Compounds and compositons for treating C1s-mediated diseases and conditions

• US 20020037915A1
• Filed: 09/26/2001
• Published: 03/28/2002
• Est. Priority Date: 02/09/1999
• Status: Active Grant

• Current Assignee: 3-Dimensional Pharmaceuticals, Inc. (Johnson & Johnson)
• Original Assignee: 3-Dimensional Pharmaceuticals, Inc. (Johnson & Johnson)
• Inventors: Subasinghe, Nalin L., Hoffman, James B., Randle, Troy L., Klein, Scott L., Illig, Carl R., Wilson, Kenneth J., Rudolph, M. Jonathan, Bone, Roger F.
• Granted Patent: US 6,515,002 B2
• Time in Patent Office: Days
• US Class Current: 514/426
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/12 Antivirals
• 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 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: C07D 333/38 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings

Abstract

Disclosed is a method for treating the symptoms of an acute or chronic disorder mediated by the classical pathway of the complement cascade, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I

or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein R¹, R², R³, R⁴, X, Y and Z are defined in the specification.

Claims

1. A method for treating the symptoms of an acute or chronic disorder mediated by the classical pathway of the complement cascade, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I

2. The method of claim 1, wherein said acute or chronic disorder is inflammation, tissue damage, or an autoimmune disease.

3. The method of claim 1, wherein a compound of Formula I is administered to a mammal in need of treatment of complement-mediated disease selected from the group consisting of inflammation, tissue damage and a combination thereof.

4. The method of claim 3, wherein said disease is intestinal inflammation of Crohn'"'"'s disease, thermal injury, or post pump syndrome in cardiopulmonary bypass.

5. The method of claim 1, wherein a compound of Formula I is administered to a mammal suffering from the symptoms of adult respiratory distress syndrome.

6. The method of claim 1, wherein a compound of Formula I is administered to a mammal in need of treatment of sepsis, immune-complex-induced vasculitis glomerulonephritis, hemolytic anemia, myasthenia gravis, type II collagen-induced arthritis, or allergic neuritis.

7. The method of claim 1, wherein a compound of Formula I is administered to a mammal before, during or after the transplant of an organ or a graft to ameliorate the rejection of such organ or graft by the mammal.

8. The method of claim 1, wherein a compound of Formula I is administered to a mammal before, during or after treatment of said mammal with IL-2 in an amount effective to reduce the toxicity and side-effects of the IL-2 treatment.

9. The method of claim 1, wherein a compound of Formula I is administered to a mammal that has been diagnosed with an auto-immune disease.

10. The method of claim 9, wherein a compound of Formula I is administered to a mammal that has been diagnosed with Hashimoto'"'"'s thyroiditis, glomerulonephritis and cutaneous lesions of systemic lupus erythematosus, other glomerulonephritides, bullous pemphigoid, dermatitis herpetiformis, Goodpasture'"'"'s syndrome, Graves'"'"' disease, myasthenia gravis, insulin resistance, autoimmune hemolyic anemia, autoimmune thrombocytopenic purpura, and rheumatoid arthritis.

11. The method of claim 10, wherein a compound of Formula I is administered to a mammal that has been diagnosed with myasthenia gravis (MG), rheumatoid arthritis, or systemic lupus erythematosus.

12. The method of claim 1, wherein a compound of Formula I is administered to a mammal that has been diagnosed with a neurodegenerative disease.

13. The method of claim 12, wherein said neurodegenerative disease is multiple sclerosis (MS), Guillain-Barré

syndrome (GBS), Miller-Fisher syndrome (MFS), and Alzheimer'"'"'s disease (AD).

15. The method of claim 1, wherein,

X is sulfur or oxygen;

Y is a covalent bond or —

NH—

;

R¹ is hydrogen, amino , hydroxy or halogen;

R⁴, R⁵ and R⁶ are independently hydrogen, C_1-6 alkyl, amino, cyano, C_1-4, alkoxy or hydroxy;

one of R² or R³ is hydrogen, C_1-6 alkyl, C_1-6 alkylthio or Cl₆ alkoxy, wherein said C_1-6 alkyl is optionally substituted with one or more groups selected from hydroxy, amino, carboxy or aminocarbonyl;

and the other of R² or R³ is aminoacyl, acylamino, aminosulfonyl, sulfonylamino, aminocarbonylamino, alkoxycarbonylamino, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted benzothienyl, optionally substituted furanyl, optionally substituted pyrazolyl or optionally substituted pyridyl.

16. The method of claim 1, wherein

X is sulfur or oxygen;

Y is a covalent bond or —

NH—

;

Z is NR⁵R⁶;

R¹ is hydrogen, amino, hydroxy or halogen;

R⁴, R⁵ and R⁶ are independently hydrogen, C_1-4 alkyl, amino, C_1-4 alkoxy or hydroxy;

one of R² or R³ is hydrogen, C_1-6 alkylthio, C_1-6 alkyl optionally substituted with OH, NH₂, COOH or aminocarbonyl, or C_1-6 alkoxy;

and the other of R² or R³ is;

where;

Ar is selected from the group consisting of phenyl, thiazolyl, thiazolinyl, oxazolyl, isothiazolyl, isoxazolyl, furanyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, tetrazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, oxazolinyl, isoxazolinyl, imidazolinyl, triazolyl, pyrrolinyl, benzothiazolyl, benzothienyl, benzimidazolyl, 1,3-oxazolidin-2-onyl, imidazolin-2-onyl , any of which can optionally include an exocyclic keto or —

NR^V group, where R^V is alkyl, aryl, aralkyl, alkylamino, arylimino or aralkylimino; and

R⁸ and R⁹ are independently hydrogen, halogen, amino, mono(C_1-4)alkylamino, di(C_1-4) alkylamino, arylamino, mono- and di- (C_6-14)arylamino, mono- and di-(C6-14)ar(C_1-6)alkylamino, formylamino, C_2-6 acylamino, aminocarbonyl, C_2-8, aminoacyl, C_2-6 thioacylamino, aminothiocarbonyl, C_2-8 aminothioacyl, C_1-6 alkyl, C_3-8 cycloalkyl, C_1-6 alkoxy, carboxy, carboxy(C_1-6)alkyl, C_2-8, alkoxycarbonyl, nitro, cyano, trifluoromethyl, thiazolyl, thiazolinyl, oxazolyl, isothiazolyl, isoxazolyl, furanyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, tetrazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, oxazolinyl, isoxazolinyl, imidazolinyl, triazolyl, pyrrolinyl, benzothiazolyl, benzothienyl, benzimidazolyl, 1,3-oxazolidin-2-onyl, imidazolin-2-onyl, C_6-14 aryloxy, C_1-6 alkylthio, C_6-14 arylthio, C_6-14 aryl, or C_6-14 ar(C_1-6)alkyl, wherein the heteroaryl groups and the aryl portions of said C_6-14 aryloxy, mono- and di C_6-14 aryl amino, mono- and di- C_6-14 ar(C_1-6)alkylamino, C_6-14 arylthio, C_6-14 ar(C_1-6)alkyl, and C_6-14 aryl are further optionally substituted by one, two or three of halogen, hydroxy, amino, mono(C_1-4)alkylamino, di(C_1-4)alkylamino, formylamino, C_1-4acylamino, C_1-4aminoacyl, mono- or di-(C_1-4) alkylaminocarbonyl, thiocarbonylamino, C_1-4,thioacylamino, aminothiocarbonyl, C_1-4alkoxy, C_6-10aryloxy₇ aminocarbonyloxy, mono- or di(C_1-4)alkylaminocarbonyloxy, mono- or di(C_6-10)arylaminocarbonyloxy, mono- or di(C_7-15)aralkylaminocarbonyloxy₇ C_1-4alkylsulfonyl, C_6-10arylsulfonyl, (C_7-15)aralkylsulfonyl, C_1-4alkylsulfonylamino, C_6-10arylsulfonylamino, (C_7-15)aralkylsulfonylamino₇ aminosulfonyl, mono- and di-alkylaminosulfonyl, mono- and di-arylaminosulfonyl, mono- and di-aralkylaminosulfonyl, C_1-4 alkoxycarbonylamino, C_7-15aralkoxycarbonylamino, C_6-10aryloxycarbonylamino, mono- or di- (C_1-4)alkylaminothiocarbonyl, C_7-15,aralkoxy, carboxy, carboxy(C_1-4)alkyl, C_1-4alkoxycarbonyl, C_1-4alkoxycarbonylalkyl, carboxy(C_1-4)alkoxy, alkoxycarbonylalkoxy, nitro, cyano, trifluoromethyl, C_1-4alkylthio and C_6-10arylthio, or by 3,4-methylenedioxy, 3,4-ethylenedioxy, and 3,4-propylenedioxy; and

R² or R³ is alkyl, cycloalkyl, alkoxy, alkylthio or alkylsulfonyl, where the alkyl portion of said alkyl, cycloalkyl, alkoxy, alkylthio or alkylsulfonyl is optionally substituted with 1 to 4 substituents selected from the group consisting of halogen, hydroxy, thiol, amino, monoalkylamino, dialkylamino, formylamino, acylamino, aminoacyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, thiocarbonylamino, thioacylamino, aminothiocarbonyl, alkoxy, aryloxy, aminocarbonyloxy, monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, monoarylaminocarbonyloxy, diarylaminocarbonyloxy, monoaralkylaminocarbonyloxy, diaralkylaminocarbonyloxy, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkylsulfonylamino, arylsulfonylamino, aralkylsulfonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, monoalkylaminothiocarbonyl, dialkylaminothiocarbonyl, aralkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl, alkylthio and arylthio.

17. The method of claim 1, wherein

X is sulfur;

Y is a covalent bond;

Z is NR⁵R⁶;

R¹ is hydrogen;

R³ is methylthio or methyl;

R⁴, R⁵ and R⁶ are all hydrogen; and

R² is Formula II;

where

Ar is phenyl, thiazolyl, oxazolyl, benzothienyl, pyridyl, or imidazolyl;

R⁸ and R⁹ are independently hydrogen, C_6-10 aryl or heterocycle, wherein said C_6-10 aryl and said heterocycle are optionally substituted by one, two or three of chloro, hydroxy, C_1-4 alkyl, C_3-6 cycloalkyl, C_1-4 alkoxy, amino, carboxy, phenyl, naphthyl, biphenyl, hydroxyphenyl, methoxyphenyl, dimethoxyphenyl, carboxyalkoxyphenyl, alkoxycarbonylalkoxy, carboxyethoxy, alkylsulfonylaminophenyl, arylsulfonylaminophenyl, acylsulfonylaminophenyl, aralkylsulfonylaminophenyl, heteroarylsulfonylaminophenyl where the heteroaryl portion is optionally halo or C_1-6alkyl substituted, chlorophenyl, dichlorophenyl, aminophenyl, carboxyphenyl, nitrophenyl, or by 3,4-methylenedioxy, 3,4-ethylenedioxy, or 3 ,4-propylenedioxy.

18. The method of claim 1, wherein

X is sulfur;

Y is a covalent bond;

Z is NR⁵R⁶;

R¹ is hydrogen;

R² is alkyl, ar(alkyl), alkylsulfonyl, aminocarbonyl, amidino, or

where

Ar is an aromatic or heteroaromatic group selected from phenyl, thiazolyl, oxazolyl, imidazolyl and pyridyl;

R⁸ and R⁹ are independently selected from hydrogen, carboxy, phenyl, naphthyl, alkyl, pyridyl, oxazolyl, furanyl, cycloalkyl and amino, any of which may be optionally substituted with 1 to 3 substituents independently selected from halogen, alkyl, haloalkyl, aralkyl, heteroaryl, phenyl, naphthyl, alkoxy, aryloxy, hydroxy, amino nitro, thiophenyl, benzothiophenyl, fluorenyl, 3,4-ethylenedioxy, 3,4-methylenedioxy, 3,4-propylenedioxy, arylsulfonamido, alkylsulfonamido and aryloxy, each of said 1 to 3 substituents may be further optionally substituted with one or more groups selected from alkoxy, haloalkyl, halogen, alkyl, amino, acetyl, hydroxy, dialkylamino, dialkylaminoacyl, monoalkylaminoacyl, —

SO₂-heteroaryl, —

SO₂-aryl, or aryl;

R³ is —

SO₂-alkyl, trifluoromethyl, S(O)-alkyl, hydrogen, alkoxy, alkylthio, alkyl, or aralkylthio; and

R⁴, R⁵, R⁶ are hydrogen.

19. The method of claim 1, wherein said compound is of Formula III:

20. The method of claim 1, wherein said compound is of Formula IV:

21. The method of claim 1, wherein

X is sulfur or oxygen;

Y is a covalent bond or —

NH—

;

Z is NR⁵R⁶;

R¹ is hydrogen, amino, hydroxy or halogen;

R⁴, R⁵ and R⁶ are independently hydrogen, C_1-4 alkyl, amino, C_1-4 alkoxy or hydroxy;

R³ is hydrogen, C_1-6alkylthio, C_1-6 alkyl optionally substituted with OH, NH₂, COOH or aminocarbonyl, or C_1-6 alkoxy,; and

R²is

alkylsulfonylamino, aralkylsulfonylamino, aralkenylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, di(aralkylsulfonyl)amino, di(aralkenylsulfonyl)amino, di(arylsulfonyl)amino, or di(heteroarylsulfonyl)amino, wherein the aryl or heteroaryl moiety of any of said groups are optionally substituted;

amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, monoalkylmonoarylamino, monoaralkylamino, diaralkylamino, monoalkylmonoaralkylamino, monoheterocycleamino, diheterocycleamino, monoalkylmonoheterocycleamino, wherein the aryl or heteroaryl moiety of any of said groups are optionally substituted;

alkanoylamino, alkenoylamino, alkynoylamino, aroylamino, aralkanoylamino, aralkenoylamino, heteroaroylamino, heteroarylalkanoylamino, wherein the aryl moiety of each is optionally substituted;

alkoxy and alkylthio, either of which is optionally substituted, or aryloxy, aralkoxy, arylthio, aralkylthio, arylsulfonyl, aralkylsulfonyl, aralkenylsulfonyl, any of which is optionally substituted on the aromatic ring;

alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, wherein the aryl moiety of any of said groups is optionally substituted;

or

formylamino, H(S)CNH—

, or thioacylamino.

22. The method of claim 1, wherein said compound is Formula V:

23. The method of claim 22, wherein said compound is selected from

4-(4-{3-[(4-fluorophenyl)sulfonylamino]phenyl } (1 ,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine;

4-(4-{3-[(2,4-difluorophenyl)sulfonylamino]phenyl } (1 ,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine;

4-(4-{3-[(4-fluorophenyl)carbonylamino]phenyl } (1 ,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine;

4-(4-{3-[(3,4-difluorophenyl)sulfonylamino]phenyl } (1 ,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine;

4-(4-{3-[(4-methoxyphenyl)carbonylamino]phenyl } (1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine;

4-(4-{3-[(4-methoxyphenyl)sulfonylamino]phenyl } (1 ,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine;

4-(4-{3-[(4-chlorophenyl)carbonylamino]phenyl}(1 ,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine;

or

4-(4-{3-[(2,4-difluorophenyl)carbonylamino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine.

24. The method of claim 1, wherein said compound is of Formula VI:

25. The method of claim 24, wherein said compound is selected from

4-[4-(1-phenyl-5-propylpyrazol-4-yl)( 1 ,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine;

4-[4-(1-(4-chlorophenyl)-5-amidinopyrazol-4-yl)( 1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine;

or 2-[4-(5-(tert-butyl)l-benzylpyrazol-4-yl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine.

27. A compound of claim 26, which is selected from

4-(4-{3-[(4-fluorophenyl)sulfonylamino]phenyl } (1 ,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine;

4-(4-{3-[(2,4-difluorophenyl)sulfonylamino]phenyl }(1,³-thiazol-²-yl))-5-methylthiothiophene-2-carboxamidine;

4-(4-{3-[(4-fluorophenyl)carbonylamino]phenyl}(1 ,3-thiazol-2-yl))-5 -methylthiothiophene-2-carboxamidine;

4-(4-{3-[(3,4-difluorophenyl)sulfonylamino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine;

4-(4-{3-[(4-methoxyphenyl)carbonylarnino]phenyl }(1,³-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine;

4-(4-{3-[(4-methoxyphenyl)sulfonylamino]phenyl }(1 ,³-thiazol-²-yl))-5-methylthiothiophene-2-carboxamidine;

4-(4-{3-[(4-chlorophenyl)carbonylamino]phenyl } (1,³-thiazol-²-yl))-5-methylthiothiophene-2-carboxamidine;

or

4-(4-{3-[(2,4-difluorophenyl)carbonylamino]phenyl} (1 ,³-thiazol-²-yl))-5-methylthiothiophene-2-carboxamidine.

28. A compound of claim 27, which is 4-(4-{3-[(2,4-difluorophenyl)-sulfonylamino]phenyl }(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamijdine.

30. A compound of claim 29, which is selected from

4-[4-(1-phenyl-5-propylpyrazol4-yl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine;

4-[4-(1-(4-chlorophenyl)-5-amidinopyrazol-4-yl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine;

or 2-[4-(5-(tert-butyl)1-benzylpyrazol-4-yl)( 1,3 -thiazol-2-yl)]-5 -methylthiothiophene-2-carboxamidine.

31. A pharmaceutical composition, comprising a compound of claim 25 and a pharmaceutically-acceptable carrier or diluent.

32. A pharmaceutical composition, comprising a compound of claim 29 and a pharmaceutically-acceptable carrier or diluent.

14. A pharmaceutical composition for treating a complement-mediated disease state comprsing a compound of Formula I in an amount effective to inhibit C1s protease function in a mammal, and a pharmaceutically acceptable carrier or diluent.

26. A compound of Formula V:

29. A compound of Formula VI:

Rx

or a pharmaceutically acceptable salt or prodrug thereof, wherein;

R^x is aryl or aralkyl, wherein the aryl moiety of said aryl or aralkyl is optionally substituted;

R^p is optionally substituted alkyl;

Z is NR⁵R⁶;

R¹ is hydrogen, amino, hydroxy or halogen; and

R⁴, R⁵ and R⁶ are independently hydrogen, C_1-4 alkyl, amino, C_1-4 alkoxy or hydroxy.