Piperazino-derivatives and their use as PDE4 inhibitor

• US 7,022,696 B2
• Filed: 04/24/2002
• Issued: 04/04/2006
• Est. Priority Date: 04/25/2001
• Status: Expired due to Fees

• Current Assignee: Atlanta Pharma AG
• Original Assignee: Altana Pharma AG (Takeda Pharmaceutical Company Limited)
• Inventors: Schmidt, Beate, Sterk, Geert Jan, Grundler, Gerhard
• Primary Examiner(s): Bernhardt, Emily
• Application Number:
  US10/475,656
• Publication Number:
  US 20040132721A1
• Time in Patent Office: 1,441 Days
• Field of Search: 544/237, 540/575, 514/218, 514/248
• US Class Current: 514/218
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/04 for urolithiasis
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/08 Antiseborrheics
• CPC Class Codes: A61P 17/10 Anti-acne agents
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 17/16 Emollients or protectives, e.g. against radiation
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/14 Decongestants or antiallergics
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/12 : Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: C07D 237/32 : with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond

Abstract

The compounds of formula I
in which R1, R2, R3, A, X, s and R9 have the meanings as given in the description are novel effective PDE4 inhibitors.

Claims

1. A compound of formula I

in which

R1 and R2 are both hydrogen or together form an additional bond,

R3 represents a benzene derivative of formula (a) or (b)

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,

A is a bond or methylene (—

CH₂—

),

R9 is —

C(O)R10, —

(CH₂)_m—

C(O)R11, —

(CH₂)_nR12, Aryl, Hetaryl, phenylprop-1-en-3-yl or 1-methyl-piperidin-4-yl,

R10 hydrogen, 1–

4C-alkyl, —

OR13, furanyl, indolyl, phenyl, pyridyl, phenyl substituted by R16 and/or R17 or pyridyl substituted by R18 and/or R19,

R11 is —

N(R14)R15,

R12 is —

N(R14)R15, tetrahydrofuranyl or pyridinyl,

R13 is 1–

4C-alkyl,

R14 is hydrogen, 1–

4C-alkyl, 3–

7C-cycloalkyl or 3–

7C-cycloalkylmethyl,

R15 is hydrogen, 1–

4C-alkyl, 3–

7C-cycloalkyl or 3–

7C-cycloalkylmethyl,

or R14 and R15 together and with inclusion of the nitrogen atom to which they are bonded, form a 4-morpholinyl-, 1-pyrrolidinyl-, 1-piperidinyl- or 1-hexahydroazepinyl-ring,

Aryl is phenyl, pyridyl, pyrimidinyl, phenyl substituted by R16 and/or R17, pyridyl substituted by R18 and/or R19,

R16 is halogen, nitro, 1–

4C-alkyl, trifluoromethyl or 1–

4C-alkoxy,

R17 is halogen or 1–

4C-alkyl,

R18 is halogen, nitro, 1–

4C-alkyl, trifluoromethyl or 1–

4C-alkoxy,

R19 is halogen or 1–

4C-alkyl,

Hetaryl is indol-4-yl, 2-methyl-quinolin-4-yl, 5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl, 3-phenyl-1,2,4-thiadiazol-5-yl or 3-o-tolyl-1,2,4-thiadiazol-5-yl,

n is an integer from 1 to 4,

m is an integer from 1 to 4,

s is an integer from 1 to 2,

X is —

C(O)—

or —

S(O)₂—

,

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)

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,

A is a bond or methylene (—

CH₂—

),

R9 is —

C(O)R10, —

(CH₂)_m—

C(O)R11, —

(CH₂)_nR12, Aryl, Hetaryl, phenylprop-1-en-3-yl or 1-methyl-piperidin-4-yl,

R10 hydrogen, 1–

4C-alkyl, —

OR13, furanyl, indolyl, pyridyl or pyridyl substituted by R18 and/or R19,

R11 is —

N(R14)R15,

R12 is —

N(R14)R15, tetrahydrofuranyl or pyridinyl,

R13 is 1–

4C-alkyl,

R14 is hydrogen, 1–

4C-alkyl, 3–

7C-cycloalkyl or 3–

7C-cycloalkylmethyl,

R15 is hydrogen, 1–

4C-alkyl, 3–

7C-cycloalkyl or 3–

7C-cycloalkylmethyl,

or R14 and R15 together and with inclusion of the nitrogen atom to which they are bonded, form a 4-morpholinyl-, 1-pyrrolidinyl-, 1-piperidinyl- or 1-hexahydroazepinyl-ring,

Aryl is phenyl, pyridyl, pyrimidinyl, phenyl substituted by R16 and/or R17, pyridyl substituted by R18 and/or R19,

R16 is halogen, nitro, 1–

4C-alkyl, trifluoromethyl or 1–

4C-alkoxy,

R17 is halogen or 1–

4C-alkyl,

R18 is halogen, nitro, 1–

4C-alkyl, trifluoromethyl or 1–

4C-alkoxy,

R19 is halogen or 1–

4C-alkyl,

Hetaryl is indol-4-yl, 2-methyl-quinolin-4-yl, 5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl, 3-phenyl-1,2,4-thiadiazol-5-yl or 3-o-tolyl-1,2,4-thiadiazol-5-yl,

n is an integer from 1 to 4,

m is an integer from 1 to 4,

s is 1,

X is —

C(O)—

or —

S(O)₂—

,

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 together form an additional bond,

R3 represents a benzene derivative of formula (a) or (b)

wherein

R4 is methoxy or ethoxy,

R5 is methoxy or ethoxy,

R6 is methoxy,

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 cyclohexane ring,

A is a bond or methylene (—

CH₂—

),

R9 is phenyl, pyrid-2-yl, pyrid-4-yl, pyrimidin-2-yl, 3-dimethylaminopropyl, 2-dimethylaminoethyl, dimethylaminocarbonylmethyl, furan-2-yl-methanoyl, formyl, ethoxycarbonyl, 5-nitropyridin-2-yl, 3,5-dichloropyridin-4-yl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, 2-morpholin-4-yl-2-oxo-ethyl, 2-oxo-2-pyrrolidin-1-yl-ethyl, 1H-indol-4-yl, tetrahydrofuran-2-ylmethyl, 2-(pyrrolidin-1-yl)-ethyl, pyridin-4-ylmethyl, 2-methyl-quinolin-4-yl, 1-methyl-piperidin-4-yl, 5-trifluoromethyl-pyridin-2-yl, 5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl, 3-phenyl-1,2,4-thiadiazol-5-yl, 3-o-tolyl-1,2,4-thiadiazol-5-yl or (E)-3-phenylallyl,

s is 1,

X is —

C(O)—

or —

S(O)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 together form an additional bond,

R3 represents a benzene derivative of formula (a) or (b)

wherein

R4 is methoxy or ethoxy,

R5 is methoxy or ethoxy,

R6 is methoxy,

R7 is methyl and

R8 is hydrogen,

A is a bond,

R9 is phenyl, pyrid-2-yl, pyrid-4-yl, 3-dimethylaminopropyl, 2-dimethylaminoethyl, dimethylaminocarbonylmethyl, furan-2-yl-methanoyl, formyl, ethoxycarbonyl, 5-nitropyridin-2-yl, 3,5-dichloropyridin-4-yl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, 2-morpholin-4-yl-2-oxo-ethyl, 2-oxo-2-pyrrolidin-1-yl-ethyl, 1H-indol-4-yl, tetrahydrofuran-2-ylmethyl, 2-(pyrrolidin-1-yl)ethyl, pyridin-4-ylmethyl, 2-methyl-quinolin-4-yl, 1-methyl-piperidin-4-yl, 5-trifluoromethyl-pyridin-2-yl, 5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl, 3-phenyl-1,2,4-thiadiazol-5-yl, 3-o-tolyl-1,2,4-thiadiazol-5-yl or (E)-3-phenylallyl,

s is 1,

X is —

C(O)—

,

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 (b)

wherein

R6 is methoxy,

R7 is methyl and

R8 is hydrogen,

A is methylene (—

CH₂—

),

R9 is pyrimidin-2-yl, 3-dimethylaminopropyl or 2-(morpholin-4-yl)ethyl,

s is 1,

X is —

C(O)—

,

or a hydrate, salt, or hydrate of a salt thereof.

6. 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)

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,

A is a bond,

R9 is —

C(O)R10, —

(CH₂)_m—

C(O)R11, —

(CH₂)_nR12, Aryl, Hetaryl, phenylprop-1-en-3-yl or 1-methyl-piperidin-4-yl,

R10 hydrogen, 1–

4C-alkyl, —

OR13, furanyl, indolyl, phenyl, pyridyl, phenyl substituted by R16 and/or R17 or pyridyl substituted by R18 and/or R19,

R11 is —

N(R14)R15,

R12 is —

N(R14)R15, tetrahydrofuranyl or pyridinyl,

R13 is 1–

4C-alkyl,

R14 is hydrogen, 1–

4C-alkyl, 3–

7C-cycloalkyl or 3–

7C-cycloalkylmethyl,

R15 is hydrogen or 1–

4C-alkyl, 3–

7C-cycloalkyl or 3–

7C-cycloalkylmethyl,

or R14 and R15 together and with inclusion of the nitrogen atom to which they are bonded, form a 4-morpholiny-, 1-pyrrolidiny-, 1-piperidinyl- or 1-hexahydroazepinyl-ring,

Aryl is phenyl, pyridyl, phenyl substituted by R16 and/or R17, pyridyl substituted by R18 and/or R19,

R16 is halogen, nitro, 1–

4C-alkyl, trifluoromethyl or 1–

4C-alkoxy,

R17 is halogen or 1–

4C-alkyl,

R18 is halogen, nitro, 1–

4C-alkyl, trifluoromethyl or 1–

4C-alkoxy,

R19 is halogen or 1–

4C-alkyl,

Hetaryl is indol-4-yl, 2-methyl-quinolin-4-yl, 5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl or 3-phenyl-1,2,4-thiadiazol-5-yl,

n is an integer from 1 to 4,

m is an integer from 1 to 4,

s is an integer from 1 to 2,

X is —

C(O)—

or —

S(O)₂—

,

or a hydrate, salt, or hydrate of a salt thereof.

7. 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)

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,

A is a bond,

R9 is —

C(O)R10, —

(CH₂)_m—

C(O)R11, —

(CH₂)_nR12, Aryl, Hetaryl, phenylprop-1-en-3-yl or 1-methyl-piperidin-4-yl,

R10 hydrogen, 1–

4C-alkyl, —

OR13, furanyl, indolyl, pyridyl or pyridyl substituted by R18 and/or R19,

R11 is —

N(R14)R15,

R12 is —

N(R14)R15, tetrahydrofuranyl or pyridinyl,

R13 is 1–

4C-alkyl,

R14 is hydrogen, 1–

4C-alkyl, 3–

7C-cycloalkyl or 3–

7C-cycloalkylmethyl,

R15 is hydrogen or 1–

4C-alkyl, 3–

7C-cycloalkyl or 3–

7C-cycloalkylmethyl,

or R14 and R15 together and with inclusion of the nitrogen atom to which they are bonded, form a 4-morpholinyl-, 1-pyrrolidinyl-, 1-piperidinyl- or 1-hexahydroazepinyl-ring,

Aryl is phenyl, pyridyl, phenyl substituted by R16 and/or R17, pyridyl substituted by R18 and/or R19,

R16 is halogen, nitro, 1–

4C-alkyl, trifluoromethyl or 1–

4C-alkoxy,

R17 is halogen or 1–

4C-alkyl,

R18 is halogen, nitro, 1–

4C-alkyl, trifluoromethyl or 1–

4C-alkoxy,

R19 is halogen or 1–

4C-alkyl,

Hetaryl is indol-4-yl, 2-methyl-quinolin-4-yl, 5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl or 3-phenyl-1,2,4-thiadiazol-5-yl,

n is an integer from 1 to 4,

m is an integer from 1 to 4,

s is 1,

X is —

C(O)—

or —

S(O)₂—

,

or a hydrate, salt, or hydrate of a salt thereof.

8. 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)

wherein

R4 is methoxy or ethoxy,

R5 is methoxy or ethoxy,

R6 is methoxy,

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 cyclohexane ring,

A is a bond,

R9 is phenyl, pyrid-2-yl, dimethylaminopropyl, dimethylaminoethyl, furan-2-yl-methanoyl, formyl, ethoxycarbonyl, 5-nitropyridin-2-yl, 3,5-dichloropyridin-4-yl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, indol-4-yl, tetrahydrofuran-2-ylmethyl, 2-(pyrrolidin-1-yl)ethyl, pyridin-4-ylmethyl, 2-methyl-quinolin-4-yl, 1-methyl-piperidin-yl, 5-trifluoromethyl-pyridin-2-yl, 5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl, 3-phenyl-1,2,4-thiadiazol-5-yl or phenylprop-1-en-3-yl,

s is 1,

X is —

C(O)—

or —

S(O)₂—

,

or a hydrate, salt, or hydrate of a salt thereof.

9. 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)

wherein

R4 is methoxy or ethoxy,

R5 is methoxy or ethoxy,

R6 is methoxy,

R7 is methyl and

R8 is hydrogen,

A is a bond,

R9 is phenyl, pyrid-2-yl, dimethylaminoethyl, dimethylaminopropyl, furan-2-yl-methanoyl, formyl, ethoxycarbonyl, 5-nitropyridin-2-yl, 3,5-dichloropyridin-4-yl, 2-(morpholin-4-yl)ethyl, 5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl, 3-phenyl-1,2,4-thiadiazol-5-yl or phenylprop-1-en-3-yl,

s is 1,

X is —

C(O)—

or —

S(O)₂—

,

or a hydrate, salt, or hydrate of a salt thereof.

10. A compound of formula I according to claim 1 in which the hydrogen atoms in the positions 4a and 8a are cis-configurated, or a hydrate, salt, or hydrate of a salt thereof.

11. A compound of formula I according to claim 1 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, or a hydrate, salt, or hydrate of a salt thereof.

12. A method of treating asthma, COPD, rheumatoid arthritis, dermatoses or Crohn'"'"'s disease in a patient comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I as claimed in claim 1 or a pharmaceutically acceptable hydrate, salt, or hydrate of a salt thereof.

13. A pharmaceutical composition comprising one or more compounds of formula I according to claim 1, or a pharmaceutically acceptable hydrate, salt, or hydrate of a salt thereof together with one or more pharmaceutically acceptable auxiliaries and/or carrier materials.

14. A method of treating asthma and/or COPD in a patient comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I as claimed in claim 1 or a pharmaceutically acceptable hydrate, salt, or hydrate of a salt thereof.