Title: Phthalazinone-piperidino-derivatives as PDE4 inhibitors
Abstract: The compounds of a formula I, in which the given substituents have the meanings as given in the description, are novel effective PDE4 inhibitors ##STR1##
Patent Number: 6,953,853 Issued on 10/11/2005 to Grundler, et al.
| Inventors:
|
Grundler; Gerhard (Constance, DE);
Schmidt; Beate (Allensbach, DE);
Sterk; Geert Jan (JJ Utecht, NL)
|
| Assignee:
|
Altana Pharma AG (Constance, DE)
|
| Appl. No.:
|
467832 |
| Filed:
|
February 14, 2002 |
| PCT Filed:
|
February 14, 2002
|
| PCT NO:
|
PCT/EP02/01547
|
| 371 Date:
|
August 13, 2003
|
| 102(e) Date:
|
August 13, 2003
|
| PCT PUB.NO.:
|
WO02/06458 |
| PCT PUB. Date:
|
August 22, 2002 |
Foreign Application Priority Data
| Current U.S. Class: |
544/237 |
| Intern'l Class: |
C07D 237/30 |
| Field of Search: |
544/237
514/248
|
References Cited [Referenced By]
| Foreign Patent Documents |
| 0 763 534 | Mar., 1997 | EP.
| |
| 0 934 933 | Aug., 1999 | EP.
| |
| WO 93/0714/6 | Apr., 1993 | WO.
| |
| WO 94/1246/1 | Jun., 1994 | WO.
| |
| WO 98/3167/4 | Jul., 1998 | WO.
| |
| WO 99/3107/1 | Jun., 1999 | WO.
| |
| WO 99/3109/0 | Jun., 1999 | WO.
| |
| WO 99/4750/5 | Sep., 1999 | WO.
| |
| WO 01/1981/8 | Mar., 2001 | WO.
| |
| WO 01/3076/6 | May., 2001 | WO.
| |
| WO 01/3077/7 | May., 2001 | WO.
| |
| WO 01/9431/9 | Dec., 2001 | WO.
| |
Other References
Van der Mey, M., et al., "Novel Selective Phosphodiesterase (PDE4) Inhibitors.
4. Resolution, Absolute Configuration, and PDE4 Inhibitory Activity of cis-Tetra-
and cis-Hexahydrophthalazinones". J. Med. Chem., 45, 2526-2533, 2002.
Van der Mey, M., et al., "Novel Selective PDE4 Inhibitors. 2. Synthesis and Structure-Activity
Relationships of 4-Aryl-Substituted cis-Tetra- and cis-Hexahydrophthalazinones".
J. Med. Chem., 44, 2523-2535, 2001.
Norman, Peter, "PDE4 inhibitors 2001. Patent and literature activity 2000-Sep.
2001". Expert Opinion on Therapeutic Patents, 1, 93-111, 2002.
Van der Mey, M., et al., "Novel Selective PDE4 Inhibitors. 1. Synthesis, Structure-Activity
Relationships, and Molecular Modeling of 4-(3,4-Dimethoxyphenyl)-2H-phthalazin-1-ones
and Analogues". J. Med. Chem., 2001, 44, 2511-2522.
Van der Mey, M., et al., "Novel Selective PDE4 Inhibitors. 3. In Vivo Anti-inflammatory
Activity of a New Series of N-Substituted cis-Tetra- and cis-Hexahydrophthalazinones".
J. Med. Chem., 2002, 45, 2520-2525.
|
Primary Examiner: Wilson; James O.
Assistant Examiner: Tucker; Zachary C.
Attorney, Agent or Firm: Nath & Associates PLLC, Goldberg; Joshua B., McGee; Sheldon M.
Claims
1. A compound of formula I
##STR12##
in which
R1 and R2 are both hydrogen or together form an additional bond,
R3 represents a benzene derivative of formula (a) or (b)
##STR13##
wherein
R4 is 1-4C-alkoxy or 1-4C-alkoxy which is completely or predominantly substituted
by fluorine,
R5 is 1-8C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or 1-4C-alkoxy which
is completely or predominantly substituted by fluorine,
R6 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or 1-4C-alkoxy which
is completely or predominantly substituted by fluorine,
R7 is 1-4C-alkyl and
R8 is hydrogen or 1-4C-alkyl,
or wherein
R7 and R8 together, and with inclusion of the two carbon atoms, to which they
are bonded, form a spiro-linked 5-, 6- or 7-membered hydrocarbon ring, optionally
interrupted by an oxygen or sulphur atom,
R9 is —S(O)
2—R10, —S(O)
2—(CH
2)
n—R11,
—(CH
2)
m—S(O)
2—R12, —C(O)R13,
—C(O)—(CH
2)
n—R14, —(CH
2)
m—C(O)—R15,
Hetaryl, Aryl1 or Aryl2-1-4C-alkyl,
R10 is 1-4C-alkyl, 5-dimethylaminonaphthalin-1-yl, —N(R16)R17, phenyl or
phenyl substituted by R18 and/or R19,
R11 is —N(R16)R17,
R12 is —N(R16)R17,
R13 is 1-4C-alkyl, hydroxycarbonyl-1-4C-alkyl, phenyl, pyridyl, 4-ethyl-piperazin-2,3-dion-1-yl
or —N(R16)R17,
R14 is —N(R16)R17,
R15 is —N(R16)R17, phenyl or phenyl substituted by R18 and/or R19 and/or
R20,
R16 and R17 are independent from each other and are hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl,
3-7C-cycloalkylmethyl, phenyl or phenyl substituted by R18 and/or R19 and/or R20,
or R16 and R17 together and with inclusion of the nitrogen atom to which they are
bonded, form a 4-morpholinyl-, 1-pyrrolidinyl-, 1-piperidinyl-, 1-hexahydroazepino-
or a 1-piperazinyl-ring of formula (c)
##STR14##
wherein
R21 is pyrid-4-yl, pyrid-4-ylmethyl, 1-4C-alkyl-dimethylamino, dimethylaminocarbonylmethyl,
N-methyl-piperidin- 4-yl, 4-morpholino-ethyl or tetrahydrofuran-2-ylmethyl,
R18 is halogen, nitro, cyano, carboxyl, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy,
1-4C-alkoxycarbonyl, amino, mono- or di-1-4C-alkylamino, aminocarbonyl 1-4C-alkylcarbonylamino
or mono- or di-1-4C-alkylaminocarbonyl,
R19 is halogen, amino, nitro, 1-4C-alkyl or 1-4C-alkoxy,
R20 is halogen,
Hetaryl is pyrimidin-2-yl, thieno-[2,3-d]pyrimidin-4-yl, 1-methyl-1H-pyrazolo-[3,4-d]pyrimidin-4-yl,
thiazolyl, imidazolyl or furanyl,
Aryl1 is pyridyl, phenyl or phenyl substituted by R18 and/or R19,
Aryl2 is pyridyl, phenyl, phenyl substituted by R18 and/or R19, 2-oxo-2H-chromen-7-yl
or 4-(1,2,3-thiadiazol-4-yl)phenyl,
n is an integer from 1 to 4,
m is an integer from 1 to 4,
or a hydrate, salt or hydrate of a salt thereof.
2. A compound of formula I according to claim 1, in which
R1 and R2 are both hydrogen or together form an additional bond,
R3 represents a benzene derivative of formula (a) or (b)
##STR15##
wherein
R4 is 1-4C-alkoxy or 1-4C-alkoxy which is completely or predominantly substituted
by fluorine,
R5 is 1-8C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or 1-4C-alkoxy which
is completely or predominantly substituted by fluorine,
R6 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or 1-4C-alkoxy which
is completely or predominantly substituted by fluorine,
R7 is 1-4C-alkyl and
R8 is hydrogen or 1-4C-alkyl,
or wherein
R7 and R8 together and with inclusion of the two carbon atoms, to which they
are bonded, form a spiro-linked 5-, 6- or 7-membered hydrocarbon ring, optionally
interrupted by an oxygen or sulphur atom,
R9 is —S(O)
2—R10, —S(O)
2—(CH
2)
n—R11,
—(CH
2)
m—S(O)
2—R12, —C(O)R13,
—C(O)—(CH
2)
n—R14, —(CH
2)
m—C(O)—R15,
Hetaryl, Aryl1 or Aryl2-1-4C-alkyl,
R10 is 1-4C-alkyl, 5-dimethylaminonaphthalin-1-yl, —N(R16)R17, phenyl or
phenyl substituted by R18 and/or R19,
R11 is —N(R16)R17,
R12 is —N(R16)R17,
R13 is 1-4C-alkyl, hydroxycarbonyl-1-4C-alkyl, phenyl, pyridyl, 4-ethyl-piperazin-2,3-dion-1-yl
or —N(R16)R17,
R14 is —N(R16)R17,
R15 is —N(R16)R17, phenyl, phenyl substituted by R18 and/or R19 and/or
R20,
R16 and R17 are independent from each other and are hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl,
3-7C-cycloalkylmethyl or phenyl, or R16 and R17 together, and with inclusion of
the nitrogen atom to which they are bonded, form a 4-morpholinyl-, 1-pyrrolidinyl-,
1-piperidinyl-, 1-hexahydroazepino- or a 1-piperazinyl-ring of formula (c)
##STR16##
wherein
R21 is pyrid-4-yl, pyrid-4-ylmethyl, 1-4C-alkyl-dimethylamino, dimethylaminocarbonylmethyl,
N-methyl-piperidin-4-yl, 4-morpholino-ethyl or tetrahydrofuran-2-ylmethyl,
R18 is halogen, nitro, cyano, carboxyl, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy,
1-4C-alkoxycarbonyl, amino, mono- or di-1-4C-alkylamino, aminocarbonyl 1-4C-alkylcarbonylamino
or mono- or di-1-4C-alkylaminocarbonyl,
R19 is halogen, amino, nitro, 1-4C-alkyl or 1-4C-alkoxy,
R20 is halogen,
Hetaryl is pyrimidin-2-yl, thieno-[2,3-d]pyrimidin-4-yl, 1-methyl-1H-pyrazolo-[3,4-d]pyrimidin-4-yl,
thiazolyl, imidazolyl or furanyl,
Aryl1 is pyridyl, phenyl or phenyl substituted by R18 and/or R19,
Aryl2 is pyridyl, phenyl, phenyl substituted by R18 and/or R19, 2-oxo-2H-chromen-7-yl
or 4-(1,2,3-thiadiazol-4-yl)phenyl,
n is an integer from 1 to 4,
m is an integer from 1 to 4,
or a hydrate, salt or hydrate of a salt thereof.
3. A compound of formula I according to claim 1, in which
R1 and R2 are both hydrogen or together form an additional bond,
R3 represents a benzene derivative of formula (a) or (b)
##STR17##
wherein
R4 is 1-4C-alkoxy or 1-2C-alkoxy which is completely or predominantly substituted
by fluorine,
R5 is 1-4C-alkoxy,
R6 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or predominantly substituted
by fluorine,
R7 is methyl and
R8 is hydrogen,
or wherein
R7 and R8 together and with inclusion of the two carbon atoms, to which they
are bonded, form a spiro-linked cyclopentane, cyclohexane, tetrahydrofurane or
tetrahydropyran ring,
R9 is —S(O)
2—R10, —S(O)
2—(CH
2)
n—R11,
—C(O)R13, —C(O)—(CH
2)
n—R14, —(CH
2)
m—C(O)—R15,
Hetaryl, Aryl1 or Aryl2-1-2C-alkyl,
R10 is 1-4C-alkyl, 5-dimethylaminonaphthalin-1-yl, —N(R16)R17, phenyl or
phenyl substituted by R18,
R11 is —N(R16)R17,
R13 is 1-4C-alkyl, hydroxycarbonyl-1-4C-alkyl, phenyl, pyridyl, 4-ethyl-piperazin-2,3-dion-1-yl
or —N(R16)R17,
R14 is —N(R16)R17,
R15 is —N(R16)R17, phenyl or phenyl substituted by R18 and/or R19 and/or
R20,
R16 and R17 are independent from each other and are hydrogen, 1-4C-alkyl, phenyl
or phenyl substituted by R18 and/or R19 and/or R20, or R16 and R17 together and
with inclusion of the nitrogen atom to which they are bonded, form a 4-morpholinyl
ring, a 1-piperidinyl ring or a 1-piperazinyl ring of formula (c)
##STR18##
wherein
R21 is pyrid-4-yl, pyrid-4-ylmethyl, dimethylamino-1-4C-alkyl, dimethylaminocarbonylmethyl,
N-methyl-piperidin-4-yl, 4-morpholino-ethyl or tetrahydrofuran-2-ylmethyl,
R18 is halogen, nitro, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy or 1-4C-alkoxycarbonyl,
R19 is halogen, amino, nitro, 1-4C-alkyl or 1-4C-alkoxy,
R20 is halogen,
Hetaryl is pyrimidin-2-yl, thieno-[2,3-d]pyrimidin-4-yl or 1-methyl-1H-pyrazolo-[3,4-d]pyrimidin-4-yl,
Aryl1 is pyridyl, phenyl or phenyl substituted by R18,
Aryl2 is pyridyl, phenyl, phenyl substituted by R18, 2-oxo-2H-chromen-7-yl or
4-(1,2,3-thiadiazol-4-yl)phenyl,
n is 1 or 2,
m is 1 or 2,
or a hydrate, salt or hydrate of a salt thereof.
4. A compound of formula I according to claim 1, in which
R1 and R2 are both hydrogen or together form an additional bond,
R3 represents a benzene derivative of formula (a) or (b)
##STR19##
wherein
R4 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or predominantly substituted
by fluorine,
R5 is 1-4C-alkoxy,
R6 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or predominantly substituted
by fluorine,
R7 is methyl and
R8 is hydrogen,
or wherein
R7 and R8 together and with inclusion of the two carbon atoms, to which they
are bonded, form a spiro-linked cyclopentane, cyclohexane, tetrahydrofurane or
tetrahydropyran ring,
R9 is —S(O)
2—10, —S(O)
2—(CH
2)
n—R11,
—C(O)R13, —C(O)—(CH
2)
n—R14, —(CH
2)
m—C(O)—R15,
Hetaryl, Aryl1 or Aryl2-1-2C-alkyl,
R10 is 1-4C-alkyl, 5-dimethylaminonaphthalin-1-yl, —N(R16)R17, phenyl or
phenyl substituted by R18,
R11 is —N(R16)R17,
R13 is 14C-alkyl, hydroxycarbonyl-1-4C-alkyl, phenyl, pyridyl, 4-ethyl-piperazin-2,3-dion-1-yl
or —N(R16)R17,
R14 is —N(R16)R17,
R15 is —N(R16)R17, phenyl or phenyl substituted by R18 and/or R19 and/or
R20,
R16 and R17 are independent from each other and are hydrogen, 1-4C-alkyl or phenyl,
or —R16 and R17 together and with inclusion of the nitrogen atom to which
they are bonded, form a 4-morpholinyl-, a 1-piperidinyl or a 1-piperazinyl-ring
of formula (c)
##STR20##
wherein
R21 is pyrid-4-yl, pyrid-4-ylmethyl, 1-4C-alkyl-dimethylamino, dimethylaminocarbonylmethyl,
N-methyl-piperidin-4-yl, 4-morpholino-ethyl or tetrahydrofuran-2-ylmethyl,
R18 is halogen, nitro, 1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy,
R19 is halogen, amino, nitro, 1-4C-alkyl or 1-4C-alkoxy,
R20 is halogen,
Hetaryl is pyrimidin-2-yl, thieno-[2,3-d]pyrimidin-4-yl or 1-methyl-1H-pyrazolo-[3,4-d]pyrimidin-4-yl,
Aryl1 is pyridyl, phenyl or phenyl substituted by R18,
Aryl2 is pyridyl, phenyl, phenyl substituted by R18, 2-oxo-2H-chromen-7-yl or
4-(1,2,3-thiadiazol-4-yl)phenyl,
n is 1 or 2,
m is 1 or 2,
or a hydrate, salt or hydrate of a salt thereof.
5. A compound of formula I according to claim 1, in which
R1 and R2 together form an additional bond,
R3 represents a benzene derivative of formula (a) or (b)
##STR21##
wherein
R4 is 1-4C-alkoxy,
R5 is 1-4C-alkoxy,
R6 is 1-2C-alkoxy,
R7 is methyl and
R8 is hydrogen,
R9 is —S(O)
2—R10, —C(O)R13, —C(O)—(CH
2)
n—R14,
—(CH
2)
m—C(O)—R15, Hetaryl, Aryl1 or Aryl2-1-2C-alkyl,
R10 is 1-4C-alkyl, 5-dimethylaminonaphthalin-1-yl, phenyl or phenyl substituted
by R18,
R13 is 1-4C-alkyl, hydroxycarbonyl-1-4C-alkyl, pyridyl, 4-ethyl-piperazin-2,3-dion-1-yl
or —N(R16)R17,
R14 is —N(R16)R17,
R15 is —N(R16)R17, phenyl or phenyl substituted by R18 and/or R19 and/or
R20,
R16 and R17 are independent from each other and are hydrogen, 1-4C-alkyl, phenyl
or phenyl substituted by R18 and/or R19 and/or R20, or R16 and R17 together and
with inclusion of the nitrogen atom to which they are bonded, form a 4-morpholinyl
ring or a 1-piperazinyl ring of formula (c)
##STR22##
wherein
R21 is dimethylamino-1-4C-alkyl,
R18 is halogen, nitro, 1-4C-alkyl or 1-4C-alkoxycarbonyl,
R19 is amino,
R20 is halogen,
Hetaryl is pyrimidin-2-yl, thieno-[2,3-d]pyrimidin-4-yl or 1-methyl-1H-pyrazolo-[3,4-d]pyrimidin-4-yl,
Aryl1 is phenyl or phenyl substituted by R18,
Aryl2 is pyridyl, phenyl, 2-oxo-2H-chromen-7-yl or 4-(1,2,3-thiadiazol-4-yl)phenyl,
n is 1 or 2,
m is 1 or 2,
or a hydrate, salt or hydrate of a salt thereof.
6. A compound of formula I
##STR23##
in which
R1 and R2 together form an additional bond,
R3 represents a benzene derivative of formula (a) or (b)
##STR24##
wherein
R4 is methoxy or ethoxy,
R5 is methoxy or ethoxy,
R6 is methoxy or ethoxy,
R7 is methyl and
R8 is hydrogen,
R9 is toluene-4-sulfonyl, methanesulfonyl, acetyl, 5oxo-pentanoic acid, pyridin-4-yl-carbonyl,
tert-butylaminocarbonyl, phenylaminocarbonyl, 5-dimethylamino-naphthalene-1-sulfonyl,
4-nitrophenyl, pyridin-4-ylmethyl, morpholine-4-carbonyl, 2-(4-amino-3,5-dichlorophenyl)-2-oxo-ethyl,
1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl, thieno[2,3-d]pyrimidin-4-yl, pyrimidin-2-yl,
2-oxo-2H-chromen-7-ylmethyl, isopropyl, morpholin-4-yl-2-oxo-ethyl, phenethyl,
pyridin-3-ylmethyl, pyridin-2-ylmethyl, pyridin-4-ylmethyl, 2-morpholin-4-ylethanoyl,
2-[(4-(2-dimethylaminoethyl)-piperazin-1-yl]-ethanoyl, isopropylaminocarbonylmethyl,
4ethyl-piperazine-2,3-dione-1-carbonyl, 4-(1,2,3-thiadiazol-4-yl-)benzyl, 4-ethoxycarbonylphenylamino-2-oxo-ethyl
or aminocarbonylmethyl,
or a hydrate, salt or hydrate of a salt thereof.
7. A compound of formula I
##STR25##
in which
R1 and R2 together form an additional bond,
R3 represents a benzene derivative of formula (a) or (b)
##STR26##
wherein
R4 is methoxy or ethoxy,
R5 is methoxy or ethoxy,
R6 is methoxy or ethoxy,
R7 is methyl and
R8 is hydrogen,
or wherein
R7 and R8 together and with inclusion of the two carbon atoms, to which they
are bonded, form a cyclopentane or cyclohexan ring,
R9 is toluene-4-sulfonyl, methanesulfonyl, acetyl, 5oxo-pentanoic acid, pyridin-4-yl-carbonyl,
tert-butylaminocarbonyl, phenylaminocarbonyl, 5-dimethylamino-naphthalene-1-sulfonyl,
4-nitrophenyl, pyridin-4-ylmethyl, morpholine-4-carbonyl, 2-(4-amino-3,5-dichlorophenyl)-2-oxo-ethyl,
1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl, thieno[2,3-d]pyrimidin-4-yl, pyrimidin-2-yl,
2-oxo-2H-chromen-7-ylmethyl, isopropyl, morpholin-4-yl-2-oxo-ethyl, phenethyl,
pyridin-3-ylmethyl, pyridin-2-ylmethyl, pyridin-4-ylmethyl, 2-morpholin-4-ylethanoyl,
2-[4-(2-dimethylaminoethyl)-piperazin-1-yl]-ethanoyl, isopropylaminocarbonylmethyl,
4-ethyl-piperazine-2,3-dione-1-carbonyl or 4-(1,2,3-thiadiazol-4-yl-)benzyl,
or a hydrate, salt or hydrate of a salt thereof.
8. A compound of formula I according to claim 1 or a hydrate, salt or hydrate
of a salt thereof, in which the hydrogen atoms in the positions 4a and 8a are cis-configurated.
9. A compound of formula I according to claim 1 or a hydrate, salt or hydrate
of a salt thereof, in which the absolute configuration is S in the position 4a
and R in the position 8a.
10. A compound of formula I according to claim 1 or a hydrate, salt or hydrate
of a salt thereof, in which R3 represents a benzene derivative of formula (a).
11. A compound of formula I according to claim 1, selected from the group consisting of
(4aS,8aR)-4-(3,4-Diethoxyphenyl)2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,
(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-methanesulfonyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,
(4aS,8aR)-2-(1-Acetyl-piperidin-4-yl)-4-(3,4-diethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,
5-(4-[(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl)-5-oxo-pentanoic
acid,
(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(1-pyridin-4-yl-methanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,
4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic
acid tert-butylamide,
4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic
acid phenylamide,
4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic
acid tert-butylamide,
(cis)-4-[4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic
acid tert-butylamide,
(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(5-dimethylamino-naphthalene-1-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,
(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-nitro-phenyl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,
(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,
(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,
(4aS,8aR)-2-{1-[2-(4-Amino-3,5dichloro-phenyl)-2-oxo-ethyl]-piperidin-4-yl}-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,
4-(3,4-Dimethoxyphenyl)-2-[1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-naphthalen-1-one,
(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-thieno[2,3-d]pyrimidin-4-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,
(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyrimidin-2-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,
(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-oxo-2H-chromen-7-ylmethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,
(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-morpholin-4-yl-2-oxo-ethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,
(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-phenethyl-piperidin-4-yl)-4a,5,8,8tetrahydro-2H-phthalazin-1-one,
(4aS,8aR)4-(3,4-Diethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,
(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-3-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1
one,
(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-pyridin-2-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,
(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(2-morpholin-4-yl-ethanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,
(4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-{2-[4-(2-dimethylamino-ethyl-piperazin-1-yl]-ethanoyl}-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,
2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-2H-isopropyl-acetamide,
(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-1,2,3-thiadiazol-4-yl-benzyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,
1-(1 {4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-methanoyl)-4-ethyl-piperazine-2,3-dione,
4-(2{4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-ethanoylamino)-benzoic
acid ethyl ester,
2-{4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl}-acetamide,
and the hydrates, salts and hydrates of the salts thereof.
12. A compound of formula I according to claim 2 or a hydrate, salter hydrate
of a salt thereof, in which the hydrogen atoms in the positions 4a and 8a are cis-configurated.
13. A compound of formula I according to claim 2 or a hydrate, salt or hydrate
of a salt thereof, in which the absolute configuration is S in the position 4a
and R in the position 8a.
14. A compound of formula I according to claim 2 or a hydrate, salt or hydrate
of a salt thereof, in which R3 represents a benzene derivative of formula (a).
15. A compound of formula I according to claim 3 or a hydrate, salt or hydrate
of a salt thereof, in which the hydrogen atoms in the positions 4a and 8a are cis-configurated.
16. A compound of formula I according to claim 3 or a hydrate, salt or hydrate
of a salt thereof, In which the absolute configuration is S in the position 4a
and P in the position 8a.
17. A compound of formula I according to claim 3 or a hydrate, salt or hydrate
of a salt thereof, in which R3 represents a benzene derivative of formula (a).
18. A compound of formula I according to claim 4 or a hydrate, salt or hydrate
of a salt thereof, in which the hydrogen atoms in the positions 4a and 8a are cis-configurated.
19. A compound of formula I according to claim 4 or a hydrate, salt or hydrate
of a salt thereof, in which the absolute configuration is S in the position 4a
and R in the position 8a.
20. A compound of formula I according to claim 4 or a hydrate, salt or hydrate
of a salt thereof, in which R3 represents a benzene derivative of formula (a).
21. A compound of formula I according to claim 5 or a hydrate, salt or hydrate
of a salt thereof, in which the hydrogen atoms in the positions 4a and 8a are cis-configurated.
22. A compound of formula I according to claim 5 or a hydrate, salt or hydrate
of a salt thereof, in which the absolute configuration is S in the position 4a
and R in the position 8a.
23. A compound of formula I according to claim 5 or a hydrate, salt or hydrate
of a salt thereof, in which R3 represents a benzene derivative of formula (a).
24. A compound of formula I according to claim 6 or a hydrate, salt or hydrate
of a salt thereof, in which the hydrogen atoms in the positions 4a and 8a are cis-configurated.
25. A compound of formula I according to claim 6 or a hydrate, salt or hydrate
of a salt thereof, in which the absolute configuration is S in the position 4a
and R in the position 8a.
26. A compound of formula I according to claim 6 or a hydrate, salt or hydrate
of a salt thereof, in which R3 represents a benzene derivative of formula (a).
27. A compound of formula I according to claim 7 or a hydrate, salt or hydrate
of a salt thereof, in which the hydrogen atoms in the positions 4a and 8a are cis-configurated.
28. A compound of formula I according to claim 7 or a hydrate, salt or hydrate
of a salt thereof, in which the absolute configuration is S in the position 4a
and R in the position 8a.
29. A compound of formula I according to claim 7 or a hydrate, salt or hydrate
or a salt thereof, in which R3 represents a benzene derivative of formula (a).
Description
FIELD OF APPLICATION OF THE INVENTION
The invention relates to novel piperidino-derivatives, which are used in the
pharmaceutical industry for the production of medicaments.
KNOWN TECHNICAL BACKGROUND
International Patent Applications WO98/31674 (=U.S. Pat. No. 6,103,718),
WO99/31071, WO99/31090 and WO99/47505 (=U.S. Pat. No. 6,255,303) disclose phthalazinone
derivatives having selective PDE4 inhibitory properties. In the International Patent
Application WO94/12461 and in the European Patent Application EP 0 763 534 3-aryl-pyridazin-6-one
and arylalkyl-diazinone derivatives are described as selective PDE4 inhibitors.
International Patent Application WO93/07146 (=U.S. Pat. No. 5,716,954) discloses
benzo and pyrido pyridazinone and pyridazinthione compounds with PDEIV inhibiting activity.
DESCRIPTION OF THE INVENTION
It has now been found that the piperidino-derivatives, which are described in
greater details below, have surprising and particularly advantageous properties.
The invention thus relates to compounds of formula I
##STR2##
in which
R1 and R2 are both hydrogen or together form an additional bond,
R3 represents a benzene derivative of formula (a) or (b)
##STR3##
wherein
- R4 is 1-4C-alkoxy or 1-4C-alkoxy which is completely or predominantly
substituted by fluorine,
- R5 is 1-8C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or 1-4C-alkoxy
which is completely or predominantly substituted by fluorine,
- R6 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or 1-4C-alkoxy
which is completely or predominantly substituted by fluorine,
- R7 is 1-4C-alkyl and
- R8 is hydrogen or 1-4C-alkyl,
- or wherein
- R7 and R8 together and with inclusion of the two carbon atoms, to which
they are bonded, form a spiro-linked 5-, 6- or 7-membered hydrocarbon ring, optionally
interrupted by an oxygen or sulphur atom,
R9 is 1-4C-alkyl, —S(O)2—R10, —S(O)2—(CH2)n—R11,
—(CH2)mS(O)2—R12, —C(O)R13,
—C(O)—(CH2)n—R14, —(CH2)m—C(O)—R15,
Hetaryl, Aryl1 or 1-4C-alkyl-Aryl2,
R10 is 1-4C-alkyl, 5-dimethylaminonaphthalin-1-yl, —N(R16)R17, phenyl
or phenyl substituted by R18 and/or R19,
R11 is —N(R16)R17,
R12 is —N(R16)R17,
R13 is 1-4C-alkyl, hydroxycarbonyl-1-4C-alkyl, phenyl, pyridyl, 4-ethyl-piperazin-2,3-dion-1-yl
or —N(R16)R17,
R14 is —N(R16)R17,
R15 is —N(R16)R17, phenyl, phenyl substituted by R18 and/or R19 and/or R20,
R16 and R17 are independent from each other hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl,
3-7C-cycloalkylmethyl, phenyl or phenyl substituted by R18 and/or R19 and/or R20,
or R16 and R17 together and with inclusion of the nitrogen atom to which they are
bonded, form a 4-morpholinyl-, 1-pyrrolidinyl-, 1-piperidinyl-, 1-hexahydroazepino-
or a 1-piperazinyl-ring of formula (c)
##STR4##
- wherein
- R21 is pyrid-4-yl, pyrid-4-ylmethyl, 1-4C-alkyl-dimethylamino, dimethylaminocarbonylmethyl,
N-methyl-piperidin-4-yl, 4-morpholino-ethyl or tetrahydrofuran-2-ylmethyl,
R18 is halogen, nitro, cyano, carboxyl, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy,
1-4C-alkoxycarbonyl, amino, mono-or di-1-4C-alkylamino, aminocarbonyl 1-4C-alkylcarbonylamino
or mono-or di-1-4C-alkylaminocarbonyl,
R19 is halogen, amino, nitro, 1-4C-alkyl or 1-4C-alkoxy,
R20 is halogen,
Hetaryl is pyrimidin-2-yl, thieno-[2,3-d]pyrimidin-4-yl, 1-methyl-1H-pyrazolo-[3,4-d]pyrimidin-4-yl,
thiazolyl, imidazolyl or furanyl,
Aryl1 is pyridyl, phenyl or phenyl substituted by R18 and/or R19,
Aryl2 is pyridyl, phenyl, phenyl substituted by R18 and/or R19, 2-oxo-2H-chromen-7-yl
or 4-(1,2,3-thiadiazol-4-yl)phenyl,
n is an integer from 1 to 4,
m is an integer from 1 to 4,
and the salts of these compounds.
1-4C-Alkyl is a straight-chain or branched alkyl radical having 1 to 4
carbon atoms. Examples are the butyl, isobutyl, sec-butyl, tert-butyl, propyl,
isopropyl, ethyl and methyl radicals.
1-4C-Alkoxy is a radical which, in addition to the oxygen atom, contains
a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Alkoxy radicals
having 1 to 4 carbon atoms which may be mentioned in this context are, for example,
the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, iso-propoxy, ethoxy and
methoxy radicals.
1-8C-Alkoxy is a radical which, in addition to the oxygen atom, contains
a straight-chain or branched alkyl radical having 1 to 8 carbon atoms. Alkoxy radicals
having 1 to 8 carbon atoms which may be mentioned in this context are, for example,
the octyloxy, heptyloxy, isoheptyloxy (5-methylhexyloxy), hexyloxy, isohexyloxy
(4-methylpentyloxy), neohexyloxy (3,3-dimethylbutoxy), pentyloxy, isopentyloxy
(3-methylbutoxy), neopentyloxy (2,2-dimethylpropoxy), butoxy, isobutoxy, sec-butoxy,
tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals.
Halogen within the meaning of the present invention is bromine, chlorine
or fluorine.
3-7C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,
cyclohexyloxy or cycloheptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy
are preferred.
3-7C-Cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxy,
cyclopentylmethoxy, cyclohexylmethoxy or cycloheptylmethoxy, of which cyclopropylmethoxy,
cyclobutylmethoxy and cyclopentylmethoxy are preferred.
3-5C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy and cyclopentyloxy.
3-5C-Cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxy
and cyclopentylmethoxy.
1-4C-Alkoxy which is completely or predominantly substituted by fluorine
is, for example, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1,2,2-trifluoroethoxy
and in particular the 1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the
trifluoromethoxy and the difluoromethoxy radical, of which the difluoromethoxy
radical is preferred. "Predominantly" in this connection means that more than half
of the hydrogen atoms of the 1-4C-alkoxy group are replaced by fluorine atoms.
As spiro-linked 5-, 6- or 7-membered hydrocarbon rings, optionally interrupted
by an oxygen or sulphur atom, may be mentioned the cyclopentane, cyclohexane, cycloheptane,
tetrahydrofuran, tetrahydropyran and the tetrahydrothiophen ring.
1-4C-Alkylcarbonyl is a carbonyl group to which one of the abovementioned
1-4C-alkyl radicals is bonded. An example is the acetyl radical [CH
3C(O)—].
An 1-4C-Alkylcarbonylamino radical is, for example, the propionylamino [C
3H
7C(O)NH—]
and the acetylamino radical [CH
3C(O)NH—].
Mono- or Di-1-4C-alkylamino radicals contain in addition to the nitrogen atom,
one or two of the abovementioned 1-4C-alkyl radicals. Preferred are the di-1-4C-alkylamino
radicals, especially the dimethylamino, the diethylamino and the diisopropylamino radical.
Mono- or Di-1-4C-alkylaminocarbonyl radicals contain in addition to the carbonyl
group one of the abovementioned mono- or di-1-4C-alkylamino radicals. Examples
which may be mentioned are the N-methyl- the N,N-dimethyl-, the N-ethyl-, the N-propyl-,
the N,N-diethyl- and the N-isopropylaminocarbonyl radical.
Suitable salts for compounds of the formula I are all acid addition salts.
Particular mention may be made of the pharmacologically tolerable inorganic and
organic acids customarily used in pharmacy. Those suitable are water-soluble and
water-insoluble acid addition salts with acids such as, for example, hydrochloric
acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, acetic acid,
citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric
acid, sulphosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid,
succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulphonic
acid, methanesulphonic acid or 3-hydroxy-2-naphthoic acid, the acids being employed
in salt preparation—depending on whether a mono- or polybasic acid is concerned
and depending on which salt is desired—in an equimolar quantitative ratio
or one differing therefrom.
Pharmacologically intolerable salts, which can be obtained, for
example, as process products during the preparation of the compounds according
to the invention on an industrial scale, are converted into pharmacologically tolerable
salts by processes known to the person skilled in the art.
According to expert's knowledge the compounds of the invention as well
as their salts may contain, e.g. when isolated in crystalline form, varying amounts
of solvents. Included within the scope of the invention are therefore all solvates
and in particular all hydrates of the compounds of formula I as well as all solvates
and in particular all hydrates of the salts of the compounds of formula I.
Compound of formula I to be emphasized are those in which
R1 and R2 are both hydrogen or together form an additional bond,
R3 represents a benzene derivative of formula (a) or (b)
##STR5##
wherein
- R4 is 1-4C-alkoxy or 1-2C-alkoxy which is completely or predominantly
substituted by fluorine,
- R5 is 1-4C-alkoxy,
- R6 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or predominantly
substituted by fluorine,
- R7 is methyl and
- R8 is hydrogen,
- or wherein
R7 and R8 together and with inclusion of the two carbon atoms, to which they
are
bonded, form a spiro-linked cyclopentane, cyclohexane, tetrahydrofurane or tetrahydropyran ring,
R9 is 1-4C-alkyl, —S(O)2—R10, —S(O)2—(CH2)n—R11,
—C(O)R13, —C(O)—(CH2)n—R14, —(CH2)m—C(O)—R15,
Hetaryl, Aryl1 or 1-2C-alkyl-Aryl2,
R10 is 1-4C-alkyl, 5-dimethylaminonaphthalin-1-yl, —N(R16)R17, phenyl
or phenyl substituted by R18,
R11 is —N(R16)R17,
R13 is 1-4C-alkyl, hydroxycarbonyl-1-4C-alkyl, phenyl, pyridyl, 4-ethyl-piperazin-2,3-dion-1-yl
or —N(R16)R17,
R14 is —N(R16)R17,
R15 is —N(R16)R17, phenyl, phenyl substituted by R18 and/or R19 and/or R20,
R16 and R17 are independent from each other hydrogen, 1-4C-alkyl, phenyl
or phenyl substituted by R18 and/or R19 and/or R20, or R16 and R17 together and
with inclusion of the nitrogen atom to which they are bonded, form a 4-morpholinyl
ring, a 1-piperidinyl ring or a 1-piperazinyl ring of formula (c)
##STR6##
wherein
- R21 is pyrid-4-yl, pyrid-4-ylmethyl, dimethylamino-1-4C-alkyl, dimethylaminocarbonylmethyl,
N-methyl-piperidin-4-yl, 4-morpholino-ethyl or tetrahydrofuran-2-ylmethyl,
R18 is halogen, nitro, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy or 1-4C-alkoxycarbonyl,
R19 is halogen, amino, nitro, 1-4C-alkyl or 1-4C-alkoxy,
R20 is halogen,
Hetaryl is pyrimidin-2-yl, thieno-[2,3-d]pyrimidin-4-yl or 1-methyl-1H-pyrazolo-[3,4-d]pyrimidin-4-yl,
Aryl1 is pyridyl, phenyl or phenyl substituted by R18,
Aryl2 is pyridyl, phenyl, phenyl substituted by R18, 2-oxo-2H-chromen-7-yl
or 4-(1,2,3-thiadiazol-4-yl)phenyl,
n is 1 or 2,
m is 1 or 2,
and the salts of these compounds.
Preferred compounds of formula I are those, in which
R1 and R2 together form an additional bond,
R3 represents a benzene derivative-of formula (a) or (b)
##STR7##
wherein
- R4 is 1-4C-alkoxy,
- R5 is 1-4C-alkoxy,
- R6 is 1-2C-alkoxy,
- R7 is methyl and
- R8 is hydrogen,
R9 is 1-4C-alkyl, —S(O)2—R10, —C(O)R13, —C(O)—(CH2)n—R14,
—(CH2)m—C(O)—R15, Hetaryl, Aryl1 or 1-2C-alkyl-Aryl2,
R10 is 1-4C-alkyl, 5-dimethylaminonaphthalin-1-yl, phenyl or phenyl substituted
by R18,
R13 is 1-4C-alkyl, hydroxycarbonyl-1-4C-alkyl, pyridyl, 4-ethyl-piperazin-2,3-dion-1-yl
or —N(R16)R17,
R14 is —N(R16)R17,
R15 is —N(R16)R17, phenyl or phenyl substituted by R18 and/or R19
and/or R20,
R16 and R17 are independent from each other hydrogen, 1-4C-alkyl, phenyl
or phenyl substituted by R18 and/or R19 and/or R20, or R16 and R17 together and
with inclusion of the nitrogen atom to which they are bonded, form a 4-morpholinyl
ring or a 1-piperazinyl ring of formula (c)
##STR8##
wherein
- R21 is dimethylamino-1-4C-alkyl,
R18 is halogen, nitro, 1-4C-alkyl or 1-4C-alkoxycarbonyl,
R19 is amino,
R20 is halogen,
Hetaryl is pyrimidin-2-yl, thieno-[2,3-d]pyrimidin-4-yl or 1-methyl-1H-pyrazolo-[3,4-d]pyrimidin-4-yl,
Aryl1 is phenyl or phenyl substituted by R18,
Aryl2 is pyridyl, phenyl, 2-oxo-2H-chromen-7-yl or 4-(1,2,3-thiadiazol-4-yl)phenyl,
n is 1 or 2,
m is 1 or 2,
and the salts of these compounds.
Particularly preferred compounds of formula I are those in which
R1 and R2 together form an additional bond,
R3 represents a benzene derivative of formula (a) or (b)
##STR9##
wherein
- R4 is methoxy or ethoxy,
- R5 is methoxy or ethoxy,
- R6 is methoxy or ethoxy,
- R7 is methyl and
- R8 is hydrogen,
R9 is toluene-4-sulfonyl, methanesulfonyl, acetyl, 5-oxo-pentanoic acid,
pyridin-4-yl-carbonyl, tert-butylaminocarbonyl, phenylaminocarbonyl, 5-dimethylamino-naphthalene-1-sulfonyl,
4-nitrophenyl, pyridin-4-ylmethyl, morpholine-4-carbonyl, 2-(4-amino-3,5-dichlorophenyl-2-oxo-ethyl,
1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl, thieno[2,3-d]pyrimidin-4-yl, pyrimidin-2-yl,
2-oxo-2H-chromen-7-ylmethyl, isopropyl, morpholin-4-yl-2-oxo-ethyl, phenethyl,
pyridin-3-ylmethyl, pyridin-2-ylmethyl, pyridin-4-ylmethyl, 2-morpholin-4-ylethanoyl,
2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-ethanoyl, isopropylaminocarbonylmethyl,
4-ethyl-piperazine-2,3-dione-1-carbonyl, 4-(1,2,3-thiadiazol-4-yl-)benzyl, 4-ethoxycarbonylphenylamino-2-oxo-ethyl
or amino-carbonylmethyl,
and the salts of these compounds.
The compounds of formula I are chiral compounds. Chiral centers exist in the
compounds of formula I in the positions 4a and 8a. In case R3 represents a benzene
derivative of formula (b) there is one further chiral center in the dihydrofuran-ring,
if the substituents —R7 and —CH
2R8 are not identical. However,
preferred are in this connection those compounds, in which the substituents —R7
and —CH
2R8 are identical or together and with inclusion of the
two carbon atoms to which they are-bonded form a spiro-connected 5-, 6- or 7-membered
hydrocarbon ring.
##STR10##
Therefore the invention includes all conceivable pure diastereomers and
pure enantiomers of the compounds of formula I, as well as all mixtures thereof
independent from the ratio, including the racemates. Preferred are those compounds
of formula I, in which the hydrogen atoms in the positions 4a and 8a are cis-configurated.
Especially preferred in this connection are those compounds, in which the absolute
configuration (according to the rules of Cahn, Ingold and Prelog) is S in the position
4a and R in the position 8a. Racemates can be split up into the corresponding enantiomers
by methods known by a person skilled in the art. Preferably the racemic mixtures
are separated into two diastereomers during the preparation with the help of an
optical active separation agent on the stage of the cyclohexanecarboxylic acids
or the 1,2,3,6-tetrahydrobenzoic acids (for example, starting compounds A1, A2
and A3). As separation agents may be mentioned, for example, optical active amines
such as the (+)- and (-)-forms of 1-phenylethylamine [(R)-(+)-1-phenylethylamine=(R)-(+)-α-methylbenzylamine
or (S)-(-)-1-phenylethylamine=(S)-(-)-α-methylbenzylamine) and ephedrine,
the optical active alkaloids quinine, cinchonine, cinchonidine and brucine.
The compounds according to the invention can be prepared, for example, as described
in Reaction scheme 1.
##STR11##
Reaction scheme 1 shows that the compounds of formula I can be, for example,
prepared starting from 4-oxo-piperidine-1-carboxylic acid tert-butyl ester which
is reacted in a first reaction step with tert-butylcarbazate to give 4-(tert-Butoxycarbonyl-hydrazono)-piperidine-1-carboxylic
acid tert-butyl ester (starting compound A7). Compound A7 is reduced with, for
example, the boran tetrahydrofurane complex to give 4-(N′-tert-Butoxycarbonyl-hydrazino)piperidine-1-carboxylic
acid tert-butyl ester (starting compound A6). Treatment of compound A6 with concentrated
hydrochloric acid results in the formation of piperidin-4-yl-hydrazine dihydrochloride
(starting compound A5).
The reaction of piperidin-4-yl-hydrazine dihydrochloride with cyclohexanecarboxylic
acids or 1,2,3,6-tetrahydrobenzoic acids of formulae IIIa or IIIb leads to the
piperidino derivatives of formula II.
These are reacted in the final reaction step with compounds of formula R9-X,
wherein X represents a suitable leaving group, preferably a chlorine atom, to give
the compounds of formula I.
For some compounds of formula I, it can be advantageous, to introduce the substituent
R9 in two reaction steps. As example may be mentioned those compounds of formula
I, wherein R9 represents morpholin-4-ylethanoyl. Here, the corresponding compounds
of formula II are reacted in a first step with chloroacetylchloride and then in
a second step with morpholine.
Suitably, the conversions are carried out analogous to methods which are
familiar per se to the person skilled in the art, for example, in the manner which
is described in the following examples.
The preparation of the cyclohexanecarboxylic acids and 1,3,5,6-tetrahydrobenzoic
acids of the formulae IIIa or IIIb is described, for example, in WO98/31674, WO99/31090
and WO99/47505.
The substances according to the invention are isolated and purified in a manner
known per se, e.g. by distilling off the solvent in vacuo and recrystallising the
residue obtained from a suitable solvent or subjecting it to one of the customary
purification methods, such as column chromatography on a suitable support material.
Salts are obtained by dissolving the free compound in a suitable solvent (for
example a ketone like acetone, methylethylketone, or methylisobutylketone, an ether,
like diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon, such
as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol,
such as ethanol, isopropanol) which contains the desired acid, or to which the
desired acid is then added. The salts are obtained by filtering, reprecipitating,
precipitating with a non-solvent for the addition salt or by evaporating the solvent.
Salts obtained can be converted by basification into the free compounds which,
in turn, can be converted into salts. In this manner, pharmacologically non-tolerable
salts can be converted into pharmacologically tolerable salts.
The following examples illustrate the invention in greater detail, without restricting
it. As well, further compounds of formula I, of which the preparation is explicitly
not described, can be prepared in an analogous way or in a way which is known by
a person skilled in the art using customary preparation methods.
The compounds, which are mentioned in the examples as well as their salts are
preferred compounds of the invention.
EXAMPLES
Final Products
1. (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one
A solution of 1.0 g of starting compound A2 and 1.0 g of p-toluenesulfonyl chloride
in 50 ml of pyridine is stirred at RT for 18 h after which the mixture is evaporated.
The residue is partitioned between aqueous sodium carbonate and dichloromethane.
The dichloromethane layer is dried over magnesium sulfate and evaporated. The compound
is crystallised from methanol. M. p. 99-101° C.
2. (4aS,8aR)-4-(3,4-diethoxyphenyl)-2-(1-methanesulfonyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one
Prepared from methanesulfonylchloride and starting compound A2 as described
for compound 1. Crystallisation from methanol/water. M. p. 99-102° C.
3. (4aS,8aR)-2-(1-Acetyl-piperidin-4-yl)-4-3,4-diethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one
Prepared from acetic anhydride and starting compound A2 as described for
compound 1. Crystallised from diethyl ether. M. p. 148-150° C.
4. 5-(4-[(4aS,8aR)-4-(3,4-Diethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl)-5-oxo-pentanoic Acid
Prepared from glutaric anhydride and starting compound A2 as described for
compound 1. After evaporating the pyridine, the residue is partitioned between
ethyl acetate and 1N hydrochloric acid. The ethyl acetate solution is dried over
magnesium sulfate and evaporated. Crystallisation from diethyl ether. M. p. 133-135° C.
5. (4aS,8aR)4-(3,4-Diethoxyphenyl)-2-[1-(1-pyridin-4-yl-methanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one Hydrochloride
Prepared from isonicotinoyl chloride hydrochloride and starting compound
A2 as described for compound 1. After evaporating the dichloromethane solution,
the residue is dissolved in diethyl ether. After addition of a saturated solution
of hydrochloric acid in ether, the titel compound precipitates. M. p. 66-68° C.
6. 4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic
Acid tert-butylamide
A mixture of 1.0 g of starting compound A2, 0.5 g of t-butylisocyanate and 2
ml
of triethylamine in 50 ml of tetrahydrofurane is stirred for 18 h at RT. After
evaporating the solution, the residue is partitioned between water and ethyl acetate.
Crystallisation from a mixture of dichloromethane and petroleum ether (60-80°
C.). M. p. 145-148° C.
7. 4-[(4aS,8aR)-4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic
Acid Phenylamide
Prepared from starting compound A1 and phenylisocyanate as described for
compound 6. Crystallisation from ether. M. p. 109-112° C.
8. 4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic
Acid Tert-butylamide
Prepared from starting compound A1 and t-butylisocyanate as described for
compound 6. Crystallisation from ether. M. p. 164-166° C.
9. (cis)-4-[4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidine-1-carboxylic
Acid Tert-butylamide
Prepared from starting compound A3 and t-butylisocyanate as described for
compound 6. Crystallisation from ether. M. p. 145-147° C.
10. (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(5-dimethylamino-naphthalene-1-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one
Prepared from dansylchloride and starting compound A1 as described for compound
1. Crystallisation from methanol. M. p. 198-200° C.
11. (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(4-nitro-phenyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one
A mixture of 1.0 g of compound A1, 1.0 g of 1-Iodo-4-nitrobenzene and 1.0 g of
potassium carbonate in 20 ml of dimethylformamide is stirred for 18 h at RT after
which 100 ml of water is added to the reaction mixture. The precipitate is filtered
off and crystallised from methanol. M. p. 196-197° C.
12. (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one
Prepared from starting compound A1 and 4-picolylchloride hydrochloride as
described for compound 11. After the addition of 100 ml of water, 20 ml of diethyl
ether is added and the resulting mixture stirred for 30 min. The precipitate is
filtered off and dried. M. p. 196-197° C.
13. (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one
Prepared from 4-morpholinocarbonyl chloride and compound A1 as described
for compound 1. Crystallisation from diethyl ether. M. p. 184-185° C.
14. (4aS,8aR)-2-[1-2-(4-Amino-3,5-dichloro-phenyl)-2-oxo-ethyl]-piperidin-4-yl)-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one Hydrochloride
Prepared from (4-Amino-3,5dichloro-phenyl)-2-bromo-ethanone and starting
compound A1 as described for compound 11. After the addition of water, the mixture
is extracted with diethyl ether. The ether solution is dried over magnesium sulfate.
After the addition of a saturated solution of hydrochloric acid in ether, the compound
precipitates. Crystallisation from tetrahydrofurane. M. p. 206° C. (decomposition).
15. 4-(3,4-Dimethoxyphenyl)-2-[1-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperidin-4-yl]4a,5,8,8a-tetrahydro-2H-naphthalen-1-one
Prepared from 4-Chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine and starting
compound A1 as described for compound 11. Crystallisation from methanol. M. p.
193-194° C.
16. (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-thieno[2,3-d]pyrimidin-4-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one
Prepared from 4-Chloro-thieno[2,3-d]pyrimidine and starting compound A1
as described for compound 11. After the addition of water, the mixture is extracted
with diethyl ether. The ether solution is dried over magnesium sulfate. After the
addition of a saturated solution of hydrochloric acid in ether, the compound precipitates.
M. p. 219-220° C.
17. (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyrimidin-2-yl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one
Prepared from 2-Chloro-pyrimidine and starting compound A1 as described
for compound 11. Crystallisation from methanol. M. p. 163-166° C.
18. (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-oxo-2H-chromen-7-ylmethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one Hydrochloride
Prepared from 7-Chloromethyl-chromen-2-one and starting compound A1 as described
for compound 11. After the addition of water, the mixture is extracted with diethyl
ether. The ether solution is dried over magnesium sulfate. After the addition of
a saturated solution of hydrochloric acid in ether, the compound precipitates.
M. p. 264-267° C.
19. 4-(3,4-Dimethoxyphenyl)-2-(1-Isopropyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one Hydrochloride
Prepared from 2-iodopropane and starting compound A1 as described for compound
18. M. p. 158-159° C.
20. (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-[1-(2-morpholin-4-yl-2-x-ethyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one Hydrochloride
Prepared from 4-(2-chloroacetyl)morpholine and starting compound A1 as described
for compound 18. M. p. 159-162° C.
21. (4aS,8aR)4-(3,4-Dimethoxyphenyl)-2-(1-phenethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one Hydrochloride
Prepared from 2-bromoethylbenzene and starting compound A1 as described
for compound 18. M. p. 216-217° C.
22. (4aS,8aR)4-(3,4-Diethoxyphenyl)-2-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one
Prepared from 4-morpholinocarbonyl chloride and starting compound A2 as
described for compound 1. Crystallisation from diethyl ether. M. p. 139-141° C.
23. (4aS,8aR)-4-(3,4-Dimethoxyphenyl)-2-(1-pyridin-3-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one Dihydrochloride
Prepared from starting compound A1 and 3-picolylchloride hydrochloride as
described for compound 18. M. p. 252-254° C.
24. (4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-(1-pyridin-2-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one Dihydrochloride
Prepared from compound A1 and 2-picolylchloride hydrochloride as described
for compound 18. M. p. 214-216° C.
25. (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-[1-(2-morpholin-4-yl-ethanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one Hydrochloride
Prepared from starting compound A5 and morpholine as described for compound
18. M. p. 219° C. (decomposition).
26. (4aS,8aR)-4-(3,4-Diethoxyphenyl)-2-(1-(2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-ethanoyl)-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one Trihydrochloride
Prepared from starting compound A4 and dimethyl-(2-piperazin-1-yl-ethyl)-amine
as described for compound 18. M. p. 195-197° C.
27. 2-(4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl)-2H-isopropyl-acetamide
Prepared from starting compound A1 and N-(chloroacetyl)isopropylamine as
described for compound 11. Crystallisation from ether. M. p. 172-173° C.
28. (4aS,8aR)4-(3,4-Dimethoxyphenyl)-2-[1-(4-1,2,3-thiadiaz 1-4-yl-benzyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one Dihydrochloride
Prepared from starting compound A1 and 4-(4-Bromomethyl-phenyl)-[1,2,3]thiadiazole
as described for compound 18. M. p. 243-245° C.
29. 1(1-(4-[(4aS,8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl)-methanoyl)-4-ethyl-piperazine-2,3-dione
Prepared from 4-ethyl-2,3-dioxo-piperazine-1-carbonyl chloride and starting
compound A1 as described for compound 1. Crystallisation from ethyl acetate/diethyl
ether. M. p. 226-228° C.
30. 4-(2-(4-[(4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1-yl)-ethanoylamino)-benzoic
Acid Ethyl Ester Hydrochloride
Prepared from ethyl 4-(2-chloroacetamido)benzoate and starting compound
A1 as described in example 18. M. p. 153-156° C.
31. 2-(4[(4aS, 8aR)-4-(3,4-Dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-piperidin-1yl)-2H-acetamide Hydrochloride
Prepared from 2-chloroacetamide and starting compound A1 as described for
compound 16. M. p. 241-243° C.
Starting Compounds
A1. (4aS,8aR)-4-(3,4-Dimethoxy-phenyl)-2-piperidin-4-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one Hydrochloride
A solution of 50 mmol of the salt of (S)-(-)-α-methylbenzylamine and (cis)-2-(3,4-dimethoxybenzoyl)-1,2,3,6-tetrahydrobenzoic
acid (starting compound A8), 55 mmol of piperidin-4-yl-hydrazine dihydrochloride
and 100 mmol of triethylamine in 150 ml of 1-propanol is refluxed for 18 h. After
cooling to RT, the precipitate is filtered off and dried. M. p. 285-288° C.
A2. (4aS,8aR)-4-(3,4-Diethoxy-phenyl)-2-piperidin-4-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one Hydrochloride
Prepared from the salt of (S)-(-)-α-methylbenzylamine and (cis)-2-(3,4-diethoxybenzoyl)-1,2,3,6-tetrahydrobenzoic
acid (starting compound A9) in 2-propanol as described for compound A1. M. p. 248-250° C.
A3. (cis)-4-(7-Methoxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-yl)-2-piperidin-4-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one Hydrochloride
Prepared from (cis)-2-(2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4 carbonyl)-1,2,3,6-tetrahydrobenzoic
acid (starting compound A10) in 1-propanol as described for compound A1. After
evaporating the solvent, the residue is partitioned between dichloromethane and
aqueous sodium carbonate. The dichlormethan
