such as dibenzylamine and N,N-dibenzylethylenediamine, lower alkylamines such as methylamine, t- butylamine, procaine, lower alkylpiperidines such as N-ethylpiperidine, cycloalkyl- amines such as cyclohexylamine or dicyclohexylamine, 1-adamantylamine, benz- athine, or salts derived from amino acids like arginine, lysine or the like.
  • the physiologically acceptable salts such as the sodium or potassium salts and the amino acid salts can be used medicinally as described below and are preferred.
  • Suitable pharmaceutically acceptable salts of the compounds of the present invention that contain a basic moiety include addition salts formed with organic or inorganic acids.
  • the salt forming ion derived from such acids can be halide ions or ions of natural or unnatural carboxylic or sulfonic acids, of which a number are known for this pu ⁇ ose. Examples include chlorides, acetates, tartrates, or salts derived from amino acids like glycine or the like.
  • the physiologically acceptable salts such as the chloride salts and the amino acid salts can be used medicinally as described below and are preferred.
  • the salts are produced by reacting the acid form of the invention compound with an equivalent of the base supplying the desired basic ion or the basic form of the invention compound with an equivalent of the acid supplying the desired acid ion in a medium in which the salt precipitates or in aqueous medium and then lyophilizing.
  • the free acid or basic form of the invention compounds can be obtained from the salt by conventional neutralization techniques, e.g., with potassium bisulfate, hydrochloric acid, sodium hydroxide, sodium bicarbonate, etc.
  • the compounds according to the invention can form non covalent addition compounds such as adducts or inclusion compounds like hydrates or clathrates. This is known to the artisan and such compounds are also object of the present invention.
  • the compounds according to the invention can exist in different stereoisomeric forms, which relate to each other in a enantiomeric way (image and mirror image) or in a diastereomeric way (image and image different from mirror image).
  • the invention relates to the enantiomers and the diastereomers as well as their mixtures. They can be separated according to customary methods.
  • the compounds according to the invention can exist in tautomeric forms. This is known to the artisan and such compounds are also object of the present invention.
  • the present invention relates to a process for preparation of compounds of general formula (Nil)
  • PG 1 and PG 2 stands for a suitable protecting group of the carboxyl moiety.
  • Protecting groups of this type are known to the person skilled in the art and are described in detail in T. W. Greene, P. G. Wuts, Protective Groups in
  • the carboxyl group is preferably esterified, PG 1 ' 2 being a C ⁇ - 6 -alkyl such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, a C 3-7 - cycloalkyl such as, for example, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, an aryl such as, for example, phenyl, benzyl, tolyl or a substituted derivative thereof.
  • PG 1 ' 2 being a C ⁇ - 6 -alkyl such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopent
  • Step A Formation of the amides (IN) can take place by reacting the respective carboxylic acid (II) - activated by a coupling agent such as DCC and HOBt; EDCI and HOBt or HATU - with the desired amine (III) or an acceptable salt thereof.
  • a coupling agent such as DCC and HOBt; EDCI and HOBt or HATU -
  • Activated derivatives of the acids (II) such as anhydrides, halides, ⁇ -carboxyanhydrides and esters e.g. succinyl or pentafluorophenyl esters may also be employed.
  • amides of type (IN) can be prepared as follows:
  • a solution of carboxylic acid, HOBt and EDCI in an inert solvent is stirred at r.t..
  • amine and a non-nucleophilic base such as ethylisopropylamine stirring is continued at r.t. or elevated temperature.
  • the reaction mixture is poured into water and worked up by standard procedures.
  • biphenyl substituted acetic acid derivatives can be prepared by means of an aryl-aryl coupling of the respective phenyl acetic acid derivatives and a suitable phenyl system.
  • Possible coupling reactions are, for example, the reaction of two unsubstituted phenyl groups in the presence of A1C1 3 and an acid (Scholl reaction), the coupling of the two phenyl iodides in the presence of copper (Ullmann reaction), the reaction of the unsubstituted carboxylic acid derivative with a phenyldiazonium compound under basic conditions (Gomberg-Bachmann reaction) or coupling with participation of organometallic reagents such as coupling of a phenyl halide with an organometallic phenyl compound in the presence of a palladium compound, for example a Pd(0), a Pd(II) or a Pd(IN) compound, and of a phosphane such as triphenylphosphane (e.g. Suzuki reaction).
  • a palladium compound for example a Pd(0), a Pd(II) or a Pd(IN) compound
  • a phosphane
  • Bisarylureas can be prepared by coupling of an amino phenyl acetic acid derivative and a phenylisocyanate.
  • Bisarylamides can be prepared by coupling of an amino phenyl acetic acid and an activated benzoic acid derivative such as described under Step A.
  • Bisarylcarbamates can be prepared by coupling of an isocyanato phenyl acetic acid ester and a phenol derivative followed by saponification as described in Step B.
  • these carboxylic acid derivatives can have substituents such as described under R 3 and R 4 , for example, hydrogen, a d-Cio- alkyl, a C 3 -C 7 -cycloalkyl, an aryl, an alkenyl residue, or an alkinyl residue.
  • the alkyl, alkenyl and cycloalkyl residues and the benzyl residue can be introduced by reaction of the ester of the starting compounds with the appropriate alkyl, alkenyl, cycloalkyl or benzyl halides in basic medium, if the corresponding derivatives are not commercially available.
  • the alkinyl residue can be introduced, for example, by reaction of the bromo ester of the present starting compound with an appropriate acetylide anion.
  • the starting materials used are preferably the corresponding ⁇ -phenyl- ⁇ -aminocarboxylic acid derivatives and, if necessary, the other substituents at the ⁇ -C atom to the terminal carboxyl group are introduced via the appropriate alkyl halide.
  • substituents themselves should be substituted, e.g. by R', appropriate reactive groups should be present in the substituent to allow further functionalization. These reactive groups should be inert to the reaction conditions of the previous step.
  • the substituent can also be unsaturated to allow further functionalization such as palladium catalyzed C-C-coupling reactions (e.g. Heck-reaction or Sonogashira-reaction), eventually followed by hydrogenation (scheme 2):
  • hal stands for a leaving group such as a halogen, tosyl, mesyl or triflate
  • [Pd] stands for a Palladium(O) or Palladium(II) moiety
  • PG 3 stands for a protecting group of the amino group. Protecting groups of this type are known to the person skilled in the art and are described in detail in T. W. Greene, P. G. Wuts, Protective Groups in Organic Synthesis, 3 rd ed., John Wiley, New York, 1999.
  • the respective compounds (IN) can be prepared as follows: For example, in case A forms a sulfinamide, sulfonamide, they may be prepared as described in Step C. Oxalic amides can be prepared by the same means as the amides described above. Phosphinic acid amides and phosphonic acid amides can be prepared by coupling of activated phosphinic/phosphonic acids with amines (III). In case A is a heteroaromatic or aromatic system, the respective compounds (IN) can be prepared by nucleophilic substitution of the respective fluorosubstituted systems with a suitable amine (III).
  • Step B The removal of protecting group PG 1 can be performed either by an acid such as trifluoroacetic acid or an base such as potassium hydroxide or lithium hydroxide, depending on the nature of PG 1 . Reactions are carried out in aqueous, inert organic solvents such as alcohols e.g. methanol or ethanol, ethers e.g. tetrahydrofurane or dioxane or polar aprotic solvents e.g. dimethylformamide. If necessary, mixtures of the above solvents may be used.
  • amides (VII) can take place by reacting the respective carboxylic acids (N) - activated by a coupling agent such as DCC and HOBt; EDCI and HOBt or HATU - with the desired amines (NI) or an acceptable salt thereof.
  • a coupling agent such as DCC and HOBt; EDCI and HOBt or HATU - with the desired amines (NI) or an acceptable salt thereof.
  • Activated derivatives of the acids (N) such as anhydrides, halides, ⁇ -carboxyanhydrides and esters e.g. succinyl or pentafluorophenyl esters may also be employed.
  • amides (Nil) can be prepared as follows:
  • Y is different from carbonyl and/or D is different from nitrogen - as defined in formula (I) - the respective compounds (Nil) can be prepared as follows:
  • Y and D form an sulfinamide, or sulfonamide, they may be prepared by reacting the respective sulfinylchlorides or sulfonylchlorides with the desired amine (NI) or an acceptable salt thereof.
  • O-C or S-C- bonds are formed via alkylation of the corresponding alcohols or thiols with alkylating agents such as alkyl halides, alkyl tosylates and the like.
  • alkylating agents such as alkyl halides, alkyl tosylates and the like.
  • the thioether can be converted into the corresponding sulfoxides or sulfones by oxidation with reagents like mCPBA or hydrogen peroxide.
  • Y and D form a carbon-nitrogen-bond or a nitrogen-carbon-bond
  • the bond is established by reductive amination via the corresponding aldehyde or ketone and the corresponding amine in the presence of a reducing agent such as sodium cyanoboro- hydride.
  • the bond may be established by Wittig reaction of the corresponding ketone or aldehyde and the corresponding phos- phonium ylide followed by reduction of the double bond, e.g. by catalytic hydro- genation.
  • the bond may be formed by a Grignard type reaction of the corresponding aldehyde of Y and the corresponding Grignard-reagent of D, followed by the oxidation of the resulting alcohol to the ketone, e.g. by Swem-oxidation or Jones-oxidation.
  • Compounds of general formula (NI) are commercially available, known or can be prepared by customary methods starting from known carboxylic acid derivatives.
  • piperidine substituted esters may be obtained by catalytic hydrogenation of the corresponding, commercially available pyridine substituted esters.
  • Reactions may be carried out according to general procedure 1 :
  • the pyridine substituted esters in an acidified organic solvent such as an alcohol e.g. ethanol is hydrogenated in the presence of a suitable catalyst e.g. a suitable form of palladium or platinum. Hydrogenation may be carried out between 20 - 200°C and 1 - 300 bar hydrogen pressure.
  • the carbon chain can be elongated by Arndt-Eistert-reaction and optionally be derivatized by common methods for ⁇ - derivatization of carboxylic acids such as nucleophilic substitution.
  • Dialkyl hexahydropyrrolo[3,4-b]pyrrole-2,5(lH)-dicarboxylate derivatives can be obtained by the condensation of ethyl allyl(2-oxoethyl)carbamate with ethyl (benzylamino)acetate followed by removal of the benzy moiety employing catalytic hydrogenation.
  • 5-(3-pyrrolidinyl)-lH-tetrazole derivatives can be prepared by reaction of suitable ⁇ - protected 3-pyrrolidinecarbonitriles with azides such as tributyltinazide followed by the cleavage of the protecting group.
  • ⁇ -protecting groups of this type are known to the person skilled in the art and are described in detail in T. W. Greene, P. G. Wuts,
  • the removal of protecting group PG can be performed either by an acid such as trifiuoroacetic acid or an base such as potassium hydroxide or lithium hydroxide, depending on the nature of PG .
  • Reactions are carried out in aqueous, inert organic solvents such as alcohols e.g. methanol or ethanol, ethers e.g. tetrahydrofurane or dioxane or polar aprotic solvents e.g. dimethylformamide. If necessary, mixtures of the above solvents may be used.
  • TNF- ⁇ tumor necrosis factor ⁇ t R retention time determined by HPLC
  • the mass determinations were carried out using the electron spray ionization (ESI) method employing loop injection (ESI-MS) or split injection via a HPLC system (HPLC-MS).
  • ESI electron spray ionization
  • HPLC-MS split injection via a HPLC system
  • Methyl (3-hydroxy-4-nitrophenyl)acetate (9.5 g, 45.0 mmol) was dissolved in ethanol (150 ml). After addition of 10% Pd-C (0.95 g), the reaction mixture was hydrogenated at atmospheric pressure at room temperature. The catalyst was removed by filtration over celite.
  • VCAM-1 extracellular domains 1-3
  • Complementary D ⁇ A (cD ⁇ A) encoding 7-domain form of NCAM-1 (GenBank accession #M60335) was obtained using Rapid-ScreenTM cD ⁇ A library panels (OriGene Technologies, Inc) at Takara Gene Analysis Center (Shiga, Japan).
  • the primers used were 5'-CCA AGG CAG AGT ACG CAA AC-3' (sense) and 5'-TGG CAG GTA TTA TTA AGG AG-3' (antisense).
  • NCAM-1 cD ⁇ A was perform using Pfu D ⁇ A polymerase (Stratagene) with the following sets of primers: (U-NCAMdl-3) 5'-CCA TAT GGT ACC TGA TCA ATT TAA AAT CGA GAC CAC CCC AGA A-3'; (L-NCAMdl-3) 5'-CCA TAT AGC AAT CCT AGG TCC AGG GGA GAT CTC AAC AGT AAA-3'.
  • PCR cycle was 94°C for 45 sec, 55 °C for 45 sec, 72 °C for 2 min, repeating 15 cycles. After the purification of the PCR product, the fragment was digested with Kpnl-Avrll.
  • the digested fragment was ligated into pBluescript IISK(-) (Strategene), which was linearized by digesting with Kpnl-Xhol. The ligation was followed by transformation to a Dam/Dcm methylase-free E. coli strain SCSI 10 (Strategene) to create the donor plasmid pHH7.
  • pBluescript IISK(-) Strategene
  • SCSI 10 Dam/Dcm methylase-free E. coli strain SCSI 10
  • Baculo virus transfer vector containing first 3-domain form NCAM-1 was constructed by ligation of 0.9 kb fragment from Avrll Klenow/Bcll digests of pH7 into Sall/Klenow/BamHI digests of pMelBacB
  • Recombinant baculovirus was generated by using Bac- ⁇ -BlueTM Transfection kit (Invitrogen) according to the manufacture's instruction.
  • the recombinant virus was amplified by infection to High-FiveTM insect cells for 5 - 6 days, and virus titer was determined by plaque assay.
  • the cells were pelleted again and washed once in fresh Express FiveTM serum free medium.
  • the cells were pelleted again and finally, resuspended in 200 ml of fresh Express Five TM medium, transferred to a 1,000 ml shaker flask, and incubated in a shaker at 27°C, 130 rpm, for 48 hours before the culture supernatant was collected.
  • the purification of 3-domain form of NCAM-1 from the culture supernatant was performed by one-step anion exchange chromatography. Protein concentration was determined by using Coomassie protein assay reagent
  • each well of the microtiter plates ( ⁇ alge ⁇ unc International, Fluoronunc Cert, 437958) was coated with 100 ⁇ l of substrate or for background control with buffer alone for 15 hours at 4 C. After discarding the substrate solution, the wells were blocked using 150 ⁇ l per well of block solution (Kirkegaard Perry Laboratories, 50-61-01) for 90 minutes. The plate was washed with wash buffer containing 24 mM Tris-HCl (pH 7.4), 137 mM ⁇ aCl, 27 mM KC1 and 2 mM MnCl 2 just before addition of the assay.
  • wash buffer containing 24 mM Tris-HCl (pH 7.4), 137 mM ⁇ aCl, 27 mM KC1 and 2 mM MnCl 2 just before addition of the assay.
  • Jurkat cells (American Type Culture Collection, Clone E6-1, ATCC TIB-152) were cultured in RPMI 1640 medium ( ⁇ ikken Bio Medical Laboratory, CM1101) supple- mented with 10% fetal bovine serum (Hyclone, A-1119-L), 100 U/ml penicilin (Gibco BRL, 15140-122) and 100 ⁇ g/ml streptomycin (Gibco BRL, 15140-122) in a humidified incubator at 37°C with 5% CO2.
  • Jurkat cells were incubated with phosphate balanced solution (PBS, Nissui, 05913) containing 25 ⁇ M of 5(-and -6)-carboxyfluorescein diacetate, succinimidyle ester
  • the adhesion assay buffer was composed of 24 mM Tris-HCl (pH 7.4), 137 mM NaCl, 27 mM KC1, 4 mM glucose, 0.1 % bovine serum albumin (BSA, Sigma,
  • the assay solution containing each test compounds was transferred to the NCAM-1 coated plates.
  • the final concentration of each test compounds was 5 ⁇ M, 10 ⁇ M or various concentrations ranging from 0.0001 ⁇ M to 10 ⁇ M using a standard 5-point serial dilution.
  • the assay solution containing the labeled Jurkat cells was transferred to the NCAM-1 coated plates at a cell density of 2 x 10 5 cells per well and incubated for 1 hour at 37 C. The non-adherent cells were removed by washing the plates 3 times with wash buffer. The adherent cells were broken by addition of 1 % Triton X- 100 ( ⁇ acalai Tesque, 355-01). Released CFSC was quantified fluorescence measurement in a fluorometer (Wallac, ARNO 1420 multilabel counter).
  • Ramos cells (American Type Culture Collection, Clone CRL-1596) were cultured in RPMI 1640 medium (Nikken Bio Medical Laboratory, CMllOl) supplemented with 10% fetal bovine serum (Hyclone, A-1119-L), 100 U/ml penicilin (Gibco BRL, 15140-122) and 100 ⁇ g/ml streptomycin (Gibco BRL, 15140-122) in a humidified incubator at 37 °C with 5% CO 2 .
  • Ramos cells were incubated with phosphate balanced solution (PBS, Nissui, 05913) containing 25 ⁇ M of 5 (-and -6)-carboxyfluorescein diacetate, succinimidyle ester (CFSE, Dojindo Laboratories, 345-06441) for 20 min at room temperature while gently swirling every 5 min. After centrifugation at 1000 rpm for 5 min, the cell pellet was resuspended with adhesion assay buffer at a cell density of 4 x 10 6 cells/ml.
  • PBS phosphate balanced solution
  • CFSE succinimidyle ester
  • the adhesion assay buffer was composed of 24 mM Tris-HCl (pH 7.4), 137 mM NaCl, 27 mM KC1, 4 mM glucose, 0.1 % bovine serum albumin (BSA, Sigma, A9647) and 2 mM MnCl 2 .
  • the assay solution containing each test compounds or 5 ⁇ g/ml anti-CD49d monoclonal antibody (Immunotech, 0764) was transfened to the VCAM-1 coated plates.
  • the final concentration of each test compounds was 5 ⁇ M, 10 ⁇ M or various concentrations ranging from 0.0001 ⁇ M to 10 ⁇ M using a standard 5-point serial dilution.
  • the assay solution containing the labeled Ramos cells was transferred to the NCAM-1 coated plates at a cell density of 2 x 10 5 cells per well and incubated for 1 hour at 37 C. The non-adherent cells were removed by washing the plates 3 times with wash buffer.
  • the adherent cells were broken by addition of 1 % Triton X-100 (Nacalai Tesque, 355-01). Released CFSC was quantified fluorescence measurement in a fluorometer (Wallac, ARNO 1420 multilabel counter).
  • FTB the total fluorescent intensity from NCAM-1 coated wells without test compound
  • FBG the fluorescent intensity from wells with anti-CD49d monoclonal antibody
  • FTS the fluorescent intensity from wells containing the test compound of this invention.
  • 0.5 mg of 16 was spiked into a test tube (12 x 75 mm) containing 0.5 ml of the first fluid, pH 1.2 for dissolution test, 66 mM phosphate buffer with 50 mM NaCl (isotonic phosphate buffer) and 20 mM sodium deoxycholic acid, and then stirred at 37°C for 5 hr by magnetic stirred bar. Each solution was filtered using 0.2 ⁇ m membrane filter (Millipore, Japan). Each aliquot solution was applied to HPLC.
  • the compounds were dissolved in 10% cremophore EL in saline at a concentration of 2 mg/ml.
  • the compound at a dose of 10 mg/kg was given intraperitoneally to female BALB/c mice (JAPAN SLC Inc., Japan), and the blood sample was taken from the heart using heparinized syringes at 5, 15, 30, 60, 120 and 180 min after dosing. After centrifugation at 3,000 rpm for 5 min at 4°C, 0.25 ml of the plasma was added into 1M HCl of 0.05 ml and extracted by 7 ml of ether. The organic layer was evaporated under nitrogen stream at 40°C and the residue was dissolved in 0.25 ml of the mobile phase. 0.15 ml of the solution was applied to HPLC. 5.4 HPLC analysis
  • HPLC analysis was carried out using a reversed phase column, 3 ⁇ m Capcell pakTM C 18 UG 120, 4.6 x 100 mm (Shiseido, Japan) for the solubility and lipophilicity studies and 3.5 ⁇ m Symmetry ShieldTM RP8, 4.6 x 100 mm (Waters, USA) for the in vivo study on Hewlett Packard series 1100 equipped with a UN detector and column oven.
  • Compounds were separated by a mobile phase consisting of acetonitrile and 5 mM formic acid, pH 3.0 (42 : 52, v/v) at a column temperature of 40°C and a flow rate of 1.0 ml/min, and monitored by UN abso ⁇ tion of 258 nm.

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Abstract

The present invention relates to compounds of the general formula (I), processes for their preparation, pharmaceutical compositions containing them as well as their use for the production of pharmaceutical compositions for the treatment of inflammatory diseases.

Description

Piperidyl Carboxylic Acids as Integrin Antagonists
The present invention relates to compounds of formula (I),
Figure imgf000002_0001
their preparation and use as pharmaceutical compositions as integrin antagonists, especially as α4βj and/or α4β and/or α9βι integrin antagonists and in particular for the production of pharmaceutical compositions suitable for the inhibition or the pre- vention of cell adhesion and cell-adhesion mediated disorders. Examples are the treatment and the prophylaxis of atherosclerosis, asthma, chronic obstructive pulmonary disease (COPD), allergies, diabetes, inflammatory bowel disease, multiple sclerosis, myocardial ischemia, rheumatoid arthritis, transplant rejection and other inflammatory, autoimmune and immune disorders.
Adhesive interactions between the leukocytes and endothelial cells play a critical role in leukocyte trafficking to sites of inflammation. These events are essential for normal host defense against pathogens and repair of tissue damage, but can also contribute to the pathology of a variety of inflammatory and autoimmune disorders. Indeed, eosinophil and T cell infiltration into the tissue is known as a cardinal feature of allergic inflammation such as asthma.
The interaction of circulating leukocytes with adhesion molecules on the luminal surface of blood vessels appears to modulate leukocyte transmigration. These vascular cell adhesion molecules arrest circulating leukocytes, thereby serving as the first step in their recruitment to infected or inflamed tissue sites. Subsequently, the leukocytes reaching the extravascular space interact with connective tissue cells such as fibroblasts as well as extracellular matrix proteins such as fibronectin, laminin, and collagen. Adhesion molecules on the leukocytes and on the vascular endothelium are hence essential to leukocyte migration and attractive therapeutic targets for intervention in many inflammatory disorders.
Leukocyte recruitment to sites of inflammation occurs in a stepwise fashion beginning with leukocyte tethering to the endothelial cells lining the blood vessels.
This is followed by leukocyte rolling, activation, firm adhesion, and transmigration. A number of cell adhesion molecules involved in the those four recruitment steps have been identified and characterized to date. Among them, the interaction between vascular cell adhesion molecule 1 (NCAM-1) and very late antigen 4 (NLA-4, α4βι integrin), as well as the interaction between mucosal addressin cell adhesion molecule 1 (MAdCAM-1) and α4β integrin, has been shown to mediate the tethering, rolling, and adhesion of lymphocytes and eosinophils, but not neutrophils, to endothelial cells under a physiologic flow condition. This suggests that the NCAM-1 / NLA-4 and/or MAdCAM-1 / α4β7 integrin mediated interactions could predominantly mediate a selective recruitment of leukocyte subpopulations in vivo.
The inhibition of this interaction is a point of departure for therapeutic intervention (A. J. Wardlaw, J. Allergy Clin. Immunol 1999, 104, 917-26).
NCAM-1 is a member of immunoglobulin (Ig) superfamily and is one of the key regulators of leukocyte trafficking to sites of inflammation. NCAM-1, along with intracellular adhesion molecule 1 (ICAM-1) and E-selectin, is expressed on inflamed endothelium activated by such cytokines as interleucin 1 (IL-1) and tumor necrosis factor α (TΝF-α), as well as by lipopolysaccharide (LPS), via nuclear factor KB (ΝF- KB) dependent pathway. However, these molecules are not expressed on resting endothelium. Cell adhesion mediated by NCAM-1 may be involved in numerous physiological and pathological processes including myogenesis, hematopoiesis, inflammatory reactions, and the development of autoimmune disorders. Integrins NLA-4 and α4β7 both function as leukocyte receptors for NCAM-1.
The integrin α4βt is a heterodimeric protein expressed in substantial levels on all circulating leukocytes except mature neutrophils. It regulates cell migration into tissues during inflammatory responses and normal lymphocyte trafficking. NLA-4 binds to different primary sequence determinants, such as a QEDSP motif of NCAM- 1 and a ILDNP sequence of the major cell type-specific adhesion site of the alternatively spliced type III connecting segment domain (CS-1) of fibronectin.
In vivo studies with neutralizing monoclonal antibodies and inhibitor peptides have demonstrated a critical role for α4 integrins interaction in leukocyte-mediated inflammation. Blocking of NLA-4/ligand interactions, thus, holds promise for therapeutic intervention in a variety of inflammatory, autoimmune and immune diseases (Zimmerman, C; Exp. Opin. Ther. Patents 1999, 9, 129-133).
Furthermore, compounds containing a bisarylurea moiety as a substituent were disclosed as α4βι integrin receptor antagonists: WO 96/22966, WO 97/03094, WO 99/33789, WO 99/37605. However, no piperidyl carboxylic acids or cyclic analogs of the herein presented type have been described.
Further to their α4βj integrin antagonistic activity, the compounds of the present invention can also be used as α4β or α9βt integrin antagonists.
An object of the present invention is to provide new, alternative, piperidyl carboxylic acids or cyclic analogs derived integrin antagonists for the treatment of inflammatory, autoimmune and immune diseases. The present invention therefore relates to compounds of the general formula (I):
Figure imgf000004_0001
wherein R1 and R2 form a 4- to 8-membered saturated or unsaturated cyclic residue, which can contain 0 to 1 nitrogen atoms and 0 to 2 heteroatoms selected independently from the group S and O,
wherein the cyclic residue formed by R and R can be armulated with a 4- to 8-membered saturated, unsaturated or aromatic cyclic residue, which can contain 0 to 2 heteroatoms selected independently from the group N, S and O,
and wherein the cyclic residue formed by R1 and R2 and/or a ring armulated to the cyclic residue formed by R1 and R2 can optionally be independently substituted by 0 to 2 substituents -R1"1^1"2 -R^-Z, wherein
R represents a bond, -O-, -S-, NR1"4, d - Cι0 alkyl, C2 - Cι0 alkenyl, C2 - do alkynyl, C6 or do aryl, C3-C7 cycloalkyl, a 4- 9-membered saturated or unsaturated heterocyclic residue containing up to 3 heteroatoms selected from the group oxygen, nitrogen or sulfur, wherein
R1"1 can optionally be substituted by 1 to 2 substituents selected from the group R1"4, wherein R1"4 represents hydrogen, d - do alkyl, C2 - do alkenyl, C2 - C10 alkynyl, C6 or do aryl, C3-C7 cycloalkyl or a 4-9- membered saturated or unsaturated heterocyclic residue containing up to 3 heteroatoms selected from the group oxygen, nitrogen or sulfur, wherein
R1"4 can optionally be substituted by 1 to 3 substituents selected from the group Ci - C4 alkyl, d - C4 alkyloxy, phenyl, C - C6 cycloalkyl, halogen, nitro, cyano, oxo, R1"2 represents a bond, -O-, -S-, NR1"5, d - C10 alkyl, C2 - C10 alkenyl, C2 - Cio alkynyl, wherein
5 R1"2 can optionally be substituted by Ci - do alkyl, C2 - Cio alkenyl, C2 - Cio alkynyl or R1"5 , wherein
R1"5 represents hydrogen, Ci - do alkyl, C2 - do alkenyl,
C2 - Cio alkynyl, C6 or do aryl, C3 - C7 cycloalkyl or a
10 4-9-membered saturated or unsaturated heterocyclic residue containing up to 3 heteroatoms selected from the group oxygen, nitrogen or sulfur, wherein
R1"5 can optionally be substituted by 1 to 3 substituents 15 selected from the group d - C4 alkyl, Ci - C4 alkyloxy, phenyl, C3 - C6 cycloalkyl, halogen, nitro, cyano, oxo,
R1"3 represents a bond, Ci - Cio alkyl, C2 - Cio alkenyl, C2 - Cio alkynyl, wherein
20
R can optionally be substituted by Ci - Cio alkyl, C2 - Cio alkenyl, C2 - Cio alkynyl or R1"6 , wherein
R1"6 represents hydrogen, Ci - Cio alkyl, C2 - Cio alkenyl, 25 C2 - Cio alkynyl, C6 or Cio aryl, C3-C7 cycloalkyl or a
4-9-membered saturated or unsaturated heterocyclic residue containing up to 3 heteroatoms selected from the group oxygen, nitrogen or sulfur, wherein R1"6 can optionally be substituted by 1 to 3 substituents selected from the group Ci - C4 alkyl, Ci - C4 alkyloxy, phenyl, C3 - C6 cycloalkyl, halogen, nitro, cyano, oxo,
with the proviso that, when R " is a bond, then R " must not be a heteroatom,
and with the proviso that R1"1 and R1"2 must not be both heteroatom at the same time,
represents hydrogen, -C(O)OR , -C(O)NRZ 2R , -SO2NRz~2Rz-3, - -SSOO^ORR22""11)),, --SSOO22(((ORz l), -P(O)Rz l(ORZ 3), -PO(OR^')(OR^) or 5- tetrazolyl, wherein
R2-2 is hydrogen, -C(O)R2-4 or -§02 ZA, Ci - C4 alkyl, C2-C6 alkenyl, C2 - C6 alkynyl, C3 - C6 cycloalkyl, C6 or Cio aryl, wherein
R2"2 can optionally be substituted by 1 to 3 substituents selected from the group halogen, nitro, cyano, oxo, wherein
R2"4 is Ci - C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3 - C6 cycloalkyl, C6 or Cio aryl, wherein
R2"4 can optionally be substituted by 1 to 3 substituents selected from the group halogen, nitro, cyano, oxo,
7 \ 7 "
R " and R " are identical or different and represent hydrogen, Ci - C4 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C6 cycloalkyl, C6 or Cio aryl, wherein R2"' and R2"3 can optionally be substituted by 1 to 3 substituents selected from the group Ci - C4 alkyl, Ci - C4 alkyloxy, halogen, nitro, cyano,
and wherein the cyclic residue formed by R and R and/or a ring annulated to the cyclic residue formed by R1 and R2 can optionally be substituted by 0 to 2 substituents R " , halogen, nitro, amino, cyano and oxo, wherein
R1"8 can independently be selected from the group of Ci - C4 alkyl, Ci - C4 alkyloxy, phenyl, C3 - C6 cycloalkyl, and wherein
R1"8 can be substituted by 0-5 halogen atoms,
R3 represents hydrogen, Ci - Cio alkyl, C2 - Cio alkenyl, C2 - Cio alkynyl, C6 or Cio aryl, C3-C7 cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 3 radicals R " ,
and which can furthermore be single-foldedly substituted by C3 - C7 cycloalkyl, C6 or Cio aryl, C - C heteroaryl or a heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 3 radicals R3"1, wherein
R3"1 represents Ci - C4 alkyl, trifluoromethyl, trifluoromethoxy, -OR3"2,
-SR3"2, -NR3 3R3"4, -C(O)R3"2, S(O)R3"2, -SO2R3"2, -CO2R3"2, -OC(O)R3"2, -C(O)NR3 3R3"1, -NR3 2C(O)R3"2, -SO2NR3 3R3"t, NR3" 2SO2R3"2, -NR3"2C(O)NR3 3R3"4, -NR3 2C(O)OR3"2, -OC(O)NR3 3R3"4, halogen, cyano, nitro or oxo, wherein
R3"2 represents hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl, C6 or 5 Cio aryl which can optionally be substituted by 1 substituent selected from the group Ci - C4 alkyl, Ci - C4 alkyloxy, phenyl, C3 - C6 cycloalkyl, halogen, nitro, cyano, and wherein
R3"3 and R3"4 are identical or different and represent hydrogen, Ci - C4 10 alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl,
or
R " and R together form a 4-7-membered ring, which includes the 15 nitrogen atom to which R3"3 and R3"4 are bonded and which contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur and which contains up to 2 double bonds,
20 R4 represents hydrogen, Ci - Cio alkyl, C2 - Cio alkenyl, C2 - Cio alkynyl,
C6 or Cio aryl, C3 - C7 cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
25 which can optionally be substituted by 1 to 3 radicals R4"1,
and which can furthermore be single-foldedly substituted by C3 - C7 cycloalkyl, C6 or Cio aryl, C4 - C9 heteroaryl or a heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, 30 nitrogen or sulfur, which can optionally be substituted by 1 to 3 radicals R4"1, wherein
R4"1 represents Ci - C alkyl, trifluoromethyl, trifluoromethoxy,
-OR4"2, -SR4"2, -NR4"3R4'4, -C(O)R4"2, S(O)R4"2, -SO2R4"2,
5 -CO2R4"2, OC(O)R4"2, -C(O)NR4"3R4 -NR4 2C(O)R4"2,
-SO2NR4 3R4"4, NR4 2SO2R4"2, -NR4"2C(O)NR4"3R4^ -NR4" 2C(O)OR4"2, -OC(O)NR4"3R4"4, halogen, cyano, nitro or oxo, wherein
10 R4"2 represents hydrogen, Ci - C4 alkyl, C - C6 cycloalkyl, C6 or
Cio aryl which can optionally be substituted by 1 substituent selected from the group Ci - C4 alkyl, Ci - C4 alkyloxy, phenyl, C3-C6 cycloalkyl, halogen, nitro, cyano, and wherein
15 R4*3 and R4"4 are identical or different and represent hydrogen, C alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl,
or
20 R4"3 and R4"4 together form a 4-7-membered ring, which includes the nitrogen atom to which R4"3 and R4"4 are bonded and which contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur and which contains up to 2 double bonds,
25
R5 represents hydrogen, Ci - Cio alkyl, C2 - Cio alkenyl, C2 - Cio alkynyl, C6 or Cio aryl, C3-C7 cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
30 which can optionally be substituted by 1 to 3 radicals R " , and which can furthermore be single-foldedly substituted by C3 - C7 cycloalkyl, C6 or Cio aryl, C4 - C9 heteroaryl or a heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 3 radicals R5"1, wherein
R5"1 represents Ci - C4 alkyl, trifluoromethyl, trifluoromethoxy, 10 -OR5"2, -SR5"2, -NR5 3R5"4, -C(O)R5"2, S(O)R5"2, -SO2R5"2,
-CO2R5"2, -OC(O)R5"2, -C(O)NR5 3R5"4, -NR5 2C(O)R5"2, -SO2NR5 3R5"4, NR5 2SO2R5"2, -NR5 2C(O)NR5 3R5"4, -NR5" 2C(O)OR5"2, -OC(O)NR5 3R5"4, halogen, cyano, nitro or oxo, wherein 15
R5"2 represents hydrogen, Cj - C4 alkyl, C3 - C6 cycloalkyl,
C6 or Cio aryl which can optionally be substituted by 1 substituent selected from the group Ci - C4 alkyl,
Ci - C4 alkyloxy, phenyl, C -C cycloalkyl, halogen,
20 nitro, cyano, and wherein
R5"3 and R5"4 are identical or different and represent hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl, C6 or do aryl,
25 or
R5"3 and R5"4 together form a 4-7-membered ring, which includes the nitrogen atom to which R5"3 and R5"4 are bonded and which contains up to 2 additional hetero-
30 atoms selected from the group oxygen, nitrogen or sulfur and which contains up to 2 double bonds, R6 represents phenyl or a 5- to 6-membered aromatic heterocyclic residue containing up to 3 heteroatoms independently selected from the group of oxygen, nitrogen or sulfur, 5 which can optionally be annulated with a 5- to 8-membered saturated or unsaturated cyclic residue containing up to 2 heteroatoms independently selected from the group oxygen, nitrogen or sulfur,
10 and which can optionally be substituted by 0 to 2 substituents independently selected from the group of bond, Ci - Cio alkyl, C2 - Cio alkenyl, C2 - Cio alkynyl, C6 or Cio aryl, C3-C7 cycloalkyl or a 4-9- membered saturated or unsaturated heterocyclic residue containing up to 3 heteroatoms independently selected from the group oxygen,
15 nitrogen or sulfur, wherein these substituents can optionally be substituted by 1 to 3 radicals R6"1, wherein
R6"1 represents Ci - C4 alkyl, trifluoromethyl, trifluoromethoxy,
-OR6"2, -SR6"2, -NR6 2R6"3, -C(O)R6"2, S(O)R6"2, -SO2R6"2,
20 -CO2R6"2, -OC(O)R6"2, -C(O)NR6 2R6"3, -NR6 3C(O)R6"2,
-SO2NR6"2R6"3, NR6"3SO2R6"2, -NR6"3C(O)NR6"2R6"4,
-NR6 3C(O)OR6"2, -OC(O)NR6"2R6"3, halogen, cyano, nitro or oxo, wherein
25 R6"2 represents hydrogen, Ci - C alkyl, C3 - C6 cycloalkyl,
C6 or Cio aryl, or a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 3 heteroatoms selected from the group oxygen, nitrogen or sulfur,
30 which can optionally be substituted by 1 to 3 substituents R6"5 wherein
R6"5 represents Ci - C4 alkyl, trifluoromethyl, trifluoro- 5 methoxy, -OR6"6, -SR6"6, -NR6"7R6"8, wherein
R6"6 represents hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl,
C6 or Cio aryl which can optionally be substituted by 1 to 3 substituents selected from the group Ci - C4 alkyl,
10 Ci - C4 alkyloxy, phenyl, benzyl, C3-C6 cycloalkyl, hydroxy, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, and wherein
R6"7 and R6"8 are identical or different and represent hydrogen, 15 Ci - C alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl or a 4-
9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
20 which can optionally be substituted by 1 to 2 substituents selected from the group Ci - C4 alkyl, Ci - C4 alkyloxy, phenyl, benzyl, C3-C6 cycloalkyl, hydroxy, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,
25 or
R6"7 and R6"8 together form a 4-7-membered ring, which contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur and which contains
30 up to 2 double bonds, which can optionally be substituted by 1 to 2 substituents selected from the group Ci - C4 alkyl, Ci - C4 alkyloxy, phenyl, benzyl, C3-C6 cycloalkyl, hydroxy, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, oxo, and wherein 5
R6"3 and R6"4 are identical or different and represent hydrogen, bond, Ci - C4 alkyl, C3 - C6 cycloalkyl, C6 or Cjo aryl or a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from
10 the group oxygen, nitrogen or sulfur,
Ci - C4 alkyl, trifluoromethyl, trifluoromethoxy, -OR6"9, -SR6"9, -NR6-10R6-π, wherein
15 R6"9 represents hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl,
Figure imgf000014_0001
which can optionally be substituted by 1 to 3 substituents selected from the group Ci - C4 alkyl, Ci - C4 alkyloxy, phenyl,
20 benzyl, C3-C6 cycloalkyl, hydroxy, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, and wherein
R6"10 and R6"11 are identical or different and represent hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl or 25 a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 2 substituents 30 selected from the group Ci - C4 alkyl, Ci - C4 alkyloxy, phenyl, benzyl, C3-C6 cycloalkyl, hydroxy, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,
or
R6"9 and R6"10 together form a 4-7-membered ring, which contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur and which contains up to 2 double bonds, which can optionally be sub-
10 stituted by 1 to 2 substituents selected from the group d - C4 alkyl, d - C4 alkyloxy, phenyl, benzyl, C3-C6 cycloalkyl, hydroxy, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, oxo,
15 or
R6"2 and R6"3 and/or R6"3 and R6"4 together form a 4-7- membered ring, which includes the nitrogen atom to which R6"3, R6"3 and R6"4 are bonded and which con-
20 tains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur and which contains up to 2 double bonds, which can optionally be substituted by 1 to 2 substituents selected from the group d - C4 alkyl, d - C4 alkyloxy, phenyl, benzyl, C3-C6 cyclo-
25 alkyl, hydroxy, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, oxo,
and which can furthermore be independently substituted by 0 to 3 substituents R6"5
30 or R3 and R4 or R and R together form a 4-7-membered saturated or unsaturated ring containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur, which can optionally be substituted by 1 to 2 substituents selected from the group Ci - C4 alkyl, phenyl, benzyl,
C3 - C7 cycloalkyl, Ci - C4 alkyloxy, halogen, nitro, cyano, oxo and which can be fused with a 3-7 membered homocyclic or heterocyclic, saturated, unsaturated or aromatic ring,
A represents -C(O)-, -C(O)-C(O)-, -SO-, -SO2-, -P(O)RA 1-, -PO2-, 2- pyrimidyl, 4-pyrimidyl, 2-pyridyl, 2-imidazolyl, 4-imidazolyl, 2- benzimidazolyl or a ring selected from the following group:
Figure imgf000016_0001
wherein the abovementioned ring systems can optionally be substituted by d - C4 alkyl, Ci - C4 alkoxy, halogen, nitro, amino, cyano, wherein
RA 1 can be selected from the group of d - C4 alkyl, d - C4 alkoxy, X represents a bond, -CRX 1RX"2-, oxygen or -NRX"3, wherein
RX I, Rx"2, Rx"3 can be independently selected from the group bond, hydrogen, Ci - C4 alkyl, C2 - C4 alkenyl, C2 - C4 alkynyl,
or
together with R6 form a 4-7-membered ring, which includes the nitro- gen atom to which R6 and RX 1 or Rx"2 or Rx"3 can be attached and which can contain up to 2 additional heteroatoms independently selected from the group oxygen, nitrogen or sulfur and containing up to 2 double bonds, which can optionally be substituted by 1 to 2 substituents selected from the group Ci - C4 alkyl, phenyl, benzyl, C3 -C7 cycloalkyl, d - C4 alkyloxy, halogen, nitro, cyano, oxo,
Y represents bond, -C(O)-, -S(O)-, -SO2-, -O-, -S-, -CRY 1RY"2-, or -NRY"3, wherein Rγ_1, Rγ"2, Rγ"3 can be independently selected from the group bond, hydrogen, Ci - C4 alkyl, C2 - C4 alkenyl, C2 - C4 alk- ynyl,
and can optionally be substituted by 1 to 2 substituents independently selected from the group Cj - C alkyl, phenyl, benzyl, C3 - C7 cycloalkyl, Ci - C4 alkyloxy, halogen, nitro, cyano, oxo,
D represents N, or CR0"1, wherein
RD"' can be independently selected from the group bond, hydrogen, Ci - C4 alkyl, C2 - C4 alkenyl, C2 - C4 alkynyl, and can optionally be substituted by 1 to 2 substituents independently selected from the group Ci - C4 alkyl, phenyl, benzyl, C3 - C cycloalkyl, Ci - C4 alkyloxy, halogen, nitro, cyano, oxo,
and with the proviso that Y and D are not heteroatoms at the same time,
and pharmaceutically acceptable salts thereof.
In a preferred embodiment, the present invention relates to compounds according to the general formula (I), wherein
R1 and R2 form a 4- to 8-membered saturated or unsaturated cyclic residue,
which can contain 0 to 1 nitrogen atoms and 0 to 1 heteroatoms selected independently from the group S and O,
wherein the cyclic residue formed by R1 and R2 can be annulated with a 5- to 7-membered saturated, unsaturated or aromatic cyclic residue, which can contain 0 to 2 heteroatoms selected independently from the group N, S and O,
and wherein the cyclic residue formed by R1 and R2 and/or a ring annulated to the cyclic residue formed by R1 and R2 can optionally be independently substituted by 1 to 2 substituents -RM-R'"2 -R1 3-Z, wherein
R1"1 represents a bond, -O-, -S-, NR1"4, Ci - Cio alkyl, C2 - Cio alkenyl,
C-2 - do alkynyl, C6 or do aryl, C3 - C7 cycloalkyl, a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 3 heteroatoms selected from the group oxygen, nitrogen or sulfur, wherein R1"1 can optionally be substituted by 1 to 2 substituents selected from the group R1"4, wherein R represents hydrogen, Ci - Cio alkyl, C2 - Cio alkenyl, C2 - Cio alkynyl, C6 or Cio aryl, C3-C7 cycloalkyl or a 4-9- membered saturated or unsaturated heterocyclic residue containing up to 3 heteroatoms selected from the group oxygen, nitrogen or sulfur, wherein
R1"4 can optionally be substituted by 1 to 3 substituents selected from the group Ci - C4 alkyl, Ci - C4 alkyloxy, phenyl, C3 - C6 cycloalkyl, halo- gen, nitro, cyano, oxo,
R1"2 represents a bond, -O-, -S-, NR1"5, Ci - Cio alkyl, C2 - C10 alkenyl,
C2 - do alkynyl, wherein
R , 1-"2 can optionally be substituted by Ci - Cio alkyl, C2 - Cio alkenyl,
C2 - Cio alkynyl or R1"5 , wherein
R1"5 represents hydrogen, Ci - Cio alkyl, C2 - Cio alkenyl, C2 - Cio alkynyl,
C6 or Cio aryl, C3 - C7 cycloalkyl or a 4-9-membered saturated or un- saturated heterocyclic residue containing up to 3 heteroatoms selected from the group oxygen, nitrogen or sulfur, wherein
R1"5 can optionally be substituted by 1 to 3 substituents selected from the group Ci - C4 alkyl, Ci - C4 alkyloxy, phenyl, C3 - C6 cycloalkyl, halogen, nitro, cyano, oxo,
R1"3 represents a bond, Ci - Cio alkyl, C2 - Cio alkenyl, C2 - Cio alkynyl, wherein
R1"3 can optionally be substituted by Ci - do alkyl, C2 - do alkenyl,
C2 - Cio alkynyl or R 1-"7 , wherein R1"7 represents hydrogen, d - Cio alkyl, C2 - Cio alkenyl, C2 - Cio alkynyl, C6 or do aryl, C3 - C7 cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 3 heteroatoms selected from the group oxygen, nitrogen or sulfur, wherein
R1"7 can optionally be substituted by 1 to 3 substituents selected from the group d - C4 alkyl, Ci - C4 alkyloxy, phenyl, C3 - C6 cycloalkyl, halogen, nitro, cyano, oxo,
with the proviso that, when R1"3 is a bond, then R1"2 must not be a heteroatom,
and with the proviso that R1"1 and R1"2 must not be both heteroatom at the same time,
represents hydrogen, -C(O)OR ■ -1 , -C-V(/OΎ)WNΪTR z'-"2
Figure imgf000020_0001
-SO(ORz"1), -SO2(OR2"1), or 5-tetrazolyl, wherein
R2"2 is hydrogen, -C(O)Rz"4 or -SO2R2"4, Ci - C4 alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl, wherein
R2"2 can optionally be substituted by 1 to 3 substituents selected from the group halogen, nitro, cyano, oxo, wherein
R2"4 is Ci - C alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl, wherein
R2"4 can optionally be substituted by 1 to 3 substituents selected from the group halogen, nitro, cyano, oxo,
R2"1 and R2"3 are identical or different and represent hydrogen, Ci - C4 alkyl,
C3 - C6 cycloalkyl, C6 or Cio aryl, wherein R2"1 and Rz"3 can optionally be substituted by 1 to 3 substituents selected from the group Ci - C4 alkyl, Ci - C4 alkyloxy, halogen, nitro, cyano,
and wherein the cyclic residue formed by R and R and/or a ring annulated to the cyclic residue formed by R1 and R2 can optionally be substituted by 0 to 2 substituents R1"8, halogen, nitro, amino, cyano and oxo, wherein
R1"8 can independently be selected from the group of Ci - C alkyl, Ci - C4 alkyloxy, phenyl, C3 - C6 cycloalkyl, and wherein
R1"8 can be substituted by 0-5 halogen atoms,
R , 3 represents hydrogen, Ci - Cio alkyl, C6 or Cio aryl, C3 - C7 cycloalkyl or a 4- 9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 2 radicals R ,
and which can furthermore be single-foldedly substituted by C3 - C7 cycloalkyl, C6 or Cio aryl, C4 - C9 heteroaryl or a heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 3 radicals R 3-"1 , wherein
R " represents Ci - C4 alkyl, trifluoromethyl, trifluoromethoxy, -OR " , -NR " R , -CO2R " , halogen, cyano, nitro or oxo, wherein
R " represents hydrogen, Ci - C4 alkyl, C3 - CO cycloalkyl, C6 or Cio aryl and wherein R3"3 and R3"4 are identical or different and represent hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl,
or
R3"3 and R3"4 together form a 4-7-membered ring, which includes the nitrogen atom to which R3"3 and R3"4 are bonded and which contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur,
represents hydrogen, Ci - Cio alkyl, C6 or Cio aryl, C3 - C7 cycloalkyl or a 4- 9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 3 radicals R4"1,
and which can furthermore be single-foldedly substituted by C3-C7 cycloalkyl, C6 or Cio aryl, C4 - C9 heteroaryl or a heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 3 radicals R 4-"1 , wherein
R4"1 represents Ci - C4 alkyl, trifluoromethyl, trifluoromethoxy, -OR4"2, -NR4"3R4"4, -CO2R4"2, halogen, cyano, nitro or oxo,wherein
R4" represents hydrogen, Ci - C alkyl, C3 - C6 cycloalkyl, C6 or
Cio aryl and wherein
R4"3 and R4A are identical or different and represent hydrogen, CM alkyl, C3-C6 cycloalkyl, C6 or Cio aryl, or
R4"3 and R4^ together form a 4-7-membered ring, which includes the nitrogen atom to which R4"3 and R4"4 are bonded and which contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur,
R »5 represents hydrogen, Ci - Cio alkyl,
which can optionally be substituted by 1 to 3 radicals R5"1, and which can furthermore be single-foldedly substituted by C3 - C7 cycloalkyl, C6 or Cio aryl, C4 - C9 heteroaryl or a heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 3 radicals R 5-"1 , wherein
R5"1 represents Ci - C4 alkyl, trifluoromethyl, trifluoromethoxy, -OR5"2, -NR5"3R5"4, -CO2R5"2, halogen, cyano, nitro or oxo, wherein
R5"2 represents hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl and wherein
R5"3 and R5"4 are identical or different and represent hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl,
or
R5"3 and R together form a 4-7-membered ring, which includes the nitrogen atom to which R5"3 and R5"4 are bonded and which contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur, represents phenyl or a 6-membered aromatic heterocyclic residue containing up to 2 nitrogen atoms,
and which can optionally be independently substituted by 1 substituents independently selected from the group of bond,
wherein this substituent can optionally be substituted by 1 radical R6"1, wherein
R6"1 represents -C(O)NR6"2R6"3, -NR6"3C(O)R6"2, -SO2NR6"2R6"3, NR6 3SO2R6"2, -NR6"3C(O)NR6"2R6"4, -NR6 3C(O)OR6"2,
-OC(O)NR6 2R6"3, wherein
R6"2 represents C6 or a 5 -6-membered unsaturated heterocyclic residue containing up to 3 heteroatoms selected from the group oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 2 substituents R 6-5. wherein
R6"5 represents Ci - C4 alkyl, trifluoromethyl, trifluoromethoxy, -OR6"6, -SR6"6, -NR6"7R6"8, wherein
R6"6 represents hydrogen, Cj - C alkyl, and wherein
Figure imgf000024_0001
are identical or different and represent hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl,
or R6"7 and R6"8 together form a 5 -6-membered ring, which contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur and wherein
R6"3 and R6"4 are identical or different and represent hydrogen, bond,
Ci - C4 alkyl, C3 - C6 cycloalkyl,
and which can furthermore be independently substituted by 0 to 2 substituents R6"5
or
R3 and R4 together form a 4-7-membered saturated ring containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur, which can optionally be substituted by 1 to 2 substituents selected from the group
Ci - C alkyl, phenyl, benzyl, C3 - C7 cycloalkyl, Ci - C alkyloxy, halogen, nitro, cyano, oxo,
A represents -C(O)-, -SO2-,
X represents a bond, -CRx lRx"2-, oxygen or -NRX"3, wherein
Rx_1, Rx"2, RX"3 can be independently selected from the group bond, hydrogen, Ci - C4 alkyl,
Y represents bond, -C(O)-, -SO2-, -O-, -CRY"1RY"2-, or -NRY"3, wherein
RY 1, Rγ"2, Rγ"3 can be independently selected from the group bond, hydrogen, Ci - C4 alkyl,
D represents N, or CRD 1, wherein RD 1 can be independently selected from the group bond, hydrogen, Ci - C4 alkyl,
and with the proviso that Y and D are not heteroatoms at the same time,
and pharmaceutically acceptable salts thereof.
In a more preferred embodiment, the present invention relates to compounds according to the general formula (I), wherein
R1 and R2 form a 5- or 6-membered saturated cyclic residue, which can contain 1 nitrogen atom,
1 wherein the cyclic residue formed by R and R can be annulated with a 5- membered saturated cyclic residue, which contains 1 nitrogen atom,
and wherein the cyclic residue formed by R1 and R2 and/or a ring annulated to the cyclic residue formed by R1 and R2 can optionally be substituted independently by 1 substituent -R1 "] -R1 "2 -R1 "3-Z, wherein
R1"1 represents a bond or Ci - C2 alkyl, wherein
R1"1 can optionally be substituted by one C6 aryl,
R1"2 represents a bond,
R1"3 represents a bond,
Z represents -C(O)OR z-i , or 5-tetrazolyl, R2"1 represents hydrogen, or C2 alkyl,
and wherein the cyclic residue formed by R1 and R2 and/or a ring annulated to the cyclic residue formed by R1 and R2 can optionally be substituted by 0 or 1 substituent R1"8, wherein
R1"8 is Ci alkyl, and wherein
R1"8 is substituted by 3 fluorine atoms,
R3 represents isobutyl,
R4 and R5 represent hydrogen,
R6 represents
Figure imgf000027_0001
A represents -C(O)-,
X represents -CH2-,
Y represents -C(O)-,
D represents nitrogen,
and pharmaceutically acceptable salts thereof.
In a particularity preferred embodiment, the present invention relates to compounds according to the general formula (I), wherein R1 and R2 form a piperidine ring. In another particularily preferred embodiment, the present invention relates to compounds according to the general formula (I), wherein R and R form a pyrrolidine ring.
In yet another particularily preferred embodiment, the present invention relates to compounds according to the general formula (I), wherein R6 represents
Figure imgf000028_0001
In yet another particularily preferred embodiment, the present invention relates to compounds according to the general formula (I), wherein R6 represents
Figure imgf000028_0002
In the most preferred embodiment, the present invention relates to compounds according to the general formula (I), wherein wherein the compound is selected from the following group:
N-((lS)-3-methyl-l-{[3-(lH-tetraazol-5-yl)-l-pyrrolidinyl]carbonyl}butyl)-2- {4-[(2-toluidinocarbonyl)amino]phenyl} acetamide
1 - {( {4-[(2-toluidinocarbonyl)amino]phenyl} acetyl)-L-leucine} -2-piperidine- carboxylic acid,
1 - {( {4-[(2-toluidinocarbonyl)amino]phenyl} acetyl)-L-leucine} -3-piperidine- carboxylic acid, 1 - {( {4-[(2-toluidinocarbonyl)amino]phenyl} acetyl)-L-leucine} -4-piperidine- carboxylic acid, ( 1 - {2-( {4-[(2-toluidinocarbonyl)amino]phenyl} acetyl)-L-leucine} -2- piperidinyl)acetic acid,
( 1 - {2-( {4-[(2-toluidinocarbonyl)amino]phenyl} acetyl)-L-leucine} -3- piperidinyl)acetic acid, ( 1 - {2-( {4-[(2-toluidinocarbonyl)amino]phenyl} acetyl)-L-leucine} -4- piperidinyl)acetic acid,
( 1 - {2-( {4-[(2-toluidinocarbonyl)amino]phenyl} acetyl)-L-leucine} -3- piperidinyl)propanoic acid,
(3 S)- 1 - {2-( {4-[(2-toluidinocarbonyl)amino]phenyl} acetyl)-L-leucine} -4-(tri- fluoromethyι)-3 -pyrrolidinecarboxylic acid,
5-(ethoxycarbonyl)-l-{2-({4-[(2-toluidinocarbonyl)amino]phenyl}acetyl)-L- leucine}octahydropyrrolo[3,4-b]pyrrole-2-carboxylic acid,
(l-{2-({4-[(2-toluidinocarbonyl)amino]phenyl}acetyl)-L-leucine}-2-piperi- dinyl)(phenyl)acetic acid and ( 1 - {2-( {4-[(2-toluidinocarbonyl)amino]phenyl} acetyl)-L-leucine} -3 -oxo-2- piperazinyl)acetic acid l-(N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}glycyl)-
2-piperidinyl]acetic acid
(1 - {N-[(2-anilino- 1 ,3-benzoxazol-6-yl)acetyl]glycyl} -2-piperidinyl)acetic acid
[ 1 -(N- {[4-( {[(2-methylphenyl)amino]carbonyl} amino)phenyl]acetyl} glycyl)-
2-piperidinyl]acetic acid
(l-{N-[(2-anilino-l,3-benzoxazol-6-yl)acetyl]glycyl}-2-piperidinyl)acetic acid.
In other embodiments, the invention relates to the use of a compound according general formula (I) in the manufacture of a medicament for the treatment of a condition mediated by integrins and pharmaceutical compositions, comprising compounds according general formula (I) and a pharmaceutically acceptable carrier. In the context of the present invention alkyl stands for a straight-chain or branched alkyl residue, such as methyl, ethyl, n-propyl, iso-propyl, n-pentyl. Preferred is Ci - Cio alkyl.
Alkenyl and alkinyl stand for straight-chain or branched residues containing one or more double or triple bonds, e.g. vinyl, allyl, isopropinyl, ethinyl. Preferred is Ci - Cio alkenyl or alkinyl.
Cycloalkyl stands for a cyclic alkyl group such as cyclopropyl, cyclobutyl, cyclo- pentyl, cyclohexyl or cycleheptyl. Preferred is C3 - C cycloalkyl.
Halogen in the context of the present invention stands for fluorine, chlorine, bromine or iodine. If not specified otherwise, chlorine or fluorine are preferred.
Heteroaryl stands for a monocyclic heteroaromatic system containing 4 to 9 ring atoms, which can be attached via a carbon atom or eventually via a nitrogen atom within the ring, for example, furan-2-yl, furan-3-yl, pyrrol- 1-yl, pyrrol-2-yl, pyrrol-3- yl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl or pyridazinyl.
A saturated or unsaturated heterocyclic residue stands for a heterocyclic system containing 4 to 9 ring atoms, which can contain one or more double bonds and which can be attached via a ring carbon atom or eventually via a nitrogen atom, e.g. tetra- hydrofur-2-yl, pyrrolidine-1-yl, piperidine-1-yl, piperidine-1-yl, morpholine-1-yl, 1 ,4-diazepine- 1 -yl or 1 ,4-dihydropyrine- 1 -yl.
If not specified otherwise in the context of the present invention heteroatom stands for O, S, N or P.
Annulated describes 1,1- or 1,2-fused ring systems, e.g. spiro systems or systems with a [0] -bridge. If not stated otherwise, substituents described for the "parent" ring system (the ring to which the annulated ring is attached) can also be present on the annulated ring.
Surprisingly, the compounds of the present invention show good integrin antagonistic activity. They are therefore suitable especially as α4βι and/or α4β7 and/or α9βι integrin antagonists and in particular for the production of pharmaceutical compositions for the inhibition or the prevention of cell adhesion and cell-adhesion mediated disorders. Examples are the treatment and the prophylaxis of athero- sclerosis, asthma, chronic obstructive pulmonary disease (COPD), allergies, diabetes, inflammatory bowel disease, multiple sclerosis, myocardial ischemia, rheumatoid arthritis, transplant rejection and other inflammatory, autoimmune and immune disorders.
The integrin antagonists of the invention are useful not only for treatment of the physiological conditions discussed above, but are also useful in such activities as purification of integrins and testing for activity.
For the treatment of the abovementioned diseases, the compounds according to the invention can exhibit non-systemic or systemic activity, wherein the latter is preferred. To obtain systemic activity the active compounds can be administered, among other things, orally or parenterally, wherein oral administration is preferred.
For parenteral administration, forms of administration to the mucous membranes (i.e. buccal, lingual, sublingual, rectal, nasal, pulmonary, conjunctival or intravaginal) or into the interior of the body are particularly suitable. Administration can be carried out by avoiding absoφtion (i.e. intracardiac, intra-arterial, intravenous, intraspinal or intralumbar administration) or by including absoφtion (i.e. intracutaneous, subcutaneous, percutaneous, intramuscular or intraperitoneal administration). For the above puφose the active compounds can be administered per se or in administration forms.
Suitable administration forms for oral administration are, inter alia, normal and enteric-coated tablets, capsules, coated tablets, pills, granules, pellets, powders, solid and liquid aerosols, syrups, emulsions, suspensions and solutions. Suitable administration forms for parenteral administration are injection and infusion solutions.
The active compound can be present in the administration forms in concentrations of from 0.001 - 100 % by weight; preferably the concentration of the active compound should be 0.5 - 90% by weight, i.e. quantities which are sufficient to allow the specified range of dosage.
The active compounds can be converted in the known manner into the above- mentioned administration forms using inert non-toxic pharmaceutically suitable auxiliaries, such as for example excipients, solvents, vehicles, emulsifiers and/or dis- persants.
The following auxiliaries can be mentioned as examples: water, solid excipients such as ground natural or synthetic minerals (e.g. talcum or silicates), sugar (e.g. lactose), non-toxic organic solvents such as paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethanol, glycerol), glycols (e.g. polyethylene glycol), emulsifying agents, dispersants (e.g. polyvinylpyrrolidone) and lubricants (e.g. magnesium sulphate).
In the case of oral administration tablets can of course also contain additives such as sodium citrate as well as additives such as starch, gelatin and the like. Flavour enhancers or colorants can also be added to aqueous preparations for oral administration. For the obtainment of effective results in the case of parenteral administration it has generally proven advantageous to administer quantities of about 0.001 to 100 mg/kg, preferably about 0.01 to 1 mg/kg of body weight. In the case of oral administration the quantity is about 0.01 to 100 mg/kg, preferably about 0.1 to 10 mg/kg of body weight.
It may nevertheless be necessary to use quantities other than those mentioned above, depending on the body weight concerned, the method of administration, the individual response to the active compound, the type of preparation and the time or interval o f administration.
Suitable pharmaceutically acceptable salts of the compounds of the present invention that contain an acidic moiety include addition salts formed with organic or inorganic bases. The salt forming ion derived from such bases can be metal ions, e.g., alumi- num, alkali metal ions, such as sodium of potassium, alkaline earth metal ions such as calcium or magnesium, or an amine salt ion, of which a number are known for this puφose. Examples include ammonium salts, arylalkylamines such as dibenzylamine and N,N-dibenzylethylenediamine, lower alkylamines such as methylamine, t- butylamine, procaine, lower alkylpiperidines such as N-ethylpiperidine, cycloalkyl- amines such as cyclohexylamine or dicyclohexylamine, 1-adamantylamine, benz- athine, or salts derived from amino acids like arginine, lysine or the like. The physiologically acceptable salts such as the sodium or potassium salts and the amino acid salts can be used medicinally as described below and are preferred.
Suitable pharmaceutically acceptable salts of the compounds of the present invention that contain a basic moiety include addition salts formed with organic or inorganic acids. The salt forming ion derived from such acids can be halide ions or ions of natural or unnatural carboxylic or sulfonic acids, of which a number are known for this puφose. Examples include chlorides, acetates, tartrates, or salts derived from amino acids like glycine or the like. The physiologically acceptable salts such as the chloride salts and the amino acid salts can be used medicinally as described below and are preferred.
These and other salts which are not necessarily physiologically acceptable are useful in isolating or purifying a product acceptable for the puφoses described below.
The salts are produced by reacting the acid form of the invention compound with an equivalent of the base supplying the desired basic ion or the basic form of the invention compound with an equivalent of the acid supplying the desired acid ion in a medium in which the salt precipitates or in aqueous medium and then lyophilizing.
The free acid or basic form of the invention compounds can be obtained from the salt by conventional neutralization techniques, e.g., with potassium bisulfate, hydrochloric acid, sodium hydroxide, sodium bicarbonate, etc.
The compounds according to the invention can form non covalent addition compounds such as adducts or inclusion compounds like hydrates or clathrates. This is known to the artisan and such compounds are also object of the present invention.
The compounds according to the invention can exist in different stereoisomeric forms, which relate to each other in a enantiomeric way (image and mirror image) or in a diastereomeric way (image and image different from mirror image). The invention relates to the enantiomers and the diastereomers as well as their mixtures. They can be separated according to customary methods.
The compounds according to the invention can exist in tautomeric forms. This is known to the artisan and such compounds are also object of the present invention.
In yet another embodiment, the present invention relates to a process for preparation of compounds of general formula (Nil)
Figure imgf000035_0001
according to any one of claims 1 to 1, which comprises reaction of carboxylic acids of general formula (N)
Figure imgf000035_0002
or activated derivatives thereof with compounds of the general formula (VI)
Figure imgf000035_0003
1. General compound synthesis
The synthesis of compounds according to the general formula (I) can be illustrated by the following scheme 1 :
Figure imgf000036_0001
(II) (III) (iv)
Figure imgf000036_0002
By amide coupling of the carboxylic acids (II) with the amines (III), followed by saponification of the esters (IN) the carboxylic acids (N) can be obtained. Coupling with the cyclic amines (NI) followed by removal of the protecting group PG2 affords carboxylic acids of type (NIII). Further examples with different A, Y and D groups as defined in formula (I) are described below.
In the above scheme PG1 and PG2 stands for a suitable protecting group of the carboxyl moiety. Protecting groups of this type are known to the person skilled in the art and are described in detail in T. W. Greene, P. G. Wuts, Protective Groups in
Organic Synthesis, 3rd ed., John Wiley, New York, 1999. The carboxyl group is preferably esterified, PG1'2 being a Cι-6-alkyl such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, a C3-7- cycloalkyl such as, for example, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, an aryl such as, for example, phenyl, benzyl, tolyl or a substituted derivative thereof.
1.1 Step A Formation of the amides (IN) can take place by reacting the respective carboxylic acid (II) - activated by a coupling agent such as DCC and HOBt; EDCI and HOBt or HATU - with the desired amine (III) or an acceptable salt thereof. Activated derivatives of the acids (II) such as anhydrides, halides, Ν-carboxyanhydrides and esters e.g. succinyl or pentafluorophenyl esters may also be employed.
For example, amides of type (IN) can be prepared as follows:
A solution of carboxylic acid, HOBt and EDCI in an inert solvent is stirred at r.t.. After addition of amine and a non-nucleophilic base such as ethylisopropylamine stirring is continued at r.t. or elevated temperature. The reaction mixture is poured into water and worked up by standard procedures.
Compounds of general formula (II) are commercially available, known or can be prepared by customary methods starting from known carboxylic acid derivatives.
For example, biphenyl substituted acetic acid derivatives can be prepared by means of an aryl-aryl coupling of the respective phenyl acetic acid derivatives and a suitable phenyl system.
Possible coupling reactions are, for example, the reaction of two unsubstituted phenyl groups in the presence of A1C13 and an acid (Scholl reaction), the coupling of the two phenyl iodides in the presence of copper (Ullmann reaction), the reaction of the unsubstituted carboxylic acid derivative with a phenyldiazonium compound under basic conditions (Gomberg-Bachmann reaction) or coupling with participation of organometallic reagents such as coupling of a phenyl halide with an organometallic phenyl compound in the presence of a palladium compound, for example a Pd(0), a Pd(II) or a Pd(IN) compound, and of a phosphane such as triphenylphosphane (e.g. Suzuki reaction).
Bisarylureas can be prepared by coupling of an amino phenyl acetic acid derivative and a phenylisocyanate. Bisarylamides can be prepared by coupling of an amino phenyl acetic acid and an activated benzoic acid derivative such as described under Step A. Bisarylcarbamates can be prepared by coupling of an isocyanato phenyl acetic acid ester and a phenol derivative followed by saponification as described in Step B.
Compounds of general formula (III) are commercially available, known or can be prepared by customary methods starting from known α-amino acids or precursors for customary α-amino acid synthesis. For the preparation process according to the invention, the carboxyl group is in this case blocked by a conventional protective group PG1.
In the α-position to the carboxyl group, these carboxylic acid derivatives can have substituents such as described under R3 and R4, for example, hydrogen, a d-Cio- alkyl, a C3-C7-cycloalkyl, an aryl, an alkenyl residue, or an alkinyl residue. The alkyl, alkenyl and cycloalkyl residues and the benzyl residue can be introduced by reaction of the ester of the starting compounds with the appropriate alkyl, alkenyl, cycloalkyl or benzyl halides in basic medium, if the corresponding derivatives are not commercially available. The alkinyl residue can be introduced, for example, by reaction of the bromo ester of the present starting compound with an appropriate acetylide anion. In the case of the phenyl residue the starting materials used are preferably the corresponding α-phenyl-α-aminocarboxylic acid derivatives and, if necessary, the other substituents at the α-C atom to the terminal carboxyl group are introduced via the appropriate alkyl halide.
The above reactions and their implementation are well known to the person skilled in the art and are described in detail in standard textbooks such as, for example, Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg Thieme Nerlag, Stuttgart.
If the substituents themselves should be substituted, e.g. by R', appropriate reactive groups should be present in the substituent to allow further functionalization. These reactive groups should be inert to the reaction conditions of the previous step. For this puφose, the substituent can also be unsaturated to allow further functionalization such as palladium catalyzed C-C-coupling reactions (e.g. Heck-reaction or Sonogashira-reaction), eventually followed by hydrogenation (scheme 2):
Figure imgf000039_0001
In the abovementioned scheme, hal stands for a leaving group such as a halogen, tosyl, mesyl or triflate, [Pd] stands for a Palladium(O) or Palladium(II) moiety. PG3 stands for a protecting group of the amino group. Protecting groups of this type are known to the person skilled in the art and are described in detail in T. W. Greene, P. G. Wuts, Protective Groups in Organic Synthesis, 3rd ed., John Wiley, New York, 1999.
If the substituent R3 or R4 in the α-position to the carboxylic group carry an appropriate substituted aryl or heteroaryl unit, another method for insertion of an additional substituent are the C-C-coupling reactions as described under the synthesis of precursors (II).
In case, A - as defined in formula (I) - is different from carbonyl, the respective compounds (IN) can be prepared as follows: For example, in case A forms a sulfinamide, sulfonamide, they may be prepared as described in Step C. Oxalic amides can be prepared by the same means as the amides described above. Phosphinic acid amides and phosphonic acid amides can be prepared by coupling of activated phosphinic/phosphonic acids with amines (III). In case A is a heteroaromatic or aromatic system, the respective compounds (IN) can be prepared by nucleophilic substitution of the respective fluorosubstituted systems with a suitable amine (III).
1.2 Step B The removal of protecting group PG1 can be performed either by an acid such as trifluoroacetic acid or an base such as potassium hydroxide or lithium hydroxide, depending on the nature of PG1. Reactions are carried out in aqueous, inert organic solvents such as alcohols e.g. methanol or ethanol, ethers e.g. tetrahydrofurane or dioxane or polar aprotic solvents e.g. dimethylformamide. If necessary, mixtures of the above solvents may be used.
1.3 Step C
Formation of the amides (VII) can take place by reacting the respective carboxylic acids (N) - activated by a coupling agent such as DCC and HOBt; EDCI and HOBt or HATU - with the desired amines (NI) or an acceptable salt thereof. Activated derivatives of the acids (N) such as anhydrides, halides, Ν-carboxyanhydrides and esters e.g. succinyl or pentafluorophenyl esters may also be employed. For example, amides (Nil) can be prepared as follows:
A solution of carboxylic acid, HOBt and EDCI in an inert solvent is stirred at r.t..
After addition of amine and a non-nucleophilic base such as ethylisopropylamine stirring is continued at r.t. or elevated temperature. The reaction mixture is poured into water and worked up by standard procedures.
In case, Y is different from carbonyl and/or D is different from nitrogen - as defined in formula (I) - the respective compounds (Nil) can be prepared as follows: For example, in case Y and D form an sulfinamide, or sulfonamide, they may be prepared by reacting the respective sulfinylchlorides or sulfonylchlorides with the desired amine (NI) or an acceptable salt thereof.
For example, in case Y and D form an ether or thioether, the O-C or S-C- bonds are formed via alkylation of the corresponding alcohols or thiols with alkylating agents such as alkyl halides, alkyl tosylates and the like. The thioether can be converted into the corresponding sulfoxides or sulfones by oxidation with reagents like mCPBA or hydrogen peroxide.
In case Y and D form a carbon-nitrogen-bond or a nitrogen-carbon-bond, the bond is established by reductive amination via the corresponding aldehyde or ketone and the corresponding amine in the presence of a reducing agent such as sodium cyanoboro- hydride.
In case Y and D form a carbon-carbon-bond, the bond may be established by Wittig reaction of the corresponding ketone or aldehyde and the corresponding phos- phonium ylide followed by reduction of the double bond, e.g. by catalytic hydro- genation.
In case Y is carbonyl and D is a carbon moiety, the bond may be formed by a Grignard type reaction of the corresponding aldehyde of Y and the corresponding Grignard-reagent of D, followed by the oxidation of the resulting alcohol to the ketone, e.g. by Swem-oxidation or Jones-oxidation.
The above reactions and their implementation are well known to the person skilled in the art and are described in detail in standard textbooks such as, for example, Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg Thieme Nerlag, Stuttgart. When more than one choices of reaction methods exist, the person skilled in the art is able to choose the appropriate pathway according to selectivity and possible use of protecting groups such as described in T. W. Greene, P. G. Wuts, Protective Groups in Organic Synthesis, 3rd ed., John Wiley, New York, 1999.
Compounds of general formula (NI) are commercially available, known or can be prepared by customary methods starting from known carboxylic acid derivatives.
For example piperidine substituted esters may be obtained by catalytic hydrogenation of the corresponding, commercially available pyridine substituted esters.
Reactions may be carried out according to general procedure 1 :
The pyridine substituted esters in an acidified organic solvent such as an alcohol e.g. ethanol is hydrogenated in the presence of a suitable catalyst e.g. a suitable form of palladium or platinum. Hydrogenation may be carried out between 20 - 200°C and 1 - 300 bar hydrogen pressure.
In case R1"1, R1"2 and/or R1"3 are methylen groups, the carbon chain can be elongated by Arndt-Eistert-reaction and optionally be derivatized by common methods for α- derivatization of carboxylic acids such as nucleophilic substitution.
Dialkyl hexahydropyrrolo[3,4-b]pyrrole-2,5(lH)-dicarboxylate derivatives can be obtained by the condensation of ethyl allyl(2-oxoethyl)carbamate with ethyl (benzylamino)acetate followed by removal of the benzy moiety employing catalytic hydrogenation.
5-(3-pyrrolidinyl)-lH-tetrazole derivatives can be prepared by reaction of suitable Ν- protected 3-pyrrolidinecarbonitriles with azides such as tributyltinazide followed by the cleavage of the protecting group. Ν-protecting groups of this type are known to the person skilled in the art and are described in detail in T. W. Greene, P. G. Wuts,
Protective Groups in Organic Synthesis, 3 rd ed., John Wiley, New York, 1999.
1.4 Step D
The removal of protecting group PG can be performed either by an acid such as trifiuoroacetic acid or an base such as potassium hydroxide or lithium hydroxide, depending on the nature of PG . Reactions are carried out in aqueous, inert organic solvents such as alcohols e.g. methanol or ethanol, ethers e.g. tetrahydrofurane or dioxane or polar aprotic solvents e.g. dimethylformamide. If necessary, mixtures of the above solvents may be used.
2. Abbreviations
AcOH acetic acid
DCC dicyclohexylcarbodiimid
GC gas chromatography
EDCI 1 -Ethyl-3-(3 '-dimethylaminopropyl)carbodiimidexHCl eq. equivalents
HATU 2-(7-Aza-3-oxido-lH-l,2,3-benzotriazol-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate
HOBt N-hydroxybenzotriazole monohydrate
HPLC high performance liquid chromatography
ICAM-1 intracellular adhesion molecule 1
IL-1 interleucin 1
LPS lipopolysaccharide
MAdCAM-1 mucosal addressin cell adhesion molecule 1
MeOH methanol
M.p. melting point
NF-κB nuclear factor KB
NMR nuclear magnetic resonance min. minutes n.d. not determined r.t. room temperature
Rf TLC: Rf value = distance spot traveled / distance solvent front traveled
TLC thin layer chromatography
TNF-α tumor necrosis factor α tR retention time determined by HPLC
NCAM-1 vascular cell adhesion molecule 1
NLA-4 very late antigen 4
3. Examples
3.1 General
In the examples below, all quantitative data, if not stated otherwise, relate to percentages by weight.
Flash chromatography was carried out on silica gel 60, 40-63 μm (E. Merck, Darmstadt, Germany).
Thin layer chromatography was carried out, employing silica gel 60 F254 coated aluminum sheets (E. Merck, Darmstadt, Germany) with the mobile phase indicated.
Melting points were determined in open capillaries and are not corrected.
All retention times are indicated in minutes and, if not stated otherwise, were determined by high-performance liquid chromatography (HPLC) by means of UN detection at 210 or 250 nm and a flow rate of 1 ml/min at ambient temperature with linear gradients. An MeCΝ/H2θ mixture with 0.1% TFA (vol./vol.) was used as eluent. Method A:
Column: LiChrospher 100 RP-18, 5 μm, 250x4mm (E. Merck) Gradient: 0 min MeCN/H2O 0:100, 25 min MeCN/H2O 100:0, 31 min MeCN/H2O 100:0, 32 min MeCN/H2O 0:100, 38 min MeCN/H2O 0:100.
Method B:
Column: Purospher RP-18e, 5μm, 250x4mm (E. Merck).
Gradient: 0 min MeCN/H2O 0:100, 25 min MeCN/H2O 100:0, 31 min MeCN/H2O
100:0, 32 min MeCN/H2O 0:100, 38 min MeCN/H O 0:100.
Method C:
Column: LiChrospher 100 RP-18, 5 μm, 250x4mm (E. Merck).
Gradient: 0 min MeCN/H2O 10:90, 25 min MeCN/H2O 100:0, 31 min MeCN/H2O
100:0, 32 min MeCN/H2O 10:90, 38 min MeCN/H2O 10:90.
The mass determinations were carried out using the electron spray ionization (ESI) method employing loop injection (ESI-MS) or split injection via a HPLC system (HPLC-MS).
3.2 Precursor synthesis
3.2.1 Example I: 2-{4-[(2-Toluidinocarbonyl)amino] phenyl} acetic acid
Figure imgf000045_0001
To a solution of 2-(4-aminophenyl)acetic acid (108.8 g, 0.72 mol) in dichloromethane (1.0 1) and triethylamine (120 ml) was added a solution of 2-methylphenyl isocyanate (90.5 ml, 0.72 mol) in dichloromethane (500 ml) dropwise at r.t.. After stirring for 18 h at r.t., water (2.5 1) and dichloromethane (2.0 1) were added and the layers were separated. The organic layer was extracted with water (3 x 400 ml). The combined aqueous layers were concentrated to 3.0 1 and acidified to pH 2 by the addition of concentrated aqueous HC1. The precipitate was collected by filtration, washed with cold water and dried in an exsiccator over concentrated H2SO4 affording 166.5 g (82%) white solid.
M.p. 205-206°C; TLC (MeOH/dichloromethane 1:9): Rf 0.14. 1H-NMR (400 MHz, D6-DMSO): 12.21 (br s, IH), 9.11 (s, IH), 8.00 (s, IH), 7.83 (d, 7.6 Hz, IH), 7.40 (d, 8.5 Hz, 2H), 7.17-7.12 (m, 4H), 6.96-6.92 (m, IH), 3.48 (s, 2H), 2.24 (s, 3H).
3.2.2 Example II: (2-anilino-l,3-benzoxazol-6-yl)acetic acid
Figure imgf000046_0001
To a stirred solution of 2-nitro-5-fluorophenole (44.4 g, 283 mmol) in acetonitrile (357 ml) was added potassium carbonate (39.1 g, 283 mmol). After dropwise addition of benzylbromide (50.8 g, 297 mmol), the reaction mixture was refluxed for 2 h. Water (1 1) was added and the resulting solution was extracted with tert- butylmethylether (4x). The combined organic layers were washed with brine, dried over MgSO4 and evaporated, affording 68.9 g (99%) of 2-(benzyloxy)-4-fluoro-l- nitrobenzene as a yellow solid: mp 64-65°C; TLC (cyclohexane/ethyl acetate 8:2): Rf
0.50; 1H-NMR (400 MHz, D6-DMSO) 8.05 (dd, 9.1, 6.1 Hz, IH), 7.49 - 7.36 (m, 6H), 7.03 - 6.98 (m, IH), 5.34 (s, 2H). To a stirred solution of dimethyl malonate (123 g, 929 mmol) in l-methyl-2- pyrrolidon (554 ml) was added 60% sodium hydride in mineral oil (40.8 g, 1.02 mol) at room temperature. Stirring was continued until no further gas was formed, and 2- (benzyloxy)-4-fluoro-l -nitrobenzene (140 g, 566 mmol) was added portionwise at room temperature. After stirring at 80°C for 4 h, the reaction mixture was poured into ice water. The pH was adjusted to 7 by the addition of 5 M HC1, and the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated. The residue was triturated with tert-butylmethylether affording 197 g (97%) of dimethyl 2-[3-(benzyloxy)-4- nitrophenyljmalonate as a pale red viscous oil: TLC (cyclohexane/ethyl acetate 7:3):
Rf 0.22; Η-NMR (400 MHz, D6-DMSO) 7.92 (d, 8.6 Hz, IH), 7.51 - 7.35 (m, 6H), 7.15 (dd, 8.1, 1.5 Hz, IH), 5.28 (s, 2H), 5.22 (s, IH), 3.70 (s, 6H); ESI-MS: [M-H]- = 358.1.
Dimethyl 2-[3-(benzyloxy)-4-nitrophenyl]malonate (30.0 g, 83.5 mmol) was dissolved in a mixture of acetic acid (200 ml) and concentrated hydrochloric acid (100 ml). Heating the reaction mixture to 100°C resulted in an exothermic gas evolution, which ceased after 2.5 h. Evaporation of the solvent and drying in vacuum afforded 15.4 g (94%) of (3-hydroxy-4-nitrophenyl)acetic acid as a yellow viscous solid, which was employed in the next reaction step without further purification: TLC (cyclohexane/- ethyl acetate/acetic acid 6:4:0.1): Rf 0.14, 1H-NMR (400 MHz, D6-DMSO) 12.58 (br s, IH), 10.98 (s, IH), 7.85 (d, 8.5 Hz, IH), 7.05 (d, 1.7 Hz, IH), 6.88 (dd, 8.5, 1.7 Hz, IH), 3.64 (s, 2H).
A solution of (3-hydroxy-4-nitrophenyl)acetic acid (14.0 g, 71.0 mmol) and concentrated sulfuric acid (6 ml) in methanol (300 ml) was refluxed for 2 h. After addition of water (1 1), the solution was extracted with tert-butylmethylether (4x). The combined organic layers were washed with saturated NaHCO3 and brine, dried over MgSO4 and evaporated. The residue was triturated with petrol ether affording 11.0 g (73 %) of methyl (3-hydroxy-4-nitrophenyl)acetate as a yellow solid: mp 56-
57°C; TLC (dichloromethane): Rf 0.46; 1H-NMR (400 MHz, D6-DMSO) 10.98 (s, 1H), 7.86 (d, 8.5 Hz, IH), 7.05 (d, 1.7 Hz, IH), 6.88 (dd, 8.5, 1.7 Hz, IH), 3.76 (s, 2H), 3.63 (s, 3H); GC-MS (El): [M]+ = 211.
Methyl (3-hydroxy-4-nitrophenyl)acetate (9.5 g, 45.0 mmol) was dissolved in ethanol (150 ml). After addition of 10% Pd-C (0.95 g), the reaction mixture was hydrogenated at atmospheric pressure at room temperature. The catalyst was removed by filtration over celite. Concentrating the filtrate to dryness afforded 7.92 g (97%) methyl (4-amino-3-hydroxyphenyl)acetate as a brown solid: mp 112-114°C; TLC (dichloromethane): Rf 0.12; 1H-NMR (400 MHz, D6-DMSO) 8.98 (br s, IH), 6.56 (d, 1.8 Hz, IH), 6.50 (d, 7.8 Hz, IH), 6.42 (dd, 7.8, 1.8 Hz, IH), 4.45 (br s, 2H),
3.57 (s, 3H), 3.39 (s, 2H); GC-MS (El): [M]+ = 181.
To a solution of methyl (4-amino-3-hydroxyphenyl)acetate (1.00 g, 5.52 mmol) in ethanol (120 ml) was added dropwise phenylisothiocyanate (0.82 g, 6.07 mmol) at room temperature. After stirring for 2.5 h, 1,3-dicyclohexylcarbodiimide (1.71 g,
8.28 mmol) was added and the reaction mixture was heated to reflux for 3 h. The precipitate was removed by filtration. The filtrate was concentrated to dryness and the residue was taken up in toluene. Undissolved material was removed by filtration and the filtrate was concentrated to dryness. Purification by flash chromatography (cyclohexane/ethyl acetate 9:0.7 -> 6:4) yielded 0.85 g (55%) of methyl (2-anilino- l,3-benzoxazol-6-yl)acetate as a white solid: mp 155-157 °C; TLC (cyclohexane/- ethyl acetate 6:4): Rf 0.38; 1H-NMR (400 MHz, D6-DMSO) 10.68 (s, IH), 7.76 (d, 7.7 Hz, 2H), 7.42 - 7.36 (m, 4H), 7.12 (dd, 8.0, 1.4 Hz, IH), 7.05 - 7.02 (m, IH), 3.76 (s, 2H), 3.63 (s, 3H); ESI-MS: [M+H]+ = 282.9.
A solution of methyl (2-anilino-l,3-benzoxazol-6-yl)acetate (3.00 g, 10.6 mmol) and potassium hydroxide (892 mg, 15.9 mmol) in methanol/dioxane/water (200 ml / 80 ml / 200 ml) was stirred at room temperature for 4 h. The reaction mixture was diluted with water and washed with tert-butylmethylether. The pH was adjusted to 3 by the addition of 1 N hydrochloric acid. The precipitate was collected by filtration and dried in vacuum affording 2.71 g (95%) of (2-anilino-l,3-benzoxazol-6-yl)acetic acid as a white solid: mp 222 - 223°C; TLC (dichloromethane / methanol / acetic acid 9:0.5:0.1): Rf 0.44;. 1H-NMR (400 MHz, D6-DMSO): 12.20 (br s, IH), 10.62 (s, IH), 7.75 (d, 7.8 Hz, 2H), 7.40 - 7.35 (m, 4H), 7.11 (d, 8.1 Hz, IH), 7.05-7.01 (m, IH), 3.65 (s, 2H); ESI-MS: [M+H]+ = 268.9.
3.2.3 Preparation of piper idinecarboxylic acids
General procedure 1 (GP1)
Figure imgf000049_0001
To a solution of the pyridine derivative in ethanol was added concentrated aqueous HCl until the pH of the solution has reached 2-3. After addition of palladium-Mohr catalyst (20 % w/w), the suspension was hydrogenated for 18 h at 60°C and 3 bar hydrogen pressure. In case of incomplete conversion as judged by TLC or GC additional catalyst was added (20 % w/w) and the hydrogenation was repeated under the above conditions. The reaction mixture was filtered through celite and the filtrate was evaporated to dryness. The residue was taken up in water / ethyl acetate and the pH was adjusted to 10 by the addition of aqueous NaOH. After separation of the layers, the aqueous phase was extracted with ethyl acetate (3χ). The combined organic layers were washed with brine, dried over Na2SO4, evaporated and dried under high vacuum.
3.2.4 Example III: Ethyl 2-(2-piperidinyl)acetate
10 g ( 60.5 mmol) ethyl 2-(2-pyridinyl)acetate was dissolved in ethanol ( 100 ml) Yield: 12.0 g (95%). M.p.: 130°C Η-NMR (400 MHz, D6-DMSO) 1.23 (t, 3H); 1.40-1.85 (m, 6H); 2.70 (dd, IH); 2.83-2.93 (m, 2H); 3.19-3.25 (M, IH); 3.30-3.40 (m, IH); 4.10 (q, 2H); 9.20 (br. S, IH).
3.2.5 Example IV: Ethyl 2-(3-piperidinyl)acetate
20.0 g (121 mmol) ethyl 2-(3-pyridinyl)acetate was dissolved in ethanol (120 ml). Yield: 5.6 g (27%) pale brown oil. 1H-NMR (400 MHz, D6-DMSO) 4.05 (q, 7.2 Hz, 2H), 2.88-2.78 (m, 2H), 2.48 (br s, IH), 2.41-2.36 (m, IH), 2.20-2.09 (m, 3H), 1.82- 1.69 (m, 2H), 1.55-1.49 (m, IH), 1.39-1.30 (m, IH), 1.18 (t, 7.2 Hz, 3H), 1.09-1.01 (m, IH).
3.2.6 Example V: Ethyl 2-(4-piperidinyl)acetate
20.0 g (121 mmol) ethyl 2-(4-pyridinyl)acetate was dissolved in ethanol (150 ml). Yield: 13.2 g (64%) yellow oil. 1H-NMR (400 MHz, D6-DMSO) 4.04 (q, 7.1 Hz),
2.91-2.86 (m, 2H), 2.45-2.38 (m, 2H), 2.16 (2H, 7.1 Hz), 1.95 (br s, IH), 1.78-1.65 (m, IH), 1.57-1.55 (m, 2H), 1.17 (t, 7.1 Hz), 1.09-0.98 (m, 2H).
3.2.7 Example VI: Ethyl 3-(3-piperidinyl)propanoate
9.0 g (54.5 mmol) ethyl 3-(3-pyridinyl)propanoate was dissolved in ethanol (45 ml). Yield: 1.6 g (16%) yellow oil. 1H-NMR (400 MHz, D6-DMSO) 4.05 (q, 7.0 Hz), 2.90-2.82 (m, 3H); 2.40-2.35 (m, IH), 2.78 (t, 7.5 Hz, 2H), 2.11-2.06 (m, IH), 1.76-1.71 (m, IH), 1.54-1.51 (m, IH), 1.45-1.26 (m, 4H), 1.19 (t, 7.0 Hz), 0.99-0.91 (m, IH).
3.2.8 Example VII: Methyl 2-phenyl-2-(2-piperidinyl)acetate
4.50 g (19.8 mmol) methyl 2-phenyl-2-(2-pyridinyl)acetate was dissolved in ethanol (90 ml). Yield: 3.82 g (83%) pale brown oil. ESI-MS: 234.2 [M+H]+ 3.3 Compound Synthesis
The following examples were prepared according to scheme 2:
Figure imgf000051_0001
3.3.1 StepΛ
3.3.1.1 Example VIII: 2-{4-[(2-Toluidinocarbonyl)amino]phenyl}acetyl-L- leucine methyl ester
gy nr
Figure imgf000051_0002
A solution of 2- {4-[(2-toluidinocarbonyl)amino]phenyl} acetic acid (1.96 g, 6.89 mmol), HOBt (1.16 g, 7.58 mmol) and EDCI in 70 ml dimethylformamide was stirred 90 min at r.t.. After addition of L-leucine methyl ester hydrochloride (1.25 g, 6.89 mmol) in dimethylformamide (20 ml) and ethyldiisopropylamine (5.75 ml, 34.5 mmol) stirring at r.t. was continued for 18 h. The reaction mixture was poured into water (350 ml) and extracted with ethyl acetate (4x150 ml). The combined organic layers were washed with 0.1 N aqueous HCl, saturated aqueous Na2CO3, brine, dried (MgSO4) and evaporated. Yield: 2.49 g (88%) white solid. M.p. 166-168°C; TLC (dichloromethane/MeOH 9:1): Rf 0.56; 1H-NMR (400 MHz, D6-DMSO): 8.96 (s, IH), 8.42 (d, 7.7 Hz, IH), 7.89 (s, IH), 7.84 (d, 7.44 Hz, IH), 7.38 (d, 8.5 Hz, 2H), 7.18-7.11 (m, 4H), 6.96 (m, IH), 4.30-4.23 (m, IH), 3.61 (m, 3H), 3.43-3.36 (m, 2H), 2.24 (s, 3H), 1.67-1.45 (m, 3H), 0.89 (d, 6.4 Hz, 3H), 0.82 (d, 6.4 Hz, 3H).
3.3.2 Step B:
3.3.2.1 Example IX: 2-{4-[(2-Toluidinocarbonyl)amino]phenyl}acetyl-L- leucine
Figure imgf000052_0001
A solution of 2-{4-[(2-toluidinocarbonyl)amino]phenyl}acetyl-L-leucine methyl ester (2.42 g, 5.88 mmol) and KOH (3.30 g, 58.75 mmol) in methanol/water 1:1
(180 ml) was stirred at 50°C for 5 h. After washing with methyl-tert-butylether (80 ml) the volume of the reaction mixture was reduced until a slight turbidity was observed. The solution was acidified to pH 2 by the addition of 1 N aqueous HCl. The precipitate was collected by filtration, washed with cold water and dried in vacuum. Yield: 1.75 g (72 %) white solid.
M.p. 178-179°C, TLC (dichloromethane/MeOH/AcOH 9:1:0.1): Rf 0.16; Η-NMR (400 MHz, D6-DMSO): 12.51 (br s, IH), 9.00 (s, IH), 8.25 (d, 8.0 Hz, IH), 7.93 (s, IH), 7.83 (d, 7.5 Hz, IH), 7.36 (d, 8.5 Hz, 2H), 7.17-7.12 (m, 4H), 6.95-6.91 (m, IH), 4.23-4.17 (m, IH), 3.43-3.32 (m, 2H), 2.24 (s, 3H), 1.68-1.46 (m, 3H), 0.89 (d, 6.5 Hz, 3H), 0.82 (d, 6.5 Hz, 3H). 3.3.3 Step C:
General procedure Cl (GP Cl): Coupling of amines with carboxylic acids:
A solution of 1.0 eq. carboxylic acid, 1.1 eq. HOBt and 1.1 eq. EDCI in DMF was stirred for 2 h at r.t.. After addition of 1.0 eq. amine and 3.0 eq. ethylisopropylamine stirring was continued for 18 h at r.t.. The reaction mixture was poured into the 4- fold amount of water. The precipitate was collected by filtration, washed with cold water and dried in vacuum. If no precipitate was formed, the product was extracted with ethyl acetate (4x). The combined organic layers were washed with 1 N HCl, sat. aqueous NaHCO3 and brine and were dried over MgSO4. Evaporation of the solvent afforded the product.
3.3.3.1 Example 4: Ethyl 2-(l-{-2-(2-{4-[(2-toluidinocarbonyl)amino]phen- yl}acetyl)-L-leucine}-2-piperidinyl) acetate
Figure imgf000053_0001
A solution of 2-{4-[(2-toluidinocarbonyl)amino]phenyl}acetyl-L-leucine (2.00 g, 5.03 mmol) in dimethylformamid (20 ml) was reacted with ethyl 2-(2-piperidinyl)- acetate (1.24 g, 5.54 mmol). Flash chromatography (dichloromethane/MeOH 9:0.1 - 0.2) afforded 1.05 g (38%) white solid.
M.p. 96-98°C, TLC (dichloromethane/MeOH/AcOH 9:1:0.1): Rf 0.70; 1H-NMR (400 MHz, D6-DMSO): 8.96 (s, IH), 8.34 (d, 9.0 Hz, 0.5H), 8.16 (d, 8.5 Hz, 0.5 H), 7.90 (s, IH), 7.83 (d, 8.0 Hz, IH), 7.36 (d, 8.0 Hz, 2H), 7.18-7.10 (m, 4H), 6.95-6.90 (m,
IH), 4.97-4.89 (m, IH), 4.74-4.70 (m, 0.5H); 4.63-4.58 (m, 0.5H), 4.28-4.23 (m, 0.5H), 4.06-3.98 (m, 2H); 3.68-3.62 (m, 0.5H); 3.41-3.34 (m, 2H); 3.03-2.98 (m, 0.5H), 2.82-2.78 (m, 0.5H); 2.67-2.35 (m, 2H); 2.23 (s, 3H), 1.67-1.28 (m, 9H); 1.18- 1.10 (m, 3H), 0.88-0.82 (m, 6H). ESI-MS: 551.4 [M+H]+. 3.3.3.2 Example 7: Ethyl 3-(l-{2-(2-{4-[(2-toluidinocarbonyl)amino]phenyl}- acetyl)-L-leucine}-3-piperidinyl)propanoate
Figure imgf000054_0001
A solution of 2-{4-[(2-toluidinocarbonyl)amino]phenyl}acetyl-L-leucine (400 mg, 1.00 mmol) in dimethylformamid (20 ml) was reacted with ethyl 3-(3-piperidinyl)- propanoate (190 mg, 1.00 mmol). Flash chromatography (dichloromethane/MeOH 9:0.1 - 0.2) afforded 264 mg (47%) pale brown foam.
TLC (dichloromethane/MeOH 9:0.5): Rf 0.48; 1H-NMR (400 MHz, D6-DMSO): 8.94 (s, IH), 8.30-8.21 (m, IH), 7.87 (s, IH), 7.83 (d, 8.0 Hz, IH), 7.36 (d, 8.5 Hz, 2H), 7.17-7.11 (m, 4H), 6.95-6.91 (m, IH), 4.78-4.72 (m, IH), 4.25-4.00 (m, 3H), 3.81- 3.67 (m, IH), 3.41-3.35 (m, 2H), 3.08-2.98 (m, IH), 2.72-2.27 (m, 3H), 2.24 (s, 3H),
1.78-1.70 (m, IH), 1.65-1.10 (m, 12H), 0.87-8.82 (m, 6H); ESI-MS: 564.9 [M+H]+.
3.4 Synthesis of Example 12
3.4.1 Example 12: Ethyl [l-(N-{[4-({[(2-methylphenyl)amino]carbonyl}amino)- phenyl]acetyl}glycyl)-2-piperidinyl] acetate
Figure imgf000055_0001
A solution of N-(tert-butoxycarbonyl)-glycin-N-carboxyanhydrid (3.52 g, 17.5 mmol), ethyl 2-piperidinylacetate (2.00 g, 11.7 mmol) and 4-dimethylaminopyr- idin (140 mg, 1.17 mmol) in CH2C12 (20 ml) was stirred under reflux for 2 d. After addition of N-(tert-butoxycarbonyl)-glycin-N-carboxyanhydrid (1.65g, 8.19 mmol) stirring under reflux was continued for 18 h. The reaction mixture was poured into 1 Ν aqueous HCl. After separation of the phases the aqueous phase was extraced with CH2CI2 (2x). The combined organic phases were washed with saturated ΝaHCO and brine, dried over MgSO4 and evaporated, affording 2.25 g (59%) of ethyl {l-[N-(tert- butoxycarbonyl)glycyl]-2-piperidinyl} acetate as a brown oil. TLC (CH2Cl2/MeOH 8:2): Rf 0.08; GC-MS (El) m/z 328; HPLC analysis (Method A): tR 20.5 min.
To a solution of {l-[N-(tert-butoxycarbonyl)glycyl]-2-piperidinyl} acetate (830 mg, 2.53 mmol) in CH2C12 (10 ml), tnfluoroacetic acid (2 ml) was added at 0°C. After stirring for 5 h at room temperature, the solvents were evaporated, residual trifluoroacetic acid removed by coevaporation with CH2CI2 (2x). The resulting brown oil (1.12 g) of ethyl (l-glycyl-2-piperidinyl)acetate trifluoroacetate was used without further purification in the next reaction step. TLC (C^C^/MeOH 9:0.5): Rf 0.12; MS (ESI) m/z 228.
A solution of 2- {4-[(2-toluidinocarbonyl)amino]phenyl} acetic acid (350 mg,
1.23 mmol, Example I), EDCI (260 mg, 1.35 mmol) and HOBt (210 mg, 1.35 mmol) in dimethylformamide was stirred for 2 h at room temperature. Ethyl (l-glycyl-2- piperidinyl)acetate trifluoroacetate (550 mg) and ethyldiisopropylamine (1.90 ml, 11.08 mmol) were added and stirring at room temperature was continued for 2 d. The reaction mixture was poured into water, the precipitate was collected by filtration and washed with water. Purification by flash-chromatography (C^C^/MeOH 9:0.2) afforded 234 mg (38%) of ethyl [l-(N-{[4-({[(2-methylphenyl)amino]carbonyl}- amino)phenyl]acetyl}glycyl)-2-piperidinyl]acetate as a white solid. M.p. 79-81°C, TLC (CH2Cl2/MeOH 9:1): Rf 0.60; MS (ESI) m/z 495.3; HPLC analysis (Method C): tR 19.5 min.
The following examples were prepared according to the general procedure GP Cl :
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
3.5 Step D
General procedure DI (GP DI): ester saponification
A solution or suspension of the ester and 1.1 eq KOH in water/ethanol, methanol and/or dioxane was stirred at 25-50°C for 2-24 h. After washing with methyl-tert- butylether (80 ml) the volume of the reaction mixture was reduced until a slight turbidity was observed. The solution was acidified to pH 2 by the addition of 1 N aqueous HCl. The precipitate was collected by filtration, washed with cold water and dried in vacuum. If no precipitate was formed, the aqueous phase was extracted with ethyl acetate (4x). The combined organic phases were washed with water, dried over Na2SO4 and were evaporated.
3.5.1 2-(l-{2-(2-{4-[(2-toluidinocarbonyl)amino]phenyl}acetyl)-L-leucine}-2- piper idinyl) acetic acid
Figure imgf000060_0001
Ethyl 2-(l- {2-[(2-{4-(2-toluidinocarbonyl)amino]phenyl}acetyl)-L-leucine}- 2-piperidinyl)acetate (350 mg, 636 μmol) was dissolved in water (50 ml), ethanol
(50 ml) and dioxane (50 ml). Stirring for 6 h at 30°C afforded 236 mg (71%) white solid.
M.p. 121-123°C, TLC (dichloromethane/MeOH/AcOH 9:1:0.1) Rf 0.64; Η-NMR
(400 MHz, D6-DMSO): 12.29 (br s, IH), 8.98 (s, IH), 8.32-8.16 (m, IH), 7.91 (s, IH), 7.83 (d, 8.0 Hz, IH), 7.36 (d, 7.0 Hz; 2H), 7.37-7.13 (m, 4H), 6.95-6.91 (m,
IH), 5.03-4.87 (m, IH), 4.75-4.60 (m, IH), 4.30-4.25 (m, 0.5 H), 3.72-3.62 (m,
0.5H); 3.39-3.32 (m, 2H), 3.10-2.15 (m, 3H), 2.24 (s, 3H), 1.63-1.10 (m, 9H); 0.89-
0.81 (m, 6H). ESI-MS: 523.3 [M+H]+. General procedure D2 (GP D2): deprotection of benzyl esters
A solution or suspension of the ester and 10% Pd-C (10%) in tetrahydrofurane was hydrogenated for 18 h at r.t. under atmospheric hydrogen pressure. The reaction mixture was filtered through celite. Evaporation of the filtrated afforded the product.
The following examples were prepared according to the general procedures DI / D2:
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
In vitro assay: adhesion of Jurkat/Ramos cells to immobilized NCAM-1 (domains 1- 3)
4 Preparation of VCAM-1 (extracellular domains 1-3)
Complementary DΝA (cDΝA) encoding 7-domain form of NCAM-1 (GenBank accession #M60335) was obtained using Rapid-ScreenTM cDΝA library panels (OriGene Technologies, Inc) at Takara Gene Analysis Center (Shiga, Japan). The primers used were 5'-CCA AGG CAG AGT ACG CAA AC-3' (sense) and 5'-TGG CAG GTA TTA TTA AGG AG-3' (antisense). PCR amplification of the 3-domain
NCAM-1 cDΝA was perform using Pfu DΝA polymerase (Stratagene) with the following sets of primers: (U-NCAMdl-3) 5'-CCA TAT GGT ACC TGA TCA ATT TAA AAT CGA GAC CAC CCC AGA A-3'; (L-NCAMdl-3) 5'-CCA TAT AGC AAT CCT AGG TCC AGG GGA GAT CTC AAC AGT AAA-3'. PCR cycle was 94°C for 45 sec, 55 °C for 45 sec, 72 °C for 2 min, repeating 15 cycles. After the purification of the PCR product, the fragment was digested with Kpnl-Avrll. The digested fragment was ligated into pBluescript IISK(-) (Strategene), which was linearized by digesting with Kpnl-Xhol. The ligation was followed by transformation to a Dam/Dcm methylase-free E. coli strain SCSI 10 (Strategene) to create the donor plasmid pHH7. To direct NCAM-1 molecule into the insect cell secretory pathway, the NCAM-1 coding sequence was fused to signal peptide sequence of honeybee melittin. The resulting melittin-NCAM fusion was placed in correct orientation to the baculo virus polyhedrin promoter. Baculo virus transfer vector containing first 3-domain form NCAM-1 (pHIO) was constructed by ligation of 0.9 kb fragment from Avrll Klenow/Bcll digests of pH7 into Sall/Klenow/BamHI digests of pMelBacB
(Invitrogen). Recombinant baculovirus was generated by using Bac-Ν-Blue™ Transfection kit (Invitrogen) according to the manufacture's instruction. The recombinant virus was amplified by infection to High-Five™ insect cells for 5 - 6 days, and virus titer was determined by plaque assay. High-Five™ insect cells were pelleted in a 225 ml conical tube by centrifugation at 1000 rpm for 5 min. After discarding the supernatant, the pellet was resuspended in 1.5 x 109 pfu (MOI = 5) of high-titer virus solution, followed by incubation for 1.5 hours at room temperature. The cells were pelleted again and washed once in fresh Express Five™ serum free medium. The cells were pelleted again and finally, resuspended in 200 ml of fresh Express Five TM medium, transferred to a 1,000 ml shaker flask, and incubated in a shaker at 27°C, 130 rpm, for 48 hours before the culture supernatant was collected. The purification of 3-domain form of NCAM-1 from the culture supernatant was performed by one-step anion exchange chromatography. Protein concentration was determined by using Coomassie protein assay reagent
(Pierce) according to the manufacture's instruction.
4.1 Preparation of VCAM-1 coated microtiter plates
Recombinant human NCAM-1 (extracellular domains 1-3) was dissolved at
1.0 μg/ml in PBS. Each well of the microtiter plates (Νalge Νunc International, Fluoronunc Cert, 437958) was coated with 100 μl of substrate or for background control with buffer alone for 15 hours at 4 C. After discarding the substrate solution, the wells were blocked using 150 μl per well of block solution (Kirkegaard Perry Laboratories, 50-61-01) for 90 minutes. The plate was washed with wash buffer containing 24 mM Tris-HCl (pH 7.4), 137 mM ΝaCl, 27 mM KC1 and 2 mM MnCl2 just before addition of the assay.
4.2 In vitro assay using Jurkat cells
4.2.1 Preparation of fluorescence labeled Jurkat cells
Jurkat cells (American Type Culture Collection, Clone E6-1, ATCC TIB-152) were cultured in RPMI 1640 medium (Νikken Bio Medical Laboratory, CM1101) supple- mented with 10% fetal bovine serum (Hyclone, A-1119-L), 100 U/ml penicilin (Gibco BRL, 15140-122) and 100 μg/ml streptomycin (Gibco BRL, 15140-122) in a humidified incubator at 37°C with 5% CO2.
Jurkat cells were incubated with phosphate balanced solution (PBS, Nissui, 05913) containing 25 μM of 5(-and -6)-carboxyfluorescein diacetate, succinimidyle ester
(CFSE, Dojindo Laboratories, 345-06441) for 20 min at room temperature while gently swirling every 5 min. After centrifugation at 1000 rpm for 5 min, the cell pellet was resuspended with adhesion assay buffer at a cell density of 4 x 106 cells/ml. The adhesion assay buffer was composed of 24 mM Tris-HCl (pH 7.4), 137 mM NaCl, 27 mM KC1, 4 mM glucose, 0.1 % bovine serum albumin (BSA, Sigma,
A9647) and 2 mM MnCl2.
4.2.2 Assay procedure (Jurkat cells)
The assay solution containing each test compounds was transferred to the NCAM-1 coated plates. The final concentration of each test compounds was 5 μM, 10 μM or various concentrations ranging from 0.0001 μM to 10 μM using a standard 5-point serial dilution. The assay solution containing the labeled Jurkat cells was transferred to the NCAM-1 coated plates at a cell density of 2 x 105 cells per well and incubated for 1 hour at 37 C. The non-adherent cells were removed by washing the plates 3 times with wash buffer. The adherent cells were broken by addition of 1 % Triton X- 100 (Νacalai Tesque, 355-01). Released CFSC was quantified fluorescence measurement in a fluorometer (Wallac, ARNO 1420 multilabel counter).
The adhesion of Jurkat cells to NCAM-1 was analyzed by percent binding calculated by the formula:
100 x ( FTS - FBG ) / ( FTB - FBG ) = % binding, where FTB is the total fluorescent intensity from NCAM-1 coated wells without test compound; FBG is the fluo- rescent intensity from wells lacking NCAM-1 and FTS is the fluorescent intensity from wells containing the test compound of this invention. 4.3 In Vitro Assay using Ramos cells
4.3.1. Preparation of fluorescence labeled Ramos cells
Ramos cells (American Type Culture Collection, Clone CRL-1596) were cultured in RPMI 1640 medium (Nikken Bio Medical Laboratory, CMllOl) supplemented with 10% fetal bovine serum (Hyclone, A-1119-L), 100 U/ml penicilin (Gibco BRL, 15140-122) and 100 μg/ml streptomycin (Gibco BRL, 15140-122) in a humidified incubator at 37 °C with 5% CO2.
Ramos cells were incubated with phosphate balanced solution (PBS, Nissui, 05913) containing 25 μM of 5 (-and -6)-carboxyfluorescein diacetate, succinimidyle ester (CFSE, Dojindo Laboratories, 345-06441) for 20 min at room temperature while gently swirling every 5 min. After centrifugation at 1000 rpm for 5 min, the cell pellet was resuspended with adhesion assay buffer at a cell density of 4 x 106 cells/ml. The adhesion assay buffer was composed of 24 mM Tris-HCl (pH 7.4), 137 mM NaCl, 27 mM KC1, 4 mM glucose, 0.1 % bovine serum albumin (BSA, Sigma, A9647) and 2 mM MnCl2.
4.3.2 Assay procedure (Ramos cells)
The assay solution containing each test compounds or 5 μg/ml anti-CD49d monoclonal antibody (Immunotech, 0764) was transfened to the VCAM-1 coated plates. The final concentration of each test compounds was 5 μM, 10 μM or various concentrations ranging from 0.0001 μM to 10 μM using a standard 5-point serial dilution. The assay solution containing the labeled Ramos cells was transferred to the NCAM-1 coated plates at a cell density of 2 x 105 cells per well and incubated for 1 hour at 37 C. The non-adherent cells were removed by washing the plates 3 times with wash buffer. The adherent cells were broken by addition of 1 % Triton X-100 (Nacalai Tesque, 355-01). Released CFSC was quantified fluorescence measurement in a fluorometer (Wallac, ARNO 1420 multilabel counter).
The adhesion of Ramos cells to NCAM-1 was analyzed by percent binding calculated by the formula:
100 x ( FTS - FBG ) / ( FTB - FBG ) = % binding, where FTB is the total fluorescent intensity from NCAM-1 coated wells without test compound; FBG is the fluorescent intensity from wells with anti-CD49d monoclonal antibody and FTS is the fluorescent intensity from wells containing the test compound of this invention.
4.4 In vitro activity
In the Jurkat - NCAM-1 assay (indicated as Jurkat - NCAM-1) and the Ramos - NCAM-1 (indicated as Ramos - NCAM-1) the observed IC50 value ranges are indicated in the following table. D > 10 μM > C > 2 μM > B > 0.5 μM > A
Example No. Structure IC50 Cell Type
Figure imgf000069_0001
ExampleNo. Structure IC50 Cell Type
Figure imgf000070_0001
18 Λ θfθrH c Jurkat
Figure imgf000070_0002
Example No. Structure IC50 Cell Type
Figure imgf000071_0001
5. Pharmacokinetic study
5.1 Solubility study
0.5 mg of 16 was spiked into a test tube (12 x 75 mm) containing 0.5 ml of the first fluid, pH 1.2 for dissolution test, 66 mM phosphate buffer with 50 mM NaCl (isotonic phosphate buffer) and 20 mM sodium deoxycholic acid, and then stirred at 37°C for 5 hr by magnetic stirred bar. Each solution was filtered using 0.2 μm membrane filter (Millipore, Japan). Each aliquot solution was applied to HPLC.
5.2 Lipophilicity study
0.8 ml of 50 μg/ml compound in acetonitrile solution was added into 8 ml of the isotonic phosphate buffer, and filtrated through 0.2 m membrane filter. A filtrated solution of 2 ml was shaken (300 cycles/min.) with 2 ml of w-octanol or wo-octane preliminarily saturated with the buffer solution for 0.5 hr and centrifuged at 3,000 rpm for 15min. After removing the organic layer, an aliquot water layer was taken and diluted with a mobile phase and applied to HPLC.
5.3 In vivo study
The compounds were dissolved in 10% cremophore EL in saline at a concentration of 2 mg/ml. The compound at a dose of 10 mg/kg was given intraperitoneally to female BALB/c mice (JAPAN SLC Inc., Japan), and the blood sample was taken from the heart using heparinized syringes at 5, 15, 30, 60, 120 and 180 min after dosing. After centrifugation at 3,000 rpm for 5 min at 4°C, 0.25 ml of the plasma was added into 1M HCl of 0.05 ml and extracted by 7 ml of ether. The organic layer was evaporated under nitrogen stream at 40°C and the residue was dissolved in 0.25 ml of the mobile phase. 0.15 ml of the solution was applied to HPLC. 5.4 HPLC analysis
HPLC analysis was carried out using a reversed phase column, 3 μm Capcell pak™ C18 UG 120, 4.6 x 100 mm (Shiseido, Japan) for the solubility and lipophilicity studies and 3.5 μm Symmetry Shield™ RP8, 4.6 x 100 mm (Waters, USA) for the in vivo study on Hewlett Packard series 1100 equipped with a UN detector and column oven. Compounds were separated by a mobile phase consisting of acetonitrile and 5 mM formic acid, pH 3.0 (42 : 52, v/v) at a column temperature of 40°C and a flow rate of 1.0 ml/min, and monitored by UN absoφtion of 258 nm.
Table 3.1 Physicochemical properties of 16
16
Solubility (μg/ml) pH 1.2 buffer 99.6 pH 7.4 buffer 458 deoxycholic acid > 500
Lipophilicity
Log D octanol pH7.4 1.72
Log D isooctane pH 7.4 -0.167
Δ log P 1.89
Table 3.2 Pharmacokinetic parameters of 16 after intraperitoneal administration of 10 mg/kg to mice.
16
Cmax (ng/ml) 1436
AUC (ng*h ml) 955 tl/2 (h) 0.80

Claims

Claims
Compounds of the general formula (I),
Figure imgf000075_0001
wherein
R1 and R2 form a 4- to 8-membered saturated or unsaturated cyclic residue, which can contain 0 to 1 nitrogen atoms and 0 to 2 heteroatoms selected independently from the group S and O,
wherein the cyclic residue formed by R1 and R2 can be annulated with a 4- to 8-membered saturated, unsaturated or aromatic cyclic residue, which can contain 0 to 2 heteroatoms selected independently from the group N, S and O,
and wherein the cyclic residue formed by R1 and R2 and/or a ring annulated to the cyclic residue formed by R1 and R2 can optionally be independently substituted by 0 to 2 substituents -R^'-R1"2 -R'"3-Z, wherein
R1*1 represents a bond, -O-, -S-, NR1"4, d - Cio alkyl, C2 - C]0 alkenyl, C2 - Cio alkynyl, C6 or Cio aryl, C3-C7 cycloalkyl, a 4-
9-membered saturated or unsaturated heterocyclic residue containing up to 3 heteroatoms selected from the group oxygen, nitrogen or sulfur, wherein R1"1 can optionally be substituted by 1 to 2 substituents selected from the group R1"4, wherein R1"4 represents hydrogen, d - Cio alkyl, C2 - Cio alkenyl, C2 - Cio alkynyl, C6 or Cio aryl, C3-C7 cycloalkyl or a 4-9-
5 membered saturated or unsaturated heterocyclic residue containing up to 3 heteroatoms selected from the group oxygen, nitrogen or sulfur, wherein
R1"4 can optionally be substituted by 1 to 3 substituents 10 selected from the group Ci - C alkyl, Ci - C4 alkyloxy, phenyl, C3 - C6 cycloalkyl, halogen, nitro, cyano, oxo,
R1"2 represents a bond, -O-, -S-, NR1"5, C, - Cio alkyl, C2 - Cio alkenyl, C2 - Cio alkynyl, wherein
15
R1"2 can optionally be substituted by Ci - Cio alkyl, C2 - Cio alkenyl, C2 - Cio alkynyl or R1"5 , wherein
R1"5 represents hydrogen, Ci - Cio alkyl, C2 - Cio alkenyl, 20 C2 - Cio alkynyl, C6 or Cio aryl, C3 - C cycloalkyl or a
4-9-membered saturated or unsaturated heterocyclic residue containing up to 3 heteroatoms selected from the group oxygen, nitrogen or sulfur, wherein
25 R1'5 can optionally be substituted by 1 to 3 substituents selected from the group Ci - C4 alkyl, Ci - C4 alkyloxy, phenyl, C3 - C6 cycloalkyl, halogen, nitro, cyano, oxo,
R1"3 represents a bond, Ci - Cio alkyl, C2 - Cio alkenyl, C2 - Cio
30 alkynyl, wherein R1'3 can optionally be substituted by Ci - Cio alkyl, C2 - Cio alkenyl, C2 - Cio alkynyl or R1"6 , wherein
R1"6 represents hydrogen, Ci - Cio alkyl, C2 - Cio alkenyl, 5 C-2 - Cio alkynyl, C6 or Cio aryl, C3-C cycloalkyl or a
4-9-membered saturated or unsaturated heterocyclic residue containing up to 3 heteroatoms selected from the group oxygen, nitrogen or sulfur, wherein
10 R1"6 can optionally be substituted by 1 to 3 substituents selected from the group Ci - C4 alkyl, C\ - C4 alkyloxy, phenyl, C3 - C6 cycloalkyl, halogen, nitro, cyano, oxo,
with the proviso that, when R1"3 is a bond, then R1"2 must not be a 15 heteroatom,
and with the proviso that R " and R " must not be both heteroatom at the same time,
20 Z represents hydrogen, -C(O)ORz"1, -C(O)NRZ 2Rz"3, -SO2NRz"2Rz"3,
-SO(ORz l), -SO2(ORz l), -P(O)Rz l(ORz"3), -PO(ORz l)(ORz"3) or 5- tetrazolyl, wherein
Rz"2 is hydrogen, -CfC R2"4 or -SOzR2"4, d - C4 alkyl, C2-C6 25 alkenyl, C2 - C6 alkynyl, C3 - C6 cycloalkyl, C6 or Cio aryl, wherein
Rz"2 can optionally be substituted by 1 to 3 substituents selected from the group halogen, nitro, cyano, oxo, 30 wherein Rz_4 is Ci - C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3 - C6 cycloalkyl, C6 or Cio aryl, wherein
R2"4 can optionally be substituted by 1 to 3 substituents selected from the group halogen, nitro, cyano, oxo,
R2"1 and Rz"3 are identical or different and represent hydrogen, Ci - C4 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C6 cycloalkyl, C6 or Cio aryl, wherein
7 1 7 "
R " and R " can optionally be substituted by 1 to 3 substituents selected from the group Ci - C4 alkyl, Ci - C4 alkyloxy, halogen, nitro, cyano,
and wherein the cyclic residue formed by R1 and R2 and/or a ring annulated to the cyclic residue formed by R1 and R2 can optionally be substituted by 0 to 2 substituents R " , halogen, nitro, amino, cyano and oxo, wherein
R " can independently be selected from the group of Ci - C4 alkyl,
Ci - C4 alkyloxy, phenyl, C3 - C6 cycloalkyl, and wherein
R1"8 can be substituted by 0-5 halogen atoms,
R3 represents hydrogen, Ci - Cio alkyl, C2 - Cio alkenyl, C2 - Cio alkynyl,
C6 or Cio aryl, C3-C7 cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 3 radicals R3"1,
and which can furthermore be single-foldedly substituted by C3 - C7 cycloalkyl, C6 or Cio aryl, C4 - C9 heteroaryl or a heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 3 radicals R 3-"1 , wherein
R3"1 represents Ci - C4 alkyl, trifluoromethyl, trifluoromethoxy, -OR3"2,
-SR3"2, -NR3 3R3"4, -C(O)R3'2, S(O)R3"2, -SO2R3 2, -CO2R3"2,
-OC(O)R3"2, -C(O)NR3 3R3"4, -NR3 2C(O)R3"2, -SO2NR3 3R3"4, NR3" 2SO2R3"2, -NR3 2C(O)NR3 3R3"4, -NR3 2C(O)OR3"2, -OC(O)NR3 3R3"4, halogen, cyano, nitro or oxo, wherein
R3"2 represents hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl which can optionally be substituted by 1 substituent selected from the group Ci - C4 alkyl, Ci - C4 alkyloxy, phenyl, C3 - C6 cycloalkyl, halogen, nitro, cyano, and wherein
R3"3 and R3"4 are identical or different and represent hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl,
or
R3"3 and R3"4 together form a 4-7-membered ring, which includes the nitrogen atom to which R3"3 and R3"4 are bonded and which contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur and which contains up to 2 double bonds,
R4 represents hydrogen, Ci - Cio alkyl, C2 - Cio alkenyl, C2 - Cio alkynyl,
C6 or Cio aryl, C3 - C7 cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur, which can optionally be substituted by 1 to 3 radicals R4"1,
and which can furthermore be single-foldedly substituted by C3 - C7 cycloalkyl, C6 or Cio aryl, C4 - C9 heteroaryl or a heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 3 radicals R4"1, wherein
10
R4"1 represents Ci - C4 alkyl, trifluoromethyl, trifluoromethoxy,
-OR4"2, -SR4"2, -NR4"3R4 -C(O)R4"2, S(O)R4"2, -SO2R4"2,
-CO2R4"2, OC(O)R4"2, -C(O)NR4 3R4"4, -NR4"2C(O)R4"2,
-SO2NR4 3R4"4, NR4"2SO2R4"2, -NR4"2C(O)NR4"3R4"4, -NR4"
15 2C(O)OR4"2, -OC(O)NR4"3R4"4, halogen, cyano, nitro or oxo, wherein
R4"2 represents hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl, C6 or
Cio aryl which can optionally be substituted by 1 substituent
20 selected from the group Ci - C4 alkyl, Ci - C4 alkyloxy, phenyl,
C3-C6 cycloalkyl, halogen, nitro, cyano, and wherein
R4"3 and R4"4 are identical or different and represent hydrogen, Cμ alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl,
25 or
R4"3 and R4"4 together form a 4-7-membered ring, which includes the nitrogen atom to which R4"3 and R4"4 are bonded and which
30 contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur and which contains up to 2 double bonds,
R5 represents hydrogen, Ci - Cio alkyl, C2 - Cio alkenyl, C2 - Cio alkynyl, C6 or Cio aryl, C3-C7 cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 3 radicals R5"1,
10 and which can furthermore be single-foldedly substituted by C3 - C7 cycloalkyl, C6 or Cio aryl, C4 - C9 heteroaryl or a heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
15 which can optionally be substituted by 1 to 3 radicals R5"1, wherein
R5"1 represents Ci - C4 alkyl, trifluoromethyl, trifluoromethoxy,
-OR5"2, -SR5'2, -NR5"3R5"4, -C(O)R5"2, S(O)R5"2, -SO2R5"2,
20 -CO2R5"2, -OC(O)R5"2, -C(O)NR5 3R5"4, -NR5 2C(O)R5"2,
-SO2NR5"3R5"4, NR5 2SO2R5"2, -NR5"2C(O)NR5 3R5"4, -NR5" 2C(O)OR5"2, -OC(O)NR5 3R5 halogen, cyano, nitro or oxo, wherein
25 R5"2 represents hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl,
C6 or Cio aryl which can optionally be substituted by 1 substituent selected from the group Ci - C4 alkyl, Ci - C4 alkyloxy, phenyl, C3-C6 cycloalkyl, halogen, nitro, cyano, and wherein
30 R5"3 and R5"4 are identical or different and represent hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl,
or
R5"3 and R5"4 together form a 4-7-membered ring, which includes the nitrogen atom to which R5"3 and R5"4 are bonded and which contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or 10 sulfur and which contains up to 2 double bonds,
R6 represents phenyl or a 5- to 6-membered aromatic heterocyclic residue containing up to 3 heteroatoms independently selected from the group of oxygen, nitrogen or sulfur, 15 which can optionally be annulated with a 5- to 8-membered saturated or unsaturated cyclic residue containing up to 2 heteroatoms independently selected from the group oxygen, nitrogen or sulfur,
20 and which can optionally be substituted by 0 to 2 substituents independently selected from the group of bond, Ci - Cio alkyl, C2 - Cio alkenyl, C2 - Cio alkynyl, C6 or Cio aryl, C3-C cycloalkyl or a 4-9- membered saturated or unsaturated heterocyclic residue containing up to 3 heteroatoms independently selected from the group oxygen,
25 nitrogen or sulfur, wherein these substituents can optionally be substituted by 1 to 3 radicals R6"1, wherein
R6"1 represents Ci - C4 alkyl, trifluoromethyl, trifluoromethoxy,
-OR6"2, -SR6"2, -NR6 2R6"3, -C(O)R6"2, S(O)R6"2, -SO2R6'2,
30 -CO2R6"2, -OC(O)R6"2, -C(O)NR6"2R6"3, -NR6 3C(O)R6"2,
-SO2NR6 2R6"3, NR6 3SO2R6"2, -NR^C^NR^R6"1, -NR6 3C(O)OR6"2, -OC(O)NRo 2R0"3, halogen, cyano, nitro or oxo, wherein
R6"2 represents hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl, or a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 3 heteroatoms selected from the group oxygen, nitrogen or sulfur,
10 which can optionally be substituted by 1 to 3 substituents R6"5 wherein
R , 6-"5 represents Ci - C4 alkyl, trifluoromethyl, trifluoromethoxy, -OR6"6, -SR6"6, -NR6"7R6"8, wherein
15
R6"6 represents hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl,
C6 or Cio aryl which can optionally be substituted by 1 to 3 substituents selected from the group Ci - C alkyl,
Ci - C4 alkyloxy, phenyl, benzyl, C3-C6 cycloalkyl,
20 hydroxy, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, and wherein
R6"7 and R6"8 are identical or different and represent hydrogen,
Ci - C4 alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl or a 4-
25 9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 2 substituents 30 selected from the group Ci - C alkyl, Ci - C4 alkyloxy, phenyl, benzyl, C3-C6 cycloalkyl, hydroxy, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,
or
R " and R " together form a 4-7-membered ring, which contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur and which contains up to 2 double bonds, which can optionally be substi-
10 tuted by 1 to 2 substituents selected from the group Ci -
C4 alkyl, Ci - C4 alkyloxy, phenyl, benzyl, C3-C6 cycloalkyl, hydroxy, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, oxo, and wherein
15 R6"3 and R6"4 are identical or different and represent hydrogen, bond, Ci - C4 alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl or a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
20
Ci - C4 alkyl, trifluoromethyl, trifluoromethoxy, -OR6'9, -SR6"9, -NR6"10R6"U, wherein
R6"9 represents hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl,
Figure imgf000084_0001
which can optionally be substituted by 1 to 3 substituents selected from the group d - C4 alkyl, Ci - C4 alkyloxy, phenyl, benzyl, C3-C6 cycloalkyl, hydroxy, amino, halogen, nitro, 30 cyano, trifluoromethyl, trifluoromethoxy, and wherein R6"10 and R6"11 are identical or different and represent hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl or a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from 5 the group oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 2 substituents selected from the group Ci - C4 alkyl, Ci - C4 alkyloxy, phenyl, benzyl, C3-C cycloalkyl, hydroxy, amino, halogen, nitro, 10 cyano, trifluoromethyl, trifluoromethoxy,
or
R6"9 and R6"10 together form a 4-7-membered ring, which 15 contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur and which contains up to 2 double bonds, which can optionally be substituted by 1 to 2 substituents selected from the group Ci - C4 alkyl, Ci - C4 alkyloxy, phenyl, benzyl, 20 C3-C6 cycloalkyl, hydroxy, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, oxo,
or
25 R6"2 and R6"3 and or R6"3 and R6"4 together form a 4-7- membered ring, which includes the nitrogen atom to which R6"3, R6"3 and R6"4 are bonded and which contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur and which contains
30 up to 2 double bonds, which can optionally be substituted by 1 to 2 substituents selected from the group Ci - C4 alkyl, Ci - C4 alkyloxy, phenyl, benzyl, C3-C6 cycloalkyl, hydroxy, amino, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, oxo,
and which can furthermore be independently substituted by 0 to 3 substituents R6"5
or
R and R or R and R together form a 4-7-membered saturated or unsaturated ring containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur, which can optionally be substituted by 1 to 2 substituents selected from the group Ci - C4 alkyl, phenyl, benzyl, C3 - C7 cycloalkyl, Ci - C4 alkyloxy, halogen, nitro, cyano, oxo and which can be fused with a 3-7 membered homocyclic or heterocyclic, saturated, unsaturated or aromatic ring,
A represents -C(O)-, -C(O)-C(O)-, -SO-, -SO2-, -P(O)RA 1-, -PO2-, 2- pyrimidyl, 4-pyrimidyl, 2-pyridyl, 2-imidazolyl, 4-imidazolyl, 2-benz- imidazolyl or a ring selected from the following group:
Figure imgf000087_0001
wherein the abovementioned ring systems can optionally be substituted by Ci - C4 alkyl, Ci - C4 alkoxy, halogen, nitro, amino, cyano, wherein
RΛ_1 can be selected from the group of Ci - C4 alkyl, Ci - C4 alkoxy,
X represents a bond, -CRX_1RX"2-, oxygen or -NRX"3, wherein
10
R " , R " , R can be independently selected from the group bond, hydrogen, Ci - C4 alkyl, - C4 alkenyl, C2 - C4 alkynyl,
or
15 together with R6 form a 4-7-membered ring, which includes the nitrogen atom to which R6 and RX 1 or Rx"2 or Rx"3 can be attached and which can contain up to 2 additional heteroatoms independently selected from the group oxygen, nitrogen or sulfur and containing up to 2 double bonds, which can optionally be substituted by 1 to 2 substituents selected from the group Ci - C alkyl, phenyl, benzyl, C3 -C7 cycloalkyl, Ci - C4 alkyloxy, halogen, nitro, cyano, oxo,
Y represents bond, -C(O)-, -S(O)-, -SO2-, -O-, -S-, -CRY 1RY"2-, or
-NRY"3, wherein RY 1, Rγ"2, Rγ"3 can be independently selected from the group bond, hydrogen, Ci - C4 alkyl, C2 - C alkenyl, d - C4 alkynyl,
and can optionally be substituted by 1 to 2 substituents independently selected from the group Ci - C4 alkyl, phenyl, benzyl, C3 - C7 cycloalkyl, Ci - C4 alkyloxy, halogen, nitro, cyano, oxo,
D represents N, or CR D-"l , wherein
R , D-"1 can be independently selected from the group bond, hydrogen, Ci - C4 alkyl, C2 - C4 alkenyl, C2 - C4 alkynyl,
and can optionally be substituted by 1 to 2 substituents independently selected from the group Ci - C4 alkyl, phenyl, benzyl, C3 - C7 cycloalkyl, Ci - C4 alkyloxy, halogen, nitro, cyano, oxo,
and with the proviso that Y and D are not heteroatoms at the same time,
and pharmaceutically acceptable salts thereof.
2. Compounds according to claim 1, wherein
R1 and R2 form a 4- to 8-membered saturated or unsaturated cyclic residue, which can contain 0 to 1 nitrogen atoms and 0 to 1 heteroatoms selected independently from the group S and O,
wherein the cyclic residue formed by R and R can be annulated with 5 a 5- to 7-membered saturated, unsaturated or aromatic cyclic residue, which can contain 0 to 2 heteroatoms selected independently from the group N, S and O,
and wherein the cyclic residue formed by R1 and R2 and/or a ring 10 annulated to the cyclic residue formed by R1 and R2 can optionally be independently substituted by 1 to 2 substituents -R1"1-!*.1"2 -R1 3-Z, wherein
R1"1 represents a bond, -O-, -S-, NR1"4, Ci - Cio alkyl, C2 - Cio alk- 15 enyl, d - Cio alkynyl, C6 or Cio aryl, C3-C7 cycloalkyl, a 4-9- membered saturated or unsaturated heterocyclic residue containing up to 3 heteroatoms selected from the group oxygen, nitrogen or sulfur, wherein
20 R1"1 can optionally be substituted by 1 to 2 substituents selected from the group Rl , wherein RM represents hydrogen, Ci - Cio alkyl, C2 - Cio alkenyl, C2 - Cio alkynyl, C6 or Cio aryl, C3-C7 cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 3 heteroatoms selected from the
25 group oxygen, nitrogen or sulfur, wherein
R can optionally be substituted by 1 to 3 substituents selected from the group Ci - C4 alkyl, Ci - C alkyloxy, phenyl, C3-C6 cycloalkyl, halogen, nitro, cyano, oxo, 30 R1"2 represents a bond, -O-, -S-, NR1"5, Ci - Cio alkyl, C2 - Cio alkenyl, C2 - Cio alkynyl, wherein
R1"2 can optionally be substituted by Ci - Cio alkyl, C2 - Cio 5 alkenyl, C2 -Cio alkynyl or R1"5, wherein
R1"5 represents hydrogen, Ci - Cio alkyl, C2 - Cio alkenyl, d - Cio alkynyl, C6 or Cio aryl, C3-C7 cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 3
10 heteroatoms selected from the group oxygen, nitrogen or sulfur, wherein
R1"5 can optionally be substituted by 1 to 3 substituents selected from the group Ci - C4 alkyl, Ci - C4 alkyloxy, phenyl, C3 - C6 15 cycloalkyl, halogen, nitro, cyano, oxo,
R1"3 represents a bond, Ci - Cio alkyl, C2 - Cio alkenyl, d - Cio alkynyl, wherein
20 R1"3 can optionally be substituted by Ci - Cio alkyl, d - Cio alkenyl, C2 - Cio alkynyl or R1"7, wherein
R1"7 represents hydrogen, Ci - Cio alkyl, C2 - Cio alkenyl, d - Cio alkynyl, C6 or Cio aryl, C3 - C cycloalkyl or a 4-9-membered
25 saturated or unsaturated heterocyclic residue containing up to 3 heteroatoms selected from the group oxygen, nitrogen or sulfur, wherein
R1"7 can optionally be substituted by 1 to 3 substituents selected 30 from the group Ci - C4 alkyl, Ci - C4 alkyloxy, phenyl, C3 - C6 cycloalkyl, halogen, nitro, cyano, oxo, with the proviso that, when R1"3 is a bond, then R1"2 must not be a heteroatom,
and with the proviso that R1"1 and R1"2 must not be both heteroatom at the same time,
represents hydrogen, -C(O)ORz l, -C(O)NRz"2R2"3, -SO2NRZ 2Rz"3,
SO(OR > Z^-"K'), -S CO- 2(-O-MRi Z^-"1'), or 5-tetrazolyl, wherein
10
Rz"2 is hydrogen, -C(O)Rz"4 or -SOzR2"4, Ci - C4 alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl, wherein
R ,Z-"2 can optionally be substituted by 1 to 3 substituents 15 selected from the group halogen, nitro, cyano, oxo, wherein
R ,Z-4 is Ci - C4 alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl, wherein
20
R2"4 can optionally be substituted by 1 to 3 substituents selected from the group halogen, nitro, cyano, oxo,
R2"1 and Rz"3 are identical or different and represent hydrogen, Ci - C4 25 alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl, wherein
R2"1 and Rz"3 can optionally be substituted by 1 to 3 substituents selected from the group Ci - C alkyl, Ci - C4 alkyloxy, halogen, nitro, cyano, 30 and wherein the cyclic residue formed by R1 and R2 and/or a ring annulated to the cyclic residue formed by R1 and R2 can optionally be substituted by 0 to 2 substituents R1"8, halogen, nitro, amino, cyano and oxo, wherein
1 8
R " can independently be selected from the group of Ci - C4 alkyl, Ci - C4 alkyloxy, phenyl, C3-C6 cycloalkyl, and wherein
R " can be substituted by 0-5 halogen atoms,
R .3 represents hydrogen, Ci - Cio alkyl, C6 or Cio aryl, C3-C7 cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 2 radicals R3"1,
and which can furthermore be single-foldedly substituted by C3 - C cycloalkyl, C6 or Cio aryl, C4 - C9 heteroaryl or a heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 3 radicals R3"1, wherein
R3"1 represents Ci - C4 alkyl, trifluoromethyl, trifluoromethoxy, -OR3"2,
-NR3"3R3"4, -CO2R3"2, halogen, cyano, nitro or oxo, wherein
R " represents hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl, C6 or
Cio aryl and wherein R3"3 and R3"4 are identical or different and represent hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl,
or
R3"3 and R3"4 together form a 4-7-membered ring, which includes the nitrogen atom to which R3"3 and R3"4 are bonded and which contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur,
10
R represents hydrogen, d - Cio alkyl, C6 or Cio aryl, C3-C7 cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur, which can optionally be substituted by 1 to 3 radicals R4"1,
15 and which can furthermore be single-foldedly substituted by C3 - C7 cycloalkyl, C6 or Cio aryl, C4 - C9 heteroaryl or a heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur, which can optionally be substituted by 1 to 3 20 radicals R4"1, wherein
R4"1 represents Ci - C alkyl, trifluoromethyl, trifluoromethoxy, - OR4"2, -NR4"3R4-4, -CO2R4"2, halogen, cyano, nitro or oxo, wherein
25
R4"2 represents hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl and wherein
R4"3 and R4J* are identical or different and represent hydrogen,
30 C alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl, or
R4"3 and R4"4 together form a 4-7-membered ring, which includes the nitrogen atom to which R4"3 and R4"4 are bonded and which contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur,
R .5 represents hydrogen, Ci - Cio alkyl,
which can optionally be substituted by 1 to 3 radicals R5"1, and which can furthermore be single-foldedly substituted by C3 - C cycloalkyl, C6 or Cio aryl, C4 - C heteroaryl or a heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur,
which can optionally be substituted by 1 to 3 radicals R5"1, wherein
R5"1 represents Ci - C4 alkyl, trifluoromethyl, trifluoromethoxy, -OR5"2, -NR5"3R5 -CO2R5"2, halogen, cyano, nitro or oxo, wherein
R5"2 represents hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl,
C or Cio aryl and wherein
R5"3 and R5"4 are identical or different and represent hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl,
or R ,5-3 and R , 5-4 together form a 4-7-membered ring, which includes the nitrogen atom to which R5"3 and R5"4 are bonded and which contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur,
R6 represents phenyl or a 6-membered aromatic heterocyclic residue containing up to 2 nitrogen atoms,
10 and which can optionally be independently substituted by 1 substituents independently selected from the group of bond,
wherein this substituent can optionally be substituted by 1 radical R6"1, wherein
15
R6"1 represents -C(O)NR6 2R6"3, -NR6"3C(O)R6"2, -SO2NR6"2R6"3, NR6"3SO2R6"2, -NR6"3C(O)NR6"2R6"4, -NR6 3C(O)OR6"2, -OC(O)NR6 2R6"3, wherein
20 R6"2 represents C6 or a 5-6-membered unsaturated heterocyclic residue containing up to 3 heteroatoms selected from the group oxygen, nitrogen or sulfur, which can optionally be substituted by 1 to 2 substituents R6"5 wherein
25
R6"5 represents Ci - C4 alkyl, trifluoromethyl, trifluoromethoxy, -OR6"6, -SR6"6, -NR6"7R6"8,wherein
R6"6 represents hydrogen, Ci - C4 alkyl, and wherein
30 R6"7 and R6"8 are identical or different and represent hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl,
or
R6"7 and R6"8 together form a 5 -6-membered ring, which contains up to 2 additional heteroatoms selected from the group oxygen, nitrogen or sulfur and wherein
R6"3 and R6"4 are identical or different and represent hydrogen, bond, Ci - C4 alkyl, C3 - C6 cycloalkyl,
and which can furthermore be independently substituted by 0 to 2 substituents R6"5
or
R3 and R4 together form a 4-7-membered saturated ring containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur, which can optionally be substituted by 1 to 2 substituents selected from the group Ci - C alkyl, phenyl, benzyl, C3 - C7 cycloalkyl, Ci - C4 alkyloxy, halogen, nitro, cyano, oxo,
represents -C(O)-, -SO2-,
X represents a bond, -CRx"1Rx"2-, oxygen or -NRX"3, wherein
RX 1, Rx"2, RX"3 can be independently selected from the group bond, hydrogen, Ci - C4 alkyl,
Y represents bond, -C(O)-, -SO2-, -O-, -CRY 1RY"2-, or -NRY"3, wherein Rγ_1, Rγ"2, Rγ"3 can be independently selected from the group bond, hydrogen, Ci - C4 alkyl,
D represents N, or CR0"1, wherein
RD 1 can be independently selected from the group bond, hydrogen, Ci - C4 alkyl,
and with the proviso that Y and D are not heteroatoms at the same time,
and pharmaceutically acceptable salts thereof.
Compounds according to claim 1 or 2, wherein
R1 and R2 form a 5- or 6-membered saturated cyclic residue, which can contain 1 nitrogen atom,
wherein the cyclic residue formed by R1 and R2 can be annulated with a 5-membered saturated cyclic residue, which contains 1 nitrogen atom,
1 • and wherein the cyclic residue formed by R and R and/or a nng annulated to the cyclic residue formed by R and R can optionally be substituted independently by 1 substituent -R^'-R1"2 -R1 3-Z, wherein
R1"1 represents a bond or Ci - C2 alkyl, wherein
R1"1 can optionally be substituted by one C6 aryl, R1"2 represents a bond,
R1"3 represents a bond,
Z represents -C(O)ORz l , or 5-tetrazolyl,
R2"1 represents hydrogen, or C2 alkyl, and wherein
1 ? • the cyclic residue formed by R and R and/or a nng annulated to the cyclic residue formed by R1 and R2 can optionally be substituted by 0 or 1 substituent R1"8, wherein
R1"8 is Ci alkyl, and wherein
R1"8 is substituted by 3 fluorine atoms,
R3 represents isobutyl,
R4 and R5 represent hydrogen,
R6 represents
Figure imgf000098_0001
A represents -C(O)-,
X represents -CH2-,
Y represents -C(O)-, D represents nitrogen,
and pharmaceutically acceptable salts thereof.
Compounds according to any one of claims 1 to 3, wherein R and R form a piperidine ring.
1 7
Compounds according to any one of claims 1 to 3, wherein R and R form a pyrrolidine ring.
Compounds according to any one of claims 1 to 5, wherein
R represents
Figure imgf000099_0001
Compounds according to any one of claims 1 to 5, wherein
R represents
Figure imgf000099_0002
R ,6-"12 represents phenyl or a 5- to 6-membered aromatic heterocyclic residue containing up to 3 heteroatoms independently selected from the group of oxygen, nitrogen or sulfur,
which can independently be substituted by up to 3 radicals R6"13, wherein R6"13 represents Ci - C4 alkyl, trifluoromethyl, trifluoromethoxy, -OR6"14, -SR6"14, -NR6 14R6"15, -C(O)R6"14, S(O)R6"14, -SO2R6"14, -CO2R6"14, halogen, cyano or nitro wherein
R6"14 represents hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl,
R6"15 represents hydrogen, Ci - C4 alkyl, C3 - C6 cycloalkyl, C6 or Cio aryl.
8. Compounds according to any one of claims 1 to 7, wherein the compound is selected from the following group:
N-((lS)-3-methyl-l-{[3-(lH-tetraazol-5-yl)-l-pyrrolidinyl]carbonyl}butyl)-2- {4-[(2-toluidinocarbonyl)amino]phenyl } acetamide
1 - {( {4-[(2-toluidinocarbonyι)amino]phenyl} acetyl)-L-leucine} -2-piperidine- carboxylic acid,
1 - {( {4-[(2-toluidinocarbonyl)amino]phenyl} acetyl)-L-leucine} -3-piperidine- carboxylic acid, l-{({4-[(2-toluidinocarbonyl)amino]phenyl}acetyl)-L-leucine}-4-piperidine- carboxylic acid,
(1 - {2-( {4-[(2-toluidinocarbonyl)amino]phenyl} acetyl)-L-leucine} -2- piperidinyl)acetic acid,
( 1 - {2-( {4-[(2-toluidinocarbonyl)amino]phenyl} acetyl)-L-leucine} -3- piperidinyl)acetic acid,
( 1 - {2-( {4-[(2-toluidinocarbonyl)amino]phenyl} acetyl)-L-leucine} -4- piperidinyl)acetic acid,
(1 - {2-( {4-[(2-toluidinocarbonyl)amino]phenyl} acetyl)-L-leucine} -3- piperidinyl)propanoic acid, (3S)- 1 - {2-( {4-[(2-toluidinocarbonyl)amino]phenyl} acetyl)-L-leucine} -4-(tri- fluoromethyl)-3 -pyrrolidinecarboxylic acid, 5-(ethoxycarbonyl)- 1 - {2-( {4-[(2-toluidinocarbonyl)amino]phenyl} acetyl)-L- leucine}octahydropyrrolo[3,4-b]pyrrole-2-carboxylic acid,
(l-{2-({4-[(2-toluidinocarbonyl)amino]phenyl}acetyl)-L-leucine}-2-piperi- dinyl)(phenyl)acetic acid and (l-{2-({4-[(2-toluidinocarbonyl)amino]phenyl}acetyl)-L-leucine}-3-oxo-2- piperazinyl)acetic acid
1 -(N- {[4-( {[(2-methylphenyl)amino]carbonyl) amino)phenyl]acetyl} glycyl)-
2-piperidinyl] acetic acid
(l-{N-[(2-anilino-l,3-benzoxazol-6-yl)acetyl]glycyl}-2-piperidinyl)acetic acid
[ 1 -(N- {[4-( {[(2-methylphenyl)amino]carbonyl} amino)phenyl]acetyl} glycyl)-
2-piperidinyl] acetic acid
( 1 - {N-[(2-anilino- 1 ,3-benzoxazol-6-yl)acetyl]glycyl} -2-piperidinyl)acetic acid
9. The use of a compound according to any one of claims 1 to 8 in the manufacture of a medicament.
10. The use of a compound according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment of a condition mediated by integrins.
11. Pharmaceutical composition, comprising compounds according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier.
12. A process for preparation of compounds of general formula (Nil)
Figure imgf000102_0001
according to any one of claims 1 to 7, which comprises reaction of carboxylic acids of general formula (N)
Figure imgf000102_0002
or activated derivatives thereof with compounds of the general formula (NI)
Figure imgf000102_0003
PCT/EP2001/001491 2000-02-14 2001-02-12 Piperidyl carboxylic acids as integrin antagonists WO2001058871A1 (en)

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