DORN CONRAD P (US)
DURETTE PHILIPPE L (US)
FINKE PAUL E (US)
MACCOSS MALCOM (US)
MILLS SANDER G (US)
SHAH SHRENIK K (US)
SAHOO SOUMYA P (US)
HALE JEFFREY J (US)
LANZA THOMAS J (US)
HAGMANN WILLIAM K (US)
DOHERTY JAMES P (US)
DORN CONRAD P (US)
DURETTE PHILIPPE L (US)
FINKE PAUL E (US)
MACCOSS MALCOM (US)
MILLS SANDER G (US)
SHAH SHRENIK K (US)
SAHOO SOUMYA P (US)
HALE JEFFREY J (US)
LANZA THOMAS J (US)
HAGMANN WILLIAM K (US)
EP0337549A1 | 1989-10-18 | |||
EP0481671A1 | 1992-04-22 | |||
EP0525973A2 | 1993-02-03 |
1. | A compound of Formula (I) li ϋtituii ShccT Ill *& 10. |
2. | 15*& 20. |
3. | 25*& 30. |
4. | SUBSTITUTE SHEET (16) amino wherein the amino is optionally mono or di substituted with C**__£alkyl, with the proviso that R~~ and R3 may be joined together to form a methylenedioxy group or a furan ring, (17) morpholinocarbonyl; KB O ( £0 Q C ORx vώiere Rx is carboxy Chalky!, benzyloxycarbonylCj^alkyl , or tbutoxycarbonylC*L_3alkyl , wherein Q is a covalent bond or C κ6 wherein R. |
5. | and R6 are each individually or hydrogen, SUBSTITUTESHEET or a covalent bond; R*L2 is hydrogen or Cj^alkyl; 15 R7 and R. |
6. | re each individually (a) hydrogen, (b) C^alkyl, (c) C1_6alkyloxy C2_3alkyl, (d) hydroxy C2_6alkyl, 20 (e) polyhydroxyC2_6alkyl, (f) carboxamido C _6alkyl, (g) polyacyloxyC2_6alkyl (h) C ^alkanoyl, (i) substituted phenyl or phenyl 25 Cχ_6alkyl, wherein the substitutents are X^ and X2 as defined immediately below. (j) C2_ealkenyl, 30 (1) heteroaryl C*j__^alkyl wherein the hetero aryl includes pyridinyl, imidazolyl, triazolyl, benzylimidazolyl, and furyl, SUBSTITUTE SHEET (m) carboxy C*^_galkyl, (n) carbo C _galkoxy C _3alkyl, (o) phenylsulfonyl, (p) C1_6alkylsulfonyl, 5 (q) benzyloxy, (r) morpholinyl Cj^alkylsulfonyl, (s) tetrahydropyranyl, (t) aminoC*_3alkylsulfonyl wherein the amino is optionally mono or di 10 substituted with Cj__6alkyl, (u) aminocarbonyl wherein the amino is optionally mono or di substituted with C*j__6alkyl, (v) aminocarbonyloxyC2_6alkyl wherein 15 the amino is optionally mono or di substituted with C^^alkyl, (w) azabicyclo of 7 to 12 atoms, (x) di Cj^alkylamino C2_galk l wherein the amino is optionally mono or di 20 substituted with C^^alkyl, (y) bicycloalkyl of 7 to 12 atoms, (z) C3_ ocycloalkyl optionally substituted with Cj^alkyl, (aa) pyrazolidinyl, 25 (bb) substituted piperidinyl or prrrolidinyl wherein the substitutent is hydrogen, C*]__3alkyl, hydroxyCj^alkylbenzyl , carboxamido or amino wherein the 30 amino is optionally mono or di substituted with C _6alkyl, SUBSTITUTESHEET (cc) substituted pyrrolidinyl wherein the substitutent is carboxamido or amino wherein the amino is optionally mono or di substituted with C]__6alkyl, (dd) pyrimidinyl, (ee) NcyanoN'phenylamidino, (ff) phosphonoC*L_6alkyl, or (gg) αCj^alkyl benzyl or mono or di substituted benzyl or mono or di substituted pyridylmethyl, wherein the substitutents are X^ and X2, X2 is hydrogen, halo or C _^alkyl; SUBSTITUTESHEET n i s 1 , 2 , 3 , 4 or 5 ; Rg is selected from hydrogen, C*j__ alkyl, and C*)__3alkoxyC2_3alkyl; or phenyl, phenyl C*L_3alkyl, pyridyl, and pyridyl C1_3alkyl; RJ^ and R are each independently selected from hydrogen, Cj^alk l, and C*j__3alkoxy Cj^alkyl, or aryl as defined above, or are together 0=; or wherein R7 and R8 are joined together to form mono or di substituted ring of 4, 5, 6, or 7 atoms or 7 to 12 atoms such as (1) piperidinyl or homopiperdinyl, (2) piperazinyl, (3) morpholinyl, thiomorpholinyl or 1,ldioxo4thiomorpholinyl, (4) pyrroylidinyl, (5) pyrryl, (6) imidazolyl, (7) triazolyl, (8) saturated azabicyclo of 7 to 12 atoms, (9) azaspiro having 3 to 9 carbon atoms, said ring being saturated, (10) tetrazolyl, (11) pyrazolidinyl, (12) dihydrodimethoxyisoquinolyl, (13) azetidinyl, or (14)diazabicyclo ring of 712 atoms, wherein the substituents are each selected from the group consisting of hydrogen and C]__3alkyl, SUBSTITUTESHEET benzyloxycarbonyl, carboxy, phenyl Cj^alkyl amino earbonyl, pyrrolidinylmethyl, hydroxy Cj^alkyl, Cj^alkyloxy, C _4alkyloxy earbonyl, aminocarbonyl wherein the amino is optionally mono or di substituted with C _6alkyl, and oxo; or N(R7)R8 may be an amino acid residue including natural amino acids such as lysine; or R8 and Rg are joined together to form a mono or di substituted saturated monocyclic ring of 6 to 7 atoms and having two hetero atoms which are the nitrogens to which R8 and Rg are attached; said rings to include piperazinyl and piperazinyl; or Rg and R*J_Q are joined together to form a momo or di substituted monocyclic saturated ring of 5 to 7 atoms and having one hetero atom which is the nitrogen to which Rg is attached; or wherein Rg and R^2 are joined together to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 atoms, said ring having one hetero atom which is the nitrogen to which Rg is attached; or wherein R^Q and 2 are joined together to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 carbon atoms; or wherein R3 and Rχι are joined together to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 atoms, said ring having one hetero atom which is the nitrogen to which Rg is attached; and the substituents are independently selected from Hydrogen and Cl3alkyl. |
7. | 2 A compound of formula 1 wherein Q is a covalent bond, SUBSTITUTESHEET R 15 3. A compound according to Claim 2 wherein R is C _5alkyl; R**** is C _6alkyl or Ci.galko yCi.galkyl; M is (1) hydrogen, 20 (2) C^alkyl, (3) hydroxy C*j__6alkyl, (4) halo Cχ_6alkyl, (5) C2_6alkenyl, or (6) C1_6alkoxyC1_6alkyl; 25 Ra is (1) hydrogen, (2) C^alkyl, (3) halo, (4) carboxy, 30 (5) C*]__6alkoxy, (6) phenyl, (7) Cχ_6alkylcarbonyl, SUBSTITUTESHEET (8) amino wherein the amino may be optionally mono or di substituted with Cj^alk l; Rb is hydrogen or Cj^alkyl, R2 and R; are each independently (1) hydrogen, (2) Cχ_6alkyl, (3) halo, (4) carboxy, (5) C^galkoxy, (6) phenyl, (7) C^.^alkylcarbonyl, with the proviso that when Rb is hydrogen, R2 and R~ may be joined together to form a methylenedioxy group or a furan ring; wherein Q is a covalent bond SUBSTITUTE SHEET *& 10. |
8. | R*L2 is hydrogen or Cj^alkyl; R7 and R3 are each individually 15 (a) hydrogen, (b) C1_6alkyl, (c) C*jL_6alkyloxy C2_3 lkyl, (d) hydroxy C2_6alkyl, (e) carboxamido Cj^alkyl, 20 (f) C1_6alkanoyl, (g) phenyl or phenyl Cj^alkyl, (h) C2_6alkenyl, (i) C6_10cycloalkenyl, (j) heteroaryl C*]__^alkyl wherein the 25 heteroaryl selected form pyridinyl, imidazolyl, triazolyl, benzylimidazolyl, and furyl, (k) carboxy C*j__^alkyl, (1) C*|__^alkylsulfonyl, 30 (m) benzyloxy, (n) morpholinyl C^alkylsulfonyl, SUBSTITUTESHEET (o) aminoCj^alkylsulfonyl wherein the amino is optionally substituted with Cl6 alkyl, (p) aminocarbonyl wherein the amino is optionally substituted with Cl6 alkyl, (q) aminocarbonyloxyC2_6alkyl wherein the amino is optionally substituted with Cl6 alkyl, (r) amino C2_6alkyl wherein the amino is optionally substituted with Cl6 alkyl, (s) pyrazolidinyl, (t) piperidinyl, (u) pyrrolidinyl (v) pyrimidinyl, (w) C3_7cycloalkyl, (x) αC*L_3alkyl benzyl or mono or di substituted benzyl or mono or di substituted pyridylmethyl, wherein the substitutents are X^ and X2, wherein is SUBSTITUTESHEET (9) amino wherein the amino is optionally substituted with C*^_^alkyl; or (10) carboxy, ∑2 is hydrogen, halo or C^.^alkyl; n is 1, 2, 3 or 4; RJ^Q and R*_χ are each independently selected from hydrogen, Cj^alkyl, and Cj^alkoxy Cj^alkyl; or wherein R7 and Q are joined together to form mono or di substituted ring of selected from (1) piperidinyl, (2) piperazinyl, (3) morpholinyl, (4) pyrroylidinyl, (5) pyrryl, (6) imidazolyl, (7) triazolyl, (8) tetrazolyl, (9) pyrazolidinyl, or (10) azetidinyl, wherein the substituents are each selected from the group consisting of hydrogen and benzyloxycarbonyl, carboxy, phenyl Cj^alkyl amino earbonyl, pyrrolidinyl, methyl, hydroxy C*j__3alkyl, Cj^alkyloxy, C*__4alkyloxy earbonyl, and oxo; or wherein R^Q and R*_2 are joined together to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 carbon atoms; or ϋSSTiTUTESHEET wherein R8 and R are joined together to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 atoms, said ring having one hetero atom which is the nitrogen to which R3 is attached; and the substituents are independently selected from Hydrogen and C*|__3alkyl. |
9. | 4 A compound according to Claim 3 wherein R is C*)__3 alkyl; Rl is C*L_3 alkyl; M is (a) C*^ alkyl, or (b) C _e alkenyl; R2 is (a) hydrogen (b) C*L_ alkyl, or C*^ alkoxy, and R3 is hydrogen, or R2 and R are joined together to form a methylenedioxy group or a furan ring; 7 and R3 are each independently selected from (a) hydrogen, (b) Cλ_3 alkyl, (c) _3 alkoxy C2_3 alkyl, (d) substituted benzyl wherein the substituents are X^ and X2 wherein X^ is hydrogen and X2 is (1) hydrogen, (2) halo, or (3) Cχ_3 alkyl; SUBSTITUTE SHEET n is 1 , 2 or 3 , and RLø and R]_*j_ are each independently selected from hydrogen, C^_4 alkyl, and C*L_3 alkoxy C _3alkyl; or R7 and Rg are joined together to form a substituted ring selected from (a) piperidinyl, (b) cyclopropyl, (c) piperazinyl, and (d) morpholinyl; or wherein R^Q and R***^ are joined together to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 carbon atoms; or wherein R8 and R are joined together to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 atoms, said ring having one hetero atom which is the nitrogen to which Rg is attached; and the substituents are independently selected from Hydrogen and Cι_3alkyl. |
10. | 5 A compound according to Claim 4 wherein R is methyl or ethyl; R*l is methyl or ethyl; M is (a) C*j__4 alkyl, or (b) C2_3 alkenyl; SUBSTITUTESHEET R2 is (a) hydrogen, (b) C*_3 alkyl, or Cι_3 alkoxy, and R~ is hydrogen, or R2 and R^ are joined together to form a methylenedioxy group or a furan ring; n is 1 or 2; R*Lø is selected from (a) Ci.3 alkyl, (b) C 3 alkoxy C2_3 alkyl, (c) hydrogen, R7 and R8 are independently selected from (a) hydrogen, (b) cyclopropyl, (c) Cχ_3 alkyl, (d) C*^ alkoxy C2_3 alkyl, or R7 and R8 are joined together to form a substituted ring selected from (a) piperidinyl, and (c) morpholinyl; or wherein are joined together to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 carbon atoms; or wherein R3 and R^ are joined together to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 atoms, said ring having one hetero atom which is the nitrogen to which Rg is attached; and the substituents are independently selected from Hydrogen and C*|__3alkyl. CUBSTiTUTΞSHEET 6 A compound according to Claim 1 wherein Q is a covalent bond, JR. R is QCYN or a covalent bond; 7 A compound according to Claim 6 wherein R is C1_6alkyl; R~ is C _ alkyl or Cχ_6alkoxyC1_6alkyl; M is (1) hydrogen, (2) C^alkyl, (3) hydroxy C1_6alkyl, (4) halo C;L_6alkyl, (5) C2_6alkenyl, or (6) C1_6alkoxyC1_6alkyl; Ra is (1) hydrogen, (2) C1_6alkyl, (3) halo, (4) carboxy, (5) C1_6alkoxy, SUBSTITUTESHEET Q is a covalent bond, or a covalent bond; R^2 i*3 hydrogen or Cj^alkyl; SUBSTITUTESHEET R7 and R8 are each individually (a) hydrogen, (b) C^alkyl, (c) C*L_6alkyloxy C2_3alkyl, (d) hydroxy C2_ealkyl, (e) carboxamido Cι_6alkyl, (f) Cχ_6alkanoyl, (g) phenyl or phenyl Cj^alkyl, (h) C2_6alkenyl, (i) C6_10cycloalkenyl, *& 10. |
11. | (j) heteroaryl C _^alkyl wherein the heteroaryl selected form pyridinyl, imidazolyl, triazolyl, benzylimidazolyl, and furyl, (1) C^galkylsulfonyl, (m) benzyloxy, (n) morpholinyl Cj^alkylsulfonyl, (o) aminoCj^alkylsulfonyl wherein the 20 amino may be optionally substituted with C _ alkyl, (p) aminocarbonyl wherein the amino may be optionally substituted with C1_6alkyl, *& 25. |
12. | (q) aminocarbonyloxyC _galkyl wherein the amino may be optionally substituted with C*j__^alkyl, (r) amino Cj^alkyl wherein the amino may be optionally substituted with *& 30. |
13. | C^alkyl, (s) pyrazolidinyl, (t) piperidinyl, •j UBSTiTUTESHEET (u) pyrrolidinyl (v) pyrimidinyl, (w) C3_7cycloalkyl, (x) αC**__3alkyl benzyl or mono or di substituted benzyl or mono or di substituted pyridylmethyl, wherein the substitutents are X^ and X2, wherein ∑! is (1) hydrogen, (2) halo, (3) C^alkyl, (4) haloC1_6alkyl, (5) C2_6alkenyl, (6) hydroxyC*L_6alkyl, (7) Cι_6alkylcarbonyl, (8) Cj^alkylcarbonylamino; (9) diCj^alkylamino; or (10) carboxy, ∑2 is hydrogen, halo or C^galkyl; n is 1, 2, 3 or 4; Rg is selected from hydrogen, alkyl, and Cj^alkoxyCj^alkyl; R^ø and R*j_χ are each independently selected from hydrogen, Cj^alkyl, and Cι_3alkoxy C^alkyl; or wherein R7 and Ro are joined together to form mono or 7 di substituted ring of selected from (1) piperidinyl, SUBSTITUTE SHEET (2) piperazinyl, (3) morpholinyl, (4) pyrroylidinyl, (5) pyrryl, (6) imidazolyl, (7) triazolyl, (8) tetrayolyl, (9) pyrazolidinyl, or (10) azetidinyl, wherein the substituents are each selected from the group consisting of hydrogen and Cj^al yl, benzyloxycarbonyl, carboxy, phenyl amino earbonyl, pyrrolidinyl, methyl, hydroxy Cj^alkyl, Cι_4alkyloxy earbonyl, and oxo; or Rg and Rg are joined together to form a mono or di substituted saturated monocyclic ring of 6 to 7 atoms and having two hetero atoms which are the nitrogens to which Rg and Rg are attached; said rings to include piperazinyl and homopiperazinyl; or Rg and R θ are joined together to form a momo or di substituted monocyclic saturated ring of 5 to 7 atoms and having one hetero atom which are the nitrogen to which Rg is attached; or wherein Rg and Rj^ are joined together to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 atoms, said ring having one hetero atom which is the nitrogen to which Rg is attached; or wherein R_Q and R^2 are joined together to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 carbon atoms; or wherein R3 and R^ are joined together to form a mono or di substituted saturated monocyclic ring of 5, 6, SUBSTITUTESHEET or 7 atoms, said ring having one hetero atom which is the nitrogen to which Re is attached; and the substituents are independently selected from Hydrogen and Cι_3alkyl. |
14. | 8 A compound according to Claim 7 wherein R is alkyl; Rl is Cι_3 alkyl; M is (a) C*^ alkyl, or (b) C2_6 alkenyl; R2 is (a) hydrogen (b) C*L_6 alkyl, or Cχ_£ alkoxy, and R3 is hydrogen, or R2 and R3 are joined together to form a methylenedioxy group or a furan ring; R7 and R8 are each independently selected from (a) hydrogen, (b) C±_3 alkyl, (c) C*L_3 alkoxy C2_3 alkyl, (d) C3_7 cycloalkyl, (e) hydroxyC2_3 alkyl, (f) carboCj^alkoxymethyl, (g) substituted benzyl wherein the substituents are X^ and X2 wherein X*j_ is hydrogen and X2 is (1) hydrogen, (2) halo, or (3) Cχ_3 alkyl; UBSTITUTESHEET n is 1 , 2 or 3 , and Rg, Rio and R are each independently selected from hydrogen, Cι_4 alkyl, and C*__3 alkoxy Cj__3al yl; or R7 and R8 are joined together to form a substituted ring selected from (a) piperidinyl, (b) piperazinyl, and (c) morpholinyl; or R8 and Rg are joined together to form a mono or di substituted saturated monocyclic ring of 6 to 7 atoms and having two hetero atoms which are the nitrogens to which R8 and Rg are attached. |
15. | 9 A compound according to Claim 8 wherein R is methyl or ethyl; R*j_ is methyl or ethyl; M is (a) Cι_4 alkyl, or (b) C2_3 alkenyl; R2 is (a) hydrogen, (b) Cι_3 alkyl, or C*__3 alkoxy, and R3 is hydrogen, or R2 and R3 are joined together to form a methylenedioxy group or a furan ring; SUBSTITUTESHEET n is 1 or 2 ; Rg and R*_Q are each independently selected from (a) hydrogen, (b) Cλ_3 alkyl, (c) C]._3 alkoxy C*j__3 alkyl, R7 and Rg are each independently selected from (a) hydrogen, (b) C±_3 alkyl, (c) cyclopropyl, (d) C*JL_3 alkoxy C*j__3 alkyl, (e) hydroxyethyl, (f) carboethoxymethyl, or R7 and Rg are joined together to form a mono or di substituted saturated monocyclic ring which is piperidinyl or morpholinyl, said ring optionally substituted with hydrogen or methyl; or Rg and Rg are joined together to form a mono or di substituted saturated monocyclic ring which is piperazinyl. |
16. | 10 A compound according to Claim 7 wherein R4 is CN(R7)R8, and R7 and Rg are each independently selected from (a) hydrogen, (b) Cχ_3 alkyl, SUBSTITUTESHEET (c) cyclopropyl, (d) C*j__3 alkoxy C _3 alkyl, (e) hydroxyethyl, (f) carboethoxymethyl, or R and Rg are joined together to form a mono or di substituted saturated monocyclic ring which is piperidinyl or morpholinyl, said ring optionally substituted with hydrogen or methyl; or 11 A compound according to Claim 1 of Formula wherein A is: 2 CH2C02H, 3 CH2C(0)N(CH2CH20H)2, 4 CH2C(0)N(CH3)CH2C(0)NH2, 5 CH2C(0)NHC(CH20H)3, 6 CH2C(0)N(CH3)2. 7 CH2CH2N(CH3)Ac, 8 CH2C(0)Pro0CH2Ph, SUBSTITUTESHEET CH2C(0)Pro0H, CH(CH3)C02CH2Ph, CH(CH3)C02H, CH(CH3)C(0)N(Et)2, CH2CH2N(Et)2, CH2CH2(4morpholinyl), CH2CH2CH2CH2N(CH3 2, CH2C(0)ProNHCH2Ph, CH2CH2N(iPr)2, CH2CH2(4carbobenzyloxylpiperazinyl), CH2CH2N(nBu)2, CH2CH2CH2CH2CH2CH2N(CH3)2, CH2CH2(lpiperazinyl), CH2CH2(4methyllpiperazinyl), CH2CH2(4acetyllpiperazinyl), CH2CH2N(Ph)2, CH2CH(Ph)N(CH3)2,or SUBSTITUTE SHEET 12 A compound according to Claim 1 of the Formula SUBSTITUTESHEET . |
17. | A compound according to Claim 1 of the Formula SUBSTITUTE SHEET 19 N(CH3)CH2CH2N(iPr)2, 20 N(nPr)2, 21 N(Et)2, 22 3chloroanilino, 23 3methoxyanilino, 24 4fluoroanilino, 25 N(CH3)CH2CH2CH2Cθ2H, 26 N(CH3)CH2CH2CH2C(0)NHS02Ph, 27 N(CH3)CH2CH2CH2N(CH3)CH2Ph, 28 N(CH3)2, 29 N(CH3)CH2Ph, 30 N(CH3)CH2CH2N(CH3)CH2Ph, 31 NH0CH2Ph, 32 N(CH3)(4carboxyphenyl), or 33 N(CH3)(4benzenesulfonyl aminocarbonylphenyl) . |
18. | A compound according to Claim 1 of the Formula wherein A is: 2 NHCH2C02H, UBSTITUTESHEET N(CH3 )CH2CH2N(CH3 )2 , NHCH2CH2N(Et )2 , NHCH2CH2(4morpho1iny1), N(CH3)CH2CH2(4morpholinyl), N(CH3)CH2CH2N(CH2CH2θCH3)2, N(CH3)CH2CH2CH2N(CH3)2, NHCH2CH2N(iPr)2, N(CH3)CH2CH2N(0)(CH3)2, N(CH3)CH2CH2N(iPr)2, NHS02CH2CH2(4morpholinyl), NHS02CH2CH2N(CH3)2. NHCH2CH2(4imidazolyl), NHCH2CH2(lpiperidinyl), N(CH3)CH2CH2(lpiperidinyl), N(CH3)CH2CH2N(CH3)Ac, NHCH2CH2(lpyrrolidinyl), N(CH3)CH2CH2(lpyrrolidinyl), NHCH2CH2(1H1,2,4triazol1yl), NHCH2CH2(limidazolyl), NHCH2CH2(3azabicyclo[3.2.2non3yl) , NHCH2CH2(3azaspiro[5.5]undec3yl, NHCH2CH2(2Htetrazol2yl), NHCH2CH2(IHtetrazol1yl), NHCH2C(0)ProNHCH2Ph, N(CH3)CH2CH2(3azabicyclo [3.2.2]non3yl), N(CH3)CH2CH2(4imidazolyl) , N(CH3)CH2CH2N(CH3)Ac, SUBSTITUTESHEET N(CH3)CH2CH2N(CH3)C(0)NHCH3, N(CH3)CH2CH2N(CH3)S02CH3, N(CH3)CH2CH2(3azabicyclo[3.2.2] non3yl, NHCH2CH2(l,ldioxo4thiamorpholinyl), 4dimethylaminobenzylamino, 3dimethylaminoanilino, N(CH3)CH2CH2(l,ldioxo4thia morpholinyl), 4dimethylaminoanilino, NHCH2CH2(lbenzyllHimidazol2yl), N(CH3)CH2CH2(2pyridyl), N(CH3)(lazabicyclo[2.2.2]oct3yl, NHCH2CH2(4benzyloxycarbonyl1 piperazinyl), 1,2diethylpyrazolidin4ylamino, 2(l£pyrrolidinylmethyl)lpyrrolidinyl, NHCH2CH2(4hydroxylpiperidinyl), NHCH2CH2(lhomopiperidinyl), N(CH3)CH2CH2(lhomopiperidinyl), NHCH2CH2(3hydroxylpiperidinyl), N(CH3)CH2CH2(3hydroxylpiperidinyl), N(CH3)CH2CH2N(CH3)CH2Ph, N(CH3)CH2CH2(4benzyloxylpiperidinyl), N(nPr)2, N(Et)2, N(CH3)CH2CH2(4hydroxylpiperidinyl) , N(CH3)CH2CH2(4oxolpiperidinyl), NHCH2CH2(3hydroxylpyrrolidinyl) , N(Et)CH2CH2(lpipεridinyl), N(CH2Ph)CH2CH2(lpiperidinyl), 4fluoroanilino, SUBSTITUTESHEET 3chloroanilino, 3methoxyani1ino, N(CH2Ph)CH2CH2N(CH3)2, N(CH3)CH2CH2(3hydroxylpyrrolidinyl), N(3picolyl)CH2CH2(lpiperidinyl), NHCH(CH3)CH2CH2CH2N(Et)2, NHCH2CH2(2 hydroxymethyll pyrrolidinyl, N(CH3)CH2CH2(4tbutoxycarbonyll piperazinyl), N(CH3)CH2CH2N(CH3)(3picolyl), 3,5dimethyllpiperazinyl, N(CH3)CH2CH2N(0)(CH3)CH2Ph, N(CH3)CH2CH2N(CH3)(4picolyl), 2£(NbenzylNmethylaminomethyl)l pyrrolidinyl, N(CH3)CH2CH2N(CH3)(2picolyl), N(CH3)CH2CH2(lpiperazinyl), 1homopiperazinyl, N(CH3)CH2CH2N(CH3)CH2CH2Ph, 2(lRpyrrolidinylmethyl)lpyrrolidinyl, 4benzyllhomopiperazinyl, N(CH3)CH2CCH(0H)]4CH20H, N(CH3)CH2[CH(0Ac)]4CH20Ac, N(CH3)CH2CH2N(CH3)(lnaphthalenylmethyl), N(CH3)CH2CH2N(CH3)(2naphthalenylmethyl), N(CH3)CH2CH2 (CH3)CH(CH3)Ph, N(CH3)CH2CH2N(CH2Ph)2, lethyl3piperidinylamino, N(CH3)CH2CH2N(CH3)(2furfuryl), SUBSTITUTESHEET 92 N(CH3)CH2CH2CH2C02H, 93 N(CH3)CH2CH2CH2C(0)NHS02Ph, 95 N(CH3)CH2CH2CH2N(CH3)CH2Ph, 96 N(CH3)(CH2)6N(CH3)CH2Ph, 97 N(CH3)CH2CH20H, 98 N(CH3)CH2CH2θC(0) (CH3)2, 99 N(CH3)CH2CH2N(CH3)CH2C02tBu, N(CH3)(lethyl3piperidinyl), N(CH3)CH2CH2N(CH3)(tetrahydro2H pyran2ylmethyl), 2,2,6,6tetramethylpiperidin4ylamino, N(CH3)(4carboxyphenyl), N(CH3)(4benzenesulfonylaminocarbonyl, phenyl N(CH3)CH2CH2N(CH3)(4cyanobenzyl), N(CH3)CH2CH2N(CH3)(4methylbenzyl), N(CH3)CH2CH2N(CH3)(3cyanobenzyl), N(CH3)CH2CH2N(CH3)(4trifluoro methylbenzyl, N(CH3)CH2CH2N(CH3)(3trifluoromethyl benzyl), N(CH3)CH2CH2(CH3)( fluorobenzyl) , NHCH(CH3)PH(0)0H, Llysine (αN), N(CH3)CH2CH2N(CH3)(cyclopropylmethyl), N(CH3)CH2CH(Ph)N(CH3)2, N(CH3)2, N(CH3)CH2Ph, N(CH3)(lbenzyl3piperidinyl) , NH0CH2Ph, N(3picolyl)CH2CH2N(CH3)CH2PH, SUBSTITUTE SHEET N(CH3)CH2CH2N(CH3)(4methoxybenzyl), N(4picolyl)CH2CH2N(CH3)CH2Ph, N(2picolyl)CH2CH2N(CH3)CH2Ph, N(CH3)CH2CH2N(CH3)(2,4dimethylbenzyl), N(CH3)CH2CH2(2,6dimethyl4morpholinyl), NH2, NHCH3, 4morpholinyl, cis2,6dimethyl4morpholinyl, 130 N(CH3)CH2CH2N(CH3)C(=NCN)NHPh, N(CH3)CH2CH2N(CH3)(3fluorobenzyl), N(CH3)CH2CH2N(CH3)(2chlorobenzyl), N(CH3)CH2CH2N(CH3)(3methoxybenzyl), N(CH3)CH2CH2N(CH3)(3,5dimethoxybenzyl), 3,4dihydro6,7dimethoxy2(lH)iso quinolinyl, N(CH3)(lbenzyl4piperidinyl), Llysine (εN), N(CH3)CH2CH2N(CH3)(2adamantyl), 139 N(CH3)(4piperidinyl), 5Methyl2,5diazabicyclo[2.2.l]hept2yl, N(CH3)CH2C02H, N(CH3)CH2CH2CH2N(CH3)CH2CH3, N(CH )(lmethyl4piperidinyl), N(CH3)(lpropyl4piperidinyl), 45 N(CH3)(lethyl4piperidinyl), 46 N(CH3)CH2CH CH3)N(CH3)CH2Ph, 47 N(CH3)CH2CH(CH3) (CH3)2, 48 N(CH3)CH2CH2N(CH3)(bicyclo[2.2.1] hept2yl), 49 N(CH3)CH2CH2NH(2adamantyl), SUBSTITUTE SHEET N(CH3)CH2CH2N(CH3)(6,6dimethylbicyclo [3.1.1]hept2yl, N(CH3)CH2CH2N(CH3)(bicyclo[3.2.1] oct2yl), NH(tBu), 153 N(CH3)CH2CH2N(CH3)(lcyclohexenlyl), 25.carboxamidolpyrrolidinyl, 2hydroxymethyllpiperidinyl, 3dimethylaminolpyrrolidinyl, N(CH3)CH2CH2N(CH3)(cyclohexylmethyl), N(CH3)CH2CH2N(CH2CH=CH2)C(CH3)2CH=CH2, N(CH3)CH2CH2N(CH3)(4ethylcyclohexyl) , N(CH3)CH2CH2N(CH3)(2ethylcyclohexyl), N(CH3)CH2CH2N(CH3)(4methylcyclohexyl), 163 N(CH3)CH2CH2N(CH3)(cyclohexyl), N(CH3)CH2CH2N(CH3)CH2C02H*TFA , N(CH3 CH2CH2N(CH3)CH2C(0)N(CH3*)2, 3dimethylaminolazetidinyl, ldiphenylmethyl3azetidinyl, 168 N(CH)CH2CH2N(CH3)(cyclohexylmethyl), or NHCH2CH2N(Et)CH2CH2θCH3. SUBSTITUTESHEET 15 A compound according to Claim 1 of the Formula SUBSTITUTESHEET 16A compound according to Claim 1 of the Formula SUBSTITUTE SHEET 17 A compound according to CLaim 1 of the formula wherein n, R2, and A are: SUBSTITUTE SHEET 18 A compound according to Claim 1 of the Formula wherein n, R3 and A are SUBSTITUTESHEET 19 A compound according to Claim 1 of the Formula where n, R3, R4, and A are: SUBSTITUTE SHEET 4methyllpiperazinyl , N(CH3)CH2CH2N(CH3)2 , N(CH3)CH2CH2N(Et)2, N(CH3)CH2CH2N( iPr)2, N(CH3)CH2CH2N(CH3)CH2Ph , or N(CH3)CH2CH2N(CH3)2. |
19. | A compound according to Claim 1 of the Formula where n, R2, R^, and A are: SUBSTITUTE SHEET . |
20. | A compound according to Claim 1 selected from the group consisting of: (a) tButoxycarbonylmethyl [S(R*, S*)]4((3,3 diethyll(((l(4methylphenyl)butyl)amino) carbonyl)4oxo2azetidinyl)oxy)benzoate, (b) 2(bis(2hydroxyethyl)amino)2oxoethyl(S(R*, S*))4((3,3diethyll(((l(4methylphenyl) butyl)amino)earbonyl)4oxo2azetidinyl) oxy)benzoate, (c) 1methy120X02(phenylmethyloxy)ethyl (2S(1(S*),2R*, (R)))4((3,3diethyll (((1(4methylpheny1)butyl)amino)earbonyl) 4oxo2azetidinyl)oxy)benzoate, (d) 1carboxyethyl [S(R*,S*)]4((3,3diethyll (((l(4methylphenyl)butyl)amino)carbonyl)4oxo 2 azetidinyl)oxy)benzoate, (e) 2(diethylamino)lmethyl2oxoethyl [S(R*,S*)] 4((3,3diethyll(((l( methylphenyl)butyl) amino)earbonyl)4oxo2 azetidinyl)oxy)benzoate (f) (S(R*,S*))l(((4((3,3diethyll(((l(4methyl phenyl)butyl)amino)earbonyl)4oxo2azetidinyl) oxy) benzoyl)oxy)acetyl)Lproline, (g) [S(R*,S*)]l(((4((3,3diethyll(((l(4methyl pheny1)butyl)amino)carbonyl4oxo2azetidiny1) oxy) benzoyl)oxy)acetylNbenzylLprolinamide, SUBSTITUTESHEET (h) 2(dimethylamino)ethyl(S(R*,S*))4((3,3diethyl 1(((1(4methylphenyl)butyl)amino)carbonyl)4 oxo2azetidinyl)oxy)benzoate, (i) lDimethylamino2propyl [S(R*,S*)]~ 4[[3,3 diethyll[[[l(4methylphenyl)butyl]amino] carbonyl]4oxo2azetidinyl]oxy]benzoate, (j) 3Dimethylaminolpropyl [S(R*,S*)] 4[[3,3 diethyll[[[l(4methylphenyl)butyl]amino] earbonyl]4oxo2azetidinyl]oxy]benzoate, ( ) 2Diethylaminoethyl [S(R*,S*)]~ 4[[3,3 diethyll[[[l(4methylphenyl)butyl]amino] earbonyl]4oxo2azetidinyl]oxy]benzoate, (1) 2(l[4morpholino]ethyl) [S(R*,S*)] 4[[3,3 diethyll[[[l(4methylphenyl)butyl]amino] earbonyl]4oxo2azetidinyl]oxy]benzoate, (m) 4dimethylaminobutyl [S(R*,S*)] 4[[3,3 diethyl1[[[1(4methylphenyl)butyl]amino] carbonyl]4oxo2azetidinyl]oxy]benzoate, (n) 2dimethylamino2methyllpropyl [S(R*,S*)] 4[[3,3diethyll[[[l(4methylphenyl)butyl] amino] carbonyl]4oxo2azetidinyl]oxy]benzoate, (o) 2(diisopropylamino)ethyl [S(R»,',S*)]4[[3,3 diethyll[[[l(4methylphenyl)butyl] amino] earbonyl]4oxo2azetidinyl]oxy]benzoate, (p) Benzyl [S(R*,S*)]4[2[[4[[3,3diethyll [[[1(4methylphenyl)butyl]amino]carbonyl]4oxo 2azetidinyl]oxy]benzoyl]oxy]ethyl]lpiperazine carboxylate, (q) 2(dibutylamino)ethyl [S(R^,S*)]4[[3,3 diethyl1[[[1(4methylphenyl)butyl]amino] carbonyl]4oxo2azetidinyl]oxy]benzoate, SUBSTITUTESHEET (r) [S(R>'sS>O]6(dimethylamino)hexyl4[[3,3diethyl 1 C[[l(4methylphenyl)butyl]amino]carbonyl]4 oxo2azetidinyl]oxy]benzoate, (s) 2(4methyllpiperazinyl)ethyl [S(R*,S*)] 4[[3,3diethyl1[[[l(4methylphenyl)butyl] amino]earbonyl]4oxo2azetidinyl]oxy]benzoate, (t) 2(diphenylamino)ethyl[S(R*,S*)]4[[3,3diethyl 1[[[1(4methy1pheny1)butyl]amino]carbonyl]4 oxo2azetidinyl] oxy]benzoate, (u) 2(di2propenylamino)ethyl [S(R*,S*)] [[3,3 diethyl1[[[1(4methylphenyl)butyl]amino] earbonyl]4oxo2azetidinyl]oxy]benzoate, (v) 2(dimethylamino)2phenylethyl[S(R*,S*)]'4 [[3,3diethyl1[[[l(4methylphenyl)butyl]amino] earbonyl]4oxo2azetidinyl] oxy]benzoate, (w) 2[methyl(phenylmethyl)amino]ethyl [S(R*,S*)]~ 4[[3,3diethyll[[[l(4methylphenyl)butyl] amino]carbonyl]4oxo2azetidinyl]oxy]benzoate, (x) 2(dimethylamino)ethyl[S,(R*,S*)]4[[3,3diethyl l[[[l(4methylphenyl)butyl]amino]earbonyl]4 oxo2azetidinyl] oxy]2,6dimethylbenzoate, (y) 2(diethylamino)ethyl[S(R*,S*)]4[[3,3 diethyl1[[[1(4methylphenyl)butyl]amino] carbonyl]4oxo2azetidinyl]oxy]2,6dimethyl benzoate, (z) 2[bis(lmethylethyl)amino]ethyl [S(R*,S*)] 4[[3,3diethyll[[[l(4methylphenyl)butyl] amino]carbonyl] oxo2azetidinyl]oxy]2,6 dimethylbenzoate. SUBSTITUTESHEET . |
21. | A compound selected from the group consisting of: (a) [S(R*,S*)]2[4[[[2(dimethylamino)ethyl]methyl amino]carbonyl]phenoxy]3,3diethylN[l(4 methylphenyl]butyl]4oxolazetidinecarboxamide, (b) [S(R^S*)]2[4[[[2(dimethylamino)ethyl]methyl amino]earbonyl]phenoxy]3,3diethylN[l(3,4 methylenedioxyphenyl]butyl]4oxolazetidine carboxamide, (c) [S(R*,S*)]2[4[[[4methylpiperazinlyl]earbon¬ yl]phenoxy]3,3diethylN[l(4methylphenyl]but¬ yl]4oxolazetidinecarboxamide, (d) [S(R*,S*)]2[4[[[4methylpiperazinlyl]earbon¬ yl]phenoxy]3,3diethylN[1(3,4methylenedioxy¬ phenyl] butyl]4oxolazetidinecarboxamide, (e) [S(R*,S*)]2[4[[[4cyclopropylpiperazinlyl] carbonyl]phenoxy]3,3diethylN[1(4methylphen yl]butyl]4oxolazetidinecarboxamide, (f) [S(R*,S*)]2[4[[[4cyclopropylpiperazinlyl] earbonyl]phenoxy]3,3diethylN[l(3,4methylene dioxyphenyl] butyl]4oxolazetidinecarboxamide, (g) [S(R*,S*)]2[4[[[piperazinlyl]carbonyl] phenoxy]3,3diethylN[l(4methylphenyl]butyl] 4oxolazetidinecarboxamide, or (h) [S(R*,S*)]2[4[[[piperazinlyl]carbonyl] phenoxy]3,3diethylN[l(3,4methylenedioxyphen¬ yl] butyl]4oxolazetidinecarboxamide, (i) [S(R*,S*)]2[4[[((2dimethylamino)ethyl) ethylamino]carbonyl]phenoxy]((3,3diethylN[l(4 methylphenyl)butyl]4oxolazetidinecarboxamide, (j) [S(R*,S*)]2[4[[((2diethylamino)ethyl) ethylamino]carbonyl]phenoxy]((3,3diethylN[l(4 methylphenyl)butyl]4oxolazetidinecarboxamide, SUBSTITUTESHEET (k) [S(R*,S*)]2[4[[(4(2Hydroxyethyl))piperazinl yl]earbonyl]phenoxy]((3,3diethylN[1(4methyl phenyl)butyl]4oxolazetidinecarboxamide, (1) [S(R*,S*)]2[4[[(4(2Hydroxyethyl))piperazin 1yl]earbonyl]phenoxy]((3,3diethylN[l(3,4, methylenedioxyphenyl)butyl]4oxolazetidine carboxamide, or (m) [S(R>'sS*)]2[4[[(4(ethoxycarbonylmethyl))piper azinlyl]carbonyl]phenoxy]((3,3diethylN[l(3, 4methylenedioxyphenyl)butyl]4oxolazetidinecar boxamide. |
22. | A compound according to Claim 1 which is (a) [S(R* , S*)] 2 [4 [(4morpholinyl) earbonyl ]phenoxy] ( ( 3 , 3d i ethylN [ 1 ( methylphenyl ) butyl ] 4oxol azetidinecarboxamide, or (b) [S(R*,S*)]2[4[(4morpholinylyl)carbonyl]phenox y]( (3 , 3d i ethylN [l( 3 , 4methylenedioxyphenyl)bu tyl]4oxolazet id inecarboxamide. |
23. | A compound according to Claim 1 which is (a) [S(RΛ,S*)]2[4[[((2Dimethylamino)ethyl)methyl amino]carbonyl]phenoxy]((3,3diethylN[l4 methylphenyl)butyl]4oxolazetidinecarboxamide, (b) [S(R*,S*)]2[4[[(4~Methyl)piperazin lyl]carbonyl]phenoxy]((3 , 3d i ethylN [l(t*— methylphenyl ) butyl ]•— oxo1azet id ine¬ carboxamide, SUBSTITUTE SHEET (c ) [S(R* , S*) ]2[4[ [ (4Methyl)piperazin 1yl]earbonyl]phenoxy]((3,3diethylN[l(3,4,■ methylenedioxyphenyl)butyl]4oxolazetidine¬ carboxamide, (d) [S(R*,S*)]2[4[[(4Cyclopropyl)piperazin lyl]carbonyl]phenoxy]((3,3diethylN[l(4 methylphenyl)butyl]4oxolazetidine¬ carboxamide, (e) [S(R*,S*)]2[4[[(4Cyclopropyl)piperazin lyl]carbonyl]phenoxy]((3,3diethylN[l(3,4 methylenedioxyphenyl)butyl]4oxolazetidine¬ carboxamide, (f) [S(R*,S*)]2[4[(piperazin lyl)carbonyl]phenoxy]((3,3diethylN[l(4 methyIphenyl)butyl]4oxolazetidine carboxamide, or (g) [S(R*,S*)]2[4[(piperazin lyl)carbonyl]ρhenoxy]((3,3diethylN[l(3,4 methylenedioxyphenyl)butyl]4oxolazetidine¬ carboxamide. |
24. | A pharmaceutical composition for the inhibition of human leukocyte elastase which comprises a nontoxic therapeutically effective amount of a compound of Claim 1 and a pharmaceutically acceptable carrier. |
25. | A method of treatment for the inhibition of human leukocyte elastase which comprises the administration to a subject in need of such inhibition a nontoxic therapeutically effective amount of a compound of Claim 1. SUBSTITUTESHEET . |
26. | A process for the preparation of a compound of Claim 1 which comprises treating a compound having the formula: with a compound having the formula: HYN R( where R, R1 , R2, R3, R7, R8, Ra, M, Q and Y are as defined in Claim 1. SUBSTITUTE SHEET. |
BACKGROUND OF THE INVENTION
We have found that a group of new substituted azetidinones are potent elastase inhibitors and therefore are useful anti-inflammatory and antidegenerative agents.
Proteases from granulocytes and macrophages have been reported to be responsible for the chronic tissue destruction mechanisms associated with inflammation, including rheumatoid arthritis and emphysema. Accordingly, specific and selective inhibitors of these proteases are candidates for potent anti-inflammatory agents useful in the treatment of inflammatory conditions resulting in connective tissue destruction, e.g. rheumatoid arthritis, emphysema, bronchial inflammation, chronic bronchitis, glomerulonephritis, osteoarthritis, spondylitis, lupus, psoriasis, atherosclerosis,
SUBSTITUTESHEET
sepsis, septicemia, shock, myocardial infarction, reperfusion injury, periodontitis, cystic fibrosis and acute respiratory distress syndrome.
The role of proteases from granulocytes, leukocytes or macrophages are related to a rapid series of events which occurs during the progression of an inflammatory condition:
(1) There is a rapid production of prostaglandins (PG) and related compounds synthesized from arachidonic acid. This PG synthesis has been shown to be inhibited by aspirin-related nonsteroidal anti-inflammatory agents including indomethacin and phenylbutazone. There is some evidence that protease inhibitors prevent PG production; (2) There is also a change in vascular permeability which causes a leakage of fluid into the inflamed site and the resulting edema is generally used as a marker for measuring the degree of inflammation. This process has been found to be induced by the proteolytic or peptide cleaving activity of proteases, especially those contained in the granulocyte, and thereby can be inhibited by various synthetic protease inhibitors, for example, N-acyl benzisothiazolones and the respective 1,1-dioxides. Morris Zimmerman et al., J. Biol. Chem.. 255. 9848 (1980); and
(3) There is an appearance and/or presence of lymphoid cells, especially macrophages and polymorphonuclear leukocytes (PMN). It has been known that a variety of proteases are released from the macrophages and PMN, further indicating that the proteases do play an important role in inflammation. In general, proteases are an important
SUBSTITUTE SHEET
family of enzymes within the peptide bond cleaving enzymes whose members are essential to a variety of normal biological activities, such as digestion, formation and dissolution of blood clots, the formation of active forms of hormones, the immune reaction to foreign cells and organisms, etc., and in pathological conditions such as the degradation of structural proteins at the articular cartilage/pannus junction in rheumatoid arthritis etc. Elastase is one of the proteases. It is an enzyme capable of hydrolyzing the connective tissue component elastin, a property not contained by the bulk of the proteases present in mammals. It acts on a protein's nonterminal bonds which are adjacent to an aliphatic amino acid. Neutrophil elastase is of particular interest because it has the broadest spectrum of activity against natural connective tissue substrates. In particular, the elastase of the granulocyte is important because, as described above, granulocytes participate in acute inflammation and in acute exacerbation of chronic forms of inflammation which characterize many clinically important inflammatory diseases.
Proteases may be inactivated by inhibitors which block the active site of the enzyme by binding tightly thereto. Naturally occurring protease inhibitors form part of the control or defense mechanisms that are crucial to the well-being of an organism. Without these control mechanisms, the proteases would destroy any protein within reach. The naturally occurring enzyme inhibitors have been shown to have appropriate configurations which allow them to bind tightly to the enzyme. This
....—-_. ,,_. *•*-*-•-**•*» j •_» * ~* • )
configuration is part of the reason that inhibitors bind to the enzyme so tightly (see Stroud, "A Family of Protein-Cutting Proteins" Sci . Am. July 1974, pp. 74-88). For example, one of the natural inhibitors, α*L-Antitrypsin, is a glycoprotein contained in human serum that has a wide inhibitory spectrum covering, among other enzymes, elastase both from the pancreas and the PMN. This inhibitor is hydrolyzed by the proteases to form a stable acyl enzyme in which the active site is no longer available. Marked reduction in serum α-^-antitrypsin, either genetic or due to oxidants, has been associated with pulmonary emphysema which is a disease characterized by a progressive loss of lung elasticity and resulting respiratory difficulty. It has been reported that this loss of lung elasticity is caused by the progressive, uncontrolled proteolysis or destruction of the structure of lung tissue by proteases such as elastase released from leukocytes. J. C. Powers, TIBS. 211 (1976).
Rheumatoid arthritis is characterized by a progressive destruction of articular cartilage both on the free surface bordering the joint space and at the erosion front built up by synovial tissue toward the cartilage. This destruction process, in turn, is attributed to the protein-cutting enzyme elastase which is a neutral protease present in human granulocytes. This conclusion has been supported by the following observations: (1) Recent histochemical investigations showed the accumulation of granulocytes at the cartilage/ pannus junction in rheumatoid arthritis; and (2) a recent investigation of mechanical
SUBSTITUTE SHEET
behavior of cartilage in response to attack by purified elastase demonstrated the direct participation of granulocyte enzymes, especially elastase, in rheumatoid cartilage destruction. H. Menninger et al., in Biological Functions of Proteinases. H. Holzer and H. Tschesche, eds. Springer-Verlag, Berlin, Heidelberg, New York, pp. 196-206, 1979.
In a second aspect this invention concerns the use of novel azetidinones in the treatment of certain cancers including nonlymphoblastic leukemias, acute myelogenous leukemia (FAB Ml and FAB M2), acute promyelocytic leukemia (FAB M3), acute myelomonocytic leukemia (FAB M4), acute monocytic leukemia (FAB M5), erythroleukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, chronic monocytic leukemia and conditions associated with leukemia involving activity of PMN neutral proteases e.g. disseminated intravascular coagulation. We have found that the substituted azetidinones disclosed herein are inhibitors of proteinase 3 (PR-3), also known as myeloblastin.
See C. Labbaye, si. al- , Proc. Natl. Acad. Sci. USA, vol. 88, 9253-9256, (1991), Wegner autoantigen and myeloblastin are encoded by a single mRNA; D. Campanelli, ≤£. al- . J- Exp. Med., vol. 172, 1709-1714, (1990), Cloning of cDNA for proteinase 3: A serine protease, antibiotic, and autoantigen from human neutrophils; and Bories, et.. al- . Cell vol. 59, 959-968, (1989) Down-regulation of a serine protease, myeloblastin, causes growth arrest and differentiation of promyelocytic leukemia cells.
Recently, down regulation of PR-3 has been
SUBSTITUTE SHEET
implicated in the proliferation and maintenance of a differentiated state of certain leukemia cells. In particular, Bories, ≤i. al- . have shown that expression of this enzyme, hereinafter designated proteinase 3/myeloblastin, can be inhibited by treatment of HL-60 human leukemia cells with an antisense oligodeoxynucleotide and that such treatment induces differentiation and inhibits proliferation of these cells. Moreover, we have now demonstrated that the treatment of the HL-60 cell human leukemia cell line, among others, with the compounds of the instant invention, likewise results in the inhibition of proliferation and induction of differentiation in such cells. Accordingly, we believe that treatment of leukemia such as nonlymphoblastic leukemias, acute myelogenous leukemia (FAB Ml and FAB M2), acute promyelocytic leukemia (FAB M3), acute myelomonocytic leukemia (FAB M4), acute monocytic leukemia (FAB M5), erythroleukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, chronic monocytic leukemia and conditions associated with leukemia involving activity of PMN neutral proteases e.g. disseminated intravascular coagulation, comprising: administration of a therapeutically effective amount of compound of Formula I will result in remission of the disease state. Administration may be either oral or parenteral.
BRIEF DESCRIPTION OF THE INVENTION
The instantly claimed invention is directed to specifically substituted azetidinones of Formula I
SUBSTITUTESHEET
These substituted azetidinones have been found to be useful anti-inflammatory and antidegenerative agents. This invention is also directed to pharmaceutical compositions and methods of using these specifically substituted azetidinones These compounds will also be useful in the treatment of certain leukemias and leukemia related conditions
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to potent elastase inhibitors of Formula (I),
SUBSTITUTE SHEET
which are useful in the prevention, control and treatment of inflammatory and degenerative conditions especially arthritis and emphysema.
More particularly, the instant invention is directed to the compounds of the Formula (I)
and pharmaceutically acceptable salts thereof wherein: R is C 1 _ 6 alkyl;
R 1 is C-^alkyl or C*- L _6alkoxy-C*-__6alkyl; M is
SUBSTITUTE SHEET
(7) C* j __ alkylcarbonyl,
(8) di-(C*L_6alkyl)amino;
(9) hydroxy;
R-2 and R-* are each independently
5 (1) hydrogen,
(2) C 1 _ 6 alkyl,
(3) halo,
(4) carboxy,
(5) C- j ^alkoxy, 10 (6) phenyl,
(8) aminoC2_3alkyloxy earbonyl wherein the amino is optionally mono or di
15 substituted with C-j^alkyl,
(9) aminoC2_3alkylamino earbonyl wherein the amino is optionally mono or di substituted with
20 (10) hydroxy,
(11) aminocarbonyl wherein the amino is optionally mono or di substituted with C- j ^alk l,
(12) hydroxymethyl,
25 (13) aminocarbonyloxy C- j ^alkyloxy wherein the amino is optionally mono or di substituted with C*-__ 6 alkyl, (14) cyano, 30 (15) morpholinocarbonylphenyl,
(16) amino wherein the amino is optionally mono or di substituted with Cι_ 6 alkyl,
SUBSTITUTESHEET
with the proviso that R^ and R- * may be joined together to form a methylenedioxy group or a furan ring, (17) morpholinocarbonyl;
O .R _
R 4 is ( a) Q-C- Y- N or
R,
O
( b) Q-C-OR x -where R x is carboxy C-j -galkyl,
benzyloxycarbonylC* ) __3alkyl, or t-butoxycarbonylCι_3alkyl,
wherein
Q is a covalent bond or
— c —
R,
wherein R5 and R^ are each individually or hydrogen,
SUBSTITUTESHEET
15 or a covalent bond ;
R*L2 is hydrogen or C-^alkyl; R*7 and Rg are each individually
20 (a) hydrogen,
(c) Cι_galkyloxy C2_3alkyl,
(d) hydroxy C2_6alkyl,
(e) polyhydroxyC 2 _6alkyl,
25 (f) carboxamido C-^.^alkyl,
(g) polyacyloxyC 2 _6alkyl
(i) substituted phenyl or phenyl
C- j ^alkyl, wherein the substitutent is
30 ∑l as defined immediately below,
(j) C 2 _6alkenyl,
(k) C 6 _ 10 cycloalkenyl,
SUBS J iT s ιz on e. ;
(1) heteroaryl C- j ^al yl wherein the hetero aryl includes pyridinyl, imidazolyl, triazolyl, benzylimidazolyl, and furyl,
5 ( ) carboxy Cι__ 6 alkyl,
(n) carbo C 1 _ 6 alkoxy C- j ^alkyl, (o) phenylsulfonyl, (P) C 1 _ 6 alkylsulfonyl, (q) benzyloxy,
10 (r) morpholinyl C* j __3alkylsulfonyl,
(s) tetrahydropyranyl, (t) aminoC*L_3alkylsulfonyl wherein the amino is optionally mono or di substituted with
15 (u) aminocarbonyl wherein the amino is optionally mono or di substituted with C 1 _ 6 alkyl,
(v) aminocarbonyloxyC2_6*--**lkyl wherein the amino is optionally mono or di
20 substituted with C^_ 6 alkyl,
(w) azabicyclo of 7 to 12 atoms, (x) di C*L_3alkylamino C2_galkyl wherein the amino is optionally mono or di substituted with C j _^alkyl,
25 (y) bicycloalkyl of 7 to 12 atoms,
(z) C3_ιøcycloal yl optionally substituted with C*-__ 6 alkyl, (aa) pyrazolidinyl, (bb) substituted piperidinyl or
30 prrrolidinyl wherein the substitutent is hydrogen,
SUBSTITUTESHEE1
C* j _3alkyl, hydroxyC- j ^alkylbenzyl, carboxamido or amino wherein the amino is optionally mono or di substituted with C-^.^alkyl, (cc) substituted pyrrolidinyl wherein the substitutent is carboxamido or amino wherein the amino is optionally mono or di substituted with C- j ^al yl, (dd) pyrimidinyl,
(ee) N-cyano-N'-phenylamidino, (ff) phosphonoC*L_5alkyl, or (gg) α-C*L_3alkyl benzyl or mono or di substituted benzyl or mono or di substituted pyridylmethyl, wherein the substitutents are X* ] _ and X£,
SUBSTITUTESHEET
(14) phenylsulfonylaminocarbonyl; X 2 is hydrogen, halo or C-^alkyl;
n is 1, 2, 3, 4 or 5;
Rg is selected from hydrogen, C*^_ alkyl, and or phenyl, phenyl C*L_3alkyl, pyridyl, and pyridyl C 1 _ 3 alkyl; R* Q and R^ are each independently selected from hydrogen, C- j ^alk l, and C* j __3alkoxy or aryl as defined above, or are together 0=; or
wherein Ry and Rg are joined together to form mono or di substituted ring of 4, 5, 6, or 7 atoms or 7 to 12 atoms such as
(1) piperidinyl or homopiperdinyl,
(2) piperazinyl, (3) morpholinyl, thiomorpholinyl or
1,l-dioxo-4-thiomorpholinyl,
(4) pyrroylidinyl,
(5) pyrryl,
(6) imidazolyl, (7) triazolyl,
(8) saturated azabicyclo of 7 to 12 atoms,
(9) azaspiro having 3 to 9 carbon atoms, said ring being saturated, (10) tetrazolyl,
(11) pyrazolidinyl,
(12) dihydodimethoxyisoquinolyl,
(13) azetidinyl, or
* . :- ;
(14) diazabicyclo ring of 7-12 atoms, wherein the substituents are each selected from the group consisting of hydrogen and C-^alkyl, benzyloxycarbonyl, carboxy, phenyl C-^alkyl amino earbonyl, pyrrolidinylmethyl, hydroxy C*L_6alk loxy, C- j ^alkyloxy earbonyl, aminocarbonyl wherein the amino is optionally mono or di substituted with C*^_ 6 alkyl, and oxo; or -N(R7)R8 may be an amino acid residue including natural amino acids such as lysine; or
Rg and Rg are joined together to form a mono or di substituted saturated monocyclic ring of 6 to 7 atoms and having two hetero atoms which are the nitrogens to which Rg and Rg are attached; said rings to include piperazinyl and homopiperazinyl; or Rg and R*Lø are joined together to form a mono or di substituted monocyclic saturated ring of 5 to 7 atoms and having one hetero atom which is the nitrogen to which Rg is attached; or wherein Rg and R- j ^ are joined together to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 atoms, said ring having one hetero atom which is the nitrogen to which Rg is attached; or wherein R*-_Q and R- j ^ are joined together to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 carbon atoms ; or wherein Rg and R- are joined together to form a mono or di substituted saturated monocyclic ring of 5, 6, or 7 atoms, said ring having one hetero atom which is the nitrogen to which Rg is attached; and the substituents are independently selected from Hydrogen and C1-3alkyl.
SUBSTITUTESHEET
As appreciated by those of Skill in the art the term "alkyl" such as in C* j __^alkyl, includes, methyl, ethyl, propyl, butyl, pentyl, and hexyl, and where appropriate, branched chained forms including isopropyl and tert-butyl.
As may also be appreciated by those of skill H
in the art, the (-CR-*^*-) 11 spacer in definition Y, may, in the alternative be placed to the right of CR 10 R U .
R.
As may also be appreciated, the group -N
R 7 may also be oxidized to the corresponding oxide -N 0
R 8 In one Class the instant invention is directed to the compounds of the Formula (I)
SUBSTITUTESHEET
and pharmaceutically acceptable salts thereof wherein: R is C 1 _ 6 alkyl; R **** is C* | __^alkyl or C^.^alkox -C^.^alkyl;
M is
Ra is
S' BΞTiTU-c SHEET
Rb is hydrogen, or C-^alkyl, R2 and R^ are each independently
(1) hydrogen,
(2) C-^alkyl, (3) halo,
(4) carboxy,
(5) C 1 _ 6 alkoxy,
(6) phenyl,
(7) C-^alkylcarbonyl, (8) amino wherein the amino is optionally mono or di substituted with C* j __6alkyl, or with the proviso that R^ and R~- may be joined together to form a methylenedioxy group or a furan ring;
O .R .
R 4 is ( a) -Q- C- Y- N or
C -b) -Q- C- OR x -where R x is carboxy- C.. - 6 alkyl,
benzyloxycarbonylC* | __3alkyl , or t-butoxycarbonylC* j __3alkyl ,
wherein
Q is a covalent bond or
SUBSTITUTE SHEET
wherein R5 and R $ are each individually Cι_3alkyl or hydrogen
a covalent bond;
R 12 is hydrogen or C-^alkyl; R*7 and Rg are each individually
(a) hydrogen,
(b) C-^alkyl,
(c) C* j __ 6 alkyloxy C 2 _3alkyl,
(d) hydroxy C 2 _6alk l,
(e) carboxamido C*^_^alkyl,
(f) C 1 _ 6 alkanoyl,
SUBSTITUTESHEET
(g) substituted phenyl or phenyl C* j __^alkyl wherein the substitutents are X * L , and X (h) C 2 _6alkenyl,
5 (i) Cg.iøcycloalkenyl,
(j) heteroaryl C- j ^alkyl wherein the hetero aryl includes pyridinyl, imidazolyl, triazolyl, benzylimidazolyl, and furyl,
10 (k) carboxy C-^alkyl,
(1) C 1 _ 6 alkylsulfonyl, (m) carboCι_£alkylox C2_3alkyl, (n) morpholinyl C*-__3alkylsulfonyl, (o) aminoC- j ^alkylsulfonyl wherein the
15 amino is optionally mono or di substituted with C-^alkyl, (p)aminocarbonyl wherein the amino is optionally mono or di substituted with C- j ^alkyl,
20 (q) aminocarbonyloxyC- j ^alkyl wherein the amino is optionally mono or di substituted with C*^_^alkyl, (r) di C*L_3alkylamino C*^_^alkyl wherein the amino is optionally mono or di
25 substituted with C 1 _ 6 alkyl,
(s) pyrazolidinyl, (t) substituted piperidinyl as defined above, (u) substituted pyrrolidinyl as defined
30 above,
(v) pyrimidinyl,
(w) benzyloxy,
(x) C 3 _ 10 cycloalkyl,
SUBSTITUTESHEET
(z) α-C- j ^alkyl benzyl or mono or di substituted benzyl or mono or di substituted pyridylmethyl, wherein the substitutents are X^ and X2, wherein
(1) hydrogen,
(2) halo,
(3) C-^alkyl, (4) halo-C 1 _ 6 alkyl,
(5) C 2 _6alkenyl,
(6) hydroxy-C* j __ 6 alkyl,
(7) C- j ^alkylcarbonyl,
(8) Cι_6alkylcarbonylamino;
(10) carboxy, X 2 is hydrogen, halo or C^.^alkyl;
n is 1, 2, 3, 4 or 5;
Rg is selected from hydrogen, C*^_ alkyl, and C- j ^alkox C- j ^alkyl; R*L and R- j ^ are each independently selected from hydrogen, C* j __4alkyl, and C*L_3alkoxy C- j ^alkyl; or
wherein R7 and Rg are joined together to form mono or di substituted ring of 4, 5, 6, or 7 atoms such as
(1) piperidinyl, (2) piperazinyl,
(3) morpholinyl,
(4) pyrroylidinyl,
(5) pyrryl,
SUB S TITUTE SHEET
(6) imidazolyl,
(7) triazolyl,
(8) tetrazolyl,
(9) pyrazolidinyl, (10) azetidinyl, wherein the substituents are each selected from the group consisting of hydrogen and C- j ^alkyl, benzyloxycarbonyl, carboxy, phenyl C* j __ 3 alkyl amino earbonyl, pyrrolidinyl, methyl, hydroxy C- j ^alkyl, C* j L_ 6 alkyloxy, C j ^alkyloxy earbonyl, and oxo; or Rg and Rg are joined together to form a saturated ring of 5 to 7 atoms and having two hetero atoms; or Rg and R-^ are joined together to form a saturated ring of 5 to 7 atoms and having one hetero atom; or wherein Rg and R12 are joined together to form a ring of 5, 6, or 7 atoms, said ring being saturated; or wherein are joined together to form a ring of 5, 6, or 7 atoms, said ring being saturated; or wherein Rg and R*^ are joined together to form a ring of 5, 6, or 7 atoms, said ring being saturated and having one hetero atom.
In one subclass, the invention concerns compounds of Formula I wherein
R is C*L_3alkyl; R*L is Cι_3alkyl; M is
(a) C 1 _ 6 alkyl, or (b) C 2 _ 6 alkenyl;
R 2 is
(a) hydrogen,
(b) C-L_galkyl, or C* j __^alkoxy, and
SUBSTITUTE SHEET
R-* ** is hydrogen, or
R 2 and R 3 are joined together to form a methylenedioxy group or a furan ring; R5 and R ( *, are each individually hydrogen or C 1 _ 3 alkyl;
R*7 and Rg are each independently selected from
(a) hydrogen,
(b) C-^alkyl, (c) C- j ^alkoxy C 2 _ 3 alkyl,
(d) C3_7cycloalkyl,
(e) hydroxyC 2 _ 3 alkyl,
(d) carbo ,
(g) substituted benzyl wherein the substituents are X^ and X 2 wherein X^ is hydrogen and X 2 is
(1) hydrogen,
(2) halo, or
(3) C-^alkyl;
n is 1, 2 or 3, and
Rg, R*LØ and R* j _* j _ are each independently selected from hydrogen, C- j ^alkyl, and C- j ^alkoxy
C*L_3alkyl; or R*7 and Rg are joined together to form a substituted ring selected from (a) piperidinyl, (b) piperazinyl, and
(c) morpholinyl; or g and Rg are joined together to form a ring of 6 to
SUBSTITUTESHEET
7 atoms and having two hetero atoms; Rg and R-^Q are joined together to form a saturated ring of 5 to 7 atoms and having one hetero atom; or wherein Rg and R^ 2 are joined together to form a ring of 5, 6, or 7 atoms, said ring being saturated; or wherein R-^ Q and R* j _ 2 are joined together to form a ring of 5, 6, or 7 atoms, said ring being saturated; or wherein Rg and R-Q are joined together to form a ring of 5, 6, or 7 atoms, said ring being saturated and having one hetero atom.
In a narrower sub-class are the compounds wherein
Q is a covalent bond; R is methyl or ethyl; R* is methyl or ethyl; M is
(a) C* j _4alkyl, or
(b) C 2 _3alkenyl; R 2 is
(a) hydrogen,
(b) C-L_3alk l, or C- j ^alkoxy, and R3 is hydrogen, or
R 2 and R 3 are joined together to form a furan or dioxacyclopentane ring; n is 1 or 2;
Rg and R*-_ Q are each independently selected from
(a ) C 1 _ 3 alkyl ,
(b) C*L_3alkoxy C-^alkyl ,
(c ) hydrogen ,
SUBSTITUTE SHEET
R*7 and Rg are each independently selected from
(a) C 1 _ 3 alkyl,
(b) C-^alkoxy C 2 _3alkyl, (c) hydrogen,
(d) hydroxyethyl,
(e) carboethoxymethyl,
(f) cyclopropyl, or R and Rg are joined together to form a substituted ring selected from
(a) piperidinyl, and
(b) morpholinyl, or
Rg and Rg are joined together to form a piperazine ring.
(~ ' "..T
V_r * \J '.J ~* c n !
As is defined above, various rings are formed when R8, R9, RIO and R12 are joined. The following is a non-limiting description of some of the preferred rings that are formed when these various substituents are joined.
R8 and R9 are joined
R9 and R10 are joined
SUBSTITUTE SHEET
R9 and R12 are joined
SUBSTITUTE SHEET
R10and R12 are joined
SUBSTITUTE SHEET
d R12 are joined
ouBεπri" SHEET
In another aspect the present invention is directed to the treatment of leukemia, such as . nonlymphoblastic leukemias, acute myelogenous leukemia (FAB Ml and FAB M2), acute promyelocytic leukemia (FAB M3), acute myelomonocytic leukemia (FAB M4), acute monocytic leukemia (FAB M5), erythroleukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, chronic monocytic leukemia and conditions associated with leukemia involving activity of PMN neutral proteases e.g. disseminated intravascular coagulation with compounds of Formula I .
Treatment of leukemia cells comprises: administration of a therapeutically effective amount of a compound of Formula I results in the inhibition of proteinase 3/myeloblastin, inhibition of elastase, inhibition of proliferation of the leukemia cells, induction of differentiation of the leukemia cells, and remission of the disease state. In one alternative embodiment the invention concerns a method of treating leukemia comprising: administration to a patient in need of such treatment of a therapeutically effective amount of compound of Formula I .
In a second alternative embodiment the invention concerns a method of inhibiting proteinase 3/myeloblastin, comprising: administration to a patient in need of such inhibition of a therapeutically effective amount of compound of Formula I as defined above.
SUBSTITUTE SHEET
In a third alternative embodiment the invention concerns a method of inhibiting proteinase 3/myeloblastin and elastase, comprising: administration to a patient in need of such inhibition of a therapeutically effective amount of compound of Formula I as or a pharmaceutically acceptable salt thereof as defined above.
In a fourth embodiment the invention concerns a method of inducing cellular differentiation in leukemia cells comprising: administration to a patient in need of such inhibition of a therapeutically effective amount of compound of Formula I or a pharmaceutically acceptable salt thereof as defined above. Each of the above alternative embodiments
(i.e., those relating to PR3 or cancer), also concerns co-administration of a compound of Formula I as defined above, with an agent or agents known in the art for treatment of leukemia, including, but not limited to epsilon-aminocaproic acid, heparin, trasylol (aprotinin); prednisolone; cytosine arabinoside; β-mercaptopurine; cytarabine; an anthracycline (see Young et. al. (1981) N. Engl. J. Med. 305:139) such as daunorubicin, doxorubicin and epidoxorubicin; Vitamin A derivatives including retinoids and all-trans-retinoic acid (See Ellison R.R. et.al. (1968) Blood 32:507, Arabinoεyl Cytosine: A useful agent in the treatment of leukemia in adults; Cytarabine: Therapeutic new dimensions, Semin. Oncol. 12:1 (1985, supp 3); Weinstein H.J. et. al. (1983) Blood 62:315, Chemotherapy for acute myelogenous leukemia in children and adults results in an enhanced therapeutic response.
SUBSTITUTESHEET
Accordingly, in a fifth alternative embodiment the invention concerns a pharmaceutical composition comprising: a pharmaceutical carrier, a therapeutically effective amount of compound selected from the group consisting of epsilon-aminocaproic acid, heparin, trasylol, prednisolone, cytosine arabinoside, β-mercaptopurine, cytarabine, an anthracycline and a vitamin A derivative; and a therapeutically effective amount of compound of Formula I as defined above.
In a sixth alternative embodiment the invention concerns a method of treating leukemia comprising: co-administration to a patient in need of such treatment of a therepeutically effective amount of compound selected from the group consisting of epsilon-aminocaproic acid, heparin, trasylol, prednisolone, cytosine arabinoside, b-mercaptopurine, cytarabine, an anthracycline, and a vitamin A derivative; and a therapeutically effective amount of compound of Formula I as defined above.
In a seventh alternative embodiment the invention concerns a method of inhibiting proteinase 3/myeloblastin, comprising: co-administration to a patient in need of such inhibition of a therapeutically effective amount of compound selected from the group consisting of epsilon-aminocaproic acid, heparin, trasylol, prednisolone, cytosine arabinoside, β-mercaptopurine, cytarabine, an anthracycline, and a vitamin A derivative; and a therapeutically effective amount of compound of Formula I as defined above.
SUBSTITUTESHEET
In an eighth alternative embodiment the invention concerns a method of inhibiting proteinase 3/myeloblastin and elastase, comprising: administration to a patient in need of such inhibition of a therapeutically effective amount of compound selected from the group consisting of epsilon-aminocaproic acid, heparin, trasylol, prednisolone, cytosine arabinoside, β-mercaptopurine, cytarabine, an anthracycline, and a vitamin A derivative; and a therapeutically effective amount of compound of Formula I as defined above.
In a ninth alternative embodiment the invention concerns a method of inducing cell differentiation in leukemia cells comprising: administration to a patient in need of such inducing of a therapeutically effective amount of compound selected from the group consisting of epsilon-amino¬ caproic acid, heparin, trasylol, prednisolone, cytosine arabinoside, β-mercaptopurine, cytarabine, an anthracycline and a vitamin A derivative; and a therapeutically effective amount of compound of Formula I as defined above.
In a tenth alternative embodiment of the invention the instant compounds can also be used in the treatment of diseases associated with over-expression of cDNa, such as those pulmonary diseases is with abnormal, viscous, or inspissated purulent secretions. Such conditions are found in acute or chronic bronchopulmonary disease including infectious pneumonia, bronchitis or tracheobronchitis, bronchiectasis, cystic fibrosis, asthma, tuberculosis or fungal infections. Utility
SUBSTITUTESHEET
is also found in atelactasis due to tracheal or btonchial impaction and complications of tracheostomy.
In addition, the instant compounds can be co-administered with cDNase which also finds utility in these pulmonary diseases, and which is described in WO 90/07572.
The compounds of the invention are prepared by known methods or are prepared among other methods by the following representative schemes. For example, methods for making such compounds are disclosed in EP 0 337 549, published October 18, 1989, which is hereby incorporated by reference.
This invention also relates to a method of treating inflammation in patients using a compound of Formula (I), particularly a preferred compound as the active constituent.
It has been found that the following compound are effective inhibitors of the proteolytic function of human neutrophil elastase as shown below in Table 1 to 10.
TABLE 1
SUBSTITUTESHEET
TABLE 2
1,993,000 1,151,000 1,339,000 1,725,000 1,688,000 2,100,000 1,008,000 751,000
SUBSTITUTE SHEET
TABLE 3
SUBSTITUTE SHEET
1,634,000 1,144,000 1,079,000 733,000 1,621,000
917,000 1,335,000 1,355,000
942,000 1,897,000 2,792,000 2,371,000 1,508,000
3,284,000
73 -NHCH 2 CH 2 N(CH 3 ) 2 968,000
74 -NH-CH 2 C0 2 H 1,434,000
75 -N(CH 3 )CH 2 CH 2 N(CH 3 ) 2 1,916,000 76 -N(Et)CH 2 CH 2 N(CH 3 ) 2 1,436,000
77 -NHCH 2 CH 2 N(Et) 2 1,187,000
78 -NHCH 2 CH 2 -(4-morpholinyl) 1,841,000
79 -N(CH 3 )CH 2 CH 2 -(4-morpholinyl) 2,118,000
80 -N(CH 3 )CH 2 CH 2 N(CH 2 CH 2 OCH 3 ) 2 2,078,000 81 -N(CH 3 )CH 2 CH 2 N(Et) 2 2,191,000
82 -N(Ph)CH 2 CH 2 N(CH 3 ) 2 2,504,000
83 -N(CH 3 )CH 2 CH 2 CH 2 N(CH 3 ) 2 1,797,000
84 -NHCH 2 CH 2 N(i-Pr) 2 2,100,000
85 -N(CH 3 )CH 2 CH 2 N(0)(CH 3 ) 2 1,589,000 86 -N(CH 3 )CH 2 CH 2 N(i-Pr) 2 2,449,000
87 -NH-S0 2 CH 2 CH 2 -(4-morpholinyl) 775,000
88 -NH-S0 2 CH 2 CH 2 N(CH 3 ) 2 788,000
89 -NHCH 2 CH 2 -(4-imidazolyl) 2,092,000
90 -NHCH 2 CH 2 -(l-piperidinyl) 941,000 91 -N(CH 3 )CH 2 CH 2 -(l-piperidinyl) 892,000
92 -N(CH 3 )CH 2 CH 2 NHCH 3 1,453,000
93 -N(CH 3 )CH 2 CH 2 N(CH 3 )Ac 1,960,000
94 -NHCH 2 CH 2 -(l-pyrrolidinyl) 1,239,000
95 -N(CH 3 )CH 2 CH 2 -(l-pyrrolidinyl) 1,005,000 96 -NHCH 2 CH 2 -(lH-l,2,4-triazol-l-yl) 1,397,000
97 -NH-CH 2 CH 2 -(l-imidazolyl) 1,070,000
98 -NH-CH 2 CH 2 -(3-azabicyclo-[3.2.2-non-3-yl) 3,043,000
99 -NH-CH 2 CH 2 -(3-azaspiro[5.5J-undec-3-yl) 2,583,000
100 -NH-CH 2 CH 2 -(2H-tetrazol-2-yl) 2,006,000 101 -NH-CH 2 CH 2 -(lH-tetrazol-l-yl) 2,053,000
102 -NHCH 2 C(0)-Pro-NHCH 2 Ph 2,747,000
SUBSTITUTESHEET
103 -N(CH 3 )CH 2 CH 2 -(3-azabicyclo-
[3.2.2]non-3-yl) 2,996,000
104 -N(CH 3 )CH 2 CH 2 -(4-imidazolyl) 2,389,000 105 -N(CH 3 )CH 2 CH 2 N(CH 3 )Ac 2,398,000 106 -N(CH 3 )CH 2 CH 2 N(CH 3 )C(0)NHCH 3 2,486,000 107 -N(CH 3 )CH 2 CH 2 N(CH 3 )S0 2 CH 3 2,530,000 108 -N(CH 3 )CH 2 CH 2 (3-azabicyclo-[3.2.2]- non-3-yl) 2,953,000
109 -NHCH 2 CH 2 -(1,l-dioxo-4-thiamorpholinyl) 1,275,000 110 4-dimethylaminobenzylamino 5,598,000 111 3-dimethylaminoanilino 2,286,000 112 -N(CH 3 )CH 2 CH 2 -(l,l-dioxo-4-thia- morpholinyl) 1,596,000 113 4-dimethylaminoanilino 2,591,000 114 -NHCH 2 CH 2 -(l-benzyl-lH-imidazol-2-yl) 3,853,000 115 -N(CH 3 )CH 2 CH 2 (2-pyridyl) 2,272,000 116 -N(CH 3 )(l-azabicyclo[2.2.2]oct-3-yl 3, 80,000 117 -NHCH 2 CH 2 (4-benzyloxycarbonyl-l- piperazinyl) 6,231,000
118 1,2-diethylpyrazolidin-4-ylamino 1,001,000 119 2-(l-ϋ-pyrrolidinylmethyl)-l-pyrrolidinyl 2,692,000 120 -NHCH 2 CH 2 (4-hydroxy-l-piperidinyl) 1,728,000 121 -NHCH 2 CH 2 (l-homopiperidinyl) 2,069,000 122 -N(CH 3 )CH 2 CH 2 (l-homopiperidinyl) 2,899,000 123 -NHCH 2 CH 2 (3-hydroxy-l-piperidinyl) 1,534,000 124 -N(CH3)CH 2 CH 2 (3-hydroxy-l-piperidinyl) 1,963,000 125 -N(CH 3 )CH 2 CH 2 N(CH 3 )CH 2 Ph 2,054,000 126 -N(CH 3 )CH 2 CH 2 (4-benzyloxy-l-piperidinyl) 3,476,000 127 -N(n-Pr) 2 990,000 128 -N(Et) 2 1,454,000
SUBSTITUTESHEET
129 -N(CH 3 )CH 2 CH 2 (4-hydroxy-l-piperidinyl) 1,994,000
130 -N(CH 3 )CH 2 CH 2 (4-oxo-l-piperidinyl) 2,297,000
131 -NHCH 2 CH 2 (3-hydroxy-l-pyrrolidinyl) 1,111,000 132 -N(Et)CH 2 CH 2 (l-piperidinyl) 1,244,000
133 -N(CH 2 Ph)CH 2 CH 2 (l-piperidinyl) 1,521,000
134 4-fluoroanilino- 724,000
135 3-chloroanilino- 201,000
136 3-methoxyanilino 137 -N(CH 2 Ph)CH 2 CH 2 N(CH 3 ) 2 1,380,000
138 -N(CH 3 )CH 2 CH 2 (3-hydroxy-l-pyrrolidinyl) 960,000
139 -N(3-picolyl)CH 2 CH 2 (l-piperidinyl) 1,189,000
140 -NHCH(CH 3 )CH 2 CH 2 CH 2 N(Et) 2 1,361,000
141 -NHCH 2 CH 2 (2-£-hydroxymethyl-l- pyrrolidinyl 1,507,000
142 -N(CH 3 )CH 2 CH 2 (4-t-butoxycarbonyl-l- piperazinyl) 3,471,000
143 -N[CH 2 CH 2 N(CH 3 ) 2 ] 2 1,878,000
144 -N[CH 2 CH 2 N(Et) 2 ] 2 1,508,000 145 -N(CH 3 )CH 2 CH 2 N(CH 3 )(3-picolyl) 2,877,000
146 3,5-dimethyl-l-piperazinyl 1,518,000
147 -N(CH 3 )CH 2 CH 2 N(0)(CH 3 )CH 2 Ph 2,493,000
148 -N(CH 3 )CH 2 CH 2 N(CH 3 )(4-picolyl) 2,389,000
149 2-j>.-(N-benzyl-N-methylaminomethyl)-l- pyrrolidinyl 3,268,000
150 -N(CH 3 )CH 2 CH 2 N(CH 3 )(2-picolyl) 2,165,000
151 -N(CH 3 )CH 2 CH 2 (l-piperazinyl) 1,191,000
152 1-homopiperazinyl 1,951,000
153 -N(CH 3 )CH 2 CH 2 N(CH 3 )CH 2 CH2Ph 2,797,000 154 2-(l-R-pyrrolidinylmethyl)-l-pyrrolidinyl 1.666,000
155 4-benzyl-l-homopiperazinyl 1,979,000
, &&
~β) s fTϊ ^ e
156 -N(CH 3 )CH 2 -[CH(0H)] 4 CH 2 0H 1,198,000
157 -N(CH 3 )CH 2 -[CH(0Ac)] 4 CH 2 0Ac 1,171,000
158 -N(CH 3 )CH 2 CH 2 N(CH 3 )(1-Naphthalenylmethyl) 1,075,000 159 -N(CH 3 )CH 2 CH 2 N(CH 3 )(2-Naphthalenylmethyl) 1,337,000
160 -N(CH 3 )CH 2 CH 2 N(CH 3 )CH(CH 3 )Ph 1,569,000
161 -N(CH 3 )CH 2 CH 2 N(CH 2 Ph) 2 1,021,000
162 l-ethyl-3-ρiperidinylamino 949,000
163 -N(CH 3 )CH 2 CH 2 N(CH 3 )(2-furfuryl) 1,818,000 164 -N(CH 3 )CH 2 CH 2 CH 2 C0 2 H 1,064,000
165 -N(CH 3 )CH 2 CH 2 CH 2 C(0)NHS0 2 Ph 1,550,000
166 -N(CH 3 )CH 2 CH 2 N(CH 3 )CH 2 CH=CH 2 1,359,000
167 -N(CH 3 )CH 2 CH 2 CH 2 N(CH 3 )CH 2 Ph 1,293,000
168 -N(CH 3 )-(CH 2 ) 6 -N(CH 3 )CH 2 Ph 2,157,000 169 -N(CH 3 )CH 2 CH 2 0H 1,457,000
170 -N(CH 3 )CH 2 CH 2 OC(0)N(CH 3 ) 2 1,518,000
171 -N(CH 3 )CH 2 CH 2 N(CH 3 )CH 2 C0 2 -t-Bu 1,831,000
172 -N(CH 3 )(l-ethyl-3-piperidinyl) 1,545,000
173 -N(CH 3 )CH 2 CH 2 N(CH 3 )(tetrahydro-2H- pyran-2-yl-methyl) 2,943,000
174 2,2,6,6-tetramethylpiperidin-4-ylamino 869,000
175 -N(CH 3 )(4-carboxyphenyl) 1,055,000
176 -N(CH 3 )(4-benzenesulfonylaminocarbonyl- 3,231,000 phenyl 177 -N(CH 3 )CH 2 CH 2 N(CH 3 )(4-cyanobenzyl) 2,201,000
178 -N(CH 3 )CH 2 CH 2 N(CH 3 )(4-methylbenzyl) 1,870,000
179 -N(CH 3 )CH 2 CH 2 N(CH 3 )(3-cyanobenzyl) 2,448,000
180 -N(CH 3 )CH 2 CH 2 N(CH 3 ) ( 4-trif luoro- methylbenzyl 905 , 000 181 -N(CH3 )CH 2 CH2N( CH 3 ) ( 3-tr if luoromet__yl- benzyl ) 564 , 000
SUBSTITUTE SHEET
182 -N(CH 3 )CH 2 CH 2 (CH 3 )(4-fluorobenzyl) 2,137,000
183 -NHCH(CH 3 )PH(0)OH 977,000
184 L-lysine (α-N) 755,000 185 -N(CH 3 )CH 2 CH 2 N(CH 3 )(cyclopropylmethyl) 1,787,000
186 -N(CH 3 )CH 2 CH(Ph)N(CH 3 ) 2 1,053,000
187 -N(CH 3 ) 2 1,749,000
188 -N(CH 3 )CH 2 Ph 1,837,000
189 -N(CH 3 )(l-benzyl-3-piperidinyl) 1,879,000 190 -NH-0-CH 2 Ph 1,797,000
191 -N(3-picolyl)CH 2 CH 2 N(CH 3 )CH 2 PH 2,538,000
192 -N(CH 3 )CH 2 CH 2 N(CH 3 )(4-methoxybenzyl) 1,785,000
193 -N(4-picolyl)CH 2 CH 2 N(CH 3 )CH 2 Ph 2,243,000
194 -N(2-picolyl)CH 2 CH 2 N(CH 3 )CH 2 Ph 2,473,000 195 -N(CH 3 )CH 2 CH 2 N(CH 3 )(2,4-dimethylbenzyl) 1,119,000
196 -N(CH 3 )CH 2 CH 2 (2,6-dimethyl-4-morpholinyl) 1,530,000
197 -NH 2 1,638,000
198 -NHCH 3 1,825,000
199 4-morpholinyl 2,376,000 200 cis-2,6-dimethyl-4-morpholinyl 1,837,000
201 -NH-CH 2 CH 2 CH 2 CH 3 2,460,000
202 -N(CH 3 )CH 2 CH 2 N(CH 3 )C(=N-CN)NHPh 1,763,000
203 -N(CH 3 )CH 2 CH 2 N(CH 3 )(3-fluorobenzyl) 1,262,000
204 -N(CH 3 )CH 2 CH 2 N(CH 3 )(2-chlorobenzyl) 1,591,000 205 -N(CH 3 )CH 2 CH 2 N(CH 3 )(3-methoxybenzyl) 1,911,000
206 -N(CH 3 )CH 2 CH 2 N(CH 3 )(3,5-dimethoxybenzyl) 1,735,000
207 3,4-dihydro-6,7-dimethoxy-2-(lH)iso- quinolinyl 2,698,000
208 -N(CH 3 )(l-benzyl-4-piperidinyl) 1,948,000 209 L-lysine (ε-N) 929,000
210 -N(CH 3 )CH 2 CH 2 N(CH 3 )(2-adamantyl) 2,132,000
SUBSTITUTESHEET
211 -N(CH 3 )(4-piperidinyl) 85,000
212 5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl 860,000
213 -N(CH 3 )CH 2 C0 2 H 984,000 214 -N(CH 3 )CH 2 CH 2 CH 2 N(CΞ 3 )CH 2 CH 3 1,099,000
215 -N(CH 3 )(l-methyl-4-piperidinyl) 1,283,000
216 -N(CH 3 )(l-propyl-4-piperidinyl) 1,312,000
217 -N(CH 3 )(l-ethyl-4-piperidinyl) 1,422,000
218 -N(CH 3 )CH 2 CH(CH 3 )N(CH 3 )CH 2 Ph 2,123,000 219 -N(CH 3 )CH 2 CH(CH 3 )N(CH 3 ) 2 1,588,000
220 -N(CH 3 )CH 2 CH 2 N(CH 3 )(bicyclo[2.2.1]- hept-2-yl) 1,874,000
221 -N(CH 3 )CH 2 CH 2 NH(2-adamantyl) 3,010,000
222 -N(CH 3 )CH 2 CH 2 N(CH 3 )(6,6-dimethylbicyclo- [3.1.1]hept-2-yl 2,288,000
223 -N(CH 3 )CH 2 CH 2 N(CH 3 )(bicyclo[3.2.1]- oct-2-yl) 2,584,000
224 -NH(t-Bu)
225 -N(CH 3 )CH 2 CH 2 N(CH 3 )(l-cyclohexen-l-yl) 1,839,000 226 -N(CH 3 )CH 2 CH 2 NHC(CH 3 ) 2 CH=CH 2 1,309,000
227 2-£-carboxamido-l-pyrrolidinyl 931,000
228 2-hydroxymethyl-l-piperidinyl 50,000
229 3-dimethylamino-l-pyrrolidinyl 1,336,000
230 -N(CH 3 )CH 2 CH 2 N(CH 3 )(cyclohexylmethyl) 231 -N(CH 3 )CH 2 CH 2 N(CH 2 CH=CH 2 )C(CH 3 ) 2 CH=CH 2 925,000
232 -N(CH 3 )CH 2 CH 2 N(CH 3 )(4-ethylcyclohexyl) 2,476,000
233 -N(CH 3 )CH 2 CH 2 N(CH 3 )(2-ethylcyclohexyl) 2.030,000
234 -N(CH 3 )CH 2 CH 2 N(CH 3 )(4-methylcyclohexyl) 2,166,000
235 -N(CH 3 )CH 2 CH 2 N(CH 3 )(cyclohexyl) 1,952,000 236 -N(CH 3 )CH2CH 2 N(CH3)CH2C0 2 H'*TFA 31,000
237 -N(CH 3 )CH 2 CH 2 N(CH 3 )CH 2 C(0)N(CH 3 * ) 2 2,679,000
SUBSTITUTESHEET
238 3-dimethylamino-l-azetidinyl
239 l-diphenylmethyl-3-azetidinyl
240 -N(CH)CH 2 CH 2 N(CH 3 )(cyclohexylmethyl) 3,003,000
241 - HCH 2 CH2N(Et)CH 2 CH2θCH 3 1,090,000
TABLE 5
1,700,000 7,486,000 2,453,000 5,276,000 5,171,000 1,100,000 2,392,000 2,476,000 1,571,000 1,947,000 2,324,000 1,768,000
SUBSTITUTE SHEET
254 2-pyrimidinyl 2,142,000
255 -CH 2 CH 2 0C(0)NHCH 3 2,548,000
256 cyclopropyl 3,587,000 256a -CH 2 CH 2 0H 2,000,000
TABLE 6
NH 2 2,342,000
4-morpholinyl 1,785,000
-N(CH 3 )CH 2 CH 2 N(CH 3 ) 2 2,522,000
-N(CH 3 )CH 2 CH 2 N(CH 3 ) 2 3,317,000
-N(Et) 2 3,207,000
-N(CH 3 )(n-Bu) 3,125,000
4-methyl-l-piperazinyl 3,805,000
-N(CH 3 )CH 2 CE 2 N(CH 3 )CH 2 Ph 3,427,000
4-cyclopropyl-l-piperazinyl 4,500,000
1-piperazinyl 3,250,000 4-(2-hydroxyethyl)-l-piperazinyl 4,800,000 4-morpholinyl 3,700,000
SUBSTITUTE SHEET
TABLE 7
SUBSTITUTE SHEET
TABLE 8
SUBSTITUTE SHEET
TABLE 9
SUBSTITUTE SHEET
OCH, 4-methyl-l-piperaz.nyl 1,845,000
CI -N(CH 3 )CH 2 CH 2 N(CH 3 ) 2 1,475,000 CI -N(CH 3 )CH 2 CH 2 N(Et) 2 1,282,000 CI -N(CH 3 )CH 2 CH 2 N(i-Pr) 2 1,497,000 CI -N(CH 3 )CH 2 CH 2 N(CH 3 )CH 2 Ph 1 ,462,000 CH, -N(CH 3 )CH 2 CH 2 N(CH 3 ) 2
TABLE 10
-0CH 2 CH 2 N(CH 3 ) 2 563,000
-OCH 2 CH 2 N(Et) 2 749,000
-OCH 2 CH 2 N(i-Pr) 2 612,000
- (CH 3 )CH 2 CH 2 N(CH 3 ) 2 352,000
-N(CH 3 )CH 2 CH 2 N(Et) 2 377,000
-N(Et)CH 2 CH 2 N(CH 3 )2 398,000 -N(CH 3 )CH 2 CH 2 N(CH 3 ) 2 838,000
SUBSTITUTE SHEET
Enzyme Assays for the Inhibition of Human Polymorphonuclear Leukocyte Elastase Via Hydrolysis of N-t-Boc-alanyl-alanyl-prolylalanine-p-nitroanilide (Boc-AAPAN) or N-t-Boc-alanyl-prolylvaline-p-nitro- anilide (Boc-AAPVN'. Reagent:
0.05M TES (N-tris[hydroxymethyl]methyl-2- mino-ethanesulfonic acid) Buffer, pH 7.5. 0.2 mM Boc-AAPAN or Boc-AAPVN. To prepare substrate, the solid was first dissolved in 10.0 ml DMSO. Buffer at pH 7.5 was then added to a final volume of 100 ml.
Crude extract of human polymorphonuclear leukocytes (PMN) containing elastase activity. Inhibitors (azetidinones) to be tested dissolved in DMSO just before use.
To 1.0 ml of 0.2 mM Boc-AAPAN in a cuvette, 0.01-0.1 ml of DMSO with or without inhibitor was added. After mixing, a measurement was taken at 410 mμ to detect any spontaneous hydrolysis due to presence of test compound. 0.05 Milliliters of PMN extract was then added and the ΔOD/min at 410 mμ was measured and recorded. Beckman model 35 spectro- photometer was used.
Results were expressed to the nearest thousand ^obs/I which is the second order rate constant in per mole per second for inactivation of the enzyme.
SUBSTITUTE SHEET
The elastase activity in the crude PMN extract may vary from one preparation to another. A control of each new batch is run, and the volume added in the assay procedure is adjusted according to activity.
This invention also relates to a method of treating inflammation in patients using a compound of Formula (I), particularly a preferred compound as the active constituent. It has been found that the compounds of
Formula (I) are effective inhibitors of the proteolytic function of human neutrophil elastase.
Accordingly, the compounds of Formula (I), can be used to reduce inflammation and/or relieve pain in diseases such as emphysema, rheumatoid arthritis, osteoarthritis, gout, bronchial inflammation, chronic or acute bronchitis, cystic fibrosis, adult respiratory distress syndrome, atherosclerosis, sepsis, septicemia, shock, periodontitis , glomerular nephritis or nephosis, myocardial infarction, reperfusion injury, infectious arthritis, rheumatic fever and the like, and may reduce hemorrhage in acute promyelocytic leukemia and the like. In this capacity, and as appreciated by those of skill in the art, therapy comprising administration of compounds of Formula I may actually include co-administration of one or more additional active agents. Classes of active agents include, but are not limited to β 2 -adrenergic agonists; anti-cholinergic agents; steroids; non-steroidal
;_. υBo .Tϋ r c onc ι
anti-inflammatory agents (NSAID's); mucolytic agents; most all stabilizers; and antibacterials .
For purposes of this specification, p2~adrenergic agonists are intended to include, but are not limited to, metaproterenol, terbutaline, isoetharine, albuterol, and ritodrine, carbuterol, fenoterol, quinterenol, rimiterol, salmefamol, soterenol, and tretoquinol.
For purposes of this specification, anti- cholinergic agents are intended to include, but are not limited to, atropine, and iptratropium-bromide.
For purposes of this specification, mucolytic agents are intened to include, but are not limited to acetylcysteine and guattenesin. For purposes of this specification, steroids are intended to include, but are not limited to, prednisone, beclomethasone, budesonide, solumedrol, triamcinolone, and methyl-prednisolone.
For purposes of this specification most cell stabilizers are intended to include, but are not limited to cromolyn and ketotafin.
For purposes of this specification, non¬ steroidal anti-inflammatory agents are intended to include, but are not limited to aspirin, diflunisal, naphthylsalicylate, phenylbutazolone, oxyphenbuta- zolone, indomethacin, sulindac, mefenamic acid, meclofenamate sodium, tolmetin, ibuprofen, naproxen, fenoprofen and piroxicam.
For the purposes of this specification, antibacterial agents are intended to include the broad classes of penicillins, cephalosporins and
SUBSTITUTESHEET
other beta-lactams, aminoglycosides, quinolones, macrolides, tetracyclines , sulfonamides, lincosamides and polymyxins . The penicillins, in turn, are intended to include, but are not limited to penicillin G, penicillin V, methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, floxacillin, ampicillin, ampicillin/sulbactam, amoxicillin, amoxicillin/clavulanate, hetacillin, cyclacillin, bacampicillin, carbenicillin, carbenicillin indanyl, ticarcillin, ticarcillin/clavulanate, azlocillin, mezlocillin, peperacillin, and mecillinam. The cephalosporins and other beta-lactams are intended to include, but are not limited to cephalothin, cephapirin, cephalexin, cephradine, cefazolin, cefadroxil, cefaclor, cefamandole, cefotetan, cefoxitin, ceruroxime, cefonicid, ceforadine, cefixime, cefotaxime, moxalactam, ceftizoxime, cetriaxome, ceftizoxime, cetriaxone, cephoperazone, ceftazidime, imipenem and aztreonam. The aminoglycosides are intended to include, but are not limited to streptomycin, gentamicin, tobramycin, amikacin, netilmicin, kanamycin and neomycin. The quinolones are intended to include, but are not limited to nalidixic acid, norfloxacin, enoxacin, ciprofloxacin, ofloxacin, sparfloxacin and temafloxacin. The macrolides are intended to include, but are not limited to erythomycin, spiramycin and azithromycin. The tetracyclines are intended to include, but are not limited to doxycycline, minocycline and tetracycline . The sulfonamides are intended to include, but are not
SUBSTITUTE SHEET
limited to sulfanilamide, sulfamethoxazole, sulfacetamide, sulfadiazine, sulfisoxazole and co-trimoxazole (trimethoprim/sulfamethoxazole) . The lincosamides are intended to include, but are not limited to clindamycin and lincomycin. The polymyxins (polypeptides) are intended to include, but are not limited to polymyxin B and colistin.
Alternatively, compounds of Formula I are useful in the treatment of certain cancers including nonlymphoblastic leukemias, acute myelogenous leukemia (FAB Ml and FAB M2), acute promyelocytic leukemia (FAB M3), acute myelomonocytic leukemia (FAB M4), acute monocyte leukemia (FAB M5), erythroleukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, chronic monocytic leukemia and conditions associated with leukemia involving activity of PMN neutral proteases e.g. disseminated intravascular coagulation.
Similarly, compounds of Formula I are useful for the inhibition of proteinase 3/myeloblastin, inhibition of elastase, inhibition of proliferation of leukemia cells, inducing differentiation of leukemia cells and remission of the disease state of leukemia. Moreover, as described above, such treatment may optionally comprise the co-administration of an agent such as a compound selected from the group consisting of epsilon-aminocaproic acid, heparin, trasylol, prednisolone, cytosine arabinoside, b-mercaptopurine, cytarabine, an anthracycline and a vitamin A derivative such as retinoic acid.
*-_ , __»<»_«-_.-». .Iiii m ;wιaιι»i
For each of the uses, the compounds of Formula (I) and optional treatment agents, may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit Formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, dogs, cats, etc., the compounds of the invention are effective in the treatment of humans.
For treatment as described above the compounds of Formula (I) may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit Formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, dogs, cats, etc., the compounds of the invention are effective in the treatment of humans.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may
SUBSTITUTESHEET
be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
SUBSTITUTE SHEET
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinyl- pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally- occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyl- eneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol mono- oleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The said aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspension may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin
Sα. *Sc_»r«τT , s!TT_u ' * T i ~ ~ ~~ ~- •*■*» ' r—r— •* *■"
or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oils, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan mono-oleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
SUBSTITUTE SHEET
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution glucose in water and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides . In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of Formula (I) may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols .
SUBSTITUTESHEET
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the anti-inflammatory agents are employed.
The amount of active ingredient(s) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 5 mg to 2000 mg or 5000 mg of each active agent(s) compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. For purposes of this specification, this broad dosage range is specifically intended to include, but is not limited to, range of 5 mg to 2000 mg; 25 mg to 2000 mg; 5 mg to 1000 mg; 25 mg to 1000 mg; 5 mg to 500 mg; and 25 mg to 500 mg. Dosage unit forms will generally contain between from about 25 mg to about 500 mg of active ingredient(s).
Furthermore, it is also possible that most effective treatment may warrent administration of an initial dosage of one range (e.g. 1-5 mg of active agent per kg of patient weight) followed by administration of a second range (e.g. 0.1 to 1 mg of active agent per kg of pateint weight).
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of
SUBSTITUTESHEET
excretion, drug combination and the severity of the particular disease undergoing therapy.
The following example illustrates the preparation of the compounds useful in the method of treatment of the present invention, but does not limit the scope of the invention. Starting materials may be optionally prepared as disclosed in EPO 337 549 published October 18, 1989 which is hereby incorporated by reference. Where appropriate, compounds may be produced and used in the form of pharmaceutically acceptable salts. For example, the basic coumpounds may be used in the form of a hydrochloride or mesylate or other acceptable salt. See Preformulation in Remington's Pharmaceutical Sciences, Mack Publishing, Easton PA.
SUBSTITUTESHEET
SCHEME 1
M oxalyl chloride
-
SUBSTITUTE SHEET
SCHEME 1 CONT'D
15
20
25
30
SUBSTITUTE SHEET
SCHEME 2
chloride Ex 3a Br 2 CH 2 C0 2 - - base
20 Ex IA
CH,
Ex 3B HO-CH-C0 2 Bn
25 TEA
TFA Ex 1 B anisole
30
SUBSTITUTE SHEET
SCHEME 2 CONT'D
8
SUBSTITUTE SHEET
The glycolic acid derivatives described herein can be prepared according to the following scheme. The starting acid (as earboxylate anion) may be alkylated (Ex IA) with a suitably protected α-halo acetic acid derivative to give the glycolate ester 4 which can be deprotected (Ex IB) to the glycolic acid ester 5_. Treatment of ϋ with an amine utilizing a condensing agent such as dicyclohexylcarbodiimide or carbomyldiinidazole (Ex 2) affords the deserved amide 6.. Alternately, the starting acid 1 may be converted to its acid chloride 2 (Ex 3A) and treated with a suitably protected α-hydroxyalkanoic acid (Ex 3B) in the presence of base to give the protected ester 1_. Deprotection (Ex 4), followed by conversion to the acid chloride and treatment with the appropriate amine (Ex 5) affords the desired amide 5..
Example 1
A. t-Butoxycarbonylmethyl [S-(R*. S*)]4-((3,3- diethy1-1-(((1-(4-methylphenyl)butyl)amino)- earbonyl)-4-oxo-2-azetidinyl)oxy)benzoate.
To a solution of 0.806 gm of [S-(R*, S*)] 4-((3,3-diethyl-l-(((l-(4-methylphenyl)butyl)amino)- carbonyl)-4-0X0-2- azetidinyl)oxy)benzoic acid in ~-3ml DMF is added 0.23 gm. triethylamine followed by 0.50 gm of t-butyl bromoacetate and the mixture stirred overnight at room temperature. Ethyl acetate (25 ml) is then added and the resultant mixture is washed with 2 x 10 ml water, 10 ml saturated sodium bicarbonate, and 20 ml brine. The organic layer is dried through sodium sulfate and concentrated in vacuo. Chromatography on Silica gel 60 (350 ml
SUBSTITUTE SHEET
column) and elution with 10% ethyl acetate in hexanes gave 0.67 gm of the t-Butoxycarbonylmethyl [S-(R*, S*)]4-((3,3-diethyl-l-(((l-(4-methyl- phenyl)butyl)amino)earbonyl)-4-oxo-2-azetidinyl)oxy) benzoate.
In a similar manner can be prepared 2-(dimethylamino)-2-oxoethyl, (S-(R*,S*))-4-((3,3- Diethyl-l-(((l-(4-methyl-phenyl)butyl)amino) earbonyl)-4-oxo-2-azetidinyl)oxy)-benzoate (Compound 6), and 2-(N-methylacetamido)ethyl. {2-(R*,S*)>-
4-{{3,3-Diethyl-l-{{{l-(4-methyl-phenyl)butyl}amino} carbonyl>-4-oxo-2-azetidinyl}oxy}-benzoate, (Compound 7).
B ^ Carboxymethyl [S-(R*,S*)]4-((3,3-diethyl-l- (((1-(4-methyl-phenyl)butyl)amino)earbonyl) -4-oxo-2-azetidinyl)oxy)benzoate
To the above ester is added 2 ml of anisole and the resulting mixture is cooled in an ice bath and 5 ml of ice cold trifluoroacetic acid is added. The reaction mixture is stirred cold for three hours then allowed to come to room temperature. After 30 minutes, the reaction mixture is concentrated in vacuo and the residue chromatographed on silica gel 60. Elution with 207. ethyl acetate in hexanes containing 17. acetic acid gives 0.53 gm of desired carboxymethyl [S-(R* f S*)]4-((3,3-diethyl-l- (((l-(4-methyl- phenyl)butyl)amino)earbonyl) -4-oxo-2-azetidinyl)oxy)benzoate.
SUBSTITUTE SHEET
Compound 2
Analysis: C28H3 N2O-7+O.3H2O
Calc: C, 65.19; H, 6.75; N, 5.43 Found: C, 65.30; H, 6.76; N, 5.23
Compound 6
Analysis: C3oH39N 3 0 6 +0.5H 2 0
Calc: C, 65.91; H, 7.38; N, 7.60 Found: C, 65.71; H, 7.63; N, 7.50.
Compound 7
Analysis: C 3 * | _H 1 N3θ 6 +0.6EtOAc
Calc: C, 66.35; H, 7.64; N, 6.95 Found: C, 66.52; H, 7.89; N, 6.83.
Example 2
2-(bis(2-hydroxyethyl)amino)-2-oxoethyl(S-(R>'sS* )-4- ((3,3-diethyl-l-(((l-(4-methyl-phenyl)butyl)amino)- earbonyl)-4-oxo-2-azetidinyl)oxy) benzoate.
To a solution of 0.125 gm of the acid from IB in 2-3 ml of methylene chloride is added 0.050 gm of carbonyldiimidazole. The mixture is stirred for 30 minutes at room temperature at which time 0.060 gm of diethanolamine is added along with 1 ml of DMF and 2 ml of methylene chloride. The resulting mixture is stirred overnight at room temperature then concentrated in vacuo. Silica gel chromatography of the residue using 2.5 to 5.07, methanol in methylene chloride gives 0.123 gm of the desired Compound 3,
2-(bis(2-hydroxyethyl)amino)-2-oxoethyl(S-(R*,S*))-4- ((3,3-diethyl-l-(((l-(4-methy1-phenyl)butyl)amino)- earbonyl)-4-oxo-2-azetidinyl)oxy) benzoate.
SUBSTITUTE SHEET
Compound 3
Analysis: C32H43N3O8, +0.4H 2 0
Calc: C, 63.53; H, 7.30; N, 6.95 Found: C, 63,51; H, 7.45; N, 6.95.
Similarly were prepared Compound 4
Analysis: C 3 *LH Q N 07 Calc: C, 64.12; H, 6.94; N, 9.65
Found: C, 64.12; H, 7.18; N, 9.44
Compound 5
Analysis: C32H43N3O9 +0.3H 2 0 Calc: C, 62.08; H, 7.09; N, 6.79 Found: C, 61.89; H, 7.39; N, 6.88.
Compound 8
Analysis: C 0H47N3O8 Calc: C, 68.85; H, 6.79; N, 6.02
Found: C, 68.79; H, 7.06, N, 5.88.
Example 3 - Preparation of
l-Methyl-2-oxo-2-(phenylmethoxy ) ethyl(2S-(l(S*),R*,- (R)))-4-((3,3-diethyl-l-(((l-(4-methylphenyl)butyl)- amino)carbonyl)-4-oxo-2-azetidinyl)oxy) benzoate, Compound 10.
SUBSTITUTESHEET
To a solution of 1.0 gm [S-(R*, S*)]4-((3,3- diethyl-1-(((1-(4-methylphenyl)butyl)amino)carbonyl)- 4-oxo-2-azetidinyl)oxy)benzoic acid in 10 ml methylene chloride is added 2 ml of oxalyl chloride followed by a catalytic amount of DMF. The reaction is stirred 1 hour at room temperature then concentrated in vacuo to yield the acid chloride which is used as is in the next step.
B__.
A solution of the above acid chloride in 10 ml of methylene chloride is cooled in an ice bath and a solution of 1.25 gm benzyl L-lactate and 2.0 gm of triethylamine in 10 ml of methylene chloride is added. The mixture is stirred at room temperature overnight then concentrated in vacuo. Chromatography of the residue on silica gel using methylene chloride as the eluent yields 0.795 of the desired l-Methyl-2-oxo-2-(phenylmethoxy)ethyl
(2S-(1(S*) ,R*, (R)))-4-((3,3-diethyl-l-(((l-(4-methyl- pheny1)butyl)amino)earbonyl)-4-oxo-2-azetidinyl)oxy) benzoate, Compound 10.
Analysis: C3 6 H42N 2 0 7
Calc: C, 70.34; H, 6.89; N, 4.56. Found: C, 70.45; H, 7.05; N, 4.48.
SUBSTITUTE SHEET
Example 4 Preparation of
1-carboxyethyl [S-(R*,S*)] 4-((3,3-diethyl-l-(((l-(4- methyl-phenyl)butyl)amino)earbonyl)-4-oxo-2-azetidin- yl)oxy)benzoate
A mixture of 0.69 gm of the benzylester prepared in Example 3 and 0.2 gm 107, Pd/C in 10 ml of EtOAc is treated with hydrogen at 40 psi. When the reaction is complete the mixture is filtered and concentrated in vacuo to yield 0.56 gm of 1-carboxy- ethyl [S-(R*,S*)]4-((3,3-diethyl-l-(((l-(4-methyl- phenyl)butyl)amino)earbonyl)-4-oxo-2- azetidinyl)oxy) benzoate, Compound 11.
Analysis: C29H36N2O7
Calc: C, 66.40; H, 6.92; N, 5.34. Found: C, 66.66; H, 7.26; N, 5.05.
Example 5
2-(diethylamino)-l-methyl-2-oxoethyl[S-(R*,S*)]-4- ((3,3-diethyl-l-(((l-(4-methy1-phenyl)butyl)amino)- earbonyl)-4-oxo-2-azetidinyl)oxy) benzoate
The acid (.250 gm) from Example 4 is treated with oxalyl chloride according to the procedure of Example 3A and the corresponding acid chloride is obtained. This material is dissolved in 5 ml methylene chloride and 0.4 ml of diethylamine added. After 1 hour the reaction mixture is concentrated n vacuo and the residue taken in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer is dried through sodium sulfate,
SUBSTITUTE SHEET
concentrated and the residue chromatographed on silica gel. Elution with 57o of ethyl acetate in methylene chloride gives Compound 12.
Analysis: C33H45N3O Calc: C, 68.37; H, 7.82, N, 7.25
Found: C, 68.40; H, 7.93, N, 7.40.
Example 6
(S(R>'sS*))-l-(((4-((3,3-diethyl-l-(((l-(4-methyl- phenyl)butyl)amino)earbonyl)-4-oxo-2-azetidinyl)oxy) benzoyl)oxy)acetyl) L-proline,
A ^ When benzyl -lactate is replaced by
L-proline benzyl ester hydrochloride and triethylamine in the procedure of Example 3 the corresponding amide with L-proline benzyl ester, Compound 8, is obtained.
Analysis: C4 Q H47N3O8
Calc: C, 68.85; H, 6.79, N, 6.02 Found: C, 68.79; H, 7.06, N, 5.88.
B ^
Reduction of the material obtained in Example 6A according to the procedure of Example 4 affords Compound 9.
Analysis: C 3 3H 41 N 3 0 8 +0.5H 2 0
Calc: C, 64.27; H, 6.86; N, 6.81. Found: C, 64.49; H, 6.90; N, 6.68.
SUBSTITUTE SHEET
Example 7
[S-(R*,S*)] l-(((4-((3,3-diethyl-l-(((l-(4-methyl- phenyl)butyl)amino) carbonyl-4-oxo-2-azetidinyl)oxy) benzoyl)oxy)acetyl-N-benzyl-L-prolinamide.
Treatment of the acid obtained in Example 6B, Compound 9, with oxalyl chloride according to Example 3A gives the corresponding acid chloride which when treated with benzylamine gives the desired benzyl amide, Compound 19.
Analysis: C4 0 H4 8 N θ 7
Calc: C, 68.95; H, 6.94; N, 8.04. Found: C, 68.93, H, 7.02; N, 7.96.
Example 8
To a solution of the acid chloride (prepared from 0.55 gm of [S-(R*, S*)] 4-((3,3-diethyl-l-(((l- (4-methylphenyl)butyl)amino)earbonyl)-4-oxo-2- azetidinyl)oxy)benzoic acid according to the procedure of Example 3A) in 3 ml of methylene chloride is added 0.15 gm of N,N-dimethyl- aminoethanol. The reaction mixture is stirred overnight at room temperature, concentrated in vacuo. then taken up in ethyl acetate (25 ml) and washed with saturated sodium bicarbonate solution. The organic layer is dried through sodium sulfate and concentrated in vacuo. Silica gel chromatography of the residue using 2.57, methanol in methylene chloride gives 0.59 gm of Compound 1,
SUBSTITUTE SHEET
2-(dimethylamino)ethyl (S-(R*,S*))-4-((3,3-diethyl-l- (((1-(4-methyl-phenyl)butyl)amino)earbonyl)-4-oxo-2- azetidinyl)oxy)benzoate
Analysis: Calc: C, 68.81; H, 7.89; N, 8.02.
Found: C, 68.85; H, 8.09; N, 7.97.
When N,N-dimethylaminoethanolamine is replaced by the appropriate amino alcohols the correponding esters are obtained.
Compound 13 l-Dimethylamino-2-propyl [S-(R*,S*)]- 4-[[3,3-diethyl-l-[[[l-(4-methyl-phenyl) butyl]amino]earbonyl]-4-oxo-2-azetidin¬ yl]oxy]benzoate
Analysis C 31 H 43 N 3°5 Calc: C, 69.25; H, 8.06; N, 7.82. Found: C 68.97; H, 8.01; N, 7.80.
Compound 14 3-Dimethylamino-l-propyl [S-(R*,S*)]-
4-[[3,3-diethyl-l-[[[l-(4-methyl-phenyl) butyl]amino] earbonyl]-4-oxo-2-azetidin¬ yl]oxy]benzoate Analysis: C3 H43N3O5 Calc: C, 69.25; H, 8.06; N, 7.81. Found: C, 68.85; H, 8.19; N, 7.72.
Compound 16 2-Diethylaminoethyl [S-(R*,S*)]-
4-[[3,3-diethyl-1-[[[1-( -methyl-phenyl) butyl]amino] carbonyl]-4-oxo-2
-azetidinyl]oxy]benzoate Analysis: C32H45N3O Calc: C, 69.66; H, 8.22; N, 7.62. Found: C, 69.37; H, 8.41; N, 7.51.
SUBSTITUTE SHEET
Compound 17 2-(l-[4-morpholino]ethyl) [S-(R*,S*)]~ 4-[[3,3-diethyl-l-[[[l-(4-methyl-phenyl) butyl]amino] earbonyl]-4-oxo-2 -azetidinyl]oxy]benzoate
Analysis C 32 H43N 3 0 6 Calc: C, 67.94; H, 7.66; N, 7.43. Found: C 67.67; H, 7.90; N, 7.26.
Compound 18 4-dimethylaminobutyl [S-(R*,S*)]-
4-[[3,3-diethyl-l-[[[l-(4-methyl-phenyl) butyl]amino] earbonyl]-4-oxo-2
-azetidinyl]oxy]benzoate
Analysis: C 32 H 45 N 3 0 5 +0.2 H 2 0 Calc: C, 69.21; H, 8.24; N, 7.56. Found: C. 69.35; H, 8.24; N, 7.29.
Compound 20 2-dimethylamino-2-methyl-l-propyl [S-(R*,S*)]-4-[[3,3-diethyl-l-[[[l-(4-me thyl-phenyl)butyl] amino]earbonyl] -4-oxo-2-azetidinyl]oxy]benzoate
Analysis C 32 H 45 N 3°5 Calc: C 69.66; H, 8.22; N, 7.62. Found: C. 69.52; H, 8.47; N, 7.59.
Compound 21 2-(diisopropylamino)ethyl [S-(R*,S*)]-
4-[[3,3-diethy1-1-[[[1-(4-methyl-phenyl) butyl] amino] earbonyl]-4-oxo-2 -aze idinyl]oxy]benzoate Analysis: C34H49N3O5 Calc: C, 70.44; H, 8.52; N, 7.25. Found: C, 70.28; H, 8.76; N, 7.13.
SUBSTITUTESHEET
Compound 22 Benzyl [S-(R*,S*)]-4-[2-[[4-[[3,3-di- ethyl-1-C[[l-(4-methylphenyl)butyl]- amino]earbonyl]-4-oxo-2-azetidinyl]oxy]* benzoyl] oxy]-ethyl]-l-Piperazine- carboxylate
Analysis: C4 H5 Q N O7
Calc: C, 68.75; H, 7.21; N, 8.02.
Found: C, 68.39; H, 7.30; N, 7.84.
Compound 23 2-(dibutylamino)ethyl [S-(R*,S*)]-4- [[3,3-diethyl-l-[[[l-(4-methyl-phenyl)- butyl]amino]carbonyl]-4-oxo-2-azetidin- yl]oxy]benzoate,
Analysis C 36 H 53 N 3°5
Calc: C, 71.14; H, 8.79; N, 6.91. Found: C, 71.00; H, 9.03; N, 6.81
Compound 24 [S-(R*,S*)]-6-(dimethylamino)hexyl-4- [[3,3-diethyl-l-[[[l-(4-methyl-phenyl)- butyl]amino]carbonyl]-4-oxo-2-azetidin¬ yl]oxy]-benzoate
Analysis: C 34 H 49 N 3°5 +1H 2° Calc: C. 68.31; H, 8.60; N, 7.03. Found: C, 68.34; H, 8.29; N, 6.86.
Compound 26 2-(4-methyl-l-piperazinyl)ethyl[S-
(R*,S*)]-4-[[3,3-diethyl-l-[[[l-(4- methy 1-phenyl) butyl] amino] car bonyl] -4- oxo-2-azetidinyl]oxy]benzoate,
Analysis C 33 H 46 N θ 5 + 0-8H 2 0 Calc: C, 66.82; H, 8.09; N, 9.44. Found: C. 67.28; H, 8.10; N, 8.96.
SυBciinϋi E SHEET
Compound 28 2-(diphenylamino)ethyl[S-(R*,S*)]-4-
[[3,3-diethyl-l-[[[l-(4-methylphenyl)- butyl]amino]carbonyl]-4-oxo-2-azetidin¬ yl] oxy]benzoate, Analysis: C40H45N3O5 +1.4H 2 0 Calc: C, 71.40; H, 7.16; N, 6.25. Found: C, 71.62; H, 6.99; N, 5.99.
Compound 29 2-(di-2-propenylamino)ethyl [S-(R*,S*)]- 4-[[3,3-diethyl-l-[[[l-(4-methylphenyl)- butyl]amino]earbonyl]-4-oxo-2-azetidin- yl]oxy]benzoate, Analysis: C34H45N3O5 Calc: C, 70.93; H, 7.88; N, 7.30. Found: C, 71.18; H, 8.06; N, 7.34.
Compound 30 2-(dimethylamino)-2-phenylethyl [S-(R*,- S*)]-4-[[3,3-diethyl-l-[[[l- (4-methyl- phenyl)butyl]amino]earbonyl]-4-oxo-2- azetidinyl] oxy]benzoate,
Analysis: C 36 H 45 N 3°5 Calc. C , 72.09; H, 7.56; N, 7.00. Found: C. 71.75; H, 7.67; N, 6.70.
Compound 31 2-[methyl(phenylmethyl)amino]ethyl [S- (R*,S*)]-4-[[3,3-diethyl-l-[[[l-(4- methyl-phenyl)butyl]amino]carbonyl]-4- oxo-2-azetidinyl]oxy]benzoate,
When [S-(R*,S*)]-4-[[3,3-diethyl-l-[[[l-
(4-methylphenyl ) butyl ] amino] car bonyl ]-4-oxo-2-azet i- dinyl]oxy]-2 , 6-dimethyl benzoic acid is used in place
SUBSTITUTE SHEET
of [S(R* t S*)]-4-[[3,3-diethyl-l-[[[l-(4-methylphenyl)- butyl]amino]earbonyl]- 4-oxo-2-azetidinyl]oxy]benzoic acid in the procedure of Example 3A and allowed to react with the appropriate amino alcohols the following esters are obtained.
Compound 304 2-(dimethylamino)ethyl [S, (R*,S*)]-4- [[3,3-diethyl-l-[[[l-(4-methylphenyl)- butyl]amino]earbonyl]-4-oxo-2-azetidin- yl]oxy]-2,6-dimethyl-benzoate,
Compound 305 2-(diethylamino)ethyl [S-(R*,S*)]-4- [[3,3-diethyl-l-[[[l-(4-methylphenyD- butyl]amino]earbonyl]-4-oxo-2-azetidin- yl]oxy]-2,6-dimethyl-benzoate,
Compound 306 2-[bis(l-methylethyl)amino]-ethyl [S- (R*,S*)]-4-[[3,3-diethyl-l-[[[l-(4- methylpheny1)butyl]amino]carbonyl]-4- oxo-2-azetidinyl]oxy]-2,6-dimethyl- benzoate.
Treatment of the acid [S-(R*,S*)]-4-[[3,3- diethyl-l-[[[l-(4-methylphenyl)butyl]amino]carbonyl]- 4-oxo-2-azetidinyl]oxy]benzeneacetic acid with oxalyl chloride according to the procedure of Example 3A affords the corresponding acid chloride which when allowed to react with the appropriate amino alcohol according to the procedure of Example 8 gives the following amino esters:
SUBSTITUTE SHEET
Compound 32
Analysis: C31H 3N3O5
Calc: C, 69.25; H, 8.06; N, 7.82, Found: C, 69.02; H, 7.86; N, 7.74.
Compound 33 Analysis: C32H45N3O5
Calc: C, 69.66; H, 8.22; N, 7.62. Found: C, 69.10; H, 8.17; N, 7.50.
Compound 34 Analysis: C33H47N3O5
Calc: O, 70.06; H, 8.38; N, 7.43. Found: C, 69.70; H, 8.41; N, 7.05.
Compound 35 Analysis: C33H45N3O
Calc: C, 68.37; H, 7.82; N, 7.25. Found: C, 68.55; H, 8.19; N, 7.08.
Compound 36 Analysis: C32H 5N3O5
Calc: C, 69.66; H, 8.22; N, 7.62. Found: C, 69.60; H, 8.49; N, 7.55.
Example 9
To a solution of 0.247 g of Compound 1 in 2 ml of ethyl acetate is added 0.125 gm of m-chloroperoxy benzoic acid. After 30 minutes at room temperature the reaction mixture is concentrated in vacuo. Chromatography of the residue on silica
SUBSTITUTESHEET
gel using methylene chloride/methanol/water 85/15/1.5 gives the desired N-oxide Compound 15. Analysis: Calc: 63.79; H, 7.82; N, 7.44 Found: 63.89; H, 7.85; N, 7.27
Example 10
[S-(R*,S*)] 2-[4-[[[2-(dimethylamino)-ethyl]amino]- earbonyl]phenoxy]-3,3-diethyl-N-[1-(4-meth Iphenyl)- butyl]-4-oxo-l-azetidinecarboxamide.
To a solution of 0.104 g carbonyldiimidazole in 2 ml methylene chloride is added a solution of 0.227 g of [S-(R*,S*)]-4-((3,3-diethyl-l-((-l-(4- methylphenyl)butylamino)carbonyl)-4-oxo-2-azetidinyl)- oxy)benzoic acid in 3 ml methylene chloride. The mixture is stirred at ambient temperature for 30 minutes at which time 0.100 g of N,N-dimethyl- ethylenediamine is added. After stirring overnight at room temperature the reaction mixture is poured into benzene (50 ml) and washed with water. The organic layer is separated, dried through sodium sulfate and concentrated in vacuo. Silica gel chromatography using 57o methanol in methylene chloride yields 0.160 g of 2-[4-[[[2-(dimethylamino)- ethyl]amino]earbonyl]phenoxy]-3,3-diethy1-N-[1-(4- methylphenyl)butyl]-4-oxo-l-azetidinecarboxamide. (Compound 73).
Analysis: C30H 2 4O +O.4H2O Calc: C, 68.00; H, 8.14; N, 10.57. Found: C, 68.01; H, 8.18; N, 10.62.
SUBSTITUTESHEET
Example 11
A. (S-(R*,S*))-4-((3,3-diethyl-l-((l-(4-methyl- phenyl)butylamino)earbonyl)-4-oxo-2-azetidinyl)- oxy)-benzoyl chloride.
To a solution of 0.150 g of [S-(R*,S*)] 4-((3,3-diethyl-l-(((l-(4-methylphenyl)butyl)amino)- carbonyl)-4-oxo-2-azetidinyl)oxy)benzoic acid in 5 ml methylene chloride containing a catalytic amount of dimethyIformamide is added 0.5 ml of oxalyl chloride. The mixture is stirred at room temperature for 30 minutes and then concentrated in vacuo to yield (S-(R*,S*))-4-((3,3-diethyl-l-((l-(4-methyl-phenyl)- butylamino)carbonyl)-4-oxo-2-azetidinyl)oxy)-benzoyl chloride.
B. [S-(R*,S*)]-2-[4-[[[2-(dimethylamino)ethyl]methyl- amino]earbon l]-phenoxy]-3,3-diethy1-N-[1-(4- methylphenyl]butyl]-4-oxo-l-azetidinecarboxamide. The above acid chloride is dissolved in 3 ml methylene chloride and a solution of 0.20 gm of N,N,N'-trimethylethylenediamine in 2 ml methylene chloride is added. The mixture is stirred overnight and then concentrated in vacuo. The residue is extracted between ethyl acetate and saturated sodium bicarbonate solution. The organic layer is dried through sodium sulfate and concentrated in vacuo. Silica gel chromatography of the residue (57o methanol in methylene chloride) affords 0.117 g of [S-(R*,S*)]- 2-[4-[[[2-(dimethylamino)ethyl]methylamino]carbonyl]- phenoxy]-3,3-diethyl-N-[1-(4-methylphenyl]butyl]-4- oxo-1-azetidinecarboxamide. (Compound 75).
uϋo i n u i c onc i
Analysis:
Calc: C, 68.23; H, 8.31; N, 10.27. Found: C, 68.20; H, 8.41; N, 10.10.
When N.N.N'-trimethylethylenediamine of
Example lib is replaced by the appropriate amines, there is obtained the corresponding amides.
1) Compound 76 Analysis: C 32 H 46 N4θ
Calc: C, 69.79; H, 8.42; N, 10.17. Found: C, 69.02; H, 8.60; N, 9.54.
2) Compound 77 Analysis: +0.75 H 2 0
Calc: C, 68.12; H, 8.49; N, 9.93. Found: C, 68.22; H, 8.48; N, 10.17.
3) Compound 78 Analysis: C32H44N4O5
Calc. C, 68.06; H, 7.85; N, 9.92. Found: C, 67.84; H, 8,07; N, 9.62.
4) Compound 79 Analysis: +H 2 0
Calc: C, 66.42; H, 8.11; N, 9.39. Found: C, 66.73; H, 8.19; N, 9.23.
5) Compound 80 Analysis: C3 5 H52N 4 0 6
Calc: C, 67.28; H, 8.39; N, 8.97. Found: C, 67.08; H, 8.77; N, 8.41.
SUBSTITUTE SHEET
6) Compound 81
Analysis: C33H 8N4O4 +H2O
Calc: C, 68.01; H, 8.65; N, 9.61.
Found: C, 68.42; H, 8.59; N, 9.17
7) Compound 82
Analysis: +0.5H 2 0 Calc: C, 71.14; H, 7.79; N, 9.21. Found: C, 71.41; H, 7.68; N, 9.10.
8) Compound 83
Analysis: +1.2H 2 0 Calc: C, 67.15; H, 8.52; N, 9.79. Found: C, 67.21; H, 8.26; N, 9.47.
9) Compound 84
10) Compound 86 Analysis: C35H52N4O4
Calc: C, 70.91; H, 8.84; N, 9.45. Found: C, 70.37; H, 8.84; N, 8.77.
11) Compound 89 Analysis: C 31 H3 9 N 5 θ4 +0.7H 2 0
Calc: C, 66.71; H, 7.29; N, 12.54. Found: C, 66.91: H, 7.40: N. 12.14.
12) Compound 90 * Analysis: C 33 H 6 N4θ +0.8H 2 0
Calc: C, 68.67; H, 8.31; N, 9.70. Found: C, 68.82; H, 8.11; N, 9.70.
SUBSTITUTESHEET
13) Compound 91
Analysis: C34H48N4O4 + 0.3H 2 0 Calc: C, 70.11; H, 8.41; N, 9.61. Found: C, 70.17; H, 8.64; N, 9.33.
14) Compound 92
Analysis: C30H42N4O4 + 1.2H 2 0 Calc: C, 66.14; H, 8.22; N, 10.29. Found: C, 66.18; H, 8.12; N, 10.31,
15) Compound 93
Analysis: + 0.3H 2 0 Calc: C, 65.57; H, 7.67; N, 9.56. Found: C, 65.72; H, 7.50; N, 9.34.
16) Compound 94
Analysis: C32H44N4O4 + 0.3H 2 0
Calc: C, 70.04; H, 8.08; N, 10.21. Found: C, 70.34; H, 8.90; N, 8.93.
17) Compound 95
Analysis: + .5H 2 0 Calc: C, 69.32; H, 8.28; N, 9.80. Found: C, 69.41; H, 8.25; N, 9.58.
18) Compound 99
Analysis: C38H5 O + 1.5H 2 0 Calc: C, 69.37; H, 8.72; N, 8.51 Found: C, 69.48; H, 8.44; N, 8.36
SUBSTITUTE SHEET
19) Compound 102
Analysis: + 1.0 H 2 0 Calc: C, 67.30; H, 7.20; N, 9.81 Found: C, 67.50; H, 7.24; N, 9.53
20) Compound 104
Analysis: +0.75H 2 0 Calc: C, 67.04; H, 7.47; N, 12.21. Found: C, 67.16; H, 7.56; N, 11.95
21) Compound 105
Analysis: C32H 4N4O5 +0.5H 2 0 Calc: C, 66.99; H, 7.91; N, 9.77. Found: C, 67,00; H, 8.25; N, 9.50.
22) Compound 106
Analysis: C32H45N5O5 +0.8H 2 0 Calc: C, 64.69; H, 7.90; N, 11.78. Found: C, 64.93; H, 8.25; N, 11.12.
23) Compound 107
Analysis: C 31 H44N 3 0 6 S +0.3H 2 0 Calc: C, 61.42; H, 7.41; N, 9.24. Found: C, 61.43; H, 7.54; N, 9.05.
24) Compound 110 Analysis:
Calc: C, 71.89; H, 7.58; N, 9.58. Found: C, 71.65; H, 7.55; N, 9.34.
SUBSTITUTE SHEET
25) Compound 111
Analysis: C34H42N4O +0.5H 2 0 Calc: C, 70.44; H, 7.47, N, 9.66. Found: C, 70.82, H, 7.46; N, 9.20.
26) Compound 113
Analysis: C34H42N4O4 +0.3H 2 0 Calc: C, 70.88; H, 7.45; N, 9.72. Found: C, 71.12; H, 7.44; N, 9.32.
27) Compound 115
Analysis: C34H42N4O4 +0.7H 2 0 Calc: C, 69.99; H, 7.50; N, 9.60. Found: C, 70.14, H, 7.63; N, 9.25.
28) Compound 116
Analysis: +1.4H 2 0 Calc: C, 68.06; H, 8.19; N, 9.33. Found: C, 68.40; H, 8.14; N, 8.87.
29) Compound 117
Analysis: +0.6H 2 0 Calc: C, 67.79; H, 7.42; N, 9.88. Found: C, 67.81; H, 7.58; N, 9.76.
30) Compound 118
Analysis: C33H47N5O 4 +0.7H 2 0 Calc: C, 67.14; H, 8.26; N, 11.86 Found: C, 67.54; H, 8.51; N, 11.28
SUBSTITUTE SHEET
31) Compound 119
Analysis: +1.25H 2 0 Calc: C, 68.76; H, 8.32; N, 9.16. Found: C, 69.07; H, 8.19; N, 8.75
32) Compound 121
Analysis: C34H4SN4O4 +1H 2 0
Calc: C, 68.66; H, 8.47; N, 9.42.
Found: C, 69.02; H, 8.32; N, 9.06.
33) Compound 125
Analysis: +0.5H 2 0 Calc: C, 71.47; H, 7.94; N, 9.01 Found: C, 71.65; H, 7.91; N, 8.73.
34) Compound 126
Analysis: +2H 2 0
Calc: C, 68.83; H, 8.25; N, 7.64.
Found: C, 69.03; H, 7.79; N, 7.50.
35) Compound 132 Analysis: C35H5 Q N O4
Calc: C, 71.15; H, 8.53; N, 9.48. Found: C, 70.90; H, 8.74; N, 9.12.
36) Compound 133
Analysis: C40H52 O4 +0.9H 2 0 Calc: C, 71.80; H, 8.10; N, 8.37. Found: C, 71.86; H, 8.17; N, 8.18.
SUBSTITUTESHEET
37) Compound 137
Analysis: C37H48N4O4 +0.8H 2 0 Calc. C, 70.85; H, 7.97; H, 8.93. Found: C, 71.01; H, 7.97; N, 8.54.
38) Compound 139
Analysis: +0.8H 2 0 Calc: C, 70.09; H, 7.93; N, 10.48. Found: C, 70.18; H, 7.79; N, 10.42
39) Compound 142 Analysis: C38H55N O6
Calc: C, 67.33; H, 8.18; N, 10.33. Found: C, 67.02; H, 8.31; N, 9.89.
40) Compound 143 Analysis: C34H51 5O4
Calc: C, 68.77; H, 8.66; N, 11.80. Found: C, 68.57; H, 8.50; N, 11.53
41) Compound 144
Analysis: C33H59N5O4 +0.4H 2 0 Calc: C, 69.45; Ξ, 9.17; N, 10..65. Found: C, 69.69; H, 9.02; N, 10 35.
42) Compound 145 Analysis: C3.5H47N5O4 +H 2 0
Calc: C, 68.44; H, 7.82; N, 11.08 Found: C, 68.69; H, 7.74; N, 10.76.
bub iuυic -r DΠCC I
43) Compound 148
Analysis: +0.4H 2 0 Calc: C, 69.62; H, 7.56; N, 11.27. Found: C, 69.79; H, 7.70; N, 11.12,
44) Compound 149
Analysis: C39H50N4O4 +0.4H 2 0 Calc: C, 72.50; H, 7.93; N, 8.67 Found: C, 72.44; H, 7.99; N, 8.87.
45) Compound 150
Analysis: +0.3H 2 0 Calc. C, 69.83; H, 7.74; N, 11.31. Found: C, 69.93; H, 7.65, N, 11.10.
46) Compound 151 Analysis: C33H47N5O4
Calc: C, 68.60; H, 8.20; N, 12.12. Found: C, 68.40; H, 8.16; N, 11.90.
47) Compound 245 Analysis:
Calc: C, 72.46; H, 7.43; N, 9.39 Found: C, 72.49; H, 7.49; N, 9.25
48) Compound 246
Analysis: +0.25H 2 0 Calc: C, 72.26; H. 7.61; N, 9.10. Found: C, 72.35; H, 7.83; N, 8.73.
SUBSTITUTE SHEET
49) Compound 154
Analysis: C35H43N4O4 +0.8H 2 0 Calc: C, 69.70; H, 8.29; N, 9.29 Found: C, 69.65; H, 8.27; N, 9.35
50) Compound 158
Analysis: C35H43N4O4 +0.5H 2 0 Calc: C, 73.29; H, 7.65; N, 8.33. Found: C, 73.71, H, 7.75, N, 7.75.
51) Compound 159 Analysis: C35H43N4O4
Calc: C, 73.09; H, 7.66; N, 8.31. Found: C, 73.40; H, 7.75; N, 7.80.
52) Compound 160
Analysis: C33H43N4O4 +1.0H 2 0 Calc: C, 70.78; H, 8.12; N, 8.68. Found: C, 71.00; H, 8.05; N, 8.59.
53) Compound 161
Analysis: C43H 2N4O4 +IH2O
Calc: C, 73.05; H, 7.70; N, 7.92.
Found: C, 73.29; H, 7.95; N, 7.37.
54) Compound 166
Analysis: C3 H 6N4O +1.5H 2 0 Calc. C, 67.20; H, 8.37; N, 9.50 Found: C, 67.38; H, 7.98; N, 9.41.
SUBSTITUTE SHEET
55) Compound 171
Analysis: C3 H52N4O6 +I.6H2O Calc: C, 64.95; H, 8.36; N, 8.41. Found: C, 65.26; H, 8.15; N, 8.07.
56) Compound 177 Analysis: C38H47N5O4
Calc: C, 71.56; H, 7.43; N, 10,98. Found: C, 71.64; H, 7.62; N, 10.93
57) Compound 178 Analysis: C33H Q N4O4
Calc: C, 72.81; H, 8.04; N, 8.94. Found: C, 72.96; H, 8.17; N, 8.83.
58) Compound 179 Analysis: C33H47N5O4
Calc: C, 71.56; H, 7.43; N, 10.98. Found: C, 72.00; H, 7.55; N, 10.87.
59) Compound 180 Analysis: C38H47F3N O4
Calc: C, 67.04; H, 6.96; N, 8.23. Found: C, 67.02; H, 7.25; N, 8.23.
60) Compound 181 Analysis: C38H47F3 4O
Calc: C, 67.04; H, 6.96; N, 8.23 Found: C, 66.63; H, 6.98; N, 7.94.
SUBSTITUTE SHEET
61) Compound 182 Analysis: C37H47F N4O4
Calc: C, 70.45; H, 7.51; N, 8.88 Found: C, 70.28; H, 7.74; N, 8.82
62) Compound 185 Analysis: C34H43N4O4
Calc: C, 70.80; H, 8.39; N, 9.71 Found: C, 70.44; H, 8.45; N, 9.51.
63) Compound 186
Analysis: C37H48N4O4 +0.8H 2 0 Calc: C, 70.85; H, 7.97; N, 8.93 Found: C, 71.12; H, 8.25; N, 8.45.
64) Compound 191
Analysis: C 2H51N5O +.5CH 2 C1 2 Calc: C, 69.78; H, 7.16; N, 9.58 Found: C, 69.75; H, 7.31; N, 9.68.
65) Compound 203
Analysis: C37H47N4O4 +1.1H 2 0 Calc: C, 68.31; H, 7.62; N, 8.61 Found: C, 68.32; H, 7.57; N, 8.53.
66) Compound 204 Analysis: C37H47CIN4O
Calc: C, 68.66; H, 7.32; N, 8.66. Found: C, 68.32, H, 7.48; N, 8.42.
SUS J 1 i υ 1 c once f
67) Compound 205
Analysis: C33H50N4O5 +0.7H 2 0 Calc: C, 69.63; H, 7.90; N, 8.54. Found: C, 69.72; N, 7.91; N, 8.54.
68) Compound 206
Analysis: C39H52N4O.5 +0.8H 2 0 Calc: C, 68.15; H, 7.86; N, 8.15 Found: C, 68.01; H, 8.02; N, 8.15.
Example 12
A) [S-(R*,S*)]3,3-Diethyl-2-[4-[[[2-(4-hydroxy-l- piperidinyl)ethyl]amino]earbonyl]phenoxy]-N-[l-(4- methylphenyl)butyl]-4-oxo-l-azetidinecarboxamide When l-(2-aminoethyl)-4-benzyloxypiperidine is used in place of N,N,N'-trimethylethylene diamine in the procedure of Example lib there is obtained [S-(R*,S*)] 3,3-diethyl-2-[4-[[[2-(4-benzyloxy-l- piperidinyl]ethyl]amino]earbonyl]phenoxy]-N-[l-(4- methylphenyl)butyl]-4-oxo-l-azetidinecarboxamide.
B) [S-(R+,S*)]-3,3-diethyl-2-[4-[[[2-(4-hydroxy-l- piperidinyl)ethyl]amino]earbonyl]phenox ]-N-[1-(4- methyl-phenyl)butyl]-4-oxo-l-azetidine-carboxamide
A solution of the amide from step A above in 10 ml of glacial acetic acid containing 22 mg of 10% Pd/C is hydrogenated under 42 lb hydrogen pressure. When TLC indicate completion of the reaction, the mixture is filtered and concentrated in vacuo after the addition of 50 ml toluene. The
SUBSTITUTESHEET
residue is dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution. The organic layer is dried with sodium sulfate and concentrated in vacuo. The residue is chromatographed on 15 g silica gel using 57. methanol in methylene chloride and yields 96 mg of
[S-(R+,S*)]-3,3-diethyl-2-[4-[[[2-(4-hydroxy-l- piperidinyl)ethyl]amino]carbonyl]phenoxy]-N-[l-(4- methyl-phenyl)butyl]-4-oxo-l-azetidine-carboxamide
Analysis: +1.3H 2 0 Calc: C, 65.83; H,- 8.13; N, 9.30 Found: C, 66.10; H, 8.06; N, 8.91
When l-(2-aminoethyl)-4-benzyloxypiperidine is replaced in the procedure of Example 12 by the appropriate amines, the following compounds 123, 124, 129, 131 and 138 are obtained, for example:
1) Compound 129
Analysis: C34H48N4O5
Calc: C, 68.89; H, 8.16; N, 9.45
Found: C, 68.68; H, 8.18; N, 8.65
2) Compound 131
Analysis: C32H4 N4O5 +1H 2 0 Calc: C, 65.92; H, 7.96; N, 9.61 Found: C, 66.07; H, 7.86; N, 9.45
>UBSTiTUTE SHEET
3) Compound 138
Analysis: +0.5H 2 0 Calc: C, 67.43; H, 8.06; N, 9.53 Found: C, 67.61; Ξ, 8.06; N, 9.37
Diamine Intermediates
The diamines used to prepare the amino amides described herein were commercially available or prepared according to the following routes
A N-cyanomethylhomopiperazine.
To a solution of 1.98 g homopiperazine in 50 ml acetone is added 4.25 g of powdered anhydrous sodium carbonate and 1.3 ml of ehloroacetonitrite.
After 24 hrs the reaction mixture is filtered and the filter cake washed with 100 ml acetone. The combined filtrates are concentrated in vacuo and the residue chromatographed on silica gel using methylene chloride as the eluent. The yield of N-cyanomethyl homopiperazine is 2.69 g.
SUB S TITUTESHEE T
B. N-(2-aminoethyl)homopiperazine.
To a suspension of 1.02 g lithium aluminum hydride in 50 ml of ether is slowly added a solution of 2.65 gm N-cyanomethyl homopiperazine in 25 ml
5 ether. After the addition in complete the mixture is heated at reflux for 1 hour, then cooled to room temperature and quenched carefully with 1 ml water, 1 ml of 157. sodium hydroxide solution and 3 ml water. The mixture is filtered through sodium sulfate, the
10 filter cake washed well with ether and the combined filtrates concentrated in vacuo to yield 2.60 g. N-(2-aminoethyl)homopiperazine.
15
N-CH 2 CH 2 - NH- CH 3
20
R 5
EXAMPLE 14
25 N- (2-methylaminoethyl )homopiperazine .
A) . N-(2-formamidoethyl )homopiperazine .
To a carefully prepared solution of 0. 718 g of 607o sodium hydr ide dispension in 75 ml of absolute _ 0 ethanol which has been cooled to 0 β C is added 7 . 3 ml of ethyl formate . After 5 minutes there is added a solution of 2 .55 gm of N-(2-aminoethyl )homopiperazine
SUBSTITUTE SHEET
in 25 ml absolute ethanol. The mixture is stirred at room temperature overnight. Saturated sodium bicarbonate solution (15 ml) is then added and the reaction mixture is stirred with 150 ml ethyl acetate, filtered through gS04 and the filtrate concentrated in vacuo. Chromatography of the residue on 150 gm silica gel using an eluent of methylene chloride/methanol/eonc. ammonium hydroxide (95/5/0.5) gives 2.78 g of N-(2-formamidoethyl)homopiperazine.
B) . N-(2-methylaminoethyl)homopiρerazine.
To a solution of 2.75 gm of N-(2-form- amidoethyl)homopiperazine in 20 ml of dry THF under N 2 is added carefully 60 ml of borane THF solution. After the addition is complete the reaction mixture is heated to reflux for 5 hours then stirred at room temperature overnight. The reaction mixture is quenched by the careful addition of 20 ml of 6N HCl followed by refluxing for 1 hour. The reaction mixture is cooled, 50 ml of water added and solid KOH added carefully to alkaline pH. Extraction with ether gives the desired product N-(2-methylamino) homopiperazine.
EXAMPLE 15
C
CH 3 - N- CH 2 CH 2 - NH-CH 3
SUBSTITUTE SHEET
A) N-benzyl-N,N•-dimethyl-N•-(2-phenylethyl)- ethylenediamine
A mixture of 0.900 gm N-benzyl-N,N*-di- methylethylenedia ine, 1.10 gm powdered sodium carbonate and 0.75 ml of 2-phenylethylbromide is refluxed for 5 hours. An additional 0.25 ml of bromide is added during this time. The reaction mixture is then cooled and filtered. The filterate is concentrated in vacuo and the residue chromatographed on silica gel using an eluent of CH2CI2/CH3OH/NH4OH (97/3/0.3) to yield 0.875 gm of N-benzyl-N,N'-dimethyl-N'-(2-phenylethyl)ethylene- diamine.
B) N,N'-dimethyl-N-(2-phenylethyl)ethylenediamine. To a solution 0.870 gm N-benzyl-N-N'-di¬ methyl-N'-(2-phenylethyl)ethylenediamine in 10 ml ethanol and 5 ml acetic acid is added 0.18 gm Pd (0H)2/C. The mixture is hydrogenated at 40 psi for 3.5 hours, then filtered and concentrated in vacuo. The residue is made akaline with IN NaOH and extracted well with ethyl acetate (5 X 25 ml). The combined extracts are filtered through sodium sulfate and concentrated to yield N,N*-dimethyl-N-(2-phenyl- ethyl)ethylenediamine.
SUBSTITUTE SHEET
EXAMPLE 16
N- CH 2 CH 2 - NH 2
/ 2. ) LAH
N-CH 2 CH 2 -NH-CH 2 -Ar R
A)
A solution of 1.28 gm l-(2-amino-ethyl)- piperdine and 1.07 gm pyridine-3-carboxaldehyde in 40 ml of toluene is heated to reflux under a Dean Stark trap. After 10 ml toluene distilled over the NMR of an aliquot indicated no aldehyde left. The reaction mixture was concentrated and the imine used directly in the next step.
B)
To a suspension of 0.380 gm of lithium aluminum hydride in 30 ml of dry THF which has been cooled to -10°C is added dropwise a solution of the above imine in 20 ml of dry THF. After about 1 hour the cold reaction mixture is quenched by the addition of 5 ml of 5N NaOH, then diluted with 100 ml ether and 20 ml of water. The organic layer is separated, washed with brine, filtered thru sodium sulfate and concentrated to give 2.17 gm of l-[2-(3-pyridyl- methylamino)ethyl]-piperidine suitable for use in subsequent reactions.
SUBSTITUTE SHEET
EXAMPLE 17
A r CH 2 Cl
R-NH-CH 2 -CH 2 -NH-R
R-NH-CH 2 CH 2 -N-R
To 7.50 gm of N,N'-dimethylethylenediamine which has been cooled in an ice-ethanol bath is added portionwise over a 30 minute period 1.40 gm of 3-picolyl chloride. After stirring cold for 1 hour after the addition is completed, the reaction mixture is concentrated in vacuo and the residue partitioned between 50 ml of ether and 10 ml of 5N NaOH solution. The organic layer is separated and the aqueous layer extracted 2 times with 50 ml of ether. The combined organic extracts are dried through sodium sulfate and concentrated in vacuo. Chromatography on 150 gm silica gel using CH2CI2/CH3OH/NH4OH (90/10/1) as eluent gives 0.930 g of N,N'-dimethyl-N-(3-pyridylmethyl)ethylenediamine.
EXAMPLE 18
Amino Acid → diamine
A) To an ice cooled solution of 2.29 N-CBZ-D- Proline in 50 ml of CHC1 2 is added 1.35 gm 1-hydroxybenzotriazole hydrate followed by 2.06 gm of
SUBST I TUTE SHEET
dicyclohexylcarbodiimide. After 20 minutes, 0.85 ml of pyrrolidine is added and the reaction mixture stirred overnight after which time it is filtered and the filtrate concentrated in vacuo. The residue is partitioned between 100 ml ethyl acetate and 50 ml of 2N hydrochloric acid. The organic layer is separated, washed with 50 ml of 1.0N sodium hydroxide solution, dried through sodium sulfate and concentrated in vacuo. Chromatography on 150 gm of silica gel using ethylacetate in hexanes (30 - 1007,) as eluent gives 2.04 gm of the desired pyrrolidine amide
B) To a solution of 1.519 gm of the amide (prepared in A) in 20 ml absolute ethanol is added 75 mg of 107o Pd on carbon catalyst. The mixture is hydrogenated at 40 psi for about an hour then filtrate and the filtrate concentrated to yield D-proline pyrrolidine amide.
C) To a suspension of 0.380 gm of lithium aluminum hydride in 15 ml of dry tetrahydrofuran is carefully added a solution of the D-proline amide (prepared in B above) in 10 ml tetrahydrofuran. The mixture is refluxed for 2 hrs then cooled and quenched with 2 ml of 2.5 N sodium hydroxide. The mixture is filtered through a pad of sodium sulfate and the filter cake washed with 2 x 50 ml of ether. The combined filtrates are concentrated in vacuo to yield 0.80 gm of desired 2-(l-pyrrolidinylmethyl) pyrrolidine.
SUBSTITUTESHEET
EXAMPLE 19
[S-(R>'sS*)]-2-[4-[[(4-Methyl)piperazin-l-yl]carbonyl] phenoxy]-((3,3-diethyl-N-[1-(methyIphenyl)butyl]-4- oxo-1-azetidinecarboxamide
A solution of S-(R*,S*)]-4-(((3,3-diethyl-l- ((4-methylphenyl)butylamino)earbonyl)-4-oxo-2- azetidinyl)oxy)benzoyl chloride (3.8 mmol), prepared as in Example HA, in 50 ml of methylene chloride was cooled in an ice bath and a solution of 0.70 gm of N-methylpiperazine in 10 ml of methylene chloride was added over 5 min. The reaction was stirred for 1 hr and was then poured into a mixture of ice water and 107o potassium carbonate. The product was extracted with two portions of methylene chloride and each methylene chloride layer was washed with a portion of brine. The methylene chloride layers were combined, dried over sodium sulfate and evaporated. The residue was purified with flash chromatography using ethyl acetate, then 27, triethylamine/107, methanol/887o ethyl acetate to afford 2.1 gm of the title compound as a white solid.
Analysis: C 30 H 42 N 4°4 Calc: C, 69.64; H, 7.92; N, 10.48 Found: C, 69.62; H, 8.23; N, 10.46
SUBSTITUTESHEET
Example 20
[S-(R*,S*)]-2-[4-[[(4-Methyl)piperazin-l-yl]earbonyl] phenoxy]-((3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl) butyl]-4-oxo-l-azetidinecarboxamide
When [S-(R*,S*)]-4-(((3,3-diethyl-l-((3,4- methylenedioxyphenyl)butylamino)earbonyl)-4-oxo-2- azetidinyl)oxylbenzoyl chloride (3.1 mmol), prepared as in Example HA, was reacted with
N-methylpiperazine as in Example 19, there was obtained 1.75 gm of the title compound.
Analysis: c 31 H 40 N 4^6 Calc: C, 65.94; H, 7.14; N, 9.92 Found: C, 65.80; H, 7.31; N, 10.05
Example 21
[S-(R*,S*)]-2-[4-[[(4-Hydroxyethyl)piperazin-l-yl] earbonyl]phenoxy]-((3,3-diethyl-N-[1-(methylphenyl) butyl]-4-oxo-l-azetidinecarboxamide
When [S-(R*,S*)]-4-(((3,3-diethyl-l-((4- methylphenyl)butylamino)earbonyl)-4-oxo-2- azetidinyl)oxylbenzoyl chloride (3.8 mmol), prepared as in Example HA. was reacted with N-(2-hydroxyethyl)piperazine (7.6 mmol) and diisopropylethylamine (3.8 mmol) as in Example 19, there was obtained 2.1 gm of the title compound.
Analysis: C32H44N O5
Calc: C, 68.06; H, 7.85; N, 9.92
Found: C, 67.88; H, 7.87; N, 10.17
.;' BΪ.TI. it ~ once 1
Example 22
[S-(R>'sS Λ )]-2-[4-[[(4-Hydroxyethyl)piperazin-l-yl] carbonyl]phenoxy]-((3,3-diethyl-N-[l-(3,4-methylene dioxyphenyl)butyl]-4-oxo-l-azetidinecarboxamide
When [S-(R*,S*)]-4-(((3,3-diethyl-l-((3,4- meth lenedioxyphenyl)butylamino)carbonyl)-4-oxo-2- azetidinyl)oxy)benzoyl chloride (3.1 mmol), prepared ° as in Example HA, was reacted with
N-(2-hydroxyethyl)piperazine (6.2 mmol) and diisopropylethylamine (3.1 mmol) as in Example 19, there was obtained 1.50 gm of the title compound.
5 Analysis: C32H42N4O7 -1.5H20
Calc: C, 61.94; H, 6.89; N, 9.06 Found: C, 61.95; H, 6.92; N, 8.96
Example 23
[S-(R*,S*)]-2-[4-[[(4-Cyclopropyl)piperazin-l-yl] earbonyl]phenoxy]-((3,3-diethyl-N-[1-(4-methylphenyl)b utyl]-4-oxo-l-azetidinecarboxamide
To a solution of [S-(R*,S*)]-4-(((3,3-diethyl-l-((4- methylphenyl)butylamino)earbonyl)-4-oxo-2- azetidinyl)oxy)benzoyl chloride (3.8 mmol), prepared aε in Example HA, in 50 ml of methylene chlorine was added N-(cyclopropyl)piperazine dihydrochloride (5.7 * mmol) and then a solution of diisopropylethylamine (15.8 mmol) in 10 ml of methylene chloride was added over 5 min with ice-bath cooling. The reaction was stirred for 1 hr at 0 C and then poured into ice
SUBSTITUTESHEET
water. The product was extracted with two portions of methylene chloride and each methylene chloride layer was washed with a portion of brine. The methylene chloride layers were combined, dried over sodium sulfate and ethyl acetate/507o hexanes, then 707, ethyl acetate/307, hexanes to afford 2.1 gm of the title compound as a white solid.
[S-(R*,S*)]-2-[4-[[(4-Cyclopropyl)piperazin-l-yl] carbonyl]phenoxy]-((3,3-diethyl-N-[l-(3,4-methylene dioxyphenyl)butyl]-4-oxo-l-azetidinecarboxamide
When [S-(R*,S*)]-4-(((3,3-diethyl-l-((3,4- methylenedioxyphenyl)butylamino)earbonyl)-4-oxo-2- azetidinyl)oxy)benzoyl chloride (3.1 mmol), prepared as in Example HA, was reacted with N-(cyclopropyl)piperazine (4.6 mmol) and diisopropylethylamine (9.3 mmol) as in Example 23, there was obtained 1.80 gm of the title compound.
Analysis: C3 2 H 2 N θ 7
Calc: C, 67.10; H, 7.17; N, 9.49
Found: C, 67.03; H, 7.31; N, 9.47
SUBSTITUTESHEET
Example 25
[S-(R*,S*)]-2-[4-[[(4-Piperazin-l-yl)carbonyl]phenoxy] -((3,3-diethyl-N-[l-(4-methylphenyl)butyl]-4-oxo-l- azetidinecarboxamide
Step A: [S-R*,S*)]-2-[4-[[(4-(t-Butoxycarbonyl))piper azin-l-yl]carbonyl]phenoxy]-((3,3-diethyl-N-[ l-(4-methylphenyl)butyl]-4-oxo-l-azetidinecar boxamide
[S-(R*,S*)]-4-(((3,3-Diethyl-l-((4-methylphenyl)butyla mino)carbonyl)-4-oxo-2-azetidinyl)oxy)benzoyl chloride (0.4 mmol), prepared as in Example HA, was reacted with N-(t-butoxycarbonyl)piperazine (0.6 mmol) and triethylamine (1.2 mmol) as in Example 23. The crude, title product so obtained was used directly in the following Step B.
Step B: [S-R*,S*)]-2-[4-[(Piperazin-l-yl)carbonyl]phe noxy]-((3,3-diethyl-N-[1-(4-methylphenyl)buty 1-4-oxo-l-azetidinecarboxamide
The product from Step A was dissolved in 0.5 ml of anisole and 2 ml of cold TFA was added. The reaction was stirred at 0 C for 1 hr and was then diluted with methylene chloride and evaporated. The residue was taken up in methylene chloride, washed with 107, sodium carbonate and brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography using 5, then 107. methanol/methylene chloride to afford 0.212 gm of title product.
SUBSTITUTE SHEET
Analysis: C 30 H4 0 N4θ 5 -1H20
Calc: C, 66.89; H, 7.85; N, 10.40
Found: C, 67.06; H, 7.55; N, 10.30
Example 26
[S-(R*,S*)]-2-[4-[[(4-Piperazin-l-yl)carbonyl]phenoxy] -((3,3-diethyl-N-[l-(3,4-methylenedioxyphenyl)butyl]-4 -oxo-1- azetidinecarboxamide
Step A: [S-R*,S*)]-2-[4-[[(4-Benzyloxycarbonyl)
Piperazin-l-yl]carbonyl]phenoxy]-((3,3-diethy 1-N-[1-3,4-methylenedioxyphenyl)butyl]-4-oxo- 1-azetidinecarboxamide
When [S-(R*,S*)]-4-(((3,3-diethyl-l-((3,4- methylenedioxyphenyl)butylamino)earbonyl)-4-oxo-2-azet idinyl)oxy)benzoyl chloride (0.41 mmol), prepared as in Example HA, was reacted with N-(benzyloxycarbonyl)piperazine (0.77 mmol) and diisopropylethylamine (1.6 mmol) as in Example 23, there was obtained 290 mg of the title compound.
Step B: [S-R*,S*)]-2-[4-[(Piperazin-1-yl)earbonyl]phe noxy]-((3,3-diethyl-N-[l-(3,4-methylenedioxyp henyl)butyl-4-oxo-l-azetidinecarboxamide
A solution of 250 mg of material from Example 26, Step A in 10 ml of ethanol was hydrogenated at ^0 p.s.i. over 50 mg of 107, Pd/C for 16 hrs. The reaction was filtered and evaporated. The residue was purified by preparative TLC eluting with 27,
SUBSTITUTE SHEET
TEA/107, methanol/887, ethyl acetate to afford 150 mg of title product.
Analysis: C30H33N O.5 -3H20
Calc: C, 59.59; H, 7.33; N, 9.29
Found: C, 59.66; H, 7.65; N, 9.61
-> -OϋBSTITUTESHEET