Bile-acid derived compounds for providing sustained systemic concentrations of drugs after oral administration

• US 20020151529A1
• Filed: 10/05/2001
• Published: 10/17/2002
• Est. Priority Date: 10/06/2000
• Status: Active Grant

• Current Assignee: XenoPort, Inc. (Arbor Pharmaceuticals LLC)
• Original Assignee: XenoPort, Inc. (Arbor Pharmaceuticals LLC)
• Inventors: Zhou, Cindy X., Gallop, Mark A., Cundy, Kenneth C.
• Granted Patent: US 6,992,076 B2
• Time in Patent Office: Days
• US Class Current: 514/169
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• 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: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/554 the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 47/65 Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: C07C 237/12 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups peptides C07K
• CPC Class Codes: C07C 237/20 the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 323/60 with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07K 5/0205 containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof

Abstract

This invention is directed to methods for providing sustained systemic concentrations of therapeutic or prophylactic agents such as GABA analogs following oral administration to animals. This invention is also directed to compounds and pharmaceutical compositions that are used in such methods.

Claims

1. A method for achieving sustained therapeutic or prophylactic blood concentrations of a GABA analog or an active metabolite thereof in the systemic circulation of an animal which method comprises orally administering to said animal a compound of formula (I):

2. The method of claim 1 wherein D is a GABA analog moiety preferably of the formula:

3. The method according to claim 1 wherein

R¹ and R² are both α

-OH;

or

R¹ is β

-OH and R² is hydrogen;

or

R¹ is α

-OH and R² is hydrogen;

or

R¹ is hydrogen and R² is α

-OH;

or

R¹ is β

-OH and R² is α

-OH;

or

R¹ and R² are both hydrogen.

4. The method according to claim 2 wherein D—

Q^a—

(T)— and

/or —

M—

Q^b—

D′

are selected to cleave under physiological conditions at a rate to provide a therapeutic and/or prophylactic blood concentration of the GABA analog or active metabolite thereof in the animal for a period of at least about 10% longer than when the GABA analog is orally delivered by itself at an equivalent dose.

19. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound according to any of claims 1, 5, 6, 11, 15, or 18.

20. A method for treating a disease condition in a mammal, wherein said disease condition is selected from epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathic pain, neuropathological disorders, gastrointestinal damage, inflammation and irritable bowel disease, which method comprises administering to said mammal a pharmaceutical composition according to claim 19.

5. A compound of formula (I):

6. A compound of formula (II):

7. The compound according to claim 6, wherein Q^b is a linker.

8. The compound according to claim 7, wherein Q^b is a group of formula:

—

[E—

(F*)_n—

G]_m—

Wherein;

m is an integer of from 1 to 4;

n is 0 or 1;

E is —

NH—

or —

O—

;

F* is selected from a group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkylene, substituted cycloalkylene, cycloalkenylene, substituted cycloalkenylene, arylene, substituted arylene, heteroarylene, substituted heteroarylene, heterocyclene and substituted heterocyclene; and

G is —

OC(O)—

, —

C(O)—

or —

NH—

.

9. The compound according to claim 8, wherein F* is selected from a group consisting of alkylene, alkynylene and alkylene substituted with a group selected from the group consisting of —

COOH, —

SO₃H, —

SO₂H, —

P(O)(OR¹⁹)(OH), —

OP(O)(OR¹⁹)(OH), —

OSO₃H, wherein R¹⁹ is selected from the group consisting of alkyl, substituted alkyl, aryl and substituted aryl; and

where one, two or three methylene groups are optionally replaced by a carboxy (—

C(O)O—

) group.

10. The compound according to claim 7 wherein Q^b is a cleavable linker selected from the group consisting of structures of formulae (vi) to (x):

11. A compound of formula (IIIa):

12. The compound according to claim 11, wherein R¹³ is —

CH₂CH₂CO₂H, —

CH₂CH₂C(O)NHCH₂COOH, —

CH₂CH₂C(O)NH—

(CH₂)₂SO₃H, —

CH₂CH₂CO₂Na, —

CH₂CH₂C(O)NHCH₂COONa or —

CH₂CH₂C(O)NH(CH₂)₂SO₃Na.

13. The compound according to claim 11, wherein Q′

is a group of formula;

—

E′

—

(F′

)_n1—

G′

—

Where;

n1 is 0 or 1;

G′

is —

C(O)—

, alkylene, —

O—

C(O)—

, —

NRC(O)—

, where R is hydrogen, alkyl or substituted alkyl;

F′

is selected from a group consisting of a covalent bond, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkylene, substituted cycloalkylene, cycloalkenylene, substituted cycloalkenylene, arylene, substituted arylene, heteroarylene, substituted heteroarylene, heterocyclene and substituted heterocyclene; and

E′

is a covalent bond, —

C(O)O—

or —

C(O)—

.

14. The compound according to claim 11, wherein Q′

is a cleavable linker selected from the group consisting of —

C(O)— and

the structures of formulae (i) through (v) as shown below;

16. A compound according to claim 15, wherein R¹⁴ is —

CO₂H, —

C(O)NHCH₂CO₂H, —

C(O)NH(CH₂)₂SO₃H, —

C(O)ONa, —

C(O)NHCH₂CO₂Na or —

C(O)NH(CH₂)₂SO₃Na.

17. The compound according to claim 16, wherein R¹⁵ is hydrogen, —

C(O)—

O—

R¹⁶, wherein R¹⁶ is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and —

C(O)(CR²¹R²²)NHR²⁰ where;

R²⁰ is independently hydrogen, alkyl, substituted alkyl alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;

R²¹ and R²² is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or R²¹ and R²² together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring, or, when R²⁰ and R²² are present and are on adjacent atoms, then together with the atoms to which they are attached form a heterocyclyl or substituted heterocyclyl ring.

15. A compound of formula (IIIb):

18. A compound selected from the group consisting of: