Trisubstituted carbocyclic cyclophilin binding compounds and their use

• US 6,656,971 B2
• Filed: 01/25/2002
• Issued: 12/02/2003
• Est. Priority Date: 01/25/2001
• Status: Expired due to Fees

• Current Assignee: Guilford Pharmaceuticals Inc. (M G I Pharma Incorporated)
• Original Assignee: Guilford Pharmaceuticals Inc. (M G I Pharma Incorporated)
• Inventors: Hamilton, Gregory S., Limburg, David, Wu, Yong-Qian, Wilkinson, Douglas, Belyakov, Sergei, Vaal, Mark, Steiner, Joseph P., Wei, Ling
• Primary Examiner(s): Rotman, Alan L.
• Assistant Examiner(s): DESAI, RITA J
• Application Number:
  US10/057,203
• Publication Number:
  US 20020165275A1
• Time in Patent Office: 676 Days
• Field of Search: 564/149, 564/152, 564/155, 564/156, 564/74, 514/599, 514/617
• US Class Current: 514/599
• CPC Class Codes: A61K 31/325 Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof thiurams A61K31/145
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• 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 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• 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 25/28 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 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/08 for leprosy
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 33/00 : Antiparasitic agents
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 33/10 : Anthelmintics
• CPC Class Codes: A61P 33/12 : Schistosomicides
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 39/04 : Chelating agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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: C07C 233/29 : having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 233/66 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
• CPC Class Codes: C07C 233/75 : with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 233/76 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
• CPC Class Codes: C07C 235/42 : having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
• CPC Class Codes: C07C 235/56 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 243/38 : with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 255/54 : containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
• CPC Class Codes: C07C 2602/10 : the other ring being six-membered, e.g. tetraline
• CPC Class Codes: C07C 275/42 : being further substituted by carboxyl groups
• CPC Class Codes: C07C 311/46 : Y being a hydrogen or a carbon atom
• CPC Class Codes: C07C 311/48 : having nitrogen atoms of sulfonamide groups further bound to another hetero atom
• CPC Class Codes: C07C 335/18 : being further substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 335/36 : having sulfur atoms of isothiourea groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 337/06 : Compounds containing any of the groups , e.g. thiosemicarbazides
• CPC Class Codes: C07D 209/48 : with oxygen atoms in positions 1 and 3, e.g. phthalimide
• CPC Class Codes: C07D 213/56 : Amides
• CPC Class Codes: C07D 213/74 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 249/08 : 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 295/135 : with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• 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

The present invention relates to novel, non-peptidic small organic compounds having an affinity for cyclophilin (CyP)-type immunophilin proteins, and to pharmaceutical compositions comprising one or more of the said compounds. The invention further relates to the uses of these compounds and compositions for binding CyP-type proteins, inhibiting their peptidyl-prolyl isomerase activity, and for research, development, and therapeutic applications in a variety of medical disorders.

Claims

1. A compound of the following Formula I:

and pharmaceutically acceptable derivatives thereof;

where V is Q-substituted C₁-C₆ alkyl, or —

(CH₂)_n—

W;

wherein W is Q, or —

O—

(CH₂)_m—

Q;

n and m are independently 0-4;

Z is Q or S;

and Q is a mono-, bi-, or tricyclic, carbocyclic ring which is saturated, partially saturated, or aromatic, and wherein the individual ring sizes are 5-6 members, and wherein Q is optionally substituted in one or several positions with;

halo;

hydroxyl;

mercaptyl;

nitro;

trifluoromethyl;

aminocarbonyl;

arylaminocarbonyl in which the aryl is optionally halogenated and optionally substituted with trifluoromethyl or cyano;

C₁-C₄ alkylsulfonyl;

C₁-C₄ alklylthio;

oxo;

cyano;

C₁-C₆ alkyl or alkenyl;

C₁-C₅ alkoxycarbonyl;

C₁-C₄ alkenyloxy;

phenoxy;

phenyl;

cyanophenyl;

benzyloxy;

benzyl;

amino;

C₁-C₄ alkylamino;

di-(C₁-C₄) alkylamino;

C₁-C₄ alkylcarbamoyl;

di(C₁-C₄)alkylcarbamoyl;

or a combination thereof.

2. The compound of claim 1, wherein

V is — (CH₂)_n—

W; and

W is —

O—

(CH₂)_m—

Q.

3. A pharmaceutical composition, comprising:

(i.) a compound of Formula I as defined in claim 1, and

(ii.) a pharmaceutically acceptable carrier, diluent, or excipient.

4. A compound of the following formula

and pharmaceutically acceptable derivatives thereof;

where V is —

CH₂—

O—

Q;

Z is O or S;

and Q is a mono-, bi-, or tricyclic, carbocyclic ring which is saturated, partially saturated, or aromatic, and wherein the individual ring sizes are 5-6 members, and wherein Q is optionally substituted in one or several positions with;

halo;

hydroxyl;

mercaptyl;

nitro;

trifluoromethyl;

aminocarbonyl;

arylaminocarbonyl in which the aryl is optionally halogenated and optionally substituted with trifluoromethyl or cyano;

C₁-C₄ alkylsulfonyl;

C₁-C₄ alkylthio;

oxo;

cyano;

carboxy;

C₁-C₆ alkyl or alkenyl;

C₁-C₄ alkoxy;

C₁-C₅ alkoxycarbonyl;

C₁-C₄ alkenyloxy;

phenoxy;

phenyl;

cyanophenyl;

benzyloxy;

benzyl;

amino;

C₁-C₄ alkylamino;

di-(C₁-C₄) alkylamino;

C₁-C₄ alkylcarbamoyl;

di(C₁-C₄)alkylcarbamoyl;

or a combination thereof.

5. A compound of the following formula

and pharmaceutically acceptable derivatives thereof;

where V is —

O—

CH₂—

Q;

and wherein Z and Q are as defined in claim 4, above.

6. A compound of the following formula

and pharmaceutically acceptable derivatives thereof;

wherein V is Q-substituted C₁-C₆ straight or branched chain alkyl;

and wherein Z and Q are as defined in claim 4, above.

7. A compound selected from:

5-Naphthalen-1-yl-N,N′

-bis-(3-trifluoromethyl-phenyl)isophthalamide;

(5-(2-naphthyloxy)-3-{N-[3-(trifluoromethyl)phenyl]carbamoyl}phenyl)-N-[3-(trifluoromethyl)phenyl]formamide;

(5-(2-naphthyl)-3-{N-[3-(trifluoromethyl)phenyl]carbamoyl}phenyl)-N-[3-(trifluoromethyl)phenyl]formamide;

1-[(3,4-dichlorophenyl)oxymethyl]-3,5-bis-[(3,5-dichlorophenyl) aminocarbonyl]benzene;

1-[4-(2-cyanophenyl)benzy]loxy-3,5-bis-[(3-cyanophenyl) aminocarbonyl]benzene;

(5-(2-(2-5,6,7,8-tetrahydronaphthyl)ethyl)-3-{N-[3-(trifluoromethyl) phenyl]carbamoyl}phenyl)-N-[3-(trifluoromethyl)phenyl]formamide;

(5-(2-(2-naphthyl)ethyl)-3-{N-[3-(trifluoromethyl)phenyl]carbamoyl}phenyl)-N-[3-(trifluoromethyl)phenyl]formamide;

1-(3,4-dichlorobenzyloxy)-3,5-bis-[(3,4,5-trichlorophenyl) aminocarbonyl]benzene;

3-{[(3-Trifluoromethyl-4-chlorophenyl)aminocarbonyl]benzyloxy}-1,5-bis-[(3-trifluoromethyl-4-chlorophenyl)aminocarbonyl]benzene;

3-{[(3,4-dichlorophenyl)aminocarbonyl]benzyloxy}-1,5-bis-[(3,4-dichloro-phenyl)aminocarbonyl]benzene;

1,3-Bis[(3-trifluoromethylphenyl)aminocarbonyl]-5-[(2-naphthyl) methyloxy]benzene; and

1,3-Bis-[3,4-dichlorophenyl)aminocarbonyl]-5-(benzyloxy)benzene.