Compounds useful as modulators of melanocortin receptors and pharmaceutical compositions comprising same

• US 6,713,487 B2
• Filed: 03/04/2002
• Issued: 03/30/2004
• Est. Priority Date: 03/02/2001
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Lawrence, R. Michael, Yu, Guixue, Morton, George C., Poindexter, Graham S., Macor, John, Herpin, Timothy, Ruediger, Edward H., Ruel, Rejean, Thibault, Carl
• Primary Examiner(s): DESAI, RITA J
• Application Number:
  US10/090,288
• Publication Number:
  US 20030096827A1
• Time in Patent Office: 757 Days
• Field of Search: 546/15, 546/17, 546/18, 514/278
• US Class Current: 514/278
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• 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 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• 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 17/14 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 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 : Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 : for peripheral neuropathies
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 : Antimigraine agents
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 : Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 : Anxiolytics
• 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 25/30 : for treating abuse or dependence
• CPC Class Codes: A61P 27/16 : Otologicals
• 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 3/02 : Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/06 : for tuberculosis
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/20 : for DNA viruses
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• 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 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/16 : for decreasing, blocking or antagonising the activity of the thyroid hormones
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/10 : Spiro-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 491/10 : Spiro-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: C07K 5/06139 : with the first amino acid being heterocyclic
• CPC Class Codes: C07K 5/06191 : containing heteroatoms different from O, S, or N
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Compounds having the formula (I),

—NR₁₁R₁₂; G is a novel side chain selected from C_2-6alkenyl, A₃-aryl, —OR₁₈, heteroaryl, A₁-cyano, A₂—OR₁₇, A₁—C(═O)R₁₈, A₁—CO₂R₁₈, A₁—C(═O)NR₁₈R₁₉, A₁—OC(═O)R₁₈, A₁—NR₁₈C(═O)R₁₉, A₁—OC(═O)NR₁₈R₁₉, A₁—NR₁₈CO₂R₁₉, A₁—NR₁₈SO₂R₁₇, A₁—SO₂R₁₇, A₁—NR₂₀C(═O)NR₁₈R₁₉, and A₁—SR₁₈; or when y is 0 or when W is not NHR₂₂, G may be A₁-heterocyclo, wherein A₁ is a bond, C_1-6alkylene or C₂-alkenylene, A₂ is C_1-6alkylene or C_2-6alkenylene, and A₃ is C_2-6alkenylene; W is selected from —NR₂₁R₂₂, —OR₂₃, —NR₂₁C(═O)R₂₄, —NR₂₁CO₂R₂₄, amidino, guanidino, or a heteroaryl, heterocyclo or C_3-7cycloalkyl as defined in the specification, and X and R₁ through R₂₄ are as defined in the specification, are effective as modulators of melanocortin-receptors, particularly MC-1R and MC-4R.

Claims

1. A compound of formula (I),

or a pharmaceutically-acceptable salt, hydrate, in which:

X is N;

R₁ is hydrogen or C_1-6alkyl;

R₂ is C_1-6alkyl or C_2-6alkenyl, each optionally substituted with aryl;

E is E₁ wherein

G is selected from G is C_2-4alkenyl, NHC(═

O)R₁₉, SO₂R₁₇, or when y is 0, G may also be pyrrolidinyl, piperidinyl, pyrrolidinyl(lower alkyl), or piperidinyl(lower alkyl);

W is OH, —

NH₂, NH(lower alkyl), N(lower alkyl)₂, azetidinyl, or imidazolyl, wherein the azetidinyl and imidazolyl are optionally substituted with lower alkyl;

R₄ and R₇ are independently selected from hydrogen, alkyl, substituted alkyl, halogen, hydroxy, alkoxy, and keto;

R_5a, R_5b, R₆, R_6a, R_6b, R₈ and R₉ are independently hydrogen, halogen, cyano, alkyl, substituted alkyl, alkenyl, alkynyl, cycloakyl, heterocyclo, aryl, heteroaryl, —

OR₂₅, —

NR₂₅R₂₆, —

SR₂₅, —

S(O)_pR₂₆, —

C(═

O)R₂₅, —

OC(═

O)R₂₅, —

CO₂R₂₅, —

C(═

O)NR₂₅R₂₆, —

NR₂₅C(═

O)R₂₆, —

OC(═

O)NR₂₅R₂₆, —

NR₂₅COR₂₆, —

NR₂₇C(═

O)NR₂₅R₂₆ or —

NR₂₅SO₂R₂₆;

or R_5a and R_5b, R_6a and R_6b, or R₈ and R₉ taken together form a keto group (═

C) or a monocyclic or bicyclic cycloalkyl or heterocyclo, or alternatively, R_5a and/or R_5b together with R₈ and/or R₉, or R_6a and/or R_6b together with R₈ and/or R₉, are taken to form a fused carbocyclic, heterocyclic, or heteroaryl ring;

provided that,

(1) R₈ and R₉ are other then hydrogen; and

(2) when W is NH₂ or NH (lower alkyl) and G is alkenyl, the R₈ and R₉ are other than hydrogen and at least one of R₈ and R₉ is other than alkyl, substituted alkyl, heterocyclo, aryl, heteroaryl, —

OR₂₅, —

OC(═

O)R₂₅, —

CO₂R₂₅, —

C(═

O)NR₂₅R₂₆, —

NR₂₅COR₂₆, —

NR₂₇(C═

O)NR₂₅R₂₆ or NR₂₅SO₂R₂₆;

R₁₃, R₁₄, R₁₅ and R₁₆ are selected independently of each other from hydrogen, alkyl, substituted alkyl, amino, alkylamino, hydroxy, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclo, or R₁₃ and R₁₄, R₁₅ and R₁₆, when attached to the same carbon atom, may join to form a spirocyoloalkyl ring;

R₁₇ is alkyl or phenyl;

R₁₉ is alkyl or phenyl;

R₂₅, R₂₆ and R₂₇ are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heterocyclo, or heteroaryl;

or R₂₅ and R₂₆ may join together to form a heterocyclic or heteroaryl, except R₂₆ is not hydrogen when joined to a sulfonyl group as in —

S(O)_pR₂₆ or —

NR₂₅SO₂R₂₆;

p is 1, 2, or 3;

x is 0, 1, or 2

y is 0, 1, 2, 3 or 4; and

z is 1.

2. A compound according to claim 1, or a pharmaceutically-acceptable salt or hydrate, thereof, in which W is OH, —

NH₂, —

NHalkyl, or —

N(alkyl)₂.

3. A compound according to claim 1, or a pharmaceutically-acceptable salt or hydrate, thereof, having the formula:

in which

K is phenyl or thiazolyl;

R₃₀ is selected from C_1-4alkyl, hydroxy, alkoxy, halogen, nitro, cyano, amino, alkylamino, phenyl, and —

C(═

O)phenyl;

t is 0, 1 or 2; and

y is 0, 1 or 2.

4. A compound according to claim 1, or a pharmaceutically-acceptable salt or hydrate, thereof, in which

W is a ring selected from:

R₃₄ at each occurrence is attached to any available carbon or nitrogen atom of W and is selected from C_1-6alkyl, halogen, amino, aminoalkyl, alkylamino, hydroxy, C_1-4alkoxy, hydroxyC_1-4alkyl, —

C(═

O)alkyl, —

C(═

O)aminoalkyl, —

C(═

O)phenyl, —

C(═

O)benzyl, —

CO₂alkyl, —

CO₂phenyl, —

CO₂benzyl, —

SO₂alkyl, —

SO₂aminoalkyl, —

SO₂phenyl, —

SO₂benzyl, phenyl, benzyl, phenyloxy, benzyloxy, pyrrolyl, pyrazolyl, piperidinyl, pyridinyl, pyrimidinyl, and tetrazolyl, and/or two R₃₄ when attached to two adjacent carbon atoms or adjacent carbon and nitrogen atoms may be taken together to form a fused benzo, heterocyclo, or heteroaryl ring, and/or two R₃₄ when attached to the same carbon atom (in the case of a non-aromatic ring) may form keto (═

O), and each R₃₄ in turn is optionally substituted with up to two R₃₅;

R₃₅ is selected from halogen, trifluoromethyl, C_1-4alkyl, cyano, nitro, trifluoromethoxy, amino, alkylamino, aminoalkyl, hydroxy, and C_1-4alkoxy;

u is selected from 0, 1, 2, and 3; and

v is 0, 1 or 2.

5. A compound according to claim 1, or a pharmaceutically-acceptable salt hydrate, or thereof, in which

R₈ and R₉ are selected independently from alkyl, —

(CH₂)_j-C(═

O)alkyl, —

(CH₂)_j-phenyl, —

(CH₂)_j-naphthyl, —

(CH₂)_j-C_4-7cycloalkyl, —

(CH₂)_j-heterocyclo, and —

(CH₂)_j-heteroaryl; and

j is selected from 0, 1, 2, and 3.

6. A compound according to claim 1, or a pharmaceutically-acceptable salt hydrate, or thereof, in which

7. A compound according to claim 1, or a pharmaceutically-acceptable salt thereof, in which

R₂ is selected from hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkenylene-K, and —

(CH₂)_g-K;

K is selected from phenyl or naphthyl wherein each group K in turn is optionally substituted with one to three R₃₀ or has a benzene ring fused thereto, which also may be substituted with one to three R₃₀;

R₃₀ is selected from C_1-4alkyl, hydroxy, alkoxy, halogen, nitro, cyano, amino, alkylamino, phenyl, and acylphenyl; and

g is 0, 1, 2 or 3.

8. A compound according to claim 1, or a pharmaceutically-acceptable salt thereof, in which

X is N;

R₁ is hydrogen or C_1-4alkyl;

r is 0; and

s is 0.

9. A compound according to claim 1, or a pharmaceutically-acceptable salt or hydrate, in which

G is C_2-4alkenyl, NHC(═

O)R₁₉, SO₂R₁₇, or when y is 0, G may also be pyrrolidinyl, piperidinyl, pyrrolidinyl(lower alkyl), or piperidinyl(lower alkyl);

W is azetidinyl, or imidazolyl;

R₁₇ and R₁₉ are lower alkyl, and when W is imidazolyl, R₁₉ may be joined with W to form a heterocycle;

y is 0, 1, or 2.

14. A compound according to claim 1, having the formula,

or a pharmaceutically-acceptable salt, or hydrate thereof.

15. A pharmaceutical composition comprising at least one compound according to claim 1 or a pharmaceutically-acceptable salt or hydrate, thereof;

and a pharmaceutically-acceptable carrier or diluent.

10. A compound having the formula,

or a pharmaceutically-acceptable salt, hydrate, thereof, in which:

X is N;

R₁ is hydrogen or C_1-6alkyl;

R₂ is C_1-6alkyl or C_2-6alkenyl optionally substituted with one to three of aryl;

E is E₁ wherein

G is selected from;

C_2-4alkenyl, NHC(═

O)R₁₉, SO₂R₁₇, or when y is 0, G may also be pyrrolidinyl, piperidinyl, pyrrolidinyl(lower alkyl), or piperidinyl(lower alkyl);

W is OH, —

NH₂, NH(lower alkyl), N(lower alkyl)₂, azetidinyl, or imidazolyl, wherein the azetidinyl and imidazolyl are optionally substituted with lower alkyl;

R₄ and R₇ are independently selected from hydrogen, alkyl, substituted alkyl, halogen, hydroxy, alkoxy, and keto;

R_5a, R_5b, R₆, R_6a, R_6b, R₈ and R₉ are independently hydrogen, halogen, cyano, alkyl, substituted alkyl, alkenyl, hydroxy, alkoxy, alkoxycarbonyl, acyl, cycyocloalkyl, heterocyclo, aryl, or heteroaryl;

or R_5a and R_5b, R_6a and R_6b, or R₈ and R₉ taken together form a keto group (═

O) or a monocyclic or bicyclic cycloalkyl or heterocyclo, or alternatively, R_5a and/or R_5b together with R₈ and/or R₉, or R_6a and/or R_6b together with R₈ and/or R₉, join together to form a fused benzene or heterocyolo ring;

provided that,

(1) R₈ and R₉ are other than hydrogen;

(2) when W is NH₂ or NH (lower alkyl) and G is alkenyl, then R₈ and R₉ are other than hydrogen, and at least one of R₈ and R₉ is other than alkyl, substituted alkyl, heterocyclo, aryl, heteroaryl, hydroxy, alkoxy or alkoxycarbonyl;

R₁₇ is alkyl or phenyl;

R₁₉ is alkyl or phenyl;

x is 0, 1, or 2;

y is 0, 1 , 2, 3 or 4; and

z is 1.

11. A compound according to claim 10, or a pharmaceutically-acceptable salt or hydrate, thereof, having the formula:

wherein

R₃₀ is C_1-4alkyl, hydroxy, methoxyl, ethoxy, halogen, nitro, cyano, amino, C_1-4alkylamino, phenyl, or C(═

O)phenyl; and

y is 0, 1, or 2.

12. A compound according to claim 11, or a pharmaceutically-acceptable salt or hydrate, thereof, in which E is

13. A compound according to claim 10, or a pharmaceutically-aceeptable salt thereof, in which G is NHC(═

O)(alkyl) or NHC(═

O)phenyl.