Compounds and methods for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase

• US 5,856,323 A
• Filed: 06/07/1995
• Issued: 01/05/1999
• Est. Priority Date: 07/13/1992
• Status: Expired due to Fees

• Current Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Original Assignee: CytoMed, Inc. (Takeda Pharmaceutical Company Limited)
• Inventors: Cai, Xiong, Killian, David, Hussoin, Sajjat, Hwang, San-Bao, Shen, T. Y.
• Primary Examiner(s): Kight, John
• Assistant Examiner(s): COVINGTON, RAYMOND K
• Application Number:
  US08/481,812
• Time in Patent Office: 1,308 Days
• Field of Search: 544/174, 544/176, 544/180, 546/256, 546/283, 546/284, 549/67, 549/70, 549/71, 549/72, 549/73, 549/74, 549/75, 549/78, 549/79, 549/80, 549/473, 549/478, 549/476, 549/477, 549/480, 549/483, 549/484, 549/487, 549/488, 549/491, 549/492 , 549/494, 549/495, 549/496, 549/497, 549/498, 549/499, 549/500, 549/501, 549/502, 514/231.5, 514/237.2, 514/333, 514/337, 514/438, 514/445, 514/448, 514/471, 514/472, 514/473
• US Class Current: 514/231.5
• 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 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 207/09 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 307/12 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 307/14 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 333/16 by oxygen atoms
• CPC Class Codes: C07D 333/18 by sulfur atoms
• CPC Class Codes: C07D 333/20 by nitrogen atoms nitro, nitroso radicals C07D333/12
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 407/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links

Abstract

2,5-Diaryl tetrahydrofurans, 2,5-diaryl tetrahydrothiophenes, 2,4-diaryl tetrahydrofurans, 2,4-diaryl tetrahydrothiophenes, 1,3-diaryl cyclopentanes, 2,4-diaryl pyrrolidines, and 2,5-diaryl pyrrolidines are disclosed that reduce the chemotaxis and respiratory burst leading to the formation of damaging oxygen radicals of polymorphonuclear leukocytes during an inflammatory or immune response. The compounds exhibit this biological activity by acting as PAF receptor antagonists, by inhibiting the enzyme 5-lipoxygenase, or by exhibiting dual activity, i. e., by acting as both a PAF receptor antagonist and inhibitor of 5-lipoxygenase.

A method to treat disorders mediated by PAF or leukotrienes is also disclosed, that includes administering an effective amount of one or more of the above-identified compounds or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

Claims

1. The method for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase in an animal, comprising administering an effective amount of a compound of the formula:

##STR23## wherein;

X is O, S, S(O), S(O)₂, CR⁹, or NR¹⁰ ;

W is independently;

(1) --AN(OM)C(O)N(R³)R⁴, --AN(R³)C(O)N(OM)R⁴, --AN(OM)C(O)R⁴, --AC(O)N(OM)R⁴, --N(OM)C(O)N(R³)R⁴, --N(R³) C(O)N(OM)R⁴, --N(OM)C(O)R⁴, --C(O)N(OM)R⁴, --OR⁶ N(R⁵)R⁶ --(C₅ H₄ N)R⁶ R⁷, --OR⁶ N(COR⁵)R⁶ --(C₅ H₄ N)R⁶ R⁷, --OR⁶ OC(O)N(COR⁵)R⁶ --(C₅ H₄ N)R⁶ R⁷, --OR⁶ O(CO)N(CO₂ R⁶)R⁶ (C₅ H₄ N)R⁶ R⁷, --A(C₅ H₄ N)R⁶ R⁷, or --OR⁶ N(CO₂ R⁵)R⁶ --(C₅ H₄ N)R⁶ R^7;

(2) an amidohydroxyurea of the formula;

--N(R¹⁹)C(O)C(R¹⁹)N(OM)C(O)NHR²⁰, --C(O)N(R¹⁹)C(R¹⁹)N(OM)C(O)NHR²⁰, --AN(R¹⁹)C(O)C(R¹⁹)N(OM)C(O)NHR²⁰, --AC(O)N(R¹⁹)C(R¹⁹)N(OM)C(O)NHR²⁰, --NHC(O)N(OM)C(R¹⁹)C(O)N(R¹⁹)₂ ;

or --NHC(O)N(OM)C(R¹⁹)N(R¹⁹)C(O)R¹⁹ ;

(3) an oxalkane of the structure;

##STR24## wherein n and m are independently 1-4;

(4) a thioalkane of the structure;

##STR25## or (5) a quinolylmethoxy of the structure;

##STR26## n is 1 or 2;

m is 1, 2 or 3;

p is 0 or 1;

A is alkyl, alkenyl, alkynyl, alkyaryl, aralkyl, halo lower alkyl, halo lower alkenyl, halo lower alkynyl, --C_1-10 alkyl(oxy)C_1-10 alkyl, --C_1-10 alkyl(thio)C_1-10 alkyl, --N(R³)C(O)alkyl, --N(R³)C(O)alkenyl, --N(R³)C(O)alkynyl, --N(R³)C(O)(alkyl)oxy(alkyl), --N(R³)C(O) (alkyl)thio(alkyl), --N(R³)C(O)N(alkyl), --N(R³)C(O)N(alkenyl), --N(R³)C(O)N(alkynyl), --N(R³)C(O)N(alkyl)oxy(alkyl), --N(R³)C(O)N(alkyl)thio(alkyl), --N(R³)C(O₂)alkyl, --N(R³)C(O₂)alkenyl, --N(R³)C(O₂)alkynyl, --N(R³)C(O₂)(alkyl)oxy(alkyl), --N(R³)C(O₂)(alkyl)thio(alkyl) --OC(O₂)alkyl, --OC(O₂)alkenyl, --OC(O₂)alkynyl, --OC(O₂)(alkyl)oxy(alkyl), --OC(O₂)(alkyl)thio(alkyl), --N(R³)C(S)alkyl, --N(R³)C(S)alkenyl, --N(R³)C(S)alkynyl, --N(R³)C(S)(alkyl)oxy(alkyl), --N(R³)C(S)(alkyl)thio(alkyl), --N(R³)C(S)N(alkyl), --N(R³)C(S)N(alkenyl), --N(R³)C(S)N(alkynyl), --N(R³)C(S)N(alkyl)oxy(alkyl), --N(R³)C(S)N(alkyl)thio(alkyl), --N(R³)C(S)S(alkyl), --N(R³)C(S)S(alkenyl), --N(R³)C(S)S(alkynyl), --N(R³)C(S)S(alkyl)oxy(alkyl), --N(R³)C(S)S(alkyl)thio(alkyl), --SC(S)S(alkyl), --SC(S)S(alkenyl), --SC(S)S(alkynyl), --SC(S)S(alkyl)oxy(alkyl), and --SC(S)S(alkyl)thio(alkyl);

M is hydrogen, a pharmaceutically acceptable cation, or a metabolically cleavable leaving group;

Y is independently;

(a) hydrogen;

(b) R^1-6, R⁸, R¹⁰, --OR³, --OR¹¹, --OR¹², R³ S--, R⁵ S, R³ SO--, R⁵ SO--, R³ SO₂ --, R⁵ SO₂ --, CF₃ O--, CF₃ S--, CF₃ SO--, --CF₃ SO₂, --OCH₂ oxycyclopropyl, --OCH₂ C(O)OR³, --OCH₂ OR³, --OCH₂ C(O)R³, --OCH₂ C_3-8 cycloalkyl, --OCH₂ CH(R)R³, --OCH₂ cyclopropyl, --OCH₂ --aryl, --OCH₂ CH(OH)CH₂ OH, aryl--CH₂ --SO₂ --, (R₃)₂ CHCH₂ SO₂ --, --CH₂ CH(OH)CH₂ OH, CF₃ SO₂ --, R³ R⁴ N--, --OCH₂ CO₂ R³, --NR³ COR³, --OCONH₂, --OCONR³ R⁴, --CONH₂, --CONR³ R⁴, --CR³ R³ R⁴, --SO₂ NR³ R⁴, --SONR³ R⁴, CH₃ OCH₂ ONR³ R⁶, --SNR³ R⁴, --CO₂ R³, --NR³ R⁴ SO₂ R³, --NR³ R⁴ SOR, --COR³, --CONR³, --NO₂, --CN, --N(R⁵)CONR³ R⁴, --CH₂ N(R⁵)CONR³ R⁴, --R⁶ NR³ R⁴, --OR⁶ NR³ R⁴, --O(O)CR⁵, --O(O)CNR³ R⁴, --OR⁶, --SR⁶ NR³ R⁴, --S(O)R⁶ NR³ R⁴, --SO₂ R⁶ NR³ R⁴, --SO₂ OR⁶ CO;

--SR⁶ OH;

--S(O)R⁶ OH;

--SO₂ R⁶ OH;

or --OR⁶ OC(O)N(CO₂ R⁶)R⁶ ;

(c) a heterocycle, including but not limited to, pyrryl, furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbozolyl, benzamidazolyl, and isoxazolyl, optionally substituted with a group described in Y section (b);

(d) ##STR27## wherein X'"'"' is halo, --C(O)aryl, CF₃, or OR³ ;

--NR₃ COR³ ;

--OCONH₂ ;

--CR³ R³ R⁴ ;

--CH₂ OR³ ;

--CH₂ OR³ ;

--CH₂ CO₂ R³ ;

--CH₂ OCOR³ ;

R³ CH(R³)CH₂ SO₃ --;

--NHCH₂ COOR³ ;

halo such as F, Cl, Br and I;

N⁺ R³ R³ R⁴ R⁷ ;

--NR³ SO₂ R³ ;

COR³ ;

NO₂ ;

or CN;

or ##STR28## wherein R¹³, R¹⁴ and R¹⁵ independently represents;

BO-- wherein B is --CH₂ --oxacyclopropyl, --CH₂ OR³, --CH₂ C(O)R³, --CH₂ CH(R³)R³, --CH₂ Aryl, --CH₂ CH(OH) --CH₂ OH;

R³ C(R³) ₂ CH₂ SO₂ ;

or R¹³ --R¹⁴ or R¹⁴ --R¹⁵ are joined together to form a bridge such as --OCHR² CHR² --S(O)_n wherein n is 0 to 3;

or ##STR29## where X'"'"' is halo, --C(O)aryl, CF₃, or OR³ ;

--CH₂ OR³ ;

--CH₂ CO₂ R³ ;

--CH₂ COR³ ;

--NHCH₂ COOR³ ;

--N⁺ R³ R³ R⁴ R⁷ --,

R¹ and R² are independently hydrogen, halogen, or lower alkyl, halo lower alkyl, halo, --COOH;

--CONR¹⁶ R¹⁷ wherein R¹⁶ and R¹⁷ independently represent C_1-6 alkyl and hydrogen, --COOR³, alkenyl, --COR³ ;

--CH₂ OR³ ;

lower alkynyl, CH₂ NR⁴ R³ ;

--CH₂ SR³ ;

═

O;

--OR³ ;

or --NR³ R³ ;

R³ and R⁴ are independently cyclic and acyclic alkyl, alkenyl, alkynyl, aryl, aralkyl, alkyaryl, hydrogen, C_1-6 alkoxy-C_1-10 alkyl, C_1-6 alkylthio-C_1-10 alkyl, and C_1-10 substituted alkyl (wherein the substituent is independently hydroxy or carbonyl, located on any of C_1-10);

R⁵ is cyclic and acyclic lower alkyl, lower alkenyl, lower alkynyl, halo lower alkyl, halo lower alkenyl, halo lower alkynyl, aralkyl, or aryl;

R⁶ is cyclic and acyclic lower alkyl, lower alkenyl, lower alkynyl, aralkyl, halo lower alkyl, halo lower alkenyl, halo lower alkynyl, or aryl;

R⁷ is an organic or inorganic anion;

R⁸ is halo alkyl, halo lower alkyl, halo lower alkenyl, halo lower alkynyl, lower alkenyl, lower alkynyl, aralkyl, or aryl;

R⁹ is independently hydrogen, halogen, lower alkyl, halo lower alkyl, lower alkenyl, lower alkynyl, --CONR³ R⁴, --COR⁵, --CO₂ R⁵, --CH₂ OR⁵, --CH₂ NR⁵ R⁵, --CH₂ SR⁵, ═

O, ═

NR⁵, --NR³ R⁴, --NR³ R⁴ SR⁷, or --OR⁵ ; and

R¹⁰ is --R³, --R⁸, --C(O)N(OR³)R³, or --OR³,

R¹¹ is C₁ to C₁₂ alkyl;

substituted C₁ to C₁₂ alkyl wherein the substituent is selected from the group consisting of hydroxy and amino, alkenyl, lower alkoxy-alkyl;

alkylcarbonylalkyl, --alkylamino, --alkylamino(alkyl or dialkyl), lower alkyl S(O)_m --lower alkyl in which m is 0, 1 or 2;

imidazolyl lower alkyl, morpholinyl lower alkyl, thiazolinyl lower alkyl, piperidinyl ower alkyl, imidazolylcarbonyl, morpholinyl carbonyl, amorpholinyl (lower alkyl) aminocarbonyl, N-pyrrylpyridinyl-lower alkyl;

pyridylthio-lower alkyl;

morpholinyl-lower alkyl;

hydroxyphenylthio-lower alkyl;

cyanophenylthio-lower alkyl;

imidazolylthio-lower alkyl;

triazolylthio-lower alkyl;

triazolylphenylthio-lower alkyl;

tetrazolylthio-lower alkyl;

tetrazolylphenylthio-lower alkyl;

aminophenylthio-lower alkyl;

N,N-di-substituted aminophenylthio-lower alkyl wherein the substituents each independently represent lower alkyl;

amidinophenylthio-lower alkyl;

phenylsulfinyl-lower alkyl;

or phenylsulfonyl lower alkyl;

R¹² is selected from the group consisting of;

alkyl;

substituted alkyl wherein the substituent is selected from the group consisting of hydroxy and amino;

-lower alkyl-O-R¹⁸, wherein R¹⁸ is --PO₂ (OH)^-M+ or --PO₃ (M⁺)₂, wherein M⁺ is a pharmaceutically acceptable cation;

--C(O)(CH₂)₂ CO₂^- M⁺, or --SO₃^- M⁺ ;

-lower alkylcarbonyl-lower alkyl;

-carboxy lower alkyl;

-lower alkylamino-lower alkyl;

N,N-di-substituted amino lower alkyl-, wherein the substituents each independently represent lower alkyl;

pyridyl-lower alkyl;

imidazolyl-lower alkyl;

imidazolyl-Y-lower alkyl wherein Y is thio or amino;

morpholinyl-lower alkyl;

pyrrolidinyl-lower alkyl;

thiazolinyl-lower alkyl;

piperidinyl-lower alkyl;

morpholinyl-lower hydroxyalkyl;

N-pyrryl;

piperazinyl-lower alkyl;

N-substituted piperazinyl-lower alkyl, wherein the substituent is lower alkyl;

triazolyl-lower alkyl;

tetrazolyl-lower alkyl;

tetrazolylamino-lower alkyl;

or thiazolyl-lower alkyl;

R¹⁹ is H, lower alkyl, or lower alkenyl; and

R²⁰ is H, halogen, lower alkoxy, or lower alkyl.

2. The method of claim 1, wherein the animal is a human.

3. The method of claim 1, wherein the animal is a mammal.

4. The method of claim 1, wherein the animal is equine.

5. The method of claim 1, wherein the animal is canine.

6. The method of claim 1, wherein the animal is bovine.

7. The method for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase in an animal, comprising administering an effective amount of a compound of the formula ##STR30## Ar³ and Ar⁴ are independently ##STR31## wherein:

X is O, S, S(O), S(O)₂, or NR¹⁰ ;

t is 1, 2, 3, or 4;

m is 1, 2, or 3;

Z is independently W or Y; and

all of the R groups are as defined in claim 1.

8. The method of claim 7, wherein the animal is a human.

9. The method of claim 7, wherein the animal is a mammal.

10. The method of claim 7, wherein the animal is equine.

11. The method of claim 7, wherein the animal is canine.

12. The method of claim 7, wherein the animal is bovine.

13. A method for the treatment of disorders medicated by platelet activating factor or products of 5-lipoxygenase in an animal, comprising administering an effective amount of a compound of the formula:

##STR32## wherein Ar⁵ is;

##STR33## wherein Ar⁶ is;

##STR34## wherein;

v is 0, 1, or 2;

all R groups, t, m, and n are as defined in claims 1 and 2; and

O is selected from the group consisting of substituted C₁ to C₁₂ alkyl wherein the substituent is selected from the group consisting of hydroxy and amino, alkylcarbonylalkyl, alkyl;

lower alkyl S(O)_m -lower alkyl in which m is 1 or 2;

imidazolyl lower alkyl, morpholinyl lower alkyl, thiazolinyl lower alkyl, piperidinyl ower alkyl, imidazolylcarbonyl, morpholinyl carbonyl, amorpholinyl (lower alkyl) aminocarbonyl, N-pyrrylpyridinyl-lower alkyl;

pyridylthio-lower alkyl;

morpholinyl-lower alkyl;

hydroxyphenylthio-lower alkyl;

cyanophenylthio-lower alkyl;

imidazolylthio-lower alkyl;

triazolylthio-lower alkyl;

triazolylphenylthio-lower alkyl;

tetrazolylthio-lower alkyl;

tetrazolylphenylthio-lower alkyl;

aminophenylthio-lower alkyl;

N,N-di-substituted aminophenylthio-lower alkyl wherein the amine substituents each independently represent lower alkyl amidinophenylthio-lower alkyl;

phenylsulfinyl-lower alkyl;

or phenylsulfonyl lower alkyl;

-lower alkyl-O--R¹⁸, wherein R¹⁸ is --PO₂ (OH)^- M⁺ or --PO₃ (M+)₂, wherein M⁺ is a pharmaceutically acceptable cation;

--C(O)(CH₂)₂ CO₂^- M⁺, or --SO₃ M⁺ ;

-lower alkylcarbonyl-lower alkyl;

-carboxy lower alkyl;

-lower alkylamino-lower alkyl;

N,N-di-substituted amino lower alkyl-, wherein the substituents each independently represent lower alkyl;

pyridyl-lower alkyl;

imidazolyl-lower alkyl;

imidazolyl-Y-lower alkyl wherein Y is thio or amino;

morpholinyl-lower alkyl;

pyrrolidinyl-lower alkyl;

thiazolinyl-lower alkyl;

piperidinyl-lower alkyl;

morpholinyl-lower hydroxyalkyl;

N-pyrryl;

piperazinyl-lower alkyl;

N-substituted piperazinyl-lower alkyl, wherein the amine substituent is lower alkyl;

triazolyl-lower alkyl;

tetrazolyl-lower alkyl;

tetrazolylamino-lower alkyl;

or thiazolyl-lower alkyl.

14. The method of claim 13, wherein the animal is a human.

15. The method of claim 13, wherein the animal is a mammal.

16. The method of claim 13, wherein the animal is equine.

17. The method of claim 13, wherein the animal is canine.

18. The method of claim 13, wherein the animal is bovine.