US 2006/0052434 A1Published application

Pyrrolizine compounds useful as anti-inflammatory agents

AssigneesBristol-Myers Squibb Company, Cerep SA

InventorsT. G. Dhar, Dharmpal Dodd, Dominique Potin, Michele Launay

Life of this patent

Estimating the term…

Abstract

Pyrrolizine compounds having the formula (I), or pharmaceutically-acceptable salts thereof, are effective in treating inflammatory or immune diseases, where A is a four- to seven-membered saturated ring, K is O or S, and R1, R2, R3 n, and M are defined in the specification.

Claims17

Dependent claims

A method of treating acute or chronic graft vs host reactions, acute or chronic transplant rejection, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, osteoporosis, diabetes, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, ulcerative colitis, Alzheimer's disease, shock, ankylosing spondylitis, gastritis, conjunctivitis, pancreatis, multiple organ injury syndrome, myocardial infarction, atherosclerosis, stroke, reperfusion injury, acute glomerulonephritis, vasculitis, thermal injury, necrotizing enterocolitis, granulocyte transfusion associated syndrome, Sjogren's syndrome, eczema, atopic dermatitis, contact dermatitis, urticaria, schleroderma, psoriasis, asthma, pulmonary fibrosis, allergic rhinitis, oxygen toxicity, emphysema, chronic bronchitis, acute respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), hepatitis B, hepatitis C, organ-tissue autoimmune disease, autoimmune thyroiditis, uveitis, systemic lupus erythematosis, Addison's disease, autoimmune polyglandular disease, or Grave's disease comprising:

administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I),
or a pharmaceutically-acceptable salt, enantiomer, or diastereomer, thereof, wherein:
K is O or S;
M is hydrogen, halogen, nitro, cyano, alkyl, substituted alkyl, alkenyl, alkynyl, OR14, CO2R6, C(═O)R6, C(═O)NR6R7, NR6C(═O)R7, NR6C(═O)OR7, S(O)qR6, NR6SO2R7, SO2NR6R7, NHCH(alkyl)CO2R6, aryl, heteroaryl, heterocyclo, cycloalkyl, or substituted cycloalkyl;
A is a fully or partially saturated 4- to 7-membered heterocyclo ring;
R1 is (CH2)r-Z, wherein Z is aryl, heteroaryl, cycloalkyl, or heterocyclo and each Z group is substituted, where valence allows, by zero to three R10;
R is (CH2)p-X, wherein X is aryl, heteroaryl, cycloalkyl, or heterocyclo and each X group is substituted, where valence allows, by zero to three R11;
R3 is (i) attached to any available carbon or nitrogen atom of ring A and at each occurrence is selected independently of other R3 from halogen, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, oxo, OR8, NR8R9, CO2R8, C(═O)R8, C(═O)NR8R9, NR8C(═O)R9, NR8C(═O)OR9, —OC(═O)R8, —OC(═O)NR8R9, S(O)qR8, NR8SO2R9, SO2NR8R9, aryl, heteroaryl, heterocyclo, cycloalkyl, and substituted cycloalkyl;
or (ii) a first group R3 and a second group R3, wherein the first group R3 and the second group R3 are attached to two available adjacent atoms of ring A and together form a five- to six-membered cycloalkyl, substituted cycloalkyl, heterocyclo, aryl, or heteroaryl, each of which is fused to ring A;
R6 and R7 are i) independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclo;
or (ii) are taken together form a heterocyclo ring;
R8 and R9 at each occurrence are (i) independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclo;
or (ii) taken together form a heterocyclo ring;
R10 and R11 at each occurrence are selected independently from halogen, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, oxo, OR12, NR12R13, CO2R12, and C(═O)R12;
R12 and R13 at each occurrence, are i) selected independently from hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclo;
or (ii) are taken together form a heterocyclo ring;
R14 is selected from alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclo;
n is 0, 1, 2 or 3;
p is 0, 1, 2 or 3;
q is 0, 1, 2, or 3;
and
r is 0, 1, 2 or 3.

19 more elements

A compound having the formula (Ia),

or a pharmaceutically-acceptable salt, enantiomer, or diastereomer, thereof, wherein:
K is O or S;
M is hydrogen, halogen, nitro, cyano, alkyl, substituted alkyl, alkenyl, alkynyl, OR14, CO2R6, C(═O)R6, C(═O)NR6R7, NR6C(═O)R7, NR6C(═O)OR7, S(O)qR6, NR6SO2R7, SO2NR6R7, NHCH(alkyl)CO2R6, aryl, heteroaryl, heterocyclo, cycloalkyl, or substituted cycloalkyl;
A is a fully or partially saturated 4- to 7-membered heterocyclo ring;
R1 is (CH2)r-Z, wherein Z is aryl, heteroaryl, cycloalkyl, or heterocyclo and each Z group is substituted, where valence allows, by zero to three R10;
R2 is (CH2)p-X, wherein X is aryl, heteroaryl, cycloalkyl, or heterocyclo and each X group is substituted, where valence allows, by zero to three R11;
R3is (i) attached to any available carbon or nitrogen atom of ring A and at each occurrence is selected independently of other R3 from halogen, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, oxo, OR8, NR8R9, CO2R8, C(═O)R8, C(═O)NR8R9, NR8C(═O)R9, NR8C(═O)OR9, —OC(═O)R8, —OC(═O)NR8R9, S(O)qR8, NR8SO2R9, SO2NR8R9, aryl, heteroaryl, heterocyclo, cycloalkyl, and substituted cycloalkyl;
or (ii) a first group R3 and a second group R3, wherein the first group R3 and the second group R3are attached to two available adjacent atoms of ring A and together form a five- to six-membered cycloalkyl, substituted cycloalkyl, heterocyclo, aryl, or heteroaryl, each of which is fused to ring A;
R6and R7 are i) independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclo;
or (ii) are taken together form a heterocyclo ring;
R8 and R9 at each occurrence are (i) independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclo;
or (ii) taken together form a heterocyclo ring;
R10 and R11 at each occurrence are selected independently from halogen, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, oxo, OR12, NR12R13, CO2R12, and C(═O)R12;
R12 and R13 at each occurrence, are i) selected independently from hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclo;
or (ii) are taken together form a heterocyclo ring;
R14 is selected from alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclo;
n is 0, 1, 2 or 3;
p is 0, 1, 2 or 3;
q is 0, 1, 2, or 3;
and
r is 1, 2 or 3.

18 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/206,558Filed 18 Aug 2005
Priority: 18 Aug 2004
Published: 9 Mar 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification4 codes

C07D 487/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 31/407
Having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil: condensed with other…
C07D
Heterocyclic compounds
A61K
Medicines and medical preparations

Family

Application60/602,455Us provisional application · filed 18 Aug 2004
US 7,375,237 B2Related patent
US 2006/0052434 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I),
or a pharmaceutically-acceptable salt, enantiomer, or diastereomer, thereof, wherein:
K is O or S;
M is hydrogen, halogen, nitro, cyano, alkyl, substituted alkyl, alkenyl, alkynyl, OR14, CO2R6, C(═O)R6, C(═O)NR6R7, NR6C(═O)R7, NR6C(═O)OR7, S(O)qR6, NR6SO2R7, SO2NR6R7, NHCH(alkyl)CO2R6, aryl, heteroaryl, heterocyclo, cycloalkyl, or substituted cycloalkyl;
A is a fully or partially saturated 4- to 7-membered heterocyclo ring;
R1 is (CH2)r-Z, wherein Z is aryl, heteroaryl, cycloalkyl, or heterocyclo and each Z group is substituted, where valence allows, by zero to three R10;
R is (CH2)p-X, wherein X is aryl, heteroaryl, cycloalkyl, or heterocyclo and each X group is substituted, where valence allows, by zero to three R11;
R3 is (i) attached to any available carbon or nitrogen atom of ring A and at each occurrence is selected independently of other R3 from halogen, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, oxo, OR8, NR8R9, CO2R8, C(═O)R8, C(═O)NR8R9, NR8C(═O)R9, NR8C(═O)OR9, —OC(═O)R8, —OC(═O)NR8R9, S(O)qR8, NR8SO2R9, SO2NR8R9, aryl, heteroaryl, heterocyclo, cycloalkyl, and substituted cycloalkyl;
or (ii) a first group R3 and a second group R3, wherein the first group R3 and the second group R3 are attached to two available adjacent atoms of ring A and together form a five- to six-membered cycloalkyl, substituted cycloalkyl, heterocyclo, aryl, or heteroaryl, each of which is fused to ring A;
R6 and R7 are i) independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclo;
or (ii) are taken together form a heterocyclo ring;
R8 and R9 at each occurrence are (i) independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclo;
or (ii) taken together form a heterocyclo ring;
R10 and R11 at each occurrence are selected independently from halogen, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, oxo, OR12, NR12R13, CO2R12, and C(═O)R12;
R12 and R13 at each occurrence, are i) selected independently from hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclo;
or (ii) are taken together form a heterocyclo ring;
R14 is selected from alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclo;
n is 0, 1, 2 or 3;
p is 0, 1, 2 or 3;
q is 0, 1, 2, or 3;
and
r is 0, 1, 2 or 3.

19 more elements

Facts

Application

11/206,558Filed 18 Aug 2005

Priority

18 Aug 2004

Published

9 Mar 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification4 codes

C07D 487/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 31/407
Having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil: condensed with other…
C07D
Heterocyclic compounds
A61K
Medicines and medical preparations