Anti-inflammatory compositions and methods

• US 7,186,725 B2
• Filed: 12/23/2003
• Issued: 03/06/2007
• Est. Priority Date: 01/03/2003
• Status: Active Grant

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Genzyme Corporation (Sanofi )
• Inventors: Miller, Robert J., Staveski, Mark M., Nahill, Sharon R.
• Primary Examiner(s): SEAMAN, D MARGARET M
• Application Number:
  US10/746,034
• Publication Number:
  US 20040180871A1
• Time in Patent Office: 1,169 Days
• Field of Search: 514/254.01, 514/326, 514/256, 544/333, 544/335, 546/210
• US Class Current: 514/254.01
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2602/08 the other ring being five-membered, e.g. indane
• CPC Class Codes: C07C 2603/74 Adamantanes
• CPC Class Codes: C07C 275/06 of an acyclic and saturated carbon skeleton
• CPC Class Codes: C07C 275/12 being further substituted by doubly-bound oxygen atoms
• CPC Class Codes: C07C 275/14 being further substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 275/16 being further substituted by carboxyl groups
• CPC Class Codes: C07C 275/20 of an unsaturated carbon skeleton
• CPC Class Codes: C07C 275/24 containing six-membered aromatic rings
• CPC Class Codes: C07C 275/26 having nitrogen atoms of urea groups bound to carbon atoms of rings other than six-membered aromatic rings
• CPC Class Codes: C07C 275/34 having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
• CPC Class Codes: C07C 275/42 being further substituted by carboxyl groups
• CPC Class Codes: C07C 275/64 having nitrogen atoms of urea groups singly-bound to oxygen atoms
• CPC Class Codes: C07C 311/47 Y being a hetero atom
• CPC Class Codes: C07D 211/26 with hydrocarbon radicals, substituted by nitrogen atoms
• CPC Class Codes: C07D 211/32 by oxygen atoms
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 213/74 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 217/04 : with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 217/22 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
• CPC Class Codes: C07D 231/40 : Acylated on said nitrogen atom
• CPC Class Codes: C07D 235/30 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 241/20 : Nitrogen atoms nitro radicals C07D241/16
• CPC Class Codes: C07D 249/08 : 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 257/06 : with nitrogen atoms directly attached to the ring carbon atom
• CPC Class Codes: C07D 277/58 : Nitro radicals
• CPC Class Codes: C07D 277/82 : Nitrogen atoms
• CPC Class Codes: C07D 285/01 : Five-membered rings
• CPC Class Codes: C07D 295/13 : to an acyclic saturated chain
• CPC Class Codes: C07D 295/205 : Radicals derived from carbonic acid
• CPC Class Codes: C07D 295/215 : Radicals derived from nitrogen analogues of carbonic acid
• CPC Class Codes: C07D 307/14 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/52 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 333/20 : by nitrogen atoms nitro, nitroso radicals C07D333/12
• CPC Class Codes: C07D 333/58 : Radicals substituted by nitrogen atoms
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

The present invention provides compositions and their use in the treatment of inflammatory diseases caused by T-cell proliferation such as sepsis, inflammatory bowel diseases, autoimmune encephalomyelitis, or lupus. The compositions comprise disubstituted ureas of Formulas I, II, III or IV:
R¹—NH—CO—NH-Q-R²Formula I:
Et-NH—CO—NH-Q-R²:  Formula (II)
Et-NH—CO—NH—(CH₂)₃—NR⁶R⁷:  Formula (III)
Me₂N—(CH₂)₃—NH—CO—NH-Q-R².  Formula (IV)

Claims

1. A compound of formula I:

R¹—

NH—

CO—

NH-Q-R² 

 

(I)

or a pharmaceutically acceptable salt thereof

wherein

R¹ s a lower C2–

C5 alkyl group, straight or branched chain and optionally substituted by an amino group of formula —

NR³R⁴, wherein R³ and R⁴ are independently H, or C1–

C3 alkyl group;

Q is either a bond or a divalent C1–

C5 straight or branched alkyl or aikenyl group;

R² is one of the following groups

a. C5–

C10 heteroaryl group selected from furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, dithiolyl, oxathiolyl, isoxazolyl, piridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoquinolinyl, benzimidazolyl, benzoxaziyl, benzothiadiazolyl nanhthyridinyl, pyrido[3,4-b]pyridinyl, pyrido[3,2-b]b pyridinyl, pyrido[4,3-b]hyridinyl, and 4-aminopyrazolo[3,4d]pyrimidinyl

b. C5–

C10 heterocyclic group selected from piperazyl, tetahydrofuranyl, dioxanyl, wherein the heteroaryl, or heterocyclic ring is unsubstituted or substituted by one or more of the following groups

i. R⁵, —

CN, Halogen, OR⁵, —

COR⁵, —

CO₂R⁵, OCF₃, —

CONH₂, —

SO₂NH₂, and NO₂, wherein R⁵ is a C1 to C4 straight or branched alkyl group, and

c. N⁶R ⁷, wherein R⁶ and R⁷ are

together with the N forming a 5 or 6 membered monocyclic ring having one or more ring positions occupied by another N, S, or O, wherein the heteroaryl ring thus formed is unsubstituted or substituted by one or more of the following groups

1. R⁵, —

CN, halogen, OR⁵, —

COR⁵, —

CO₂R⁵, OCF₃, —

CONH₂, —

SO₂NH₂,

2. C1–

C5 aikyl or alkylene group substituted by an aryl group, and

3. C6 or C10 aryl or heteroaryl group unsubstituted or substituted by one ore more of R⁵, CF₃, and halogen, wherein the aryl or hetero aryl may be a pending group off one position of, or a fused with, the NR⁶R⁷ ring.

2. The compound of claim 1 wherein R¹ is ethyl.

3. The cormpound of claim 1 wherein R¹ is dimethylaminopropyl.

4. The compound of claim 1 having Formula (III):

Et-NH—

OC—

NH—

(CH₂)₃—

NR⁶R⁷.

5. The compound of claim 1 having the structure of

6. The compound of claim 1 having the structure of

7. The compound of claim 1 having the structure of

8. A method of treating an inflammatory cond Won or disease by administering an effective amount of a compound of any one of the preceding claim in a pharmaceutically acceptable carrier.

9. The method of claim 8, wherein the condition is inflammatory bowel disease, autoimmune encephalomyelitis, lupus, or sepsis.

10. The method of claim 8, wherein the carrier is buffered saline.