KR20080091132A - Inhibitors of fatty acid amide hydrolase - Google Patents

Abstract

Pharmacological inhibition of fatty acid amide hydrolase (FAAH) activity leads to increased levels of fatty acid amides. Esters of alkylcarbamic acids are disclosed that are inhibitors of FAAH activity. Compounds disclosed herein inhibit FAAH activity. Described herein are processes for the preparation of esters of alkylcarbamic acid compounds, compositions that include them, and methods of use thereof.

Description

Inhibitor of fatty acid amide hydrolase {INHIBITORS OF FATTY ACID AMIDE HYDROLASE}

Related Applications

This application is incorporated by reference in US Provisional Application No. 60 / 755,035, filed Dec. 29, 2005; 60 / 828,753, filed October 9, 2006; 60 / 823,076, filed August 21, 2006; 60 / 822,877, filed August 18, 2006; 60 / 824,887, filed September 7, 2006; 60 / 827,861, filed October 2, 2006; And 60 / 866,568, filed November 20, 2006; And No. 11 / 561,774 filed November 20, 2006, with priority claims.

The present invention relates to compounds, methods for preparing the compounds, pharmaceutical compositions and medicaments comprising the compounds, methods for using the compounds, and compositions for inhibiting the activity of fatty acid amide hydrolase (FAAH).

Fatty acid amide hydrolase (FAAH) is an enzyme that hydrolyzes the fatty acid amide (FAA) system of endogenous signal lipids. Common types of FAAs include N-acylethanolamine (NAE) and fatty acid primary amides (FAPA). Examples of NAE include anandamide (AEA), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). Pharmacological inhibition of FAAH activity increases the levels of these fatty acid amides.

Summary of the Invention

Provided are compounds, compositions, and methods for inhibiting the activity of fatty acid amide hydrolase (FAAH). Among the compounds provided herein, there is provided a compound that is an inhibitor of fatty acid amide hydrolase (FAAH). A method for producing a compound that inhibits the activity of a fatty acid amide hydrolase, a composition comprising the compound, as well as a method for using the compound.

Compounds provided herein include compounds having the structure of Formula I, pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs or pharmaceuticals In general, acceptable solvates are provided:

In the above formula, D is O or NR ¹¹ ;

One of A or B is (CH ₂ ) _m C (O) -alkyl, (CH ₂ ) _m C (O) -N (R ² ) ₂ , the other is H, alkyl or heteroalkyl,

m is 0, 1, 2 or 3; or

A and B together form an optionally substituted oxo-substituted heterocycle; or

A and B together form an optionally substituted heteroaromatic group comprising at least one N, NR ² , S or O group; or

A and B together form an optionally substituted non-aromatic or aromatic carbocyclic group; or

A and B are each H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted ketoalkyl and optionally substituted ketoheteroalkyl Independently from;

R ¹ is optionally selected from C ₃ -C ₉ cycloalkyl, C ₁ -C ₄ alkyl (C ₃ -C ₉ cycloalkyl), C ₁ -C ₄ alkyl (aryl) and C ₁ -C ₄ alkyl (heteroaryl) Substituted group,

Any carbon of the R ¹ cycloalkyl ring may be optionally substituted with Y and Z, each Y and each Z is independently selected from halogen, methyl or trifluoromethyl or Y and Z together are 3-, May form 4- or 5-membered carbocyclic groups or oxo (═O);

Each R ² is independently selected from H or optionally substituted alkyl;

R ¹¹ is H or optionally substituted alkyl.

For any and all embodiments, substituents may be selected from the subexamples of the presented alternatives. For example, in certain embodiments, one of A or B is (CH ₂ ) _n C (O) -alkyl, (CH ₂ ) _n C (O) -N (R ² ) ₂ , and the other is H , Alkyl or heteroalkyl. In certain embodiments, A and B are taken together -C (O)-(CR ^q R ^q ) _n- , -C (O) -NR ^2- (CR ^q R ^q ) _n- , -NR ² -C ( O)-(CR ^q R ^q ) _n- , -C (O) -NR ² -NR ^2- (CR ^q R ^q ) _n- , -C (O) -NR ² -N = (CR ^q )-, -0-C (O) -O-, 0-C (O) -NR ^2- , -NR ² -C (O) -NR ^2- , -OC (O) -O- (CR ^q R ^q ) _n -, -OC (O)-(CR ^q R ^q ) _n -O-, -NC (O)-(CR ^q R ^q ) _n -N-, -OC (O)-(CR ^q R ^q ) _n- N-, -NC (O)-(CR ^q R ^q ) _n -O-, -OC (O) -NR ^2- (CR ^q R ^q ) _n- , -NR ² -C (O) -O- ( CR ^q R ^q ) _n- , -NR ² -C (O) -NR ^2- (CR ^q R ^q ) _n -,-(CR ^q R ^q ) _n -C (O) -O- (CR ^q R ^q ) _n -,-(CR ^q R ^q ) _n -C (O) -NR ^2- (CR ^q R ^q ) _n -,-(CR ^q R ^q ) _n -C (O) -NR ² -NR ^2- ,-(CR ^q R ^q ) _n -C (O)-(CR ^q R ^q ) _n- , -C (O) -O- (CR ^q R ^q ) _n -O-, -C (O) -O -(CR ^q R ^q ) _n -NR ^2- , -C (O) -NR ^2- (CR ^q R ^q ) _n -NR ² , -C (O) -NR ^2- (CR ^q R ^q ) _n- O-, -C (O) -NR ² -CR ^q = CR ^q- , C (O) -CR ^q = CR ^q -NR ^2- , -C (O) -CR ^q = CR ^q -O-,- Forms an optionally substituted oxo-substituted heterocycle selected from C (O) -CR ^q = CR ^q -S-;

Each n is independently 1, 2 or 3;

Each R ^q is H, alkyl, substituted alkyl, aryl, substituted aryl, ketoalkyl, substituted ketoalkyl, ketoheteroalkyl, substituted ketoheteroalkyl, heteroalkyl, substituted heteroalkyl, heterocyclic or substituted Independently selected from heterocycles; or

Any two R ^q groups may form a carbocycle or a heterocycle.

In certain embodiments, A and B together form an optionally substituted non-aromatic ring group comprising a C (O) — (CH ₂ ) _n − moiety, wherein n is 1, 2, 3 or 4. In other embodiments, A and B together form an optionally substituted heteroaromatic group comprising one or more N, NR ² , S or O groups. In certain embodiments, R ¹ is C ₃ -C ₉ cycloalkyl, C ₁ -C ₄ alkyl (C ₃ -C ₉ cycloalkyl), C ₁ -C ₄ alkyl (aryl) and C ₁ -C ₄ alkyl ( Heteroaryl), and any carbon of the R ¹ cycloalkyl ring may be optionally substituted with Y and Z, each Y and each Z is independently from halogen, methyl or trifluoromethyl Or Y and Z may be taken together to form a 3-, 4- or 5-membered carbocyclic group or oxo (═O). In certain embodiments, R ² is H or optionally substituted alkyl. In another embodiment, D is O. Other embodiments relate to pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs or pharmaceutically acceptable solvates.

In certain embodiments, R ² is H. In another embodiment, R ¹¹ is H. In certain embodiments, one of A or B is C (O) -alkyl and the other is H. In further embodiments, the alkyl group is a methyl group.

In other embodiments, 3-carbamoylphenyl cyclohexylcarbamate; 3-carbamoylphenyl cyclohexylmethylcarbamate; 3-acetylphenyl cyclohexyl carbamate; 3- acetylphenyl cyclohexylmethyl carbamate; 3-acetylphenyl isopropyl carbamate; 3-acetylphenyl isobutyl carbamate; And non-limiting examples selected from 3-acetylphenyl phenethyl carbamate. In certain embodiments, A and B together form an optionally substituted non-aromatic ring group comprising a C (O) — (CH ₂ ) _n − moiety, wherein n is 1, 2, 3 or 4. In other embodiments, n is 2. In certain embodiments, R ² is H.

In certain embodiments, 2,3-dihydro-1-oxo-1 H -inden-6-yl cyclohexyl carbamate; 2,3-dihydro-1-oxo-1 H -inden-6-yl cyclohexylmethyl carbamate; 2,3-dihydro-1-oxo-1 H -inden-5-yl cyclohexyl carbamate; And 2,3-dihydro-1-oxo-1 H -inden-5-yl cyclohexylmethyl carbamate.

In further embodiments, A and B together form an optionally substituted heteroaromatic group comprising one or more N, NR ² , S or O groups. In certain embodiments, the heteroaromatic ring further comprises a-(CH) _n -moiety, where n is 1, 2 or 3. In another embodiment, A and B together form an optionally substituted heteroaromatic group comprising a single N in the ring.

In certain embodiments, quinolin-7-yl cyclohexyl carbamate; Quinolin-7-yl cyclohexylmethyl carbamate; Quinolin-7-yl cycloheptyl carbamate; Quinolin-7-yl (furan-2-yl) methyl carbamate; Quinolin-7-yl cyclohexylmethyl carbamate; Quinolin-6-yl cyclohexyl carbamate; Quinolin-6-yl cyclohexylmethyl carbamate; Quinolin-6-yl (furan-2-yl) methyl carbamate; Isoquinolin-7-yl cyclohexyl carbamate; Isoquinolin-7-yl cyclohexylmethyl carbamate; Isoquinolin-7-yl cycloheptyl carbamate; And non-limiting examples selected from pharmaceutically acceptable N-oxides thereof.

In certain embodiments, the optionally substituted heteroaromatic group comprises two heteroatoms selected from N, S and O.

In certain embodiments, 2-methylbenzo [d] thiazol-5-yl cyclohexyl carbamate; 2-methylbenzo [d] thiazol-5-yl cyclohexylmethyl carbamate; 2-methylbenzo [d] oxazol-5-yl cyclohexyl carbamate; 2-methylbenzo [d] oxazol-5-yl cyclohexylmethyl carbamate, 2-methylbenzo [d] oxazol-6-yl cyclohexyl carbamate; 2-methylbenzo [d] oxazol-6-yl cyclohexylmethyl carbamate, 2-methylbenzo [d] thiazol-6-yl cyclohexyl carbamate; And non-limiting examples selected from the group of 2-methylbenzo [d] thiazol-6-yl cyclohexylmethyl carbamate.

In another embodiment, D is NR ¹¹ . In certain embodiments, 1- (3-acetylphenyl) -3-cyclohexyl urea, 1- (3-acetylphenyl) -3- (cyclohexylmethyl) urea, 1- (3-acetylphenyl) -3 Non-limiting examples selected from the group of isobutylurea, 1- (3-acetylphenyl) -3-isopropylurea and 1- (3-acetylphenyl) -3-phenethylurea. In certain embodiments, 1-cyclohexyl-3- (2,3-dihydro-1-oxo-1 H -inden-6-yl) urea, 1- (cyclohexylmethyl) -3- (2,3 -Dihydro-1-oxo-1 H -inden-6-yl) urea, 1-cyclohexyl-3- (2,3-dihydro-1-oxo-1 H -inden-5-yl) urea and 1 A non-limiting example is selected from-(cyclohexylmethyl) -3- (2,3-dihydro-1-oxo-1 H -inden-5-yl) urea.

In another embodiment, 1-cyclohexyl-3- (quinolin-7-yl) urea, 1- (cyclohexylmethyl) -3- (quinolin-7-yl) urea, 1-cycloheptyl-3- (quinoline -7-yl) urea, 1-((furan-2-yl) methyl) -3- (quinolin-7-yl) urea, 1-cyclohexyl-1-methyl-3- (quinolin-7-yl) urea , 1-cyclohexyl-3- (quinolin-6-yl) urea, 1- (cyclohexylmethyl) -3- (quinolin-6-yl) urea, 1-((furan-2-yl) methyl) -3 -(Quinolin-6-yl) urea, 1-cyclohexyl-3- (isoquinolin-7-yl) urea, 1- (cyclohexylmethyl) -3- (isoquinolin-7-yl) urea and 1-cyclo A non-limiting example is selected from heptyl-3- (isoquinolin-7-yl) urea.

In another embodiment, 1- (cyclohexylmethyl) -3- (2-methylbenzo [d] thiazol-5-yl) urea, 1-cyclohexyl-3- (2-methylbenzo [d] thiazole -5-yl) urea, 1-cyclohexyl-3- (2-methylbenzo [d] oxazol-5-yl) urea and 1- (cyclohexylmethyl) -3- (2-methylbenzo [d] oxa Zol-5-yl) urea.

In another embodiment, non-limiting examples are selected from any of the compounds set forth in FIGS. 1, 2, 3, 4, 5, 6, 7 and 8.

In another embodiment, a compound of Formula II: pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug or pharmaceutically acceptable It relates to solvates:

In the above formula,

D is O or NR ¹¹ ;

Each X is CH or N;

로 구성된 군으로부터 선택되고;R ¹ is

Is selected from the group consisting of;

M is a bond, optionally substituted C ₁ -C ₈ alkylene, optionally substituted 4-atom heteroalkylene, optionally substituted C ₂ -C ₈ alkenylene, optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted C ₂ -C ₈ alkynylene;

J is CH or N; K is CH or N; Provided that when K is CH, J cannot be CH;

Each R ³ is C ₁ -C ₆ alkyl- (aryl), C ₁ -C ₆ alkyl- (heteroaryl), C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamine, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ heteroalkyl, -C (O) -R ¹² , aryl, heteroaryl, heterocycloalkyl, phenyl, pyridyl, pyridazinyl , Piperazinyl, piperidinyl, morpholinyl, furanyl, thiophenyl, thiophenyl, dibenzofuranyl, dibenzothienyl, indolyl, fluorenyl, carbozolyl, pyrimidinyl, pyrazinyl, Triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxdiazolyl, thiadiazolyl, triazolyl, naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroiso Quinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnalol, imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl , Mercedes Benz Zolyl, benzothiazolyl, benzisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl, pyrazolopyridyl Is an optionally substituted group independently selected from the group consisting of oxalolopyridyl, isoxazolopyridyl or thiazolopyridyl;

Each R 'is independently H, alkyl or substituted alkyl;

Each R ⁵ is independently H, C ₁ -C ₃ alkyl or halogen;

R ⁶ is C ₁ -C ₃ alkyl or C ₃ -C ₇ cycloalkyl;

R ² and R ¹¹ are H or optionally substituted alkyl;

R ¹² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ heteroalkyl, benzyloxy, furanyl, phenyl, benzyl or pyridyl; or

을 형성하며;R ¹ and R ² together

To form;

n is 1, 2, 3 or 4; m is 1, 2, 3 or 4;

A and B together form an optionally substituted non-aromatic ring group comprising a C (O) — (CH ₂ ) _q − moiety, wherein q is 1, 2, 3 or 4; or

A and B together form an optionally substituted oxo-substituted heterocycle; or

A and B together form an optionally substituted aromatic or non-aromatic ring group comprising at least one N, NR ² , S or O group; or

One of A or B is -LG and the other is selected from H and optionally substituted C ₁ -C ₆ alkyl; or

A and B together form an optionally substituted aromatic carbocyclic group; or

A and B are each H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted ketoalkyl, optionally substituted amide and optionally Independently selected from substituted ketoheteroalkyl;

L is a bond or C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₁ -C ₆ ketoalkylene, -C (O) NR ^9- (CH ₂ ) _j- , -NR ⁹ -C (O)-(CH ₂ ) _j- , -OC (O) O- (CH ₂ ) _j- , -NHC (O) O- (CH ₂ ) _j- , -O (O) CNH- (CH ₂ ) _j- , -C (O) O- (CH ₂ ) _j- , -OC (O)-(CH ₂ ) _j- , -NR ⁹ C (O) N (R ⁹ )-(CH ₂ ) _j -, -S (O)-(CH ₂ ) _j- , -S (O) _2- (CH ₂ ) _j- , -C (= NR ¹⁰ ) N (R ⁹ )-(CH ₂ ) _j - _and- Is an optionally substituted group selected from NR ⁹ C (═NR ¹⁰ ) N (R ⁹ ) — (CH ₂ ) _j- ;

G is tetrazolyl, -NHS (= O) ₂ R ⁸ , -S (= O) ₂ NHR ⁸ , -S (= O) ₂ NH-phenyl, -OH, -SH, -OC (O) NHR ⁸ , -NHC (O) OR ⁸ , -C (O) NHC (O) R ⁸ , -C (O) NHS (= O) ₂ R ⁸ , -S (= O) ₂ NHC (O) R ⁸ , -S (= O) ₂ NHC (O) NHR ⁸ , -NHC (O) R ⁸ , -NHC (O) N (R ⁹ ) ₂ , -C (= NR ¹⁰ ) N (R ⁹ ) ₂ , -NR ⁹ C (= NR ¹⁰ ) N (R ⁹ ) ₂ , -NR ⁹ C (= NR ¹⁰ ) NHC (= NR ¹⁰ ) N (R ⁹ ) ₂ , -NR ⁹ C (= CHR ¹⁰ ) N (R ⁹ ) ₂ , -C (O) NR ⁹ C (= NR ¹⁰ ) N (R ⁹ ) ₂ , -C (O) NR ⁹ C (= CHR ¹⁰ ) N (R ⁹ ) ₂ , -CO ₂ H,-(OP (= O) OH) _x OH, -OP (= O) OR ⁸ OH, -OP (= O) R ⁸ OH, -NR ⁹ P (= O) OR ⁸ OH, -NR ⁹ P (= O) R ⁸ OH , -P (= 0) OR ⁸ OH; —P (═O) R ⁸ OH, —S (O) _y OH, —OS (O) _y OH, —NR ⁹ S (O) _y OH;

Each R ⁸ is independently substituted or unsubstituted C ₁ -C ₆ alkyl;

Each R ⁹ is independently H, substituted C ₁ -C ₆ alkyl or unsubstituted C ₁ -C ₆ alkyl;

Each R ¹⁰ is independently selected from H, —S (═O) ₂ R ⁸ , —S (═O) ₂ NH ₂ , —C (O) R ⁸ , —CN, and —NO ₂ ;

j is 0, 1, 2, 3 or 4; x is 1, 2 or 3; y is 0, 1 or 2;

Each optional substituent is C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, benzyl, halogen, nitro, cyano or benzyloxy-C (O) R ′, —C (O) — (alkyl or substituted Alkyl),-(alkyl or substituted alkyl) -C (O) R ', -C (O) N (R') ₂ , -C (O) N (R ')-(alkyl or substituted alkyl), -(Alkyl or substituted alkyl) -C (O) N (R ') ₂ , -OC (O) N (R') ₂ , -OC (O) N (R ')-(alkyl or substituted alkyl) ,-(Alkyl or substituted alkyl) -0C (O) N (R ') ₂ , -N (R') C (O) R ', -NR'C (O)-(alkyl or substituted alkyl), -(Alkyl or substituted alkyl) -NR'C (O) R ', -SR', -S- (alkyl or substituted alkyl), -S (O) _k R ', where k is 1 or 2 , -S (O) _k (alkyl or substituted alkyl), -C (S)-(alkyl or substituted alkyl), -CSN (R ') ₂ , -CSN (R')-(alkyl or substituted alkyl ), -N (R ') CO- (alkyl or substituted alkyl), -N (R') C (O) OR ',-(alkyl or substituted alkyl) -ON = C (R') ₂ ,- (alkyl or substituted alkyl) -C (O) NR '- (alkyl or substituted alkyl), - (alkyl or substituted alkyl), -S (O) _k - (alkyl addition Substituted alkyl) -SR ', - -S-SR ( alkyl or substituted _{alkyl)', -S (O) k} N (R ') 2, -N (R') C (O) N (R ') ₂ , -N (R ') C (S) N (R') ₂ , -N (R ') S (O) _k N (R') ₂ , -C (R ') = NR'-C (R ') = NN (R') ₂ and -C (R ') ₂ -N (R')-N (R ') ₂ are independently selected.

In certain embodiments, R ¹ is

로 구성된 군으로부터 선택된다. 특정의 실시태양에서, M은 결합, 임의로 C₁-C₄ 알킬렌, 임의로 치환된 4-원자 헤테로알킬렌, 임의로 치환된 C₂-C₄ 알케닐렌 또는 임의로 치환된 C₂-C₄ 알키닐렌이다. 또다른 실시태양에서, J는 CH 또는 N이고; K는 CH 또는 N이며; 단, K가 CH인 경우, J는 CH가 될 수 없다. 또다른 실시태양에서, R³은 C₁-C₃ 알킬, C₁-C₃ 알콕시, 벤질, 할로겐, 니트로, 시아노 또는 벤질옥시-C(O)R', -C(O)-(알킬 또는 치환된 알킬), -(알킬 또는 치환된 알킬)-C(O)R', -C(0)N(R')₂, -C(O)N(R')-(알킬 또는 치환된 알킬), -(알킬 또는 치환된 알킬)-C(O)N(R')₂, -OC(O)N(R')₂, -OC(O)N(R')-(알킬 또는 치환된 알킬), -(알킬 또는 치환된 알킬)-OC(O)N(R')₂, -N(R')C(O)R', -NR'C(O)-(알킬 또는 치환된 알킬), -(알킬 또는 치환된 알킬)-NR'C(O)R', -SR', -S-(알킬 또는 치환된 알킬), -S(O)_kR'(여기서 k는 1 또는 2임), -S(O)_k(알킬 또는 치환된 알킬), -C(S)-(알킬 또는 치환된 알킬), -CSN(R')₂, -CSN(R')-(알킬 또는 치환된 알킬), -N(R')CO-(알킬 또는 치환된 알킬), -N(R')C(O)OR', -(알킬 또는 치환된 알킬)-O-N=C(R')₂, -(알킬 또는 치환된 알킬)-C(O)NR'-(알킬 또는 치환된 알킬), -(알킬 또는 치환된 알킬)-S(O)_k-(알킬 또는 치환된 알킬)-SR', -(알킬 또는 치환된 알킬)-S-SR', -S(O)_kN(R')₂, -N(R')C(O)N(R')₂, -N(R')C(S)N(R')₂, -N(R')S(O)_kN(R')₂, -C(R')=NR'-C(R')=N-N(R')₂ 및 -C(R')₂-N(R')-N(R')₂로부터의 1 이상의 기로 임의로 치환되는, 임의로 치환된 C₁-C₆ 알킬, C₁-C₆ 헤테로알킬, -C(O)-R¹², 페닐, 피리딜, 피리다지닐, 피페라지닐, 피페리디닐, 모르폴리닐, 푸라닐, 티오페닐, 티오페네일, 디벤조푸라닐, 디벤조티에닐, 인돌릴, 플루오레닐, 카르보졸릴, 피리미디닐, 피라지닐, 트리아지닐, 옥사졸릴, 이속사졸릴, 티아졸릴, 이소티아졸릴, 이미다졸릴, 옥사디아졸릴, 티아디아졸릴, 트리아졸릴, 나프틸, 퀴놀릴, 테트라히드로퀴놀릴, 이소퀴놀릴, 테트라히드로이소퀴놀릴, 프탈라지닐, 퀴나졸리닐, 퀴녹살리닐, 나프티리디닐, 신놀릴, 이미다조피리미디닐, 티에노피리미디닐, 벤조푸라닐, 벤조티에닐, 벤즈이미다졸릴, 벤족사졸릴, 벤즈이속사졸릴, 벤조티아졸릴, 벤즈이소티아졸릴, 인다졸릴, 피롤로피리딜, 푸로피리딜, 디히드로푸로피리딜, 티에노피리딜, 디히드로티에노피리딜, 이미다조피리딜, 피라졸로피리딜, 옥사올로피리딜, 이속사올로피리딜 또는 티아졸로피리딜 기로 구성된 군으로부터 선택된다. 또다른 실시태양에서, 각각의 R'은 독 립적으로 H, 알킬 또는 치환된 알킬이다. 특정의 실시태양에서, 각각의 R⁵는 독립적으로 H, C₁-C₃ 알킬 또는 할로겐이다. 또다른 실시태양에서, R⁶은 C₁-C₃ 알킬 또는 C₃-C₇ 시클로알킬이다. 특정의 실시태양에서, R² 및 R¹¹은 H 또는 임의로 치환된 알킬이다. 또다른 실시태양에서, R¹²는 C₁-C₆ 알킬, C₃-C₇ 시클로알킬, C₁-C₆ 헤테로알킬, 벤질옥시, 푸라닐, 페닐, 벤질 또는 피리딜로 구성된 군으로부터 선택된다. 특정의 실시태양에서, n은 1, 2, 3 또는 4이다. 또다른 실시태양에서, m은 1, 2, 3 또는 4이다. 또다른 실시태양에서, A 및 B는 함께 C(O)-(CH₂)_q- 부분을 포함하는 임의로 치환된 비-방향족 고리 기를 형성하며, 여기서 q는 1, 2, 3 또는 4이다. 또다른 실시태양에서, A 및 B는 함께 1 이상의 N, NR², S 또는 O 기를 포함하는 임의로 치환된 방향족 또는 비-방향족 고리 기를 형성한다. 특정의 실시태양에서, A 또는 B중 하나는 -L-G이고, 다른 하나는 H 및 임의로 치환된 C₁-C₆ 알킬로부터 선택된다. 또다른 실시태양에서, A 및 B는 함께 임의로 치환된 방향족 탄소환 기를 형성한다. 특정의 실시태양에서, A 및 B는 각각 H, 임의로 치환된 알킬, 임의로 치환된 헤테로알킬, 임의로 치환된 복소환 기, 임의로 치환된 아릴 기, 임의로 치환된 헤테로아릴 기, 임의로 치환된 케토알킬 및 임의로 치환된 케토헤테로알킬로부터 독립적으로 선택된다. 특정의 실시태양에서, L은 결합이거나 또는 C₁-C₆ 알킬렌, C₁-C₆ 헤 테로알킬렌, C₁-C₆ 케토알킬렌, -C(O)NR⁹-(CH₂)_j-, -NR⁹-C(O)-(CH₂)_j-, -OC(O)O-(CH₂)_j-, -NHC(O)O-(CH₂)_j-, -O(O)CNH-(CH₂)_j-, -C(O)O-(CH₂)_j-, -OC(O)-(CH₂)_j-, -NR⁹C(O)N(R⁹)-(CH₂)_j-, -S(O)-(CH₂)_j-, -S(O)₂-(CH₂)_j-, -C(=NR¹⁰)N(R⁹)-(CH₂)_j- 및 -NR⁹C(=NR¹⁰)N(R⁹)-(CH₂)_j-로부터 선택된 임의로 치환된 기이다. 또다른 실시태양에서, G는 테트라졸릴, -NHS(=O)₂R⁸, -S(=O)₂NHR⁸, -S(=O)₂NH-페닐, -OH, -SH, -OC(O)NHR⁸, -NHC(O)OR⁸, -C(O)NHC(O)R⁸, -C(O)NHS(=O)₂R⁸, -S(=O)₂NHC(O)R⁸, -S(=O)₂NHC(O)NHR⁸, -NHC(O)R⁸, -NHC(O)N(R⁹)₂, -C(=NR¹⁰)N(R⁹)₂, -NR⁹C(=NR¹⁰)N(R⁹)₂, -NR⁹C(=NR¹⁰)NHC(=NR¹⁰)N(R⁹)₂, -NR⁹C(=CHR¹⁰)N(R⁹)₂, -C(O)NR⁹C(=NR¹⁰)N(R⁹)₂, -C(O)NR⁹C(=CHR¹⁰)N(R⁹)₂, -CO₂H, -(OP(=O)OH)_xOH, -OP(=O)OR⁸OH, -OP(=O)R⁸OH, -NR⁹P(=O)OR⁸OH, -NR⁹P(=O)R⁸OH, -P(=O)OR⁸OH, -P(=O)R⁸OH, -S(O)_yOH; -OS(O)_yOH; -NR⁹S(O)_yOH이다. 특정의 실시태양에서, 각각의 R⁸은 독립적으로 치환된 또는 비치환된 C₁-C₆ 알킬이다. 또다른 실시태양에서, 각각의 R⁹는 독립적으로 H, 치환된 C₁- C₆ 알킬 또는 비치환된 C₁-C₆ 알킬이다. 또다른 실시태양에서, 각각의 R¹⁰은 H, -S(=O)₂R⁸, -S(=O)₂NH₂, -C(O)R⁸, -CN 및 -NO₂로부터 독립적으로 선택된다. 또다른 실시태양에서, j는 0, 1, 2, 3 또는 4이다. 추가의 실시태양에서, x는 1, 2 또는 3이다. 또다른 실시태양에서, y는 0, 1 또는 2이다. 추가의 실시태양에서, 약학적으로 허용 가능한 염, 약학적으로 허용 가능한 N-옥시드, 약학적으로 활성인 대사산물, 약학적으로 허용 가능한 전구약물 또는 약학적으로 허용 가능한 용매화물에 관한 것이다.

It is selected from the group consisting of. In certain embodiments, M is a bond, optionally C ₁ -C ₄ alkylene, optionally substituted 4-atom heteroalkylene, optionally substituted C ₂ -C ₄ alkenylene or optionally substituted C ₂ -C ₄ alkynylene to be. In another embodiment, J is CH or N; K is CH or N; However, when K is CH, J cannot be CH. In another embodiment, R ³ is C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, benzyl, halogen, nitro, cyano or benzyloxy-C (O) R ′, —C (O) — (alkyl Or substituted alkyl),-(alkyl or substituted alkyl) -C (O) R ', -C (0) N (R') ₂ , -C (O) N (R ')-(alkyl or substituted Alkyl),-(alkyl or substituted alkyl) -C (O) N (R ') ₂ , -OC (O) N (R') ₂ , -OC (O) N (R ')-(alkyl or substituted Alkyl),-(alkyl or substituted alkyl) -OC (O) N (R ') ₂ , -N (R') C (O) R ', -NR'C (O)-(alkyl or substituted Alkyl),-(alkyl or substituted alkyl) -NR'C (O) R ', -SR', -S- (alkyl or substituted alkyl), -S (O) _k R 'wherein k is 1 or 2), -S (O) _k (alkyl or substituted alkyl), -C (S)-(alkyl or substituted alkyl), -CSN (R ') ₂ , -CSN (R')-(alkyl or Substituted alkyl), -N (R ') CO- (alkyl or substituted alkyl), -N (R') C (O) OR ',-(alkyl or substituted alkyl) -ON = C (R') ₂ ,-(alkyl or substituted alkyl) -C (O) NR '-(alkyl or substituted alkyl),-(alkyl or substituted alkyl) -S (O) _k- (alkyl Or substituted alkyl) -SR ',-(alkyl or substituted alkyl) -S-SR', -S (O) _k N (R ') ₂ , -N (R') C (O) N (R ' ) ₂ , -N (R ') C (S) N (R') ₂ , -N (R ') S (O) _k N (R') ₂ , -C (R ') = NR'-C ( Optionally substituted C ₁ -C ₆ alkyl optionally substituted with one or more groups from R ′) ═NN (R ′) ₂ and —C (R ′) ₂ —N (R ′) — N (R ′) ₂ , C ₁ -C ₆ heteroalkyl, -C (O) -R ¹² , phenyl, pyridyl, pyridazinyl, piperazinyl, piperidinyl, morpholinyl, furanyl, thiophenyl, thiophenyl, dibenzo Furanyl, dibenzothienyl, indolyl, fluorenyl, carbozolyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxdiazolyl , Thiadiazolyl, triazolyl, naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnoyl, imidazo Pyrimidinyl, thienopyrimidinyl, benzofuranyl, ben Thienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydro Thienopyridyl, imidazopyridyl, pyrazolopyridyl, oxalopyridyl, isoxazolopyridyl or thiazolopyridyl group. In another embodiment, each R 'is independently H, alkyl or substituted alkyl. In certain embodiments, each R ⁵ is independently H, C ₁ -C ₃ alkyl or halogen. In another embodiment, R ⁶ is C ₁ -C ₃ alkyl or C ₃ -C ₇ cycloalkyl. In certain embodiments, R ² and R ¹¹ are H or optionally substituted alkyl. In another embodiment, R ¹² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ heteroalkyl, benzyloxy, furanyl, phenyl, benzyl or pyridyl . In certain embodiments n is 1, 2, 3 or 4. In another embodiment, m is 1, 2, 3 or 4. In another embodiment, A and B together form an optionally substituted non-aromatic ring group comprising a C (O) — (CH ₂ ) _q − moiety, wherein q is 1, 2, 3 or 4. In another embodiment, A and B together form an optionally substituted aromatic or non-aromatic ring group comprising one or more N, NR ² , S or O groups. In certain embodiments, one of A or B is -LG and the other is selected from H and optionally substituted C ₁ -C ₆ alkyl. In another embodiment, A and B together form an optionally substituted aromatic carbocyclic group. In certain embodiments, A and B are each H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted ketoalkyl and Independently from optionally substituted ketoheteroalkyl. In certain embodiments, L is a bond or C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₁ -C ₆ ketoalkylene, -C (O) NR ^9- (CH ₂ ) _j- , -NR ⁹ -C (O)-(CH ₂ ) _j- , -OC (O) O- (CH ₂ ) _j- , -NHC (O) O- (CH ₂ ) _j- , -O ( O) CNH- (CH ₂ ) _j- , -C (O) O- (CH ₂ ) _j- , -OC (O)-(CH ₂ ) _j- , -NR ⁹ C (O) N (R ⁹ ) -(CH ₂ ) _j- , -S (O)-(CH ₂ ) _j- , -S (O) _2- (CH ₂ ) _j- , -C (= NR ¹⁰ ) N (R ⁹ )-(CH ₂ ) _j -and -NR ⁹ C (= NR ¹⁰ ) N (R ⁹ )-(CH ₂ ) _j- . In another embodiment, G is tetrazolyl, -NHS (= 0) ₂ R ⁸ , -S (= 0) ₂ NHR ⁸ , -S (= 0) ₂ NH-phenyl, -OH, -SH, -OC (O) NHR ⁸ , -NHC (O) OR ⁸ , -C (O) NHC (O) R ⁸ , -C (O) NHS (= O) ₂ R ⁸ , -S (= O) ₂ NHC (O ) R ⁸ , -S (= O) ₂ NHC (O) NHR ⁸ , -NHC (O) R ⁸ , -NHC (O) N (R ⁹ ) ₂ , -C (= NR ¹⁰ ) N (R ⁹ ) ₂ , -NR ⁹ C (= NR ¹⁰ ) N (R ⁹ ) ₂ , -NR ⁹ C (= NR ¹⁰ ) NHC (= NR ¹⁰ ) N (R ⁹ ) ₂ , -NR ⁹ C (= CHR ¹⁰ ) N (R ⁹ ) ₂ , -C (O) NR ⁹ C (= NR ¹⁰ ) N (R ⁹ ) ₂ , -C (O) NR ⁹ C (= CHR ¹⁰ ) N (R ⁹ ) ₂ , -CO ₂ H ,-(OP (= O) OH) _x OH, -OP (= O) OR ⁸ OH, -OP (= O) R ⁸ OH, -NR ⁹ P (= O) OR ⁸ OH, -NR ⁹ P ( ═O) R ⁸ OH, —P (═O) OR ⁸ OH, —P (═O) R ⁸ OH, —S (O) _y OH; -OS (O) _y OH; -NR ⁹ S (O) _y OH. In certain embodiments, each R ⁸ is independently substituted or unsubstituted C ₁ -C ₆ alkyl. In another embodiment, each R ⁹ is independently H, substituted C ₁ - C ₆ alkyl or an unsubstituted C ₁ -C ₆ alkyl. In another embodiment, each R ¹⁰ is independently from H, —S (═O) ₂ R ⁸ , —S (═O) ₂ NH ₂ , —C (O) R ⁸ , —CN and —NO ₂ Is selected. In another embodiment, j is 0, 1, 2, 3 or 4. In further embodiments, x is 1, 2 or 3. In another embodiment, y is 0, 1 or 2. In further embodiments, the present invention relates to pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs or pharmaceutically acceptable solvates.

In certain embodiments, A and B are taken together -C (O)-(CR ^q R ^q ) _n- , -C (O) -NR ^2- (CR ^q R ^q ) _n- , -NR ² -C ( O)-(CR ^q R ^q ) _n- , -C (O) -NR ² -NR ^2- (CR ^q R ^q ) _n- , -C (O) -NR ² -N = (CR ^q )-, -0-C (O) -O-, 0-C (O) -NR ^2- , -NR ² -C (O) -NR ^2- , -0-C (O) -O- (CR ^q R ^q ) _n- , -OC (O)-(CR ^q R ^q ) _n -O-, -NC (O)-(CR ^q R ^q ) _n -N-, -OC (O)-(CR ^q R ^q ) _n -N-, -NC (O)-(CR ^q R ^q ) _n -O-, -OC (O) -NR ^2- (CR ^q R ^q ) _n- , -NR ² -C (O) -O -(CR ^q R ^q ) _n- , -NR ² -C (O) -NR ^2- (CR ^q R ^q ) _n -,-(CR ^q R ^q ) _n -C (O) -O- (CR ^q R ^q ) _n -,-(CR ^q R ^q ) _n -C (O) -NR ^2- (CR ^q R ^q ) _n -,-(CR ^q R ^q ) _n -C (O) -NR ² -NR ² -,-(CR ^q R ^q ) _n -C (O)-(CR ^q R ^q ) _n- , -C (O) -O- (CR ^q R ^q ) _n -O-, -C (O) -O- (CR ^q R ^q ) _n -NR ^2- , -C (O) -NR ^2- (CR ^q R ^q ) _n -NR ² , -C (O) -NR ^2- (CR ^q R ^q ) _n- O-, -C (O) -NR ² -CR ^q = CR ^q- , C (O) -CR ^q = CR ^q -NR ^2- , -C (O) -CR ^q = CR ^q -O- , -C (O) -CR ^q = CR ^q -S- to form an optionally substituted oxo-substituted heterocycle; Each n is independently 1, 2 or 3; Each R ^q is H, alkyl, substituted alkyl, aryl, substituted aryl, ketoalkyl, substituted ketoalkyl, ketoheteroalkyl, substituted ketoheteroalkyl, heteroalkyl, substituted heteroalkyl, heterocyclic or substituted Independently from the heterocycle.

In certain embodiments, a compound of Formula III, pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug or pharmaceutically acceptable It relates to solvates:

In the above formula, D is O or NR ¹¹ ; Each X is CH or N;

로 구성된 군으로부터 선택되며;R ¹ is

Is selected from the group consisting of;

M is a bond, optionally substituted C ₁ -C ₈ alkylene, optionally substituted 4-atom heteroalkylene, optionally substituted C ₂ -C ₈ alkenylene, optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted C ₂ -C ₈ alkynylene;

J is CH or N; K is CH or N; Provided that when K is CH, J cannot be CH;

Each R ³ is C ₁ -C ₆ alkyl- (aryl), C ₁ -C ₆ alkyl- (heteroaryl), C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamine, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ heteroalkyl, -C (O) -R ¹² , aryl, heteroaryl, heterocycloalkyl, phenyl, pyridyl, pyridazinyl , Piperazinyl, piperidinyl, morpholinyl, furanyl, thiophenyl, thiophenyl, dibenzofuranyl, dibenzothienyl, indolyl, fluorenyl, carbozolyl, pyrimidinyl, pyrazinyl , Triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxdiazolyl, thiadiazolyl, triazolyl, naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydro Isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnalol, imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxasa Joly, Benz Sazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl, pyrazolopyri Independently selected from the group consisting of optionally substituted groups selected from dill, oxalopyridyl, isoxazolopyridyl or thiazolopyridyl;

Each R 'is independently H, alkyl or substituted alkyl;

Each R ⁵ is independently H, C ₁ -C ₃ alkyl or halogen;

R ⁶ is C ₁ -C ₃ alkyl or C ₃ -C ₇ cycloalkyl;

R ² and R ¹¹ are H or optionally substituted alkyl;

R ¹² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ heteroalkyl, benzyloxy, furanyl, phenyl, benzyl or pyridyl; or

를 형성하며;R ¹ and R ² together

To form;

n is 1, 2, 3 or 4; m is 1, 2, 3 or 4;

Each optional substituent is C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, benzyl, halogen, nitro, cyano or benzyloxy-C (O) R ′, —C (O) — (alkyl or substituted Alkyl),-(alkyl or substituted alkyl) -C (O) R ', -C (O) N (R') ₂ , -C (O) N (R ')-(alkyl or substituted alkyl), -(Alkyl or substituted alkyl) -C (O) N (R ') ₂ , -OC (O) N (R') ₂ , -OC (O) N (R ')-(alkyl or substituted alkyl) ,-(Alkyl or substituted alkyl) -OC (O) N (R ') ₂ , -N (R') C (O) R ', -NR'C (O)-(alkyl or substituted alkyl), -(Alkyl or substituted alkyl) -NR'C (O) R ', -SR', -S- (alkyl or substituted alkyl), -S (O) _k R ', where k is 1 or 2 , -S (O) _k (alkyl or substituted alkyl), -C (S)-(alkyl or substituted alkyl), -CSN (R ') ₂ , -CSN (R')-(alkyl or substituted Alkyl), -N (R ') CO- (alkyl or substituted alkyl), -N (R') C (O) OR ',-(alkyl or substituted alkyl) -ON = C (R') ₂ , - (alkyl or substituted alkyl) -C (O) NR '- (alkyl or substituted alkyl), - (alkyl or substituted alkyl), -S (O) _k - (alkyl addition Substituted alkyl) -SR ', - -S-SR ( alkyl or substituted _{alkyl)', -S (O) k} N (R ') 2, -N (R') C (O) N (R ') ₂ , -N (R ') C (S) N (R') ₂ , -N (R ') S (O) _k N (R') ₂ , -C (R ') = NR'-C (R ') = NN (R') ₂ and -C (R ') ₂ -N (R')-N (R ') ₂ are independently selected.

In another embodiment, a compound of Formula IIIa, a pharmaceutically acceptable salt, a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug or a pharmaceutically acceptable It relates to solvates:

로 구성된 군으로부터 선택되며;In the above formula, R ¹ is

Is selected from the group consisting of;

M is a bond, optionally substituted C ₁ -C ₈ alkylene, optionally substituted 4-atom heteroalkylene, optionally substituted C ₂ -C ₈ alkenylene, optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted C ₂ -C ₈ alkynylene;

J is CH or N; K is CH or N; Provided that when K is CH, J cannot be CH;

Each R ³ is C ₁ -C ₆ alkyl- (aryl), C ₁ -C ₆ alkyl- (heteroaryl), C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamine, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ heteroalkyl, -C (O) -R ¹² , aryl, heteroaryl, heterocycloalkyl, phenyl, pyridyl, pyridazinyl , Piperazinyl, piperidinyl, morpholinyl, furanyl, thiophenyl, thiophenyl, dibenzofuranyl, dibenzothienyl, indolyl, fluorenyl, carbozolyl, pyrimidinyl, pyrazinyl , Triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxdiazolyl, thiadiazolyl, triazolyl, naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydro Isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnalol, imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxasa Joly, Benz Sazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl, pyrazolopyri Independently selected from the group consisting of optionally substituted groups selected from dill, oxalopyridyl, isoxazolopyridyl or thiazolopyridyl;

Each R 'is independently H, alkyl or substituted alkyl;

Each R ⁵ is independently H, C ₁ -C ₃ alkyl or halogen;

R ⁵ is C ₁ -C ₃ alkyl or C ₃ -C ₇ cycloalkyl;

R ² and R ¹¹ is H or optionally substituted alkyl;

R ¹² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ heteroalkyl, benzyloxy, furanyl, phenyl, benzyl or pyridyl; or

를 형성하며;R ¹ and R ² together

To form;

n is 1, 2, 3 or 4; m is 1, 2, 3 or 4;

Each optional substituent is C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, benzyl, halogen, nitro, cyano or benzyloxy-C (O) R ′, —C (O) — (alkyl or substituted Alkyl),-(alkyl or substituted alkyl) -C (O) R ', -C (O) N (R') ₂ , -C (O) N (R ')-(alkyl or substituted alkyl), -(Alkyl or substituted alkyl) -C (O) N (R ') ₂ , -OC (O) N (R') ₂ , -OC (O) N (R ')-(alkyl or substituted alkyl) ,-(Alkyl or substituted alkyl) -OC (O) N (R ') ₂ , -N (R') C (O) R ', -NR'C (O)-(alkyl or substituted alkyl), -(Alkyl or substituted alkyl) -NR'C (O) R ', -SR', -S- (alkyl or substituted alkyl), -S (O) _k R ', where k is 1 or 2 , -S (O) _k (alkyl or substituted alkyl), -C (S)-(alkyl or substituted alkyl), -CSN (R ') ₂ , -CSN (R')-(alkyl or substituted alkyl ), -N (R ') CO- (alkyl or substituted alkyl), -N (R') C (O) OR ',-(alkyl or substituted alkyl) -ON = C (R') ₂ ,- (alkyl or substituted alkyl) -C (O) NR '- (alkyl or substituted alkyl), - (alkyl or substituted alkyl), -S (O) _k - (alkyl addition Substituted alkyl) -SR ', - -S-SR ( alkyl or substituted _{alkyl)', -S (O) k} N (R ') 2, -N (R') C (O) N (R ') ₂ , -N (R ') C (S) N (R') ₂ , -N (R ') S (O) _k N (R') ₂ , -C (R ') = NR'-C (R ') = NN (R') ₂ and -C (R ') ₂ -N (R')-N (R ') ₂ are independently selected.

Compounds provided herein include any of the foregoing carbamates and ureas, wherein at least one of the groups covalently bonded to the "N" portion of the carbamate, or one of the two "N" portions of the urea (CH) ₂ ) _z (C ₃ -C ₈ cycloalkyl), (CH ₂ ) _z (C ₃ -C ₈ heterocycloalkyl) or (CH ₂ ) _z (C ₇ -C ₁₂ polycycloalkyl) groups, where z is 0 or 1, at least one of the carbon atoms in the cycloalkyl ring, or optionally one of the carbon atoms in the polycycloalkyl ring, is monosubstituted or disubstituted, each substituent being methyl, halogen, trifluoromethyl or C Independently selected from the group consisting of ₃ -C ₆ cycloalkyl; Or one carbon atom in the cycloalkyl ring is substituted with an oxo group; Or one carbon atom of the cycloalkyl ring is disubstituted to form a 3-, 4- or 5-membered carbocyclic group; Or two neighboring atoms in the cycloalkyl ring are each substituted with a group to form a 3-, 4-, 5- or 6-membered carbocyclic group; At least one of the groups covalently bonded to the "N" portion of the carbamate, or one of the two "N" portions of the urea, is optionally substituted (CH ₂ ) _z (crosslinked carbocyclic group), and z is 0 or 1, wherein any substituent is a methyl, halogen or trifluoromethyl group.

, 네오펜틸, 네오헥실, 메틸렌시클로프로필, 메틸렌시클로부틸 및 메틸렌시클로펜틸로 구성된 군으로부터 선택되며, 각각의 P는 독립적으로 할로겐, 메틸, 트리플루오로메틸이거나 또는 각각의 P는 함께 3-, 4- 또는 5-원 탄소환 기를 형성할 수 있으며, 각각의 Q는 독립적으로 H, 할로겐, 메틸, 트리플루오로메틸이거나 또는 각각의 Q는 함께 3-, 4- 또는 5-원 탄소환 기를 형성할 수 있으며, T는 O, N-(C₁-C₆ 알킬) 또는 SO₂이다.Compounds provided herein include any of the foregoing carbamates and ureas, wherein at least one of the groups covalently bonded to the "N" portion of the carbamate or one of the two "N" portions of the urea

, Neopentyl, neohexyl, methylenecyclopropyl, methylenecyclobutyl and methylenecyclopentyl, wherein each P is independently halogen, methyl, trifluoromethyl or each P together is 3-, 4 Or can form a 5-membered carbocyclic group, wherein each Q is independently H, halogen, methyl, trifluoromethyl or each Q together can form a 3-, 4- or 5-membered carbocyclic group And T is O, N- (C ₁ -C ₆ alkyl) or SO ₂ .

Compounds provided herein include compounds having the structure of Formula (I), pharmaceutically acceptable salts thereof, N-oxides, solvates, esters, acids, and prodrugs. In certain embodiments, isomeric and chemically protected forms of the compounds having the structure of Formula (I) are also provided.

, 네오펜틸, 네오헥실, 메틸렌시클로프로필, 메틸렌시클로부틸 및 메틸렌시클로펜틸로 구성된 군으로부터 선택되며, 각각의 P는 독립적으로 할로겐, 메틸, 트리플루오로메틸이거나 또는 각각의 P는 함께 3-, 4- 또는 5-원 탄소환을 형성할 수 있으며; 각각의 Q는 독립적으로 H, 할로겐, 메틸, 트리플루오로메틸이거나 또는 각각의 Q는 함께 3-, 4- 또는 5-원 탄소환 기를 형성할 수 있으며; T는 O, N-(C₁-C₆ 알킬) 또는 SO₂이다.In another embodiment, to a compound of Formula (I), wherein R ¹ is

, Neopentyl, neohexyl, methylenecyclopropyl, methylenecyclobutyl and methylenecyclopentyl, wherein each P is independently halogen, methyl, trifluoromethyl or each P together is 3-, 4 Or can form a 5-membered carbocycle; Each Q is independently H, halogen, methyl, trifluoromethyl or each Q together may form a 3-, 4- or 5-membered carbocyclic group; T is O, N- (C ₁ -C ₆ alkyl) or SO ₂ .

In another embodiment, R ₁ is a (CH ₂ ) _z (C ₃ -C ₈ cycloalkyl) group wherein z is 0 or 1 and at least one of the carbon atoms in the cycloalkyl ring is monosubstituted or disubstituted Each substituent is independently selected from the group consisting of methyl, halogen, trifluoromethyl or C ₃ -C ₆ cycloalkyl; Or one carbon atom in the cycloalkyl ring is substituted with an oxo group; Or one carbon atom in the cycloalkyl ring is double substituted to form a 3-, 4- or 5-membered carbocyclic group; Or two neighboring atoms in the cycloalkyl ring are each substituted with a group to form a 3-, 4-, 5- or 6-membered carbocyclic group. In another embodiment, R ₁ is optionally substituted (CH ₂ ) _z (crosslinked carbocyclic group), z is 0 or 1, wherein any substituent is a methyl, halogen or trifluoromethyl group.

의 구조를 가지며; M은 결합, 임의로 C₁-C₄ 알킬렌, 임의로 치환된 4-원자 헤테로알킬렌, 임의로 치환된 C₂-C₄ 알케닐렌 또는 임의로 치환된 C₂-C₄ 알키닐렌이고; J는 CH 또는 N이 고; K는 CH 또는 N이며; 단, K가 CH인 경우, J는 CH가 될 수 없으며; R³은 C₁-C₃ 알킬, C₁-C₃ 알콕시, 벤질, 할로겐, 니트로, 시아노 또는 벤질옥시-C(O)R', -C(O)-(알킬 또는 치환된 알킬), -(알킬 또는 치환된 알킬)-C(O)R', -C(O)N(R')₂, -C(O)N(R')-(알킬 또는 치환된 알킬), -(알킬 또는 치환된 알킬)-C(O)N(R')₂, -OC(O)N(R')₂, -OC(O)N(R')-(알킬 또는 치환된 알킬), -(알킬 또는 치환된 알킬)-OC(O)N(R')₂, -N(R')C(O)R', -NR'C(O)-(알킬 또는 치환된 알킬), -(알킬 또는 치환된 알킬)-NR'C(O)R', -SR', -S-(알킬 또는 치환된 알킬), -S(O)_kR'(여기서 k는 1 또는 2임), -S(O)_k(알킬 또는 치환된 알킬), -C(S)-(알킬 또는 치환된 알킬), -CSN(R')₂, -CSN(R')-(알킬 또는 치환된 알킬), -N(R')CO-(알킬 또는 치환된 알킬), -N(R')C(O)OR', -(알킬 또는 치환된 알킬)-O-N=C(R')₂, -(알킬 또는 치환된 알킬)-C(O)NR'-(알킬 또는 치환된 알킬), -(알킬 또는 치환된 알킬)-S(O)_k-(알킬 또는 치환된 알킬)-SR', -(알킬 또는 치환된 알킬)-S-SR', -S(O)_kN(R')₂, -N(R')C(O)N(R')₂, -N(R')C(S)N(R')₂, -N(R')S(O)_kN(R')₂, -C(R')=NR'-C(R')=N-N(R')₂ 및 -C(R')₂-N(R')-N(R')₂로부터의 1 이상의 기로 임의로 치환되는, 임의로 치환된 C₁-C₆ 알킬, C₁-C₆ 헤테로알킬, -C(O)-R¹², 페닐, 피리딜, 피리다지닐, 피페라지 닐, 피페리디닐, 모르폴리닐, 푸라닐, 티오페닐, 티오페네일, 디벤조푸라닐, 디벤조티에닐, 인돌릴, 플루오레닐, 카르보졸릴, 피리미디닐, 피라지닐, 트리아지닐, 옥사졸릴, 이속사졸릴, 티아졸릴, 이소티아졸릴, 이미다졸릴, 옥사디아졸릴, 티아디아졸릴, 트리아졸릴, 나프틸, 퀴놀릴, 테트라히드로퀴놀릴, 이소퀴놀릴, 테트라히드로이소퀴놀릴, 프탈라지닐, 퀴나졸리닐, 퀴녹살리닐, 나프티리디닐, 신놀릴, 이미다조피리미디닐, 티에노피리미디닐, 벤조푸라닐, 벤조티에닐, 벤즈이미다졸릴, 벤족사졸릴, 벤즈이속사졸릴, 벤조티아졸릴, 벤즈이소티아졸릴, 인다졸릴, 피롤로피리딜, 푸로피리딜, 디히드로푸로피리딜, 티에노피리딜, 디히드로티에노피리딜, 이미다조피리딜, 피라졸로피리딜, 옥살로피리딜, 이속살로피리딜 또는 티아졸로피리딜 기로 구성된 군으로부터 선택되며; 각각의 R'는 독립적으로 H, 알킬 또는 치환된 알킬이고; 각각의 R⁵는 독립적으로 H, C₁-C₃ 알킬 또는 할로겐이고; R⁶은 C₁-C₃ 알킬 또는 C₃-C₇ 시클로알킬이고; R¹²는 C₁-C₆ 알킬, C₃-C₇ 시클로알킬, C₁-C₆ 헤테로알킬, 벤질옥시, 푸라닐, 페닐, 벤질 또는 피리딜로 구성된 군으로부터 선택되고; n은 1, 2, 3 또는 4이며; m은 1, 2, 3 또는 4이고; 또는 R¹ 및 R²는 함께

를 형성하며, n은 1, 2, 3 또는 4이며; m은 1, 2, 3 또는 4이다.In certain embodiments, the FAAH inhibitor is a compound of Formula 1, Formula 2, Formula 3, Formula 4, Formula 5, Formula 5, disclosed in US Provisional Application No. 60 / 755,035, filed Dec. 29, 2005, which is incorporated herein by reference. 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, Compounds having the structure of Formula 23, Formula 24, Formula 25, Formula 26, Formula 27, Formula 28 or Formula 29, pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites , Pharmaceutically acceptable prodrugs or pharmaceutically acceptable solvates; Where R ¹

Has a structure of; M is a bond, optionally C ₁ -C ₄ alkylene, optionally substituted 4-atom heteroalkylene, optionally substituted C ₂ -C ₄ alkenylene or optionally substituted C ₂ -C ₄ alkynylene; J is CH or N; K is CH or N; Provided that when K is CH, J cannot be CH; R ³ is C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, benzyl, halogen, nitro, cyano or benzyloxy-C (O) R ′, —C (O)-(alkyl or substituted alkyl), -(Alkyl or substituted alkyl) -C (O) R ', -C (O) N (R') ₂ , -C (O) N (R ')-(alkyl or substituted alkyl),-(alkyl Or substituted alkyl) -C (O) N (R ') ₂ , -OC (O) N (R') ₂ , -OC (O) N (R ')-(alkyl or substituted alkyl),-( Alkyl or substituted alkyl) -OC (O) N (R ') ₂ , -N (R') C (O) R ', -NR'C (O)-(alkyl or substituted alkyl),-(alkyl Or substituted alkyl) -NR'C (O) R ', -SR', -S- (alkyl or substituted alkyl), -S (O) _k R ', where k is 1 or 2, -S (O) _k (alkyl or substituted alkyl), -C (S)-(alkyl or substituted alkyl), -CSN (R ') ₂ , -CSN (R')-(alkyl or substituted alkyl),- N (R ') CO- (alkyl or substituted alkyl), -N (R') C (O) OR ',-(alkyl or substituted alkyl) -ON = C (R') ₂ ,-(alkyl or Substituted alkyl) -C (O) NR '-(alkyl or substituted alkyl),-(alkyl or substituted alkyl) -S (O) _k- (alkyl or substituted alkyl) -SR', -(Alkyl or substituted alkyl) -S-SR ', -S (O) _k N (R') ₂ , -N (R ') C (O) N (R') ₂ , -N (R ') C (S) N (R ') ₂ , -N (R') S (O) _k N (R ') ₂ , -C (R') = NR'-C (R ') = NN (R') Optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, optionally substituted with one or more groups from ₂ and —C (R ′) ₂ —N (R ′) — N (R ′) ₂ C (O) -R ¹² , phenyl, pyridyl, pyridazinyl, piperazinyl, piperidinyl, morpholinyl, furanyl, thiophenyl, thiophenyl, dibenzofuranyl, dibenzothienyl, indole Reel, fluorenyl, carbozolyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thidiazolyl, triazolyl, naph Teal, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnoyl, imidazopyrimidinyl, thienopyrimidinyl , Benzofuranyl, benzothienyl, benzimida Reel, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imi Is selected from the group consisting of dazopyridyl, pyrazolopyridyl, oxalopyridyl, isoxalopyridyl, or thiazolopyridyl group; Each R 'is independently H, alkyl or substituted alkyl; Each R ⁵ is independently H, C ₁ -C ₃ alkyl or halogen; R ⁶ is C ₁ -C ₃ alkyl or C ₃ -C ₇ cycloalkyl; R ¹² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ heteroalkyl, benzyloxy, furanyl, phenyl, benzyl or pyridyl; n is 1, 2, 3 or 4; m is 1, 2, 3 or 4; Or R ¹ and R ² together

And n is 1, 2, 3 or 4; m is 1, 2, 3 or 4.

Consider any combination of the groups described above for the various variables. It is to be understood that substituents and substitution patterns for the compounds provided herein can be selected to provide the compounds described herein, as well as compounds that are chemically stable by those skilled in the art and can be synthesized by techniques known in the art. .

In another embodiment, a compound of any of Formula I, Formula II, Formula III, or Formula IIIa, including any named compound or any compound set forth in the figures, a pharmaceutically acceptable salt, pharmaceutically acceptable It relates to a pharmaceutical composition comprising a possible N-oxide, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug or a pharmaceutically acceptable solvate and a pharmaceutically acceptable diluent, excipient or binder.

In certain embodiments, a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (III) or Formula (IIIa), a pharmaceutically acceptable salt of any compound, including any named compound or any compound set forth in the figures, Fatty acid amide hydrolase activity in a patient, comprising administering to the patient a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug, or a pharmaceutically acceptable solvate The present invention relates to a method for inhibiting or treating a disease, a disease or a condition of a fatty acid amide hydrolase which obtains an effect from the inhibition of a protein.

In another embodiment, a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (III) or Formula (IIIa), a pharmaceutically acceptable salt of any compound, including any named compound or any compound set forth in the figures, Inhibition of fatty acid amide hydrolase or a disease, disease by administering to the patient a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug or a pharmaceutically acceptable solvate. Or a method for treating a condition, wherein the disease, disease or condition is acute or chronic pain, eating disorders, cardiovascular disease, metabolic disease, disease or condition, renal ischemia, cancer, immune system disease, allergic disease, metabolic disease, disease Or conditions, renal ischemia, cancer, immune system diseases, allergic diseases, parasites, viral or bacterial infections, inflammatory diseases, osteoporosis, ocular conditions, State, and is selected from gastrointestinal disorders, and incontinence.

Certain embodiments provide formula (I), (II), (III) or (IIIa) for the inhibition of fatty acid amide hydrolase activity that results from the inhibition of fatty acid amide hydrolase activity or for the treatment of a disease, disease or condition. To the use of any compound), including the named compound or any compound set forth in the figures. In other embodiments, any compound of Formula (I), Formula (II), Formula (III) or Formula (IIIa), including any named compound or any compound shown in the figures, for combination of a medicament for the inhibition of fatty acid amide hydrolase It relates to the use of. In another embodiment, the packaging material, Formula I, Formula II, Formula III or Formula IIIa (any named compound or any compound set forth in the figures) effective to inhibit the activity of fatty acid amide hydrolase in the packaging material. And compounds or compositions or pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs or pharmaceutically acceptable compounds thereof. It relates to an article of manufacture comprising a label indicating that a possible solvate is used to inhibit the activity of fatty acid amide hydrolase.

In a further embodiment, the present invention relates to a therapeutic release agent having the structure:

In the above formula, R ¹ and R ² are defined in formula (I) or formula (II), Y ¹ is O or S, and HO-TA is a hydroxyl derivative of the therapeutic and therapeutic agent. Compounds of formula (XX) may release HO-TA upon interaction with acid amide hydrolase (such as FAAH). Thus, by way of example only, when a compound of Formula XX is administered to a patient, it interacts with FAAH to release HO-TA. Thus, HO-TA can provide additional therapeutic efficacy to the patient.

이 될 수 있 다.By way of example only, HO-TA is a blood pressure lowering agent

This can be.

가 될 수 있다.As another example, HO-TA is a serotonin, an adjuvant used to treat depression.

Can be

이 될 수 있다.As another example, HO-TA is a decongestant phenylephrine

This can be

및 식이 보충제가 될 수 있다.As another example, HO-TA is an amino acid tyrosine

And dietary supplements.

As a further example, HO-TA can be selected from the group consisting of hydroxy-containing NSAIDs selected from salicylic acid, salicylicamide, salsarate, diflunisal, gentisic acid, pyroxycam and meloxycam; Acetylsalicylic acid, salicylic acid, salicylate, salsarate, diflunisal, gentisic acid, indomethacin, sullindac, tolmethine, diclofenac, etodolak, nabumethone, ibuprofen, phenopropene, ketoprofen, flu Rubiprofen, suprofen, carpropene, naproxen, ketorolac, oxaprozin, mefenamic acid, meclofenamate sodium, pyroxhamm, meloxycamp, DuP 697, celecoxib, rofecoxib, Waldecoxib, nimesulide, ns-398, parecoxib and etoricoxib; Or metabolites of NSAIDs selected from acetaminophen.

As another example, HO-TA is a dietary supplement such as tyrosol, oleocantal, p-coumaric acid, resveratrol or 7-hydroxycoumarin.

As another example, HO-TA may be used to treat a digestive disorder (or a hydroxy homolog of the formulation), such as cisapride and metoclopramide; Anti-obesity agents (or hydroxy homologues of anti-obesity agents) such as marginol; Compounds (or hydroxy homologs of the compounds) for controlling blood pressure, such as beta-blockers; Or an agent for treating type II diabetes (or a hydroxy homolog of the agent), such as a compound in the glitazone system.

For example, certain HO-TAs (hereinafter “released therapeutic agents”) may have a known anti-inflammatory or analgesic effect. Certain released therapeutic agents may have therapeutic efficacy against metabolic diseases. Administration of the compound of formula (XX) may have additive or synergistic efficacy. In addition, the activity of the released therapeutic agent may antagonize or alter the potentially unwanted efficacy of the FAAH inhibitor. In one example, the cholesterol lowering efficacy of a statin (or statin-like) released therapeutic agent may lower or prevent the transient cholesterol synergism of the FAAH inhibitor under certain conditions or in certain individuals. A further advantage of the compounds of Formula (XX) is the further release of the released agent into the cytoplasm or target tissue, including the release of the pharmaceutical, diagnostic and bioactive components of the food or supplement (including nutraceuticals, dietary supplements, nutritional supplements, etc.). Includes excellent delivery.

In further embodiments, a therapeutically effective amount of one or more of the compounds or pharmaceutically acceptable salts of this specification, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable precursors It relates to a pharmaceutical composition comprising a drug or pharmaceutically acceptable solvate. In certain embodiments, the compositions provided herein further comprise pharmaceutically acceptable diluents, excipients and / or binders.

At least one compound provided herein or a pharmaceutical agent thereof at an effective concentration that is controlled or affected by FAAH activity or that delivers an amount effective for the treatment, prevention, or amelioration of one or more signs of a disease, condition or condition in which FAAH activity is involved There is provided a pharmaceutical composition formulated for administration by appropriate route and means comprising an effective derivative. Effective amounts and concentrations are effective to ameliorate any of the symptoms of any of the diseases, conditions or conditions disclosed herein.

In certain embodiments, i) a physiologically acceptable carrier, diluent and / or excipient; And ii) one or more compounds provided herein.

In one embodiment, a method is provided for treating a patient by administering a compound provided herein. In certain embodiments, any compound herein or pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug or pharmaceutically acceptable Inhibition of the activity of a fatty acid amide hydrolase, or the treatment of a disease, disease or condition, which results from the inhibition of fatty acid amide hydrolase activity in a patient comprising administering to the patient a therapeutically effective amount of one or more possible solvates. It is about a method.

In certain embodiments, acute or chronic pain, eating disorders, cardiovascular disease, metabolic disease, disease or condition, renal ischemia, cancer, immune system disease, allergic disease, parasite, virus or bacterial infection disease, inflammatory disease, osteoporosis, ocular condition Provided are compounds and compositions effective for the treatment, prevention or amelioration of one or more of the signs, diseases or conditions selected from pulmonary conditions, gastrointestinal diseases and incontinence.

In other embodiments, the compounds provided herein include pain, invasive pain, neuropathic pain, inflammatory pain, non-inflammatory pain, painful hemorrhagic cystitis, pain associated with herpes virus, pain associated with diabetes, peripheral neuropathic pain , Central pain, afferent heart blockage, chronic invasive pain, stimulation of invasive receptors, annular and transient acute pain, Parkinson's disease, muscle spasm, epilepsy, obesity, hyperlipidemia, insulin resistance syndrome, fatty liver disease, obesity , Atherosclerosis, arteriosclerosis, metabolic disease, feeding and fasting, altered appetite, hypertension, septic shock, psychogenic shock, intestinal inflammation and exercise, irritable bowel syndrome, colitis, diarrhea, ileitis, ischemia, cerebral ischemia, liver ischemia, Myocardial infarction, arthritis, rheumatoid arthritis, spondylitis, shoulder tendonitis or bursitis, gouty arthritis, rheumatoid polymyalgia, thyroiditis, hepatitis, inflammatory bowel disease, asthma, It is effective in the treatment, prevention or amelioration of one or more of the symptoms, diseases or conditions selected from multiple sclerosis, chronic obstructive pulmonary disease (COPD), allergic rhinitis and cardiovascular disease.

Certain compounds provided herein are irreversible inhibitors of fatty acid amide hydrolase (FAAH); Other compounds described herein are reversible inhibitors of FAAH. Compounds provided herein increase the levels of certain endogenous fatty acid amides. Compounds provided herein increase the levels of endogenous fatty acid amides selected from AEA, OEA and PEA.

Fatty acid amide hydrolase (FAAH) is present in the body. In certain instances, it is desirable to limit FAAH inhibitors to peripheral tissues to minimize or exclude any psychotropic efficacy. In certain embodiments, the compounds provided herein selectively inhibit FAAH activity in peripheral tissues and fluids and minimize potentially undesirable central nervous system side effects.

In certain embodiments, the compounds provided herein are administered to a human.

In certain embodiments, the compounds provided herein are administered orally.

In certain embodiments, the compounds provided herein are used to inhibit fatty acid amide hydrolase (FAAH) activity. In certain embodiments, the compounds provided herein are used for the treatment of a disease or condition that results from inhibiting the activity of fatty acid amide hydrolase or inhibiting fatty acid amide hydrolase activity.

In other embodiments, the compounds provided herein are used in the formulation of a medicament for the inhibition of fatty acid amide hydrolase (FAAH).

In certain embodiments, the compounds and compositions provided herein include acute or chronic pain, dizziness, vomiting, nausea, eating disorders, nervous and psychopathology, acute or chronic neurodegenerative diseases, epilepsy, sleep disorders, cardiovascular disease, renal ischemia For the treatment, prevention or amelioration of one or more of the signs, diseases or conditions selected from cancer, immune system diseases, allergic diseases, parasites, viral or bacterial infectious diseases, inflammatory diseases, osteoporosis, ocular conditions, lung conditions, gastrointestinal diseases and incontinence effective.

In certain embodiments, the compounds and compositions provided herein include pain, invasive pain, neuropathic pain, inflammatory pain, non-inflammatory pain, painful hemorrhagic cystitis, pain associated with herpes virus, pain associated with diabetes, peripheral nerves Painful pain, central pain, afferent heart blockage, chronic invasive pain, irritation of invasive receptors, annular and transient acute pain, depression, anxiety, generalized anxiety disorder (GAD), obsessive compulsive disorder, stress, stress incontinence, attention deficit Hyperactivity disorder, schizophrenia, psychosis, Parkinson's disease, muscle spasm, epilepsy, obesity, hyperlipidemia, insulin resistance syndrome, fatty liver disease, obesity, atherosclerosis, arteriosclerosis, metabolic diseases, feeding and fasting, altered appetite, Memory, aging, hypertension, septic shock, psychogenic shock, intestinal inflammation and exercise, irritable bowel syndrome, colitis, diarrhea, ileitis, ischemia, cerebral ischemia, liver ischemia, myocardial Syndrome, cerebral excitatory toxicity, stroke, febrile seizures, neurotoxicity, neuropathy, sleep, induction of sleep, prolonged sleep, insomnia, arthritis, rheumatoid arthritis, spondylitis, shoulder tendonitis or bursitis, gouty arthritis, rheumatoid polymyalgia, thyroiditis It is effective in the treatment, prevention or amelioration of one or more of the signs, diseases or conditions selected from hepatitis, inflammatory bowel disease, asthma, multiple sclerosis, chronic obstructive pulmonary disease (COPD), allergic rhinitis and cardiovascular disease.

In certain other embodiments, the compounds and compositions provided herein are effective for the treatment, prevention or amelioration of one or more signs of pain and / or inflammation.

In one embodiment, a method of inhibiting fatty acid amide hydrolase activity in a mammal comprising administering to a mammal a therapeutically effective amount of a compound or composition provided herein. In certain embodiments, the mammal is a human. In other embodiments, the compound or composition is administered orally.

In another embodiment, the compounds provided herein are used in the formulation of a medicament for the inhibition of fatty acid amide hydrolase (FAAH).

Packaging materials, compounds or compositions provided herein or pharmaceutically acceptable derivatives thereof, and compounds or compositions or pharmaceutically acceptable salts thereof effective for inhibiting the activity of fatty acid amide hydrolase (FAAH) in the packaging material Pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs or pharmaceutically acceptable solvates are used to inhibit the activity of fatty acid amide hydrolase (FAAH). It provides an article of manufacture comprising a label indicating that.

Any combination of the groups described above for the various variables is contemplated herein.

Other objects, features and advantages of the methods and compositions described herein will be apparent from the following detailed description. It is to be understood, however, that the detailed description and specific examples are presented by way of example only, and that various changes and modifications within the spirit and scope of the invention will be apparent to those skilled in the art from this detailed description. All references cited herein, including patents, patent applications, and literature, are incorporated herein by reference.

Quotation

All documents and patent applications mentioned herein are incorporated herein by reference to the same extent as if each individual document or patent application was specifically and individually indicated by reference herein.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION With reference to the following detailed description which sets forth exemplary embodiments using the principles of the methods, compositions, devices and devices of the present invention and the accompanying drawings, a better understanding of the features and advantages of the methods, compositions, and inventions of the present invention can be obtained will be.

1-8 show non-limiting examples of the types of compounds of formula I described herein. Such compounds may be used or included in any of the methods, compositions, techniques and strategies for the preparation, purification, characterization and use of the compounds of formula (I) described herein.

The novel features are described in detail in the appended claims. DETAILED DESCRIPTION Reference may be made to the features and advantages of the present disclosure with reference to the following detailed description, which sets forth illustrative embodiments utilizing the principles described herein.

Disclosed herein are compounds that inhibit the activity of active fatty acid amide hydrolase (FAAH), compositions comprising such compounds, and methods of use thereof. The compounds disclosed herein are inhibitors of fatty acid amide hydrolase (FAAH) and are useful in the treatment of diseases, diseases or conditions that benefit from inhibition of fatty acid amide hydrolase and increase in endogenous fatty acid amide.

Endocannabinoid system

Endocannabinoid signaling systems consist of three components (Lambert et al., J. Med. Chem . 2005, vol. 48, no. 16, 5059-5087). The first is represented by G protein-coupled receptors that bind endogenous and exogenous cannabinoid ligands. Two such receptors are found almost everywhere in the body, but the most abundant CB ₁ receptor in the central nervous system (CNS) (Freund et al., Physiol. Rev. 2003; 83: 1017-1066); CB ₂ receptors (Munro et al., Nature , 1993; 365: 61-65; Van Sickle et al., Science 2005; 310: 329-332, which are expressed mainly in immune cells and hematopoietic cells, but are present at low levels in the brain) Hanus et al., Proc. Nat. Acad. Sci, USA , 1999; 96: 14228-14233.

Component of the second is coupled to the cannabinoid receptors and activates them (Devane et al, Science 1992; 258:... 1946-1949; Mechoulam et al, Biochem Pharmacol 1995; 50:. 83-90; Sugria et al. , Biochem. Biophys. Res. Commun . 1995; 215: 89-97), produced as needed by neurons and other cells (Di Marzo et al., Nature 1994; 372: 686-691; Giuffrida et al. , Nat. Neurosci . 1999; 2: 358-363; Stella et al., Nature 2001; 388: 773-778), quickly removed (Beltramo et al., FEBS Lett . 1997; 403: 263-267; Stella et al., Nature 2001; 388: 773-778) and endocannabinoids, natural lipid molecules.

The third component appears as a protein involved in the formation and removal of various endocannabinoid ligands (Piomelli, D. Nat Rev. Neurosci . 2003; 4: 873-884).

Cannabinoid receptors may be activated by synthetic ligands as well as endocannabinoids.

Anandamide (arachidonoylethanolamide) is the first endocannabinoid material identified (Devane et al., Science 1992; 258: 1946-1949; Piomelli, D. Nat Rev. Neurosci. 2003; 4: 873-884) . Common evidence indicates that these lipid-induced mediators are released as needed by stimulated neurons (Di Marzo et al., Nature , 1994; 372: 686-691; Giuffrida et al., Nat. Neurosci . 1999, 2: 358-363); It activates a potent cannabinoid receptor (Devane et al., Science 1992; 258: 1946-1949) and is rapidly removed by a two-step process consisting of carrier-mediated internalization followed by intracellular hydrolysis (metabolic). (Beltramo et al., Science 1997; 277: 1094-1097; Di Marzo et al., Nature 1994; 372: 686-691; Hillard et al., J. Lipid Res. 1997; 38: 2383-2398).

Endocannabinoid anandamide and 2-arachidonylglycerol (2-AG), which bind to the CB ₁ receptor and produce most of its efficacy, have been shown to be tonically released and control basal invasive thresholds (Meng et al. Nature 1998; Sep 24; 395 (6700): 381-3). In particular, anandamide acts as a CB ₁ agonist and exhibits pharmacological activity in mice compared to other synthetic cannabinoids.

Fatty Acid Amide Hydrolase (FAAH)

Fatty acid amide hydrolase (FAAH) is an enzyme that hydrolyzes the fatty acid amide (FAA) system of endogenous signal lipids. Common types of fatty acid amides include N-acylethanolamine (NAE) and fatty acid primary amides (FAPA). Examples of NAE include anandamide (AEA), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). Examples of FAPA include 9-Z-octadecenamide or oleamide (McKinney MK, Cravatt BF. 2005. Annu Rev Biochem 74: 411-32). FAAH can act as a hydrolase for fatty acid ethanolamides and primary amides, as well as esters such as 2-arachidonylglycerol (2-AG) (Mechoulam et al., Biochem. Pharmacol . 1995; 50:83 -90; Stella et al., Nature , 1997; 388: 773-778; Suguria et al., Biochem. Biophys. Res. Commun. 1995; 215: 89-97).

FAAH is not only found in the CNS (Freund et al., Physiol. Rev. 2003; 83: 1017-1066), but also in peripheral tissues such as the pancreas, brain, kidney, skeletal muscle, placenta and liver (Giang, DK et al., .... Molecular Characterization of Human and Mouse Fatty Acid Amide Hydrolases Proc Natl Acad Sci USA 1997, 94, 2238-2242;.... Cravatt et al, PNAS, 2004, vol 101, no 29, 10821-10826) rich Is expressed.

Anandamide or arachidonylethanolamide are NAEs that act as endogenous ligands for cannabinoid type 1 (CB ₁ ) receptors (Devane WA, et al., 1992. Science 25 8: 1946-49). Anandamide is rapidly removed through a two-step process consisting of carrier-mediated transport followed by intracellular hydrolysis by FAAH. Hydrolysis of anandamide by FAAH forms arachidonic acid and ethanolamine. Commonly claimed catalytic mechanisms for the hydrolysis of anandamide by FAAH include the formation of arachidonic acid and ethanolamine due to the nucleophilic attack of the amino acid residue serine 241 of FAAH on the amide portion of anandamide (Deutsch et al., The fatty acid amide hydrolyse (FAAH) Prostaglandins, Leukotrienes and Essential Fatty Acids (2002) 66 (2 & 3), 201-210; Alexander et al., Chemistry & Biology , vol. 12, 1179-1187; 2005).

Mutant mice lacking the gene encoding FAAH show a significant decrease in hydrolytic activity on anandamide and other fatty acid amides, indicating a signal of improved anandamide activity at the cannabinoid receptor and thus observable physiological phenomena. Such as, for example, reduced pain sensations (Cravatt BF, et al., 2001. Proc Nat Acad Sci USA 98: 9371-9376). This suggests that therapeutic agents that alter the activity of FAAH enzymes can increase the action of anandamide and other fatty acid amides in the body. In addition, such formulations can rule out multiple, often undesirable effects produced by indiscriminate activation of cannabinoid receptors by the administration of Δ9-THC (the active ingredient of marijuana) and other direct acting cannabinoids.

Many endogenous fatty acid amides except anandamide do not bind the CB ₁ receptor. Some of these lipids have been found to produce specific cellular and behavioral efficacy and can represent large systems of endogenous signal lipids that operate in vivo in receptor systems different from CB ₁ . This is palmitoylethanolamide (PEA) (Calignano A, et al., 1998. Nature 394: 277-8 1; Jaggar SI, et al., 1998. Pain 76: 189-99; Franklin A, Parmentier-Batteur et al. , 2003.J Neurosci 23: 7767-75), stearoylethanolamide (SEA) (Terrazino et al., 2004 FASEB J : 18: 1580-82; Maccarrone M, et al., 2002. Biochem J 366: 137-44) and oleoylethanolamide (OEA) (deFonseca FR, et al., 2001. Nature 414: 209-12; Fu J, et al., 2003. Nature 425: 90-93; Fu J, et al , 2005. Neuropharmacology 48 (8): 1 147-53). Both OEA and PEA have been shown to activate peroxide diffuser-activated receptor α (PPAR-α) (Fu J, et al., 2003. Nature 425: 90-93; Guzman M, et al., 2004 J Biol Chem 279 (27): 27849-54; Lo Verme J, et al., 2005. Cell Mol Life Sci 62 (6): 708-16; LoVerme J, et al., 2005. Life Sci 77 (14 ): 1685-98; Lo Verme J, et al., 2005. Mol Pharmacol 67 (1): 15-9). These actions allow OEA and PEA to regulate several biological pathways, including but not limited to feeding, metabolism, pain and inflammation. Therefore, agents that alter FAAH enzyme activity are agents that modulate the levels of various fatty acid amides in vivo and thus have therapeutic action through various targets.

While not wishing to be bound by any theory, certain fatty acid amides, such as OEA, act through the peroxide diffuser-activated receptor α (PPAR-α) to regulate various physiological processes, including feeding and lipolysis, for example. I think that. In a similar way, human adipose tissue has been found to bind and metabolize endocannabinoids such as anandamide and 2-arachidonylglycerol. Spoto et al., August 22, 2006, Biochimie (E-publication ahead of print); And Matias et al., (2006), J. Clin. Endocrin. & Met , 91 (8): 3171-3180. Thus, inhibition of FAAH activity in vivo results in decreased body fat, body weight, calorie intake and hepatic triglyceride levels. However, unlike other antihyperlipidemic agents acting through PPAR-α, for example fibrate, FAAH inhibitors have deleterious side effects such as rash, fatigue, headache, erectile dysfunction and, more rarely, anemia, leukopenia, blood vessels Does not cause edema and hepatitis See, eg, Muscari et al., (2002), Cardiology , 97: 115-121. The additional therapeutic performance of FAAH inhibitors is due to their ability to increase anandamide levels, which effectively alleviate conditions associated with depression and anxiety, often energy metabolic disease (EMD), such as obesity. Simon et al., (2006), Archives of Gen. Psychiatry , 63 (7): 824-830]. In certain embodiments, the FAAH inhibitor compound may be peripherally limited and may not significantly affect neurological diseases such as depression and anxiety. Finally, the functionality of cannabinoid receptors also appears to reduce the progression of atherosclerosis in animal models. Steffens et al., (2005), Nature , 434: 782-786; And Steffens et al., (2006), Curr. Opin. Lipid ., 17: 519-526. Thus, increasing levels of endogenous cannabinoid functional fatty acid amides (eg, anandamides) are expected to effectively treat or reduce the risk of developing atherosclerosis.

Many fatty acid amides are produced as needed and are rapidly degraded by FAAH. As a result, hydrolysis by FAAH is believed to be one of the essential steps in the regulation of fatty acid amides in peripheral tissues and body fluids as well as the central nervous system. The wide distribution of FAAH in combination with the biological efficacy of a wide array of fatty acid amides (both endocannabinoid and non-endocannabinoid mechanisms) can lead to altered levels of fatty acid amides in tissues and body fluids with high inhibition of FAAH and many different conditions Suggests that it may be useful for treating. FAAH inhibitors increase the level of endogenous fatty acid amides. FAAH inhibitors block the degradation of endocannabinoids and increase the tissue levels of such endogenous substances. FAAH inhibitors can be used in such embodiments in the prevention and treatment of pathologies involving endogenous cannabinoids and / or any other substrate metabolized by the FAAH enzyme.

Inhibition of FAAH is expected to result in increased levels of anamide and other fatty acid amides. This increase in fatty acid amides can lead to an increase in nociceptive threshold. Thus, in one embodiment, inhibitors of FAAH are useful for the treatment of pain. Such inhibitors may be useful in the treatment of other diseases that can be treated using modulators of fatty acid amides or cannabinoid receptors such as anxiety, eating disorders, metabolic diseases, cardiovascular diseases and inflammation.

Various fatty acid ethanolamides are important and have various physiological functions. As a result, inhibitor molecules that selectively inhibit FAAH enzyme activity allow for the corresponding selective alteration of cellular and extracellular concentrations of FAAH substrates. FAAH inhibitors with biological affinity can be effective pharmaceutical compounds when formulated as therapeutic agents for any clinical indication where FAAH enzyme inhibition is desired. In certain embodiments, FAAH activity in peripheral tissues can be selectively inhibited. In certain embodiments, FAAH inhibitors that nearly cross the blood-brain-car organization can be used to selectively inhibit FAAH activity in peripheral tissues. In certain embodiments, FAAH inhibitors that selectively inhibit FAAH activity in peripheral tissues can minimize the efficacy of FAAH inhibition in the central nervous system. In certain embodiments, it is desirable to inhibit FAAH activity in peripheral tissues and to minimize FAAH inhibition in the central nervous system.

Examples of diseases, diseases, syndromes and / or conditions that benefit from inhibition of FAAH enzyme activity include Alzheimer's disease, schizophrenia, depression, alcoholism, drug addiction, suicide, Parkinson's disease, Huntington's disease, seizures, vomiting, abortion, Embryo implantation, endotoxin shock, cirrhosis, atherosclerosis, cancer, traumatic head injury, glaucoma and bone grafting syndrome.

Examples of other diseases, diseases, syndromes and / or conditions that benefit from inhibition of FAAH activity include multiple sclerosis, retinitis, amyotrophic lateral sclerosis, immunodeficiency virus-induced encephalitis, attention deficit hyperactivity disorder, pain, invasiveness Pain, neuropathic pain, inflammatory pain, non-inflammatory pain, painful hemorrhagic cystitis, obesity, hyperlipidemia, metabolic diseases, feeding and fasting, changes in appetite, stress, memory, aging, hypertension, septic shock, psychogenic shock, Intestinal inflammation and exercise, irritable bowel syndrome, colitis, diarrhea, ileitis, ischemia, cerebral ischemia, liver ischemia, myocardial infarction, cerebral excitability, seizures, recessive seizures, neurotoxicity, neuropathy, sleep, induction of sleep, sleep Prolonged, insomnia and inflammatory diseases.

Examples of neurological and psychological disorders that benefit from inhibition of FAAH activity include pain, depression, anxiety, generalized anxiety disorder (GAD), obsessive compulsive disorder, stress, stress incontinence, attention deficit hyperactivity disorder, schizophrenia, psychosis, Parkinson's disease, Muscle spasms, epilepsy, dyskinesia, seizure disorders, flight lag and insomnia.

In addition, FAAH inhibitors can be used to treat a variety of metabolic syndromes, diseases, diseases and / or conditions, including but not limited to insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis and arteriosclerosis. have.

FAAH inhibitors include, but are not limited to, non-inflammatory pain, inflammatory pain, peripheral neuropathic pain, central pain, afferent blockade pain, chronic invasive pain, stimulation of invasive receptors, phantom and transient acute pain Not useful) in the treatment of various pain syndromes, diseases, ailments and / or conditions.

In addition, inhibition of FAAH activity can be used to treat various conditions, including inflammation. Examples of these conditions include arthritis (such as rheumatoid arthritis, shoulder tendonitis or bursitis, gouty arthritis and rheumatoid polymyalgia), organ-specific inflammatory diseases (such as thyroiditis, hepatitis, inflammatory bowel disease), asthma and other autoimmune diseases (such as Multiple sclerosis), chronic obstructive pulmonary disease (COPD), allergic rhinitis and cardiovascular disease, and the like.

In certain cases, FAAH inhibitors are useful for preventing neurodegeneration or for neuroprotection.

In addition, when FAAH activity is reduced or absent, one of its substrates, anandamide, has been found to act as a substrate for COX-2, which converts anandamide to prostamide (Weber et al., J. Lipid. Res . 2004; 45: 757). The concentration of certain prostamides can be increased in the presence of FAAH inhibitors. Certain prostamides have been associated with decreased intraocular pressure and hypotony. Thus, in one embodiment, a FAAH inhibitor may be useful for treating glaucoma.

In certain embodiments, FAAH inhibitors are characterized by obesity, appetite disorders, overweight, cellulite, diabetes mellitus type I and II, hyperglycemia, hyperlipidemia, fatty liver, hepatic steatosis, non-alcoholic fatty liver, syndrome X, insulin resistance, Diabetic hyperlipidemia, anorexia, bulimia, anorexia nervosa, hyperlipidemia, hypertriglyceridemia, atherosclerosis, arteriosclerosis, inflammatory diseases or conditions, Alzheimer's disease, Crohn's disease, vascular inflammation, inflammatory bowel disease, rheumatoid arthritis, asthma, thrombosis Or to treat or reduce the risk of EMD, including but not limited to cachexia.

In other embodiments, FAAH inhibitors can be used to treat or reduce the risk of insulin resistance syndrome and diabetes, ie primary essential diabetes, such as diabetes type I or diabetes type II and secondary non-essential diabetes. Administering a composition comprising a therapeutically effective amount of an in vivo FAAH inhibitor can affect the severity of signs of diabetes or diabetes, such as atherosclerosis, hypertension, hyperlipidemia, fatty liver, nephropathy, neuropathy, retinopathy, foot ulcers or cataracts. Reduces the risk of developing symptoms

In another embodiment, FAAH inhibitors can be used to treat food abuse behavior, particularly those that are likely to cause excessive body weight, such as bulimia, appetite for sugar or fat and non-insulin-dependent diabetes.

In certain embodiments, the FAAH inhibitor can be used to treat an individual suffering from EMD and suffering from a depressive or anxiety disorder. Preferably the individual is diagnosed with depression or psychiatric disease prior to administration of the FAAH inhibitor composition. Thus, the subject is administered a therapeutically effective dose of a FAAH inhibitor for both EMD and a depression or anxiety disorder. Methods of treating anxiety and depressive disorders by FAAH inhibition are described, for example, in US Patent Applications 10 / 681,858 and 60 / 755,035.

The individual to be treated is preferably a human. However, such methods can also be used to treat non-human mammals. Animal models of EMD, such as those described in US Pat. No. 6,946,491, are particularly useful.

Signs, diagnostic tests, and prognostic tests for each of the aforementioned conditions are known in the art. See, eg, "Harrison's Principles of Internal Medicine ^© " 16th ed., 2004, The McGraw-Hill Companies, Inc. and "Diagnostic and Statistical Manual of Mental disorders ^© " 4th ed., 1994, American Psychiatric Association. "

In addition, FAAH inhibitor compositions may be used to reduce weight in an individual who wishes to lose weight for cosmetic purposes, although not necessarily for medical purposes.

FAAH inhibitor compositions can be administered in parallel with drugs that lower circulating cholesterol levels (eg, statins, niacin, fibric acid derivatives or bile acid binding resins). In addition, FAAH inhibitor compositions may be used in combination with weight loss drugs, such as orlistat or appetite suppressants such as diethylpropion, marginol, orlistat, pendimethazine, phentermin or sibutramine.

In addition, the methods described herein include providing an exercise regimen or providing a calorie-restricted diet (eg, a triglyceride-restricted diet) to an individual.

Esters of alkylcarbamic acid and alkylthiocarbamic acid show promise as selective FAAH inhibitors (Kathuria et al., Nat. Med . 2003, 9: 76-81). A series of alkylcarbamic acid aryl esters, such as cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester (also 5'-carbamoylbiphenyl-3-yl cyclohexyl carbamate, UCM597, URB597 and KDS-4103 (known as URB-597) was found to be an effective and selective inhibitor of FAAH activity. Alkylcarbamic acid aryl esters, such as cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl esters, have been found to be effective and selective inhibitors of FAAH activity that do not interact significantly with selected serine hydrolase or cannabinoid receptors. Mor et al., J. Med. Chem . 2004, 47: 4998-5008; Piomelli et al., International Patent Publication No. WO2004 / 033422; incorporated herein by reference).

Alkylcarbamic acid aryl esters inhibit FAAH activity through irreversible interaction with FAAH, possibly due to nucleophilic attack of active serine residues (serine 241) of FAAH in the carbamate portion of the alkylcarbamic acid aryl ester compound (Kathuria et al., Nature Medicine , vol. 9, no. 1, 76-81, 2003; Deutsch et al., Prostaglandins , Leukotriene and Essential Fatty Acids (2002) 66 (2 & 3), 201-210; Alexander et al , Chemistry & Biology , vol. 12, 1179-1187; 2005). Metabolism of the alkylcarbamic acid aryl ester inhibitor by FAAH enzyme results in hydrolysis of the carbamate compound and release of the aryloxy portion of the alkylcarbamic acid aryl ester inhibitor.

The present specification provides a compound which is an ester of alkyl carbamic acid, a composition comprising the same, and a method of using the same. The compounds provided herein, pharmaceutically acceptable salts thereof, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs or pharmaceutically acceptable solvates thereof are represented by the formula: Selected from II, IIa, IIb, IIc, IId, IIe and I:

Formula II

Formula I

In the above formula, D is O or NR ¹¹ ; Each X is CH or N;

One of A or B is (CH ₂ ) _n C (O) -alkyl, (CH ₂ ) _n C (O) -N (R ² ) ₂ , the other is H, alkyl or heteroalkyl, n is 0 , 1, 2, 3 or 4 and each R ² is H or optionally substituted alkyl; or

A and B together form an optionally substituted non-aromatic ring group comprising a C (O) — (CH ₂ ) _n − moiety, wherein n is 1, 2, 3 or 4; or

A and B together form an optionally substituted heteroaromatic group comprising at least one N, NR ² , S or O group; or

A and B together form an optionally substituted oxo-substituted heterocycle;

R ¹ is optionally selected from C ₃ -C ₉ cycloalkyl, C ₁ -C ₄ alkyl (C ₃ -C ₉ cycloalkyl), C ₁ -C ₄ alkyl (aryl) and C ₁ -C ₄ alkyl (heteroaryl) Substituted group, any carbon of the R ¹ cycloalkyl ring is optionally substituted with Y and Z,

Each Y and each Z are independently selected from halogen, methyl or trifluoromethyl or Y and Z together may form a 3-, 4- or 5-membered carbocyclic group or oxo (═O) ;

R ² and R ¹¹ are H or optionally substituted alkyl.

In a further embodiment, A and B together form -C (O)-(CR ^q R ^q ) _n- , -C (O) -NR ^2- (CR ^q R ^q ) _n- , -NR ² -C ( O)-(CR ^q R ^q ) _n- , -C (O) -NR ² -NR ^2- (CR ^q R ^q ) _n- , -C (O) -NR ² -N = (CR ^q )-, -0-C (O) -O-, 0-C (O) -NR ^2- , -NR ² -C (O) -NR ^2- , -OC (O) -O- (CR ^q R ^q ) _n -, -OC (O)-(CR ^q R ^q ) _n -O-, -NC (O)-(CR ^q R ^q ) _n -N-, -OC (O)-(CR ^q R ^q ) _n- N-, -NC (O)-(CR ^q R ^q ) _n -O-, -OC (O) -NR ^2- (CR ^q R ^q ) _n- , -NR ² -C (O) -O- ( CR ^q R ^q ) _n- , -NR ² -C (O) -NR ^2- (CR ^q R ^q ) _n -,-(CR ^q R ^q ) _n -C (O) -O- (CR ^q R ^q ) _n -,-(CR ^q R ^q ) _n -C (O) -NR ^2- (CR ^q R ^q ) _n -,-(CR ^q R ^q ) _n -C (O) -NR ² -NR ^2- ,-(CR ^q R ^q ) _n -C (O)-(CR ^q R ^q ) _n- , -C (O) -O- (CR ^q R ^q ) _n -O-, -C (O) -O -(CR ^q R ^q ) _n -NR ^2- , -C (O) -NR ^2- (CR ^q R ^q ) _n -NR ² , -C (O) -NR ^2- (CR ^q R ^q ) _n- O-, -C (O) -NR ² -CR ^q = CR ^q- , C (O) -CR ^q = CR ^q -NR ^2- , -C (O) -CR ^q = CR ^q -O-,- Forms an optionally substituted oxo-substituted heterocycle selected from C (O) -CR ^q = CR ^q -S-; Each n is independently 1, 2 or 3; Each R ^q is H, alkyl, substituted alkyl, aryl, substituted aryl, ketoalkyl, substituted ketoalkyl, ketoheteroalkyl, substituted ketoheteroalkyl, heteroalkyl, substituted heteroalkyl, heterocyclic or substituted Independently from the heterocycle.

In addition, the compounds provided herein include compounds having the structure of Formula III, pharmaceutically acceptable salts thereof, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable precursors Drug or pharmaceutically acceptable solvates are provided:

Formula III

In the above formula, D is O or NR ¹¹ ;

로 구성된 군으로부터 선택되며; 여기서 M은 결합, 임의로 치환된 C₁-C₈ 알킬렌, 임의로 치환된 4-원자 헤테로알킬렌, 임의로 치환된 C₂-C₈ 알케닐렌, 임의로 치환된 C₃-C₈ 시클로알킬 또는 임의로 치환된 C₂-C₈ 알키닐렌이며;R ¹ is

Is selected from the group consisting of; Wherein M is a bond, optionally substituted C ₁ -C ₈ alkylene, optionally substituted 4-atom heteroalkylene, optionally substituted C ₂ -C ₈ alkenylene, optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted C ₂ -C ₈ alkynylene;

J is CH or N; K is CH or N; Provided that when K is CH, J cannot be CH;

Each R ³ is C ₁ -C ₆ alkyl- (aryl), C ₁ -C ₆ alkyl- (heteroaryl), C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamine, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ heteroalkyl, -C (O) -R ¹² , aryl, heteroaryl, heterocycloalkyl, phenyl, pyridyl, pyridazinyl , Piperazinyl, piperidinyl, morpholinyl, furanyl, thiophenyl, thiophenyl, dibenzofuranyl, dibenzothienyl, indolyl, fluorenyl, carbozolyl, pyrimidinyl, pyrazinyl , Triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxdiazolyl, thiadiazolyl, triazolyl, naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydro Isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnalol, imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxasa Joly, Benz Soxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl, pyrazolopyri Independently selected from the group consisting of optionally substituted groups selected from dill, oxalopyridyl, isoxazolopyridyl or thiazolopyridyl;

Each R 'is independently H ₃ alkyl or substituted alkyl;

Each R ⁵ is independently H, C ₁ -C ₃ alkyl or halogen;

R ⁶ is C ₁ -C ₃ alkyl or C ₃ -C ₇ cycloalkyl;

R ² and R ¹¹ are H or optionally substituted alkyl;

R ¹² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ heteroalkyl, benzyloxy, furanyl, phenyl, benzyl or pyridyl; or

을 형성하며; n은 1, 2, 3 또는 4이며; m은 1, 2, 3 또는 4이고; R ¹ and R ² together

To form; n is 1, 2, 3 or 4; m is 1, 2, 3 or 4;

Each optional substituent is C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, benzyl, halogen, nitro, cyano or benzyloxy-C (O) R ′, —C (O) — (alkyl or substituted Alkyl),-(alkyl or substituted alkyl) -C (O) R ', -C (O) N (R') ₂ , -C (O) N (R ')-(alkyl or substituted alkyl), -(Alkyl or substituted alkyl) -C (O) N (R ') ₂ , -OC (O) N (R') ₂ , -OC (O) N (R ')-(alkyl or substituted alkyl) ,-(Alkyl or substituted alkyl) -OC (O) N (R ') ₂ , -N (R') C (O) R ', -NR'C (O)-(alkyl or substituted alkyl), -(Alkyl or substituted alkyl)--NR'C (O) R ', -SR', -S- (alkyl or substituted alkyl), -S (O) _k R ', where k is 1 or 2 ), -S (O) _k (alkyl or substituted alkyl), -C (S)-(alkyl or substituted alkyl), -CSN (R ') ₂ , -CSN (R')-(alkyl or substituted Alkyl), -N (R ') CO- (alkyl or substituted alkyl), -N (R') C (O) OR ',-(alkyl or substituted alkyl) -ON = C (R') ₂ , -(Alkyl or substituted alkyl) -C (O) NR '-(alkyl or substituted alkyl),-(alkyl or substituted alkyl) -S (O) _k- (alkyl or Is substituted alkyl) -SR ',-(alkyl or substituted alkyl) -S-SR', -S (O) _k N (R ') ₂ , -N (R') C (O) N (R ' ) ₂ , -N (R ') C (S) N (R') ₂ , -N (R ') S (O) _k N (R') ₂ , -C (R ') = NR'-C ( R ') = NN (R') ₂ and -C (R ') ₂ -N (R')-N (R ') ₂ are independently selected.

In certain embodiments, provided is a compound having a structure of Formula IIIa:

Formula IIIa

Further compounds described herein can be compounds of the formula II, pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs or pharmaceutically Provide acceptable solvates:

Formula II

In the above formula, D is O or NR ¹¹ ;

로 구성된 군으로부터 선택되며;R ¹ is

Is selected from the group consisting of;

M is a bond, optionally substituted C ₁ -C ₈ alkylene, optionally substituted 4-atom heteroalkylene, optionally substituted C ₂ -C ₈ alkenylene, optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted C ₂ -C ₈ alkynylene;

J is CH or N; K is CH or N; Provided that when K is CH, J cannot be CH;

Each R ³ is C ₁ -C ₆ alkyl- (aryl), C ₁ -C ₆ alkyl- (heteroaryl), C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamine, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ heteroalkyl, -C (O) -R ¹² , aryl, heteroaryl, heterocycloalkyl, phenyl, pyridyl, pyridazinyl , Piperazinyl, piperidinyl, morpholinyl, furanyl, thiophenyl, thiophenyl, dibenzofuranyl, dibenzothienyl, indolyl, fluorenyl, carbozolyl, pyrimidinyl, pyrazinyl , Triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxdiazolyl, thiadiazolyl, triazolyl, naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydro Isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnalol, imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxasa Joly, Benz Sazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl, pyrazolopyri Independently selected from the group consisting of optionally substituted groups selected from dill, oxalopyridyl, isoxazolopyridyl or thiazolopyridyl;

Each R 'is independently H, alkyl or substituted alkyl;

Each R ⁵ is independently H, C ₁ -C ₃ alkyl or halogen;

R ⁶ is C ₁ -C ₃ alkyl or C ₃ -C ₇ cycloalkyl;

R ² and R ¹¹ are H or optionally substituted alkyl;

R ¹² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ heteroalkyl, benzyloxy, furanyl, phenyl, benzyl or pyridyl; or

를 형성하며;R ¹ and R ² together

To form;

n is 1, 2, 3 or 4; m is 1, 2, 3 or 4;

A and B together form an optionally substituted non-aromatic ring group comprising a C (O) — (CH ₂ ) _q − moiety, q is 1, 2, 3 or 4; or

A and B together form an optionally substituted oxo-substituted heterocycle; or

A and B together form an optionally substituted aromatic or non-aromatic ring group comprising at least one N, NR ² , S or O group; or

One of A or B is -LG and the other is selected from H and optionally substituted C ₁ -C ₆ alkyl; or

A and B together form an optionally substituted aromatic carbocyclic group; or

A and B are each H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted ketoalkyl, optionally substituted amide and optionally Independently selected from substituted ketoheteroalkyl;

L is a bond or C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₁ -C ₆ ketoalkylene, -C (O) NR ^9- (CH ₂ ) _j- , -NR ^9- C (O)-(CH ₂ ) _j- , -OC (O) O- (CH ₂ ) _j- , -NHC (O) O- (CH ₂ ) _j- , -O (O) CNH- (CH ₂ ) _j- , -C (O) O- (CH ₂ ) _j- , -OC (O)-(CH ₂ ) _j- , -NR ⁹ C (O) N (R ⁹ )-(CH ₂ ) _j- , -S (O)-(CH ₂ ) _j- , -S (O) _2- (CH ₂ ) _j- , -C (= NR ¹⁰ ) N (R ⁹ )-(CH ₂ ) _j -and -NR ^An optionally substituted group selected from ⁹ C (═NR ¹⁰ ) N (R ⁹ ) — (CH ₂ ) _j- ;

G is tetrazolyl, -NHS (= O) ₂ R ⁸ , -S (= O) ₂ NHR ⁸ , -S (= O) ₂ NH-phenyl, -OH, -SH, -OC (O) NHR ⁸ , -NHC (O) OR ⁸ , -C (O) NHC (O) R ⁸ , -C (O) NHS (= O) ₂ R ⁸ , -S (= O) ₂ NHC (O) R ⁸ , -S (= O) ₂ NHC (O) NHR ⁸ , -NHC (O) R ⁸ , -NHC (O) N (R ⁹ ) ₂ , -C (= NR ¹⁰ ) N (R ⁹ ) ₂ , -NR ⁹ C (= NR ¹⁰ ) N (R ⁹ ) ₂ , -NR ⁹ C (= NR ¹⁰ ) NHC (= NR ¹⁰ ) N (R ⁹ ) ₂ , -NR ⁹ C (= CHR ¹⁰ ) N (R ⁹ ) ₂ , -C (O) NR ⁹ C (= NR ¹⁰ ) N (R ⁹ ) ₂ , -C (O) NR ⁹ C (= CHR ¹⁰ ) N (R ⁹ ) ₂ , -CO ₂ H,-(OP (= O) OH) _x OH, -OP (= O) OR ⁸ OH, -OP (= O) R ⁸ OH, -NR ⁹ P (= O) OR ⁸ OH, -NR ⁹ P (= O) R ⁸ OH , -P (= 0) OR ⁸ OH, -P (= 0) R ⁸ OH, -S (O) _y OH, -OS (O) _y OH, -NR ⁹ S (O) _y OH;

Each R ⁸ is independently substituted or unsubstituted C ₁ -C ₆ alkyl;

Each R ⁹ is independently H, substituted C ₁ -C ₆ alkyl or unsubstituted C ₁ -C ₆ alkyl;

Each R ¹⁰ is independently selected from H, —S (═O) ₂ R ⁸ , —S (═O) ₂ NH ₂ , —C (O) R ⁸ , —CN, and —NO ₂ ;

j is 0, 1, 2, 3 or 4; x is 1, 2 or 3; y is 0, 1 or 2;

Each optional substituent is C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, benzyl, halogen, nitro, cyano or benzyloxy-C (O) R ′, —C (O) — (alkyl or substituted Alkyl),-(alkyl or substituted alkyl) -C (O) R ', -C (O) N (R') ₂ , -C (O) N (R ')-(alkyl or substituted alkyl), -(Alkyl or substituted alkyl) -C (O) N (R ') ₂ , -OC (O) N (R') ₂ , -OC (O) N (R ')-(alkyl or substituted alkyl) ,-(Alkyl or substituted alkyl) -OC (O) N (R ') ₂ , -N (R') C (O) R ', -NR'C (O)-(alkyl or substituted alkyl), -(Alkyl or substituted alkyl)--NR'C (O) R ', -SR', -S- (alkyl or substituted alkyl), -S (O) _k R ', where k is 1 or 2 ), -S (O) _k (alkyl or substituted alkyl), -C (S)-(alkyl or substituted alkyl), -CSN (R ') ₂ , -CSN (R')-(alkyl or substituted Alkyl), -N (R ') CO- (alkyl or substituted alkyl), -N (R') C (O) OR ',-(alkyl or substituted alkyl) -ON = C (R') ₂ , - (alkyl or substituted alkyl) -C (O) NR '- (alkyl or substituted alkyl), - (alkyl or substituted alkyl), -S (O) _k - (alkyl Is substituted alkyl) -SR ', - (alkylene or substituted alkylene) -S-SR', -S ( O) k N (R ') 2, -N (R') C (O) N (R ' ) ₂ , -N (R ') C (S) N (R') ₂ , -N (R ') S (O) _k N (R') ₂ , -C (R ') = NR'-C ( R ') = NN (R') ₂ and -C (R ') ₂ -N (R')-N (R ') ₂ are independently selected.

In a further embodiment, A and B together form -C (O)-(CR ^q R ^q ) _n- , -C (O) -NR ^2- (CR ^q R ^q ) _n- , -NR ² -C ( O)-(CR ^q R ^q ) _n- , -C (O) -NR ² -NR ^2- (CR ^q R ^q ) _n- , -C (O) -NR ² -N = (CR ^q )-, -0-C (O) -O-, 0-C (O) -NR ^2- , -NR ² -C (O) -NR ^2- , -OC (O) -O- (CR ^q R ^q ) _n -, -OC (O)-(CR ^q R ^q ) _n -O-, -NC (O)-(CR ^q R ^q ) _n -N-, -OC (O)-(CR ^q R ^q ) _n- N-, -NC (O)-(CR ^q R ^q ) _n -O-, -OC (O) -NR ^2- (CR ^q R ^q ) _n- , -NR ² -C (O) -O- ( CR ^q R ^q ) _n- , -NR ² -C (O) -NR ^2- (CR ^q R ^q ) _n -,-(CR ^q R ^q ) _n -C (O) -O- (CR ^q R ^q ) _n -,-(CR ^q R ^q ) _n -C (O) -NR ^2- (CR ^q R ^q ) _n -,-(CR ^q R ^q ) _n -C (O) -NR ² -NR ^2- ,-(CR ^q R ^q ) _n -C (O)-(CR ^q R ^q ) _n- , -C (O) -O- (CR ^q R ^q ) _n -O-, -C (O) -O -(CR ^q R ^q ) _n -NR ^2- , -C (O) -NR ^2- (CR ^q R ^q ) _n -NR ² , -C (O) -NR ^2- (CR ^q R ^q ) _n- O-, -C (O) -NR ² -CR ^q = CR ^q- , C (O) -CR ^q = CR ^q -NR ^2- , -C (O) -CR ^q = CR ^q -O-,- Forms an optionally substituted oxo-substituted heterocycle selected from C (O) -CR ^q = CR ^q -S-;

Each n is independently 1, 2 or 3;

Each R ^q is H, alkyl, substituted alkyl, aryl, substituted aryl, ketoalkyl, substituted ketoalkyl, ketoheteroalkyl, substituted ketoheteroalkyl, heteroalkyl, substituted heteroalkyl, heterocyclic or substituted Independently from the heterocycle.

Additional compounds described herein are described in Formula 1, Formula 2, Formula 3, Formula 4, Formula 5, Formula 5, disclosed in U.S. Patent Application No. 60 / 755,035, filed Dec. 29, 2005, which is incorporated herein by reference. 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, Formula 23, Formula 24, Formula 25, Formula 26, Formula 27, Formula 28 or Formula 29, provided that the R ¹ group

로 구성된 군으로부터 선택된 구조를 가지며;

Has a structure selected from the group consisting of:

M is a bond, optionally substituted C ₁ -C ₈ alkylene, optionally substituted 4-atom heteroalkylene, optionally substituted C ₂ -C ₈ alkenylene, optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted C ₂ -C ₈ alkynylene;

J is CH or N; K is CH or N; Provided that when K is CH, J cannot be CH;

Each R ³ is C ₁ -C ₆ alkyl- (aryl), C ₁ -C ₆ alkyl- (heteroaryl), C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamine, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ heteroalkyl, -C (O) -R ¹² , aryl, heteroaryl, heterocycloalkyl, phenyl, pyridyl, pyridazinyl , Piperazinyl, piperidinyl, morpholinyl, furanyl, thiophenyl, thiophenyl, dibenzofuranyl, dibenzothienyl, indolyl, fluorenyl, carbozolyl, pyrimidinyl, pyrazinyl , Triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxdiazolyl, thiadiazolyl, triazolyl, naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydro Isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnalol, imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxasa Joly, Benz Sazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl, pyrazolopyri Independently selected from the group consisting of optionally substituted groups selected from dill, oxalopyridyl, isoxazolopyridyl or thiazolopyridyl;

Each R 'is independently H, alkyl or substituted alkyl;

Each R ⁵ is independently H, C ₁ -C ₃ alkyl or halogen;

R ⁶ is C ₁ -C ₃ alkyl or C ₃ -C ₇ cycloalkyl;

R ¹² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ heteroalkyl, benzyloxy, furanyl, phenyl, benzyl or pyridyl; or

를 형성하며;R ¹ and R ² together

To form;

n is 1, 2, 3 or 4; m is 1, 2, 3 or 4;

Each optional substituent is C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, benzyl, halogen, nitro, cyano or benzyloxy-C (O) R ′, —C (O) — (alkyl or substituted Alkyl),-(alkyl or substituted alkyl) -C (O) R ', -C (O) N (R') ₂ , -C (O) N (R ')-(alkyl or substituted alkyl), -(Alkyl or substituted alkyl) -C (O) N (R ') ₂ , -OC (O) N (R') ₂ , -OC (O) N (R ')-(alkyl or substituted alkyl) ,-(Alkyl or substituted alkyl) -OC (O) N (R ') ₂ , -N (R') C (O) R ', -NR'C (O)-(alkyl or substituted alkyl), -(Alkyl or substituted alkyl) -NR'C (O) R ', -SR', -S- (alkyl or substituted alkyl), -S (O) _k R ', where k is 1 or 2 , -S (O) _k (alkyl or substituted alkyl), -C (S)-(alkyl or substituted alkyl), -CSN (R ') ₂ , -CSN (R')-(alkyl or substituted alkyl ), -N (R ') CO- (alkyl or substituted alkyl), -N (R') C (O) OR ',-(alkyl or substituted alkyl) -ON = C (R') ₂ ,- (alkyl or substituted alkyl) -C (O) NR '- (alkyl or substituted alkyl), - (alkyl or substituted alkyl), -S (O) _k - (alkyl addition Substituted alkyl) -SR ', - -S-SR ( alkyl or substituted _{alkyl)', -S (O) k} N (R ') 2, -N (R') C (O) N (R ') ₂ , -N (R ') C (S) N (R') ₂ , -N (R ') S (O) _k N (R') ₂ , -C (R ') = NR'-C (R ') = NN (R') ₂ and -C (R ') ₂ -N (R')-N (R ') ₂ -are independently selected.

Chemical nomenclature

Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and issued documents cited throughout this specification are intended to be incorporated by reference in their entirety unless otherwise noted. In the event that there are a plurality of definitions for a term herein, the definition of this part shall prevail. When referring to a URL or other such distinguished name or address, it is understood that such distinguished name may change and certain information on the Internet may change, but equivalent information may be found by Internet search. Their citations demonstrate the availability and public dissemination of such information.

It is to be understood that the foregoing general description and the following detailed description are for purposes of illustration and description only, and do not limit any claimed subject matter. In the present application, the use of the singular includes the plural unless specifically stated otherwise. As used in the specification and the appended claims, the singular forms "a", "an" and "an" and "the" are intended to include the plural referents unless the context clearly dictates. Note that In this application, the use of “or” means “and / or” unless stated otherwise. In addition, the use of the terms "comprising" as well as other forms, such as "comprises", "comprising" and "including", is not limited.

The headings in the parts used in the present specification are used for structural purposes only and should not be regarded as limiting matters to be protected. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, papers, books, guidelines, and academic papers, are expressly incorporated by reference in their entirety for any purpose.

Application of the chemical terminology of the standard is described in Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 ^th ED." Vols. A (2000) and B (2001), Plenum Press, New York]. Unless otherwise indicated, conventional methods of mass spectrum, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology were used within the art. Unless otherwise provided, the nomenclature used in connection with the analytical chemistry, organic synthetic chemistry and medicinal and pharmaceutical chemistry described herein and in its laboratory procedures and techniques are known to those skilled in the art. Standard techniques can be used for chemical synthesis, chemical analysis, pharmaceutical preparation, combinations, and delivery and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis and tissue culture and conversion (eg, electroporation, lipofection). Reaction and purification techniques can be performed, for example, as commonly accomplished in the art or as described herein, or using kits from the manufacturer's instructions. The above techniques and procedures can generally be carried out as conventional methods known in the art and as described in various general and more specific documents cited and discussed throughout this specification.

"Alkoxy" group refers to a (alkyl) O- group, where alkyl is as defined herein.

"Alkyl" group refers to an aliphatic hydrocarbon group. The alkyl moiety can be a "saturated alkyl" group, meaning that it does not include any alkenes or alkyne moieties. In addition, the alkyl moiety can be a "unsaturated alkyl" moiety, meaning that it includes one or more alkenes or alkyne moieties. "Alkene" moiety refers to a group comprising at least one carbon-carbon double bond, and "alkyne" moiety refers to a group having at least one carbon-carbon triple bond. Whether the alkyl moiety is saturated or unsaturated, it can be branched, straight or cyclic. Depending on the structure, the alkyl group can be a single radical or a double radical (ie an alkylene group).

As used herein, C ₁ -C _x is C ₁ -C ₂ , C ₁ -C ₃ . . . C ₁ -C _x .

"Alkyl" moiety may comprise from 1 to 10 carbon atoms (when used herein, a numerical range, such as "1 to 10", refers to each integer within a given range; for example "1 to 10 carbon atoms" means that although an alkyl group includes the use of the term "alkyl," which does not indicate a numerical limitation, an alkyl group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or the like. , Meaning that it may have up to 10 carbon atoms, including 10. The alkyl groups of the compounds described herein may be represented as “C ₁ -C ₄ alkyl” or similar designations. ₁ -C ₄ alkyl "indicates that 1 to 4 carbon atoms are present in the alkyl chain, ie the alkyl chain is methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and t-butyl are selected from, so, C ₁ -C ₄ al Is C ₁ -C ₂ include alkyl and C ₁ -C ₃ alkyl; alkyl group may be unsubstituted or substituted. An example of a typical alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t -Butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, but are not limited thereto.

As used herein, the term "non-cyclic alkyl" refers to alkyl that is not cyclic (ie, straight or branched chain containing one or more carbon atoms). Non-cyclic alkyl may be fully saturated or may include non-cyclic alkenes and / or alkynes. Non-cyclic alkyl may be optionally substituted.

The term "alkylamine" refers to an N (alkyl) _x H _y group, where x and y are selected from x = 1, y = 1 and x = 2, y = 0. When x = 2, the alkyl group together with the N atom to which they are attached may optionally form a cyclic ring system.

The term "alkenyl" refers to a type of alkyl group, wherein the first two atoms of the alkyl group form a double bond that is not part of the aromatic group. That is, alkenyl groups begin with the atom —C (R) ═C (R) —R, where R refers to the remainder of the alkenyl group, which may be the same or different. Non-limiting examples of alkenyl groups include -CH = CH ₂ , -C (CH ₃ ) = CH ₂ , -CH = CHCH ₃ and -C (CH ₃ ) = CHCH ₃ . The alkenyl moiety can be branched, straight or cyclic (in this case known as a "cycloalkenyl" group). Depending on the structure, the alkenyl group can be a single radical or a double radical (ie an alkenylene group). Alkenyl groups may be optionally substituted.

The term "alkynyl" refers to the type of alkyl group in which the first two atoms of the alkyl group form a triple bond. That is, the alkynyl group begins with the atom —C≡CR where R refers to the remainder of the alkynyl group, which may be the same or different. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH ₃ and -C≡CCH ₂ CH ₃ and the like. The “R” portion of the alkynyl moiety can be branched, straight or cyclic. Depending on the structure, the alkynyl group can be a single radical or a double radical (ie an alkynylene group). Alkynyl groups may be optionally substituted.

“Amide” is a chemical moiety having the formula —C (O) NHR or —NHC (O) R, wherein R is alkyl, cycloalkyl, aryl, heteroaryl (bonded via ring carbon) and heteroalicyclic (ring) Bound through carbon). The amide moiety forms a bond between an amino acid or peptide molecule and a compound described herein, thus forming a prodrug. Any amine or carboxyl side chain in the compounds described herein can be amidated. Procedures and specific groups of generating these amides are known to those skilled in the art, e.g., literature incorporated by reference herein [[Greene and Wuts, Protective Groups in Organic Synthesis, 3 ^rd Ed., John Wiley & Sons, New York, NY, 1999].

The term "aromatic" refers to a planar ring having an unlocalized π-electron system with electrons of 4n + 2 π, where n is an integer. Aromatic rings can be formed with 5, 6, 7, 8, 9 or more than 9 atoms. Aromatics may be optionally substituted. The term “aromatic” includes both carbocyclic aryl (eg phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (eg pyridine). This term includes monocyclic or fused ring polycyclic (ie, rings which share adjacent pairs of carbon atoms) groups.

As used herein, the term “aryl” refers to an aromatic ring where each atom forming the ring is a carbon atom. The aryl ring may be formed with 5, 6, 7, 8, 9 or more than 9 carbon atoms. Aryl groups may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthalenyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl. Depending on the structure, the aryl group can be a single radical or a double radical (ie an arylene group).

"Aryloxy" group refers to a (aryl) O- group in which aryl is as defined herein.

The term "bond" or "single bond" refers to a chemical bond between two atoms or two parts when the atoms connected by the bond are considered to be part of a larger infrastructure.

The term "carbocyclic ring" refers to a compound comprising one or more covalent closed ring structures, wherein the atoms that form the backbone of the ring are all carbon atoms. Thus, this term distinguishes a carbocyclic ring from a heterocyclic ring containing at least one atom whose ring backbone differs from carbon.

등과 같은 부분을 포함하는 것이 있다. 구조에 따라서, 시클로알킬 기는 단일라디칼 또는 이중라디칼(예, 시클로알킬렌 기)이 될 수 있다.The term "cycloalkyl" refers to monocyclic or polycyclic radicals which contain only carbon and hydrogen and can be saturated, partially unsaturated or fully unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms. Examples of cycloalkyl groups include

And the like. Depending on the structure, the cycloalkyl group can be a single radical or a double radical (eg a cycloalkylene group).

As used herein, the term "carbocyclic ring" refers to a ring in which each atom forming the ring is a carbon atom. Carbocyclic rings may be formed by carbon atoms having 3, 4, 5, 6, 7, 8, 9 or more than 9. Carbocycles may be optionally substituted.

The term “ester” refers to a chemical moiety having the formula —COOR, wherein R is selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded via ring carbon) and heteroalicyclic (bonded through ring carbon) do. Any hydroxy or carboxyl side chain in the compounds described herein can be esterified. And these are known to generate the ester process, and in a particular art group, the standard literature, for example, the literature cited in the description by reference [Greene and Wuts, Protective Groups in Organic Synthesis, 3 ^rd Ed., John Wiley & Sons, New York, NY, 1999].

The term "halo" or alternatively "halogen" or "halide" means fluoro, chloro, bromo or iodo.

The terms "haloalkyl", "haloalkenyl", "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures in which one or more hydrogens have been replaced by halogen atoms. In certain embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are all the same as each other. In other embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms may not all be identical to each other. The terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, where halo is fluorine. In certain embodiments, haloalkyl is optionally substituted.

As used herein, the terms "heteroalkyl" "heteroalkenyl" and "heteroalkynyl" refer to one or more skeletal chain atoms from atoms other than carbon, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or combinations thereof. Selected are optionally substituted alkyl, alkenyl and alkynyl radicals.

The term “heteroatom” refers to an atom other than carbon or hydrogen. Heteroatoms are usually independently selected from oxygen, sulfur, nitrogen, silicon and phosphorus, but are not limited to these atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms may be all the same as one another or some or all of the two or more heteroatoms may be different from each other.

As used herein, the term “ring” refers to any covalent closed structure. Examples of rings include carbocycles (eg aryl and cycloalkyl), heterocycles (eg heteroaryl and non-aromatic heterocycles), aromatics (eg aryl and heteroaryl) and non-aromatics (eg cycloalkyl and non Aromatic heterocycle). The ring may be optionally substituted. The ring may form part of a ring system.

As used herein, the term “ring system” refers to two or more rings in which two or more rings are fused. The term "fused" refers to a structure in which two or more rings share one or more bonds.

The term "heteroaryl" or alternatively "heteroaromatic" refers to an aryl group comprising one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. An N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group wherein at least one skeletal atom of the ring is a nitrogen atom. Multicyclic heteroaryl groups may or may not be fused. Examples of heteroaryl groups are

등과 같은 부분을 포함한다. 구조에 따라, 헤테로아릴 기는 단일라디칼 또는 이중라디칼(즉, 헤테로아릴렌 기)이 될 수 있다.

And the like. Depending on the structure, the heteroaryl group can be a single radical or a double radical (ie, a heteroarylene group).

As used herein, the term "non-aromatic heterocycle", "heterocycloalkyl" or "heteroalicyclic" refers to a non-aromatic ring wherein at least one atom forming the ring is a heteroatom. A "non-aromatic heterocycle" or "heterocycloalkyl" group refers to a cycloalkyl group that includes one or more heteroatoms selected from nitrogen, oxygen, and sulfur. The radical may be fused with aryl or heteroaryl. Heterocycloalkyl rings may be formed with 3, 4, 5, 6, 7, 8, 9 or more than 9 atoms. Heterocycloalkyl rings may be optionally substituted. In certain embodiments, non-aromatic heterocycles include one or more carbonyl or thiocarbonyl groups, such as oxo- and thio-containing groups. Examples of heterocycloalkyl include lactam, lactone, cyclic imide, cyclic thiimide, cyclic carbamate, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxatian, 1,4-oxatine, 1,4-oxatian, tetrahydro-1 , 4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexa Hydro-1,3,5-triazine, tetrahydrothiophene, tetra hydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline, imidazolidine , 1,3-dioxol, 1,3-dioxolane, 1,3-dithiol, 1,3-dithiolane, isoxazolin, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thia Sleepy, thiazolidine and 1,3-oxathiolane However, the present invention is not limited thereto. Heterocycloalkyl groups referred to as non-aromatic heterocycles include

등이 있다. 또한, 용어 헤테로지환족은 단당류, 이당류 및 올리고 당을 비롯한 탄수화물의 모든 고리 형태를 포함하지만, 이에 한정되는 것은 아니다.

Etc. The term heteroalicyclic also includes, but is not limited to, all ring forms of carbohydrates including monosaccharides, disaccharides, and oligosaccharides.

The term “heterocycle” refers to heteroaromatic and heteroalicyclic groups comprising 1 to 4 heteroatoms each selected from O, S and N, wherein each heterocyclic group has 4 to 10 atoms in the ring system, provided that The ring of the group does not contain two neighboring O or S atoms. Here, when the number of carbon atoms in a heterocycle is given (eg, C ₁ -C ₆ heterocycle), at least one other atom (heteroatom) must be present in the ring. An indication, such as “C ₁ -C ₆ heterocycle,” refers only to the number of carbon atoms in the ring, but not to the total number of atoms in the ring. It is to be understood that the heterocyclic ring may contain additional heteroatoms in the ring. An indication such as “4-6 membered heterocycle” refers to the total number of atoms contained in the ring (ie, at least one atom is a carbon atom, at least one atom is a heteroatom and the remaining 2 to 4 atoms are carbon atoms or heteroatoms). , 5 or 6 membered ring). In heterocycles comprising two or more heteroatoms, two or more heteroatoms may be the same or different from one another. Heterocycles may be optionally substituted. Bonds to heterocycles may be formed at heteroatoms or via carbon atoms. Non-aromatic heterocyclic groups include groups that contain only four atoms in the ring system, but aromatic heterocyclic groups must include at least 5 atoms in the ring system. Heterocyclic groups include benzo-fused ring systems. An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5-membered heterocyclic group is thiazolyl. An example of a 6-membered heterocyclic group is pyridyl, and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholi Furnace, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazinyl, diazepinyl, thiazinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, Pyrazolinyl, ditianyl, dithiol ranyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexa Nil, 3-azabicyclo [4.1.0] heptanyl, 3H-indolyl and quinolizinyl and the like. Examples of aromatic heterocyclic groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pi Rollyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnaolinyl, indazolyl, indolinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, fr Terridinyl, furinyl, oxadiazolyl, thiadiazolyl, pyrazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl have. Groups as derived from the groups set forth above may be C-linked or N-linked if possible. For example, the group derived from pyrrole can be pyrrole-1-yl (N-linked) or pyrrole-3-yl (C-linked). In addition, groups derived from imidazole may be imidazol-1-yl or imidazol-3-yl (both N-linked) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (All C-linked). Examples of heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or two oxo (═O) moieties such as pyrrolidin-2-one. Depending on the structure, the heterocyclic group can be a single radical or a double radical (ie, a heterocycline group).

The term "membered ring" may encompass any cyclic structure. The term "-member" is meant to denote the number of skeletal atoms that make up the ring. Thus, for example, cyclohexyl, pyridine, pyran and thiopyran are 6-membered rings and cyclopentyl, pyrrole, furan and thiophene are 5-membered rings.

"Isocyanato" group refers to an -NCO group.

"Isothiocyanato" group refers to a -NCS group.

The term "ketoalkyl" group refers to an alkyl group substituted with an oxo group.

The term “heteroketoalkyl” group refers to a heteroalkyl group in which one of the carbon atoms is replaced with an oxo group.

The term "part" refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized as chemical moieties included in or added to a molecule.

The term "polycycloalkyl" refers to an alkyl group comprising a bicyclic or tricyclic ring hydrocarbon ring structure, including crosslinked cycloalkyl rings, spiro cycloalkyl rings or fused cycloalkyl rings. Examples thereof include norbornyl groups, adamantyl groups, bicyclo [x.y.z] alkyl groups, wherein each x, y and z are independently 1, 2, 3 or 4, or a tricyclic alkyl group.

A "sulfinyl" group refers to -S (= 0) -R.

A "sulfonyl" group refers to -S (= 0) ₂ -R.

A "thioalkoxy" group refers to an -S-alkyl group.

As used herein, the term “O-carboxy” refers to a group of the formula RC (═O) O—.

As used herein, the term "C-carboxy" refers to a group of the formula -C (= 0) OR.

As used herein, the term "acetyl" refers to a group of the formula -C (= 0) CH ₃ .

As used herein, the term “trihalomethanesulfonyl” refers to a group of formula X ₃ CS (═O) ₂ —, wherein X is halogen.

As used herein, the term "cyano" refers to a group of the formula -CN.

As used herein, the term “S-sulfonamido” refers to a group of the formula —S (═O) ₂ NR ₂ .

As used herein, the term “N-sulfonamido” refers to a group of the formula RS (═O) ₂ NH—.

As used herein, the term "O-carbamyl" refers to a group of the formula -OC (= 0) NR ₂ .

As used herein, the term "N-carbamyl" refers to a group of the formula ROC (= 0) NH-.

As used herein, the term "O thiocarbamyl" refers to a group of the formula -OC (= S) NR ₂ .

As used herein, the term "N thiocarbamyl" refers to a group of the formula ROC (= S) NH-.

As used herein, the term “C-amido” refers to a group of the formula —C (═O) NR ₂ .

As used herein, the term “N-amido” refers to a group of the formula RC (═O) NH—.

As used herein, the substituent "R", alone or unnumbered, is alkyl, cycloalkyl, aryl, heteroaryl (bonded via ring carbon) and non-aromatic heterocycle (bonded through ring carbon) Refers to a substituent selected from

The term “optionally substituted” or “substituted” refers to alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, including amino groups in which the groups mentioned are monosubstituted and bisubstituted and protected derivatives thereof Aryloxy, mercapto, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, aryl sulfone, cyano, halo, carbonyl, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato It means that it can be substituted with one or more additional groups substituted individually and independently selected from nitro, perhaloalkyl, perfluoroalkyl, silyl and amino. For example, any substituent may be L _s R _s , where each L _s is a bond, -O-, -C (= 0)-, -S-, -S (= 0)-,- S (= O) _2- , -NH-, -NHC (O)-, -C (O) NH-, S (= O) ₂ NH-, -NHS (= O) ₂ , -OC (O) NH -, -NHC (O) O-,-(substituted or unsubstituted C ₁ -C ₆ alkyl) or-(substituted or unsubstituted C ₂ -C ₆ alkenyl); Each R _s is independently selected from H, (substituted or unsubstituted lower alkyl), (substituted or unsubstituted lower cycloalkyl), heteroaryl or heteroalkyl. Protecting groups capable of forming protective derivatives of such substituents are known to those skilled in the art and can be found, for example, in Greene and Wuts, homology.

The compounds presented herein may have one or more stereocenters, and each center may exist in an R or S structure. The compounds presented herein include all diastereomeric, enantiomeric and epimeric forms, as well as appropriate mixtures thereof. Stereoisomers can be obtained, if desired, by methods known in the art, for example by separation of stereoisomers by chiral chromatography columns.

The methods and combinations described herein include N-oxides, crystalline forms (also known as polymorphs) or pharmaceutically acceptable salts of the compounds described herein, as well as active metabolites of these compounds having the same type of activity. It also includes use. In certain circumstances, compounds may exist as tautomers. All tautomers are intended to be included within the scope of the compounds presented herein. In addition, the compounds described herein may exist in the form of solvates with non-solvates, as well as pharmaceutically acceptable solvents such as water, ethanol and the like. In addition, the solvated forms of the compounds described herein are considered to be disclosed herein.

Throughout the specification, groups and substituents thereof may be selected by those skilled in the art to provide stable moieties and compounds.

compound

Certain compounds that inhibit the activity of fatty acid amide hydrolase (FAAH) play a role in health. In certain embodiments, the FAAH inhibitor compound is useful for treating any of a variety of diseases, conditions or conditions. In certain embodiments, the compound provided herein is a selective FAAH inhibitor compound.

FAAH inhibitor compositions are described in US Patent Application Nos. 10 / 681,858, 60 / 755,035, US Pat. Nos. 6,462,054, 6,949,574 and 6,891,043; International Patent Application Publications WO04 / 020430, WO04 / 067498, WO04 / 099176, WO05 / 033066, WO02 / 087569, WO03 / 065989, WO97 / 49667, WO99 / 26584, WO04 / 033652 and WO06 / 044617; Cravat et al., Current Opinion in Chemical Biology , 2003, 7: 469-475; Kathuria et al., Nature Medicine , vol. 9, no. 1, pp 76-81, 2003 .; Tarzia et al., J. Med. Chem. 2003, 46, 2352-2360; Drysdale et al., Current Medicinal Chemistry , 2003, 10, 2719-2732.

Also provided are pharmaceutically acceptable salts, pharmaceutically active metabolites and pharmaceutically acceptable prodrugs of the compounds. Also provided are pharmaceutical compositions comprising one or more of the above compounds or pharmaceutically acceptable salts, pharmaceutically active metabolites or pharmaceutically acceptable prodrugs of said compounds.

In certain embodiments, the compounds provided herein are ionizable and do not substantially pass through the blood brain blockers. In certain embodiments, carbamate FAAH inhibitors are provided that are ionizable at physiological pH and will pass less through the blood brain blocker. In certain embodiments, compounds provided herein have a portion that is ionizable at physiological pH. In other embodiments, the compounds provided herein have a charge at physiological pH. In certain other embodiments, the compounds provided herein are protonated at physiological pH. In other embodiments, the compounds provided herein are deprotonated at physiological pH. Such FAAH inhibitors are particularly useful when it is desired to minimize and / or exclude psychotropic efficacy caused by FAAH inhibition in the central nervous system.

In certain embodiments, a compound provided herein is a compound having a structure selected from Formula II, Formula IIa, Formula IIb, Formula IIc, Formula IId, Formula IIe, Formula I, a pharmaceutically acceptable salt thereof, pharmaceutical Pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs or pharmaceutically acceptable solvates:

Formula II

Formula IIa

Formula IIb

Formula IIc

Formula IId

Formula IIe

Formula I

In the above formula, D is O or NR ¹¹ ;

One of A or B is (CH ₂ ) _n C (O) -alkyl, (CH ₂ ) _n C (O) -N (R ² ) ₂ , the other is H, alkyl or heteroalkyl, n is 0 , 1, 2, 3 or 4; or

A and B together form an optionally substituted non-aromatic ring comprising a C (O) — (CH ₂ ) _n − moiety, wherein n is 1, 2, 3 or 4; or

A and B together form an optionally substituted heteroaromatic group comprising at least one N, NR ² , S or O group; or

A and B together form an optionally substituted non-aromatic or aromatic carbocyclic group; or

A and B together form an optionally substituted oxo-substituted heterocycle; or

A and B are each H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted ketoalkyl and optionally substituted ketoheteroalkyl Independently from;

R ¹ is optionally selected from C ₃ -C ₉ cycloalkyl, C ₁ -C ₄ alkyl (C ₃ -C ₉ cycloalkyl), C ₁ -C ₄ alkyl (aryl) and C ₁ -C ₄ alkyl (heteroaryl) Substituted group,

Any carbon of the R ¹ cycloalkyl ring is optionally substituted with Y and Z, each Y and each Z is independently selected from halogen, methyl or trifluoromethyl or Y and Z together are 3-, 4- Or 5-membered carbocyclic groups or oxo (═O);

Each R ² and R ¹¹ is independently H or optionally substituted alkyl

In a further embodiment, A and B together form -C (O)-(CR ^q R ^q ) _n- , -C (O) -NR ^2- (CR ^q R ^q ) _n- , -NR ² -C ( O)-(CR ^q R ^q ) _n- , -C (O) -NR ² -NR ^2- (CR ^q R ^q ) _n- , -C (O) -NR ² -N = (CR ^q )-, -0-C (O) -O-, 0-C (O) -NR ^2- , -NR ² -C (O) -NR ^2- , -OC (O) -O- (CR ^q R ^q ) _n , -OC (O)-(CR ^q R ^q ) _n -O-, -NC (O)-(CR ^q R ^q ) _n -N-, -OC (O)-(CR ^q R ^q ) _n -N -, -NC (O)-(CR ^q R ^q ) _n -O-, -OC (O) -NR ^2- (CR ^q R ^q ) _n- , -NR ² -C (O) -O- (CR ^q R ^q ) _n- , -NR ² -C (O) -NR ^2- (CR ^q R ^q ) _n -,-(CR ^q R ^q ) _n -C (O) -O- (CR ^q R ^q ) _n -,-(CR ^q R ^q ) _n -C (O) -NR ^2- (CR ^q R ^q ) _n -,-(CR ^q R ^q ) _n -C (O) -NR ² -NR ^2- , -(CR ^q R ^q ) _n -C (O)-(CR ^q R ^q ) _n- , -C (O) -O- (CR ^q R ^q ) _n -O-, -C (O) -O- (CR ^q R ^q ) _n -NR ^2- , -C (O) -NR ^2- (CR ^q R ^q ) _n -NR ² , -C (O) -NR ^2- (CR ^q R ^q ) _n -O -, -C (O) -NR ² -CR ^q = CR ^q- , C (O) -CR ^q = CR ^q -NR ^2- , -C (O) -CR ^q = CR ^q -O-, -C Forms an optionally substituted oxo-substituted heterocycle selected from (O) -CR ^q = CR ^q -S-; Each n is independently 1, 2 or 3;

Each R ^q is H, alkyl, substituted alkyl, aryl, substituted aryl, ketoalkyl, substituted ketoalkyl, ketoheteroalkyl, substituted ketoheteroalkyl, heteroalkyl, substituted heteroalkyl, heterocycle, or substitution Independently from the heterocycle.

In certain embodiments, a compound provided herein is a compound having a structure according to Formula II, a pharmaceutically acceptable salt, a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite, pharmaceutically Acceptable prodrugs or pharmaceutically acceptable solvates are:

Formula II

In the above formula, D is O or NR ¹¹ ,

로 구성된 군으로부터 선택되며;R ¹ is

Is selected from the group consisting of;

M is a bond, optionally substituted C ₁ -C ₈ alkylene, optionally substituted 4-atom heteroalkylene, optionally substituted C ₂ -C ₈ alkenylene, optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted C ₂ -C ₈ alkynylene;

J is CH or N; K is CH or N; Provided that when K is CH, J cannot be CH;

Each R ³ is C ₁ -C ₆ alkyl- (aryl), C ₁ -C ₆ alkyl- (heteroaryl), C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamine, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ heteroalkyl, -C (O) -R ¹² , aryl, heteroaryl, heterocycloalkyl, phenyl, pyridyl, pyridazinyl , Piperazinyl, piperidinyl, morpholinyl, furanyl, thiophenyl, thiophenyl, dibenzofuranyl, dibenzothienyl, indolyl, fluorenyl, carbozolyl, pyrimidinyl, pyrazinyl , Triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxdiazolyl, thiadiazolyl, triazolyl, naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydro Isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnalol, imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxasa Joly, Benz Sazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl, pyrazolopyri Independently selected from the group consisting of optionally substituted groups selected from dill, oxalopyridyl, isoxazolopyridyl or thiazolopyridyl;

Each R 'is independently H, alkyl or substituted alkyl;

Each R ⁵ is independently H, C ₁ -C ₃ alkyl or halogen;

R ⁶ is C ₁ -C ₃ alkyl or C ₃ -C ₇ cycloalkyl;

R ² and R ¹¹ are H or optionally substituted alkyl;

R ¹² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ heteroalkyl, benzyloxy, furanyl, phenyl, benzyl or pyridyl; or

를 형성하며;R ¹ and R ² together

To form;

n is 1, 2, 3 or 4; m is 1, 2, 3 or 4;

A and B together form an optionally substituted non-aromatic ring group comprising a C (O) — (CH ₂ ) _q − moiety, wherein q is 1, 2, 3 or 4; or

A and B together form an optionally substituted oxo-substituted heterocycle; or

A and B together form an optionally substituted aromatic or non-aromatic ring group comprising at least one N, NR ² , S or O group; or

One of A or B is -LG and the other is selected from H and optionally substituted C ₁ -C ₆ alkyl; or

A and B together form an optionally substituted aromatic carbocyclic group; or

A and B are each H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted ketoalkyl, optionally substituted amide and optionally Independently selected from substituted ketoheteroalkyl;

L is a bond or C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₁ -C ₆ ketoalkylene, -C (O) NR ^9- (CH ₂ ) _j- , -NR ^9- C (O)-(CH ₂ ) _j- , -OC (O) O- (CH ₂ ) _j- , -NHC (O) O- (CH ₂ ) _j- , -O (O) CNH- (CH ₂ ) _j- , -C (O) O- (CH ₂ ) _j- , -OC (O)-(CH ₂ ) _j- , -NR ⁹ C (O) N (R ⁹ )-(CH ₂ ) _j- , -S (O)-(CH ₂ ) _j- , -S (O) _2- (CH ₂ ) _j- , -C (= NR ¹⁰ ) N (R ⁹ )-(CH ₂ ) _j -and -NR ^An optionally substituted group selected from ⁹ C (═NR ¹⁰ ) N (R ⁹ ) — (CH ₂ ) _j- ;

G is tetrazolyl, -NHS (= O) ₂ R ⁸ , -S (= O) ₂ NHR ⁸ , -S (= O) ₂ NH-phenyl, -OH, -SH, -OC (O) NHR ⁸ , -NHC (O) OR ⁸ , -C (O) NHC (O) R ⁸ , -C (O) NHS (= O) ₂ R ⁸ , -S (O) ₂ NHC (O) R ⁸ , -S ( = O) ₂ NHC (O) NHR ⁸ , -NHC (O) R ⁸ , -NHC (O) N (R ⁹ ) ₂ , -C (= NR ¹⁰ ) N (R ⁹ ) ₂ , -NR ⁹ C ( = NR ¹⁰ ) N (R ⁹ ) ₂ , -NR ⁹ C (= NR ¹⁰ ) NHC (= NR ¹⁰ ) N (R ⁹ ) ₂ , -NR ⁹ C (= CHR ¹⁰ ) N (R ⁹ ) ₂ ,- C (O) NR ⁹ C (= NR ¹⁰ ) N (R ⁹ ) ₂ , -C (O) NR ⁹ C (= CHR ¹⁰ ) N (R ⁹ ) ₂ , -CO ₂ H,-(OP (= O ) OH) _x OH, -OP (= O) OR ⁸ OH, -OP (= O) R ⁸ OH, -NR ⁹ P (= O) OR ⁸ OH, -NR ⁹ P (= O) R ⁸ OH, -P (= 0) OR ⁸ OH, -P (= 0) R ⁸ OH, -S (O) _y OH, -OS (O) _y OH, -NR ⁹ S (O) _y OH;

Each R ⁸ is independently substituted or unsubstituted C ₁ -C ₆ alkyl;

Each R ⁹ is independently H, substituted C ₁ -C ₆ alkyl or unsubstituted C ₁ -C ₆ alkyl;

Each R ¹⁰ is independently selected from H, —S (═O) ₂ R ⁸ , —S (═O) ₂ NH ₂ , —C (O) R ⁸ , —CN, and —NO ₂ ;

j is 0, 1, 2, 3 or 4; x is 1, 2 or 3; y is 0, 1 or 2;

Each optional substituent is C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, benzyl, halogen, nitro, cyano or benzyloxy-C (O) R ′, —C (O) — (alkyl or substituted Alkyl),-(alkyl or substituted alkyl) -C (O) R ', -C (O) N (R') ₂ , -C (O) N (R ')-(alkyl or substituted alkyl), -(Alkyl or substituted alkyl) -C (O) N (R ') ₂ , -OC (O) N (R') ₂ , -OC (O) N (R ')-(alkyl or substituted alkyl) ,-(Alkyl or substituted alkyl) -OC (O) N (R ') ₂ , -N (R') C (O) R ', -NR'C (O)-(alkyl or substituted alkyl), -(Alkyl or substituted alkyl) -NR'C (O) R ', -SR', -S- (alkyl or substituted alkyl), -S (O) _k R ', where k is 1 or 2 , -S (O) _k (alkyl or substituted alkyl), -C (S)-(alkyl or substituted alkyl), -CSN (R ') ₂ , -CSN (R')-(alkyl or substituted alkyl ), -N (R ') CO- (alkyl or substituted alkyl), -N (R') C (O) OR ',-(alkyl or substituted alkyl) -ON = C (R') ₂ ,- (alkyl or substituted alkyl) -C (O) NR '- (alkyl or substituted alkyl), - (alkyl or substituted alkyl), -S (O) _k - (alkyl addition Substituted alkyl) -SR ', - -S-SR ( alkyl or substituted _{alkyl)', -S (O) k} N (R ') 2, -N (R') C (O) N (R ') ₂ , -N (R ') C (S) N (R') ₂ , -N (R ') S (O) _k N (R') ₂ , -C (R ') = NR'-C (R ') = NN (R') ₂ and -C (R ') ₂ -N (R')-N (R ') ₂ are independently selected.

In a further embodiment, A and B together form -C (O)-(CR ^q R ^q ) _n- , -C (0) -NR ^2- (CR ^q R ^q ) _n- , -NR ² -C ( O)-(CR ^q R ^q ) _n- , -C (O) -NR ² -NR ^2- (CR ^q R ^q ) _n- , -C (O) -NR ² -N = (CR ^q )-, -0-C (O) -O-, 0-C (O) -NR ^2- , -NR ² -C (O) -NR ^2- , -OC (O) -O- (CR ^q R ^q ) _n -, -OC (O)-(CR ^q R ^q ) _n -O-, -NC (O)-(CR ^q R ^q ) _n -N-, -OC (O)-(CR ^q R ^q ) _n- N-, -NC (O)-(CR ^q R ^q ) _n -O-, -OC (O) -NR ^2- (CR ^q R ^q ) _n- , -NR ² -C (O) -O- ( CR ^q R ^q ) _n- , -NR ² -C (O) -NR ^2- (CR ^q R ^q ) _n -,-(CR ^q R ^q ) _n -C (O) -O- (CR ^q R ^q ) _n -,-(CR ^q R ^q ) _n -C (O) -NR ^2- (CR ^q R ^q ) _n -,-(CR ^q R ^q ) _n -C (O) -NR ² -NR ^2- ,-(CR ^q R ^q ) _n -C (O)-(CR ^q R ^q ) _n- , -C (O) -O- (CR ^q R ^q ) _n -O-, -C (O) -O -(CR ^q R ^q ) _n -NR ^2- , -C (O) -NR ^2- (CR ^q R ^q ) _n -NR ² , -C (O) -NR ^2- (CR ^q R ^q ) _n- O-, -C (O) -NR ² -CR ^q = CR ^q- , C (O) -CR ^q = CR ^q -NR ^2- , -C (O) -CR ^q = CR ^q -O-,- Forms an optionally substituted oxo-substituted heterocycle selected from C (O) -CR ^q = CR ^q -S-;

Each n is independently 1, 2 or 3;

Each R ^q is H, alkyl, substituted alkyl, aryl, substituted aryl, ketoalkyl, substituted ketoalkyl, ketoheteroalkyl, substituted ketoheteroalkyl, heteroalkyl, substituted heteroalkyl, heterocycle, or substitution Independently from the heterocycle.

In certain embodiments, a compound provided herein has a structure of Formula IIa:

Formula IIa

In other embodiments, the compounds provided herein have the structure of Formula IIb:

Formula IIb

In certain other embodiments, the compounds provided herein have the structure of Formula IIc:

Formula IIc

In another embodiment, the compounds provided herein have a structure of Formula IId:

Formula IId

In certain other embodiments, the compounds provided herein have the structure of Formula IIe:

Formula IIe

In certain embodiments, both A and B are H, but at least one X is present and should be N. In an embodiment, when X is present, at least one X is N.

In certain embodiments, a compound provided herein is a compound having the structure of Formula I: a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite, pharmaceutically Acceptable prodrugs or pharmaceutically acceptable solvates are:

Formula I

In the above formula, D is O or NR ¹¹ ; One of A or B is (CH ₂ ) _m C (O) -alkyl, (CH ₂ ) _m C (O) -N (R ² ) ₂ , the other is H, alkyl or heteroalkyl,

m is 0, 1, 2 or 3; or

A and B together form an optionally substituted oxo-substituted heterocycle; or

A and B together form an optionally substituted heteroaromatic group comprising at least one N, NR ² , S or O group; or

A and B together form an optionally substituted non-aromatic or aromatic carbocyclic group; or

A and B are each H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted ketoalkyl and optionally substituted ketoheteroalkyl Independently from;

R ¹ is optionally selected from C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl (C ₃ -C ₉ cycloalkyl), C ₁ -C ₄ alkyl (aryl) and C ₁ -C ₄ alkyl (heteroaryl) Substituted group,

Any carbon of the R ¹ cycloalkyl ring is optionally substituted with Y and Z, each Y and each Z is independently selected from halogen, methyl or trifluoromethyl or Y and Z together are 3-, 4- Or 5-membered carbocyclic groups or oxo (═O);

Each R ² is independently selected from H or optionally substituted alkyl;

R ¹¹ is H or optionally substituted alkyl.

In any and all embodiments, substituents can be selected from the sub-examples of the presented alternatives. For example, in certain embodiments, one of A or B is C (O) -alkyl and the other is H or alkyl or heteroalkyl. In certain embodiments, A and B together form an optionally substituted non-aromatic ring group comprising a C (O) — (CH ₂ ) _n − moiety, wherein n is 1, 2, 3 or 4. In other embodiments, A and B together form an optionally substituted heteroaromatic group comprising one or more N, NR ² , S or O groups. In certain embodiments, R ¹ is C ₃ -C ₉ cycloalkyl, C ₁ -C ₄ alkyl (C ₃ -C ₉ cycloalkyl), C ₁ -C ₄ alkyl (aryl) and C ₁ -C ₄ alkyl ( Heteroaryl), and optionally carbon of the R ¹ cycloalkyl ring is optionally substituted with Y and Z, each Y and each Z is independently selected from halogen, methyl or trifluoromethyl or Or Y and Z may together form a 3-, 4- or 5-membered carbocyclic group or oxo (═O). In certain embodiments, R ² is H or optionally substituted alkyl. In certain embodiments, R ¹¹ is H. In other embodiments, pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs or pharmaceutically acceptable solvates are provided.

In a further embodiment, A and B together form -C (O)-(CR ^q R ^q ) _n- , -C (O) -NR ^2- (CR ^q R ^q ) _n- , -NR ² -C ( O)-(CR ^q R ^q ) _n- , -C (O) -NR ² -NR ^2- (CR ^q R ^q ) _n- , -C (O) -NR ² -N = (CR ^q )-, -0-C (O) -O-, 0-C (O) -NR ^2- , -NR ² -C (O) -NR ^2- , -OC (O) -O- (CR ^q R ^q ) _n -, -OC (O)-(CR ^q R ^q ) _n -O-, -NC (O)-(CR ^q R ^q ) _n -N-, -OC (O)-(CR ^q R ^q ) _n- N-, -NC (O)-(CR ^q R ^q ) _n -O-, -OC (O) -NR ^2- (CR ^q R ^q ) _n- , -NR ² -C (O) -O- ( CR ^q R ^q ) _n- , -NR ² -C (O) -NR ^2- (CR ^q R ^q ) _n -,-(CR ^q R ^q ) _n -C (O) -O- (CR ^q R ^q ) _n -,-(CR ^q R ^q ) _n -C (O) -NR ^2- (CR ^q R ^q ) _n -,-(CR ^q R ^q ) _n -C (O) -NR ² -NR ^2- ,-(CR ^q R ^q ) _n -C (O)-(CR ^q R ^q ) _n- , -C (O) -O- (CR ^q R ^q ) _n -O-, -C (O) -O -(CR ^q R ^q ) _n -NR ^2- , -C (O) -NR ^2- (CR ^q R ^q ) _n -NR ² , -C (O) -NR ^2- (CR ^q R ^q ) _n- O-, -C (O) -NR ² -CR ^q = CR ^q- , C (O) -CR ^q = CR ^q -NR ^2- , -C (O) -CR ^q = CR ^q -O-,- Forms an optionally substituted oxo-substituted heterocycle selected from C (O) -CR ^q = CR ^q -S-; Each n is independently 1, 2 or 3; Each R ^q is H, alkyl, substituted alkyl, aryl, substituted aryl, ketoalkyl, substituted ketoalkyl, ketoheteroalkyl, substituted ketoheteroalkyl, heteroalkyl, substituted heteroalkyl, heterocyclic or substituted Independently from the heterocycle.

In certain embodiments, R ² is H. In certain embodiments, one of A or B is C (O) —CH ₃ and the other is CH ₃ .

In other embodiments, 3-carbamoylphenyl cyclohexylcarbamate; 3-carbamoylphenyl cyclohexylmethylcarbamate; 3-acetylphenyl cyclohexyl carbamate; 3- acetylphenyl cyclohexylmethyl carbamate; 3-acetylphenyl isopropyl carbamate; 3-acetylphenyl isobutyl carbamate; And non-limiting examples selected from 3-acetylphenyl phenethyl carbamate. In certain embodiments, A and B together form an optionally substituted non-aromatic ring group comprising a C (O) — (CH ₂ ) _n − moiety, wherein n is 1, 2, 3 or 4. In other embodiments, n is 2. In certain embodiments, R ² is H. In other embodiments, A or B is C (O) —CH ₂ CH ₃ .

In certain embodiments, 2,3-dihydro-1-oxo-1 H -inden-6-yl cyclohexyl carbamate; 2,3-dihydro-1-oxo-1 H -inden-6-yl cyclohexylmethyl carbamate; 2,3-dihydro-1-oxo-1 H -inden-5-yl cyclohexyl carbamate; And 2,3-dihydro-1-oxo--1 H -inden-5-yl cyclohexylmethyl carbamate.

In further embodiments, A and B together form an optionally substituted heteroaromatic group comprising one or more N, NR ² , S or O groups. In certain embodiments, it further comprises _a- (CH) _n -moiety, wherein n is 1, 2 or 3. In another embodiment, there is an optionally substituted heteroaromatic group comprising a single N in the ring.

In certain embodiments, quinolin-7-yl cyclohexyl carbamate; Quinolin-7-yl cyclohexylmethyl carbamate; Quinolin-7-yl cycloheptyl carbamate; Quinolin-7-yl (furan-2-yl) methyl carbamate; Quinolin-7-yl cyclohexylmethyl carbamate; Quinolin-6-yl cyclohexyl carbamate; Quinolin-6-yl cyclohexylmethyl carbamate; Quinolin-6-yl (furan-2-yl) methyl carbamate; Isoquinolin-7-yl cyclohexyl carbamate; Isoquinolin-7-yl cyclohexylmethyl carbamate; Isoquinolin-7-yl cycloheptyl carbamate; A non-limiting example is selected from pharmaceutically acceptable N-oxides thereof.

In certain embodiments, the optionally substituted heteroaromatic group comprises two heteroatoms selected from N, S and O.

In certain embodiments, 2-methylbenzo [d] thiazol-5-yl cyclohexyl carbamate; 2-methylbenzo [d] thiazol-5-yl cyclohexylmethyl carbamate; 2-methylbenzo [d] oxazol-5-yl cyclohexyl carbamate; And non-limiting examples selected from 2-methylbenzo [d] oxazol-5-yl cyclohexylmethyl carbamate.

Further provided herein are compounds having the structure of formula III: pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs or Provide pharmaceutically acceptable solvates:

Formula III

In the above formula, D is O or NR ¹¹ ;

로 구성된 군으로부터 선택되며;R ¹ is

Is selected from the group consisting of;

M is a bond, optionally substituted C ₁ -C ₈ alkylene, optionally substituted 4-atom heteroalkylene, optionally substituted C ₂ -C ₈ alkenylene, optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted C ₂ -C ₈ alkynylene;

J is CH or N; K is CH or N; Provided that when K is CH, J cannot be CH;

Each R ³ is C ₁ -C ₆ alkyl- (aryl), C ₁ -C ₆ alkyl- (heteroaryl), C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamine, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ heteroalkyl, -C (O) -R ¹² , aryl, heteroaryl, heterocycloalkyl, phenyl, pyridyl, pyridazinyl , Piperazinyl, piperidinyl, morpholinyl, furanyl, thiophenyl, thiophenyl, dibenzofuranyl, dibenzothienyl, indolyl, fluorenyl, carbozolyl, pyrimidinyl, pyrazinyl , Triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxdiazolyl, thiadiazolyl, triazolyl, naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydro Isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnalol, imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxasa Joly, Benz Soxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl, imidazopyridyl, pyrazolopyri Independently selected from the group consisting of optionally substituted groups selected from dill, oxalopyridyl, isoxazolopyridyl or thiazolopyridyl;

Each R 'is independently H, alkyl or substituted alkyl;

Each R ⁵ is independently H, C ₁ -C ₃ alkyl or halogen;

R ⁶ is C ₁ -C ₃ alkyl or C ₃ -C ₇ cycloalkyl;

R ² and R ¹¹ are H or optionally substituted alkyl;

R ¹² is selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ heteroalkyl, benzyloxy, furanyl, phenyl, benzyl or pyridyl; or

를 형성하며;R ¹ and R ² together

To form;

n is 1, 2, 3 or 4; m is 1, 2, 3 or 4;

Each optional substituent is C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, benzyl, halogen, nitro, cyano or benzyloxy-C (O) R ′, —C (O) — (alkyl or substituted Alkyl),-(alkyl or substituted alkyl) -C (O) R ', -C (O) N (R') ₂ , -C (O) N (R ')-(alkyl or substituted alkyl), -(Alkyl or substituted alkyl) -C (O) N (R ') ₂ , ^' -OC (O) N (R ') ₂ , -OC (O) N (R')-(alkyl or substituted alkyl ),-(Alkyl or substituted alkyl) -OC (O) N (R ') ₂ , -N (R') C (O) R ', -NR'C (O)-(alkyl or substituted alkyl) ,-(Alkyl or substituted alkyl) -NR ¹ C (O) R ', -SR', -S- (alkyl or substituted alkyl), -S (O) _k R ', where k is 1 or 2 ), -S (O) _k (alkyl or substituted alkyl), -C (S)-(alkyl or substituted alkyl), -CSN (R ') ₂ , -CSN (R')-(alkyl or substituted Alkyl); -N (R ') CO- (alkyl or substituted alkyl), -N (R') C (O) OR ',-(alkyl or alkyl) -ON = C (R') ₂ ,-(alkyl or substituted Alkyl) -C (O) NR '-(alkyl or substituted alkyl),-(alkyl or substituted alkyl) -S (O) _k- (alkyl or substituted alkyl) -SR',-(alkyl or substituted Alkyl) -S-SR ', -S (O) _k N (R') ₂ , -N (R ') C (O) N (R') ₂ , -N (R ') C (S) N (R ') ₂ , -N (R') S (O) _k N (R ') ₂ , -C (R') = NR'-C (R ') = N-N (R') ₂ and- Independently from C (R ') ₂ -N (R')-N (R ') ₂ .

In certain embodiments, a compound of Formula IIIa is provided:

Formula IIIa

Preparation of the compound

Compounds provided herein that inhibit the activity of FAAH can be synthesized using standard synthetic techniques known to those skilled in the art or using methods known in the art in conjunction with the methods described herein. As further guidance, the following synthesis methods may be used.

The reaction may be used in a linear sequence to provide a compound described herein or it may be used to synthesize segments with methods described herein and / or known in the art.

Use of saver

The term “protecting group” refers to a chemical moiety that protects some or all of the reactive moiety and prevents the group from participating in the chemical reaction until the protecting group is removed. It is desirable that each protecting group can be removed in a variety of ways. A protecting group that breaks down under essentially different reaction conditions meets the requirements of a particular removal. Protectors can be removed by acid, base and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are unstable acids and are carboxy and hydroxy reactive in the presence of amino groups protected with Cbz groups which are removable by hydrogenolysis and Fmoc groups which are unstable bases. Can be used to protect parts. The carboxylic acid and hydroxy reactive moieties are base labile in the presence of an acid labile group such as t-butyl carbamate or an amine blocked with carbamate which has both acid and base stability but can be removed by hydrolysis. And may be blocked with groups such as, but not limited to, methyl, ethyl and acetyl.

Carboxylic acid and hydroxy reactive moieties may also be blocked with protecting groups, such as benzyl groups, which are removable by hydrogenolysis, and amine groups capable of forming hydrogen bonds with acids may be blocked with base labile groups such as Fmoc. The carboxylic acid reactive moiety may be protected by conversion to simple ester derivatives as exemplified herein or may be blocked with protecting groups such as 2,4-dimethoxybenzyl, which may be removed by an oxidation reaction, at the same time Amino groups present may be blocked with fluoride labile silyl carbamates. In one embodiment, a compound comprising both a carboxylic acid reactive moiety and a hydroxy reactive moiety may have one of the reactive moieties without blocking other reactive moieties.

Allyl blocking groups are useful in the presence of acid- and base-protecting groups because they are stable and can be subsequently removed by metal or pi-acid catalysts. For example, the allyl-blocked carboxylic acid can be deprotected with a Pd ⁰ -catalyzed reaction in the presence of an acid labile t-butyl carbamate or base labile acetate amine protecting group. Another form of protecting group is a resin to which a compound or intermediate may be bound. As long as the residue is bound to the resin, the functional groups are blocked and cannot react. Once the functional group is separated from the resin, the functional group can be used for the reaction.

Typically the blocking / protecting group may be selected from:

Other protecting groups are described in Greene and Wuts, Protective Groups in Organic Synthesis , 3rd Ed., John Wiley & Sons, New York, NY, 1999.

Process for preparing ester of alkyl carbamic acid

In certain embodiments, FAAH inhibitors are provided for methods of making and using the compounds provided herein. In certain embodiments, the compounds provided herein can be synthesized using the following synthetic schemes. The compounds can be synthesized in a similar manner to that described below using appropriate alternative starting materials.

The present invention discloses compounds that inhibit the activity of fatty acid amide hydrolase (FAAH) and methods for their preparation. In addition, pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites and pharmaceutically acceptable prodrugs of such compounds are disclosed. A pharmaceutical composition is provided comprising one or more of the above compounds or pharmaceutically acceptable salts of the compounds, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites or pharmaceutically acceptable prodrugs.

Esters of alkylcarbamic acids disclosed herein are produced by the general procedure shown in Scheme 1 below. Ar-OH (2) represents a hydroxy-containing compound selected from substituted phenols and heteroaryls containing a hydroxyl moiety. R ¹ and R ² are as defined herein:

Synthesis of Esters of Alkylcarbamic Acids

Treatment of Ar-OH (2) with isocyanate or isothiocyanate (3) in the presence of a base such as triethylamine in an organic solvent such as ethanol or acetonitrile results in the formation of an ester of alkylcarbamic acid having structure 1 (See, eg, US Pat. No. 5,112,859, WO2004 / 033422; US 2006/0014830; J. Med. Chem. 2004, 47 (21); 4998-5008; Tarzia et al., J. Med. Chem. 46 : 2352-2360 (2003); see Kathuria et al., Nature Medicine 9 (1): 76 (2003)). Isocyanates or isothiocyanates are commercially available. Processes for the preparation of isocyanates or thiocyanates (3) are known in the art. For example, isocyanates (3, Q═O) may be treated with an azide source such as sodium azide or diphenylphosphoryl azide followed by the corresponding carboxylic acid (ie R′-COOH) by Curtius type rearrangement. Or acid derivatives (eg, R′-C (O) Cl) (eg Synth. Commun. 1993, 23, 335; Heterocycles 1993, 36, 1305).

Alternatively, the alkylcarbamic acid ester (1) is a base, such as a tree, of Ar-OH (2) as an alkylcarbamic acid derivative of structure (4), wherein G is 4-nitrofenoxy, chlorine or imidazol-1-yl Treatment in the presence of ethylamine can provide the desired compound (1). Compounds of structure (4) may be prepared by procedures known in the art, such as those described in Greene, TW and Wuts, PGM " Protective Groups in Organic Synthesis ", 3rd Edition, p.549, New York: Wiley, 1999. Can be generated using Briefly, alkylamines (eg, R ¹ -NH ₂ ) are treated with phosgene or phosgene equivalents such as trichloromethyl chloroformate or carbonyldiimidazole to produce the compound of structure (4).

In addition, esters of alkyl (thio) carbamic acid can be synthesized by the method described in Scheme 2 below.

Ester Synthesis of Alkyl (thio) carbamic Acid

Esters of alkyl (thio) carbamic acids can be produced in a two step procedure. Thiophosgene, phosgene or equivalents thereof are first treated with Ar-OH (2) in a suitable organic solvent in the presence of a base and then with an alkylamine such as R ¹ R ² NH. The order of the reactions can be reversed, i.e. thiophosgene, phosgene or equivalent thereof can be treated with alkylamine followed by Ar-OH (2). Examples of equivalents of thiophosgene and phosgene include, but are not limited to, 1,1'-thiocarbonyldiimidazole, 1,1'-carbonyldiimidazole and trichloromethyl chloroformate.

The essential hydroxy-containing compound, Ar-OH (2), can be purchased from conventional sources or can be produced using procedures known in the art or outlined herein.

Using the reaction conditions described herein, esters of alkylcarbamic acid as disclosed herein are obtained in good yields and purity. Compounds produced by the methods disclosed herein can be purified by conventional methods known in the art, such as filtration, recrystallization, chromatography, distillation, combinations thereof, and the like.

Any combination of the groups described above for the various variables is contemplated herein.

Pharmaceutical Compositions / Combinations

The pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries which facilitate the treatment of the active compounds with preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any known technique, carrier and excipients can be used as appropriate and as understood in the art. An overview of the pharmaceutical compositions described herein is described, for example, in Remington: The Science and Practice of Pharmacy , Nineteenth Ed (Easton, Pa .: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences , Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms , Marcel Decker, New York, NY, 1980; Pharmaceutical Dosage Forms , and Drug Delivery Systems , Seventh Ed. (Lippincott Williams & Wilkins 1999).

Provided is a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable diluent (s), excipient (s) or carrier (s). In addition, the compounds described herein can be administered as pharmaceutical compositions that mix the compounds described herein with other active ingredients in a combination treatment. In certain embodiments, the pharmaceutical composition may comprise other pharmaceutical or pharmaceutical agents, carriers, adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, dissolution promoters, salts for regulating osmotic pressure and / or buffers. Can be. In addition, the pharmaceutical compositions may include other therapeutically important substances.

In certain embodiments, the composition comprises one or more pH adjusting or buffering agents, acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid and hydrochloric acid; Bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris-hydroxymethylaminomethane; And buffers such as citrate / dextrose, sodium bicarbonate, ammonium chloride, and the like. Such acids, bases and buffers are included in the amounts necessary to maintain the pH of the composition within an acceptable range.

In other embodiments, the composition may comprise one or more salts in an amount necessary to bring the osmotic pressure of the composition into an acceptable range. Such salts include sodium, potassium or ammonium cations and chlorides, citrate, ascorbates, borates, phosphates, bicarbonates, sulfates, thiosulfates or bisulfite anions; Suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

As used herein, the term "pharmaceutical combination" means a product resulting from mixing or combining more than one active ingredient, and includes fixed and non-fixed combinations of active ingredients. The term “fixed combination” refers to the administration of both the active ingredient, such as the compound and adjuvant formulations described herein, to the patient at the same time in the form of a single formulation or formulation. The term “non-fixed combination” means the administration of the active ingredient, eg, a compound described herein and an adjuvant, to a patient simultaneously, concurrently or sequentially with separate preparations without a specific time limit, wherein the administration is Two compounds are provided that are effective to the body of the patient. The latter also applies to cocktail therapy, eg the administration of three or more active ingredients.

As used herein, pharmaceutical composition refers to a mixture of a compound described herein with other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickening agents and / or excipients. Pharmaceutical compositions facilitate the administration of a compound to an organism. In practicing the treatment methods or uses provided herein, a therapeutically effective amount of a compound described herein is administered to a mammal having a disease, condition or condition to be treated in a pharmaceutical composition. The mammal is preferably a human. The therapeutically effective amount can vary greatly depending on the severity, age and relative health of the subject's disease, the potency of the compound used and other factors. The compounds can be used alone or in combination with one or more therapeutic agents as a component.

 The pharmaceutical combinations described herein may be administered to an individual by a plurality of routes of administration, including oral, parenteral (eg, intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal or transdermal routes of administration, It is not limited to this. The pharmaceutical formulations described herein include aqueous liquid dispersions, autoemulsion dispersions, solid solutions, liposome dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, quick melt formulations, tablets, capsules, pills, delayed release. Blends, extended release blends, pulsating release blends, multiparticulate blends and mixed immediate and controlled release blends, and the like.

Pharmaceutical compositions comprising the compounds described herein can be prepared by conventional methods, such as, for example, by conventional mixing, dissolving, granulating, dragee preparation, powdering, emulsifying, encapsulating, capturing or pressing processes, but not limited thereto. It doesn't happen.

Pharmaceutical compositions comprise one or more compounds described herein as active compound in free acid or free base form or in pharmaceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of compounds having the same type of activity. In certain circumstances, compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In addition, the compounds described herein may exist in unsolvated form as well as solvate forms with pharmaceutically acceptable solvents such as water, ethanol and the like. The solvate forms of the compounds presented herein are also considered to be disclosed herein.

Certain pharmaceutical terms

As used herein, the terms “treat”, “treating” or “treatment” alleviate, attenuate or ameliorate signs of a disease or condition, prevent further signs, ameliorate or prevent underlying metabolic causes of signs, Suppression of a disease or condition, such as stopping the progression of the disease or condition, alleviating the disease or condition, retreating of the disease or condition, and alleviating the condition or condition of the disease or condition caused by the disease or condition; Prophylactically and / or therapeutically.

As used herein, the term "acceptable" with respect to a combination, composition or ingredient means that there is no permanent harmful effect on the general health of the individual being treated.

As used herein, the term “selective inhibitor compound” refers to a compound that selectively inhibits the specific function / activity of one or more target proteins.

As used herein, the term “selectively inhibit” is more potent than the activity of a non-target protein, such that the selective inhibitor compound is capable of specific function / activity of the target protein, such as fatty acid amide hydrolysis of fatty acid amide hydrolases. Refers to the ability to inhibit activity. In certain embodiments, a selectively inhibiting Iranian IC ₅₀ target protein using a selective inhibitor that is at least 10 times, 50 times, 100 times, 250 times, 500 times, 1,000 times or more lower than the non-target protein activity. Refers to inhibiting activity.

As used herein, amelioration of the manifestation of a particular disease, disease or condition by administration of a particular compound or pharmaceutical composition is permanent or temporary, persistent that may be due to or associated with the administration of the compound or composition. Or a decrease in the severity of a period, delay in initiation, delay in progress or shortening in duration, whether transient or transient.

As used herein, the term "target activity" refers to a biological activity that can be modulated by selective regulators. Examples of specific exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzyme activity, tumor growth, improvement of one or more signs associated with inflammation or inflammation-related processes and diseases or conditions.

As used herein, IC ₅₀ refers to the content, concentration or dosage of a particular test compound that achieves 50% inhibition of the maximum response, such as inhibition of FAAH, in the assay measuring the response.

As used herein, EC ₅₀ is the dose, concentration, or concentration of a particular test compound that characterizes a dose dependent response at 50% of the maximum expression of a particular response that is induced, elicited, or enhanced by the particular test compound. Refers to content.

As used herein, the term "carrier" refers to a relatively nontoxic chemical compound or agent that facilitates the incorporation of the compound into cells or tissues.

As used herein, the term “simultaneous administration” and the like is intended to encompass the administration of a selected therapeutic agent to a single patient, and refers to a therapeutic regimen in which the agent is administered by the same or different route of administration or at the same or different time. I want to include it.

As used herein, the term “effective amount” or “therapeutically effective amount” refers to a sufficient amount of agent or compound administered that alleviates to some extent one or more of the signs of the disease or condition to be treated. Reduction and / or alleviation of signals, signs or causes of diseases of the biological system or any other desired modification. For example, an “effective amount” for therapeutic use is the amount of a composition comprising a compound as disclosed herein necessary to provide a clinically significant reduction in disease manifestations without excessively harmful side effects. Appropriate “effective amount” in any respective case can be measured using techniques such as dose escalation experiments. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. An “effective amount” of a compound disclosed herein is an amount effective to achieve the desired pharmacological efficacy or therapeutic improvement without excessively harmful side effects.

An "effective amount" or "therapeutically effective amount" may vary from subject to subject, depending on the change in metabolism of the compound administered, age, weight, general condition of the subject, the condition to be treated, the severity of the condition to be treated, and the judgment of the attending physician. I understand that.

As used herein, the term “improving” or “improving” means increasing or prolonging a certain effect in efficacy or duration. Thus, with regard to improving the efficacy of a therapeutic agent, the term “improving” refers to the ability to increase or prolong the efficacy of other therapeutic agents in a system or efficacy in the system. As used herein, “improving-effective amount” refers to an amount suitable to improve the efficacy of another therapeutic agent in a given system.

The terms "kit" and "article of manufacture" are used as synonyms.

A “metabolite” of a compound disclosed herein is a derivative of a compound that is formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized. As used herein, the term “metabolized” refers to the entire process in which a particular substance is altered by an organism (including but not limited to hydrolysis reactions and enzyme catalyzed reactions such as oxidation reactions, etc.) Refers to. Thus, enzymes can produce certain structural alterations of a compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphate glucuronyl transferases convert activated glucuronic acid molecules into aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. Catalyze the transition. Further information on metabolism can be obtained from The Pharmacological Basis of Therapeutics , 9th Edition, McGraw-Hill (1996). Metabolites of compounds disclosed herein can be identified by administering the compound to a host and analyzing a tissue sample from the host or by in vitro culture of the compound using hepatocytes and analysis of the resulting compound. Two methods are known in the art. In certain embodiments, metabolites of compounds are formed by oxidation processes and correspond to the corresponding hydroxy-containing compounds. In certain embodiments, the compound is metabolized into a pharmacologically active metabolite.

"Prodrug" refers to an agent that is converted to the parent drug in vivo. Prodrugs are often useful because, in certain cases, they may be easier to administer than the parent drug. Prodrugs may be bioavailable, for example by oral administration, but not the parent drug. Prodrugs may also have improved solubility in pharmaceutical compositions over parent drugs. Examples of prodrugs are administered as esters ("prodrugs") that promote delivery across cell membranes where water solubility is harmful to migration but subsequently metabolized and hydrolyzed to the active carboxylic acid, and inside the cell There are, but are not limited to, compounds described in this specification. Further examples of prodrugs may be short peptides (polyamino acids) bound to acid groups in which the peptide is metabolized and becomes the active moiety. In certain embodiments, upon in vivo administration, the prodrug is chemically converted into a biological, pharmaceutical or therapeutically more active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized into a compound in a biological, pharmaceutically or therapeutically active form by one or more steps or processes. To produce prodrugs, pharmaceutically active compounds are modified to regenerate the active compounds upon in vivo administration. Prodrugs can be designed to alter the metabolic stability or transport properties of a drug, block side effects or toxicity, and alter other properties or properties of the drug. Knowledge of pharmacodynamic processes and drug metabolism in vivo will allow those skilled in the art to design prodrugs of compounds once they know a pharmaceutically active compound. See, eg, Nogrady (1985) Medicinal Chemistry A Biochemical Approach , Oxford University Press, New York, pages 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action , Academic Press, Inc., San Diego, pages 352-401.

As used herein, "pharmaceutically acceptable" refers to a substance that does not interfere with the biological activity or properties of the compound and that is relatively nontoxic, such as a carrier or diluent, that is, the substance does not cause undesirable biological efficacy. Or may be administered to a subject without interacting with any component of the included composition in a deleterious manner.

The term “pharmaceutically acceptable salts” refers to combinations of compounds that do not cause significant irritation to the organism to be administered and do not interfere with the biological activity and properties of the compound. Pharmaceutically acceptable salts can be obtained by reacting the compounds described herein with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In addition, pharmaceutically acceptable salts may be prepared by reacting a compound described herein with a base, such as ammonium salts, alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, salts of organic bases, Obtained by, for example, forming dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methylamine and salts with amino acids such as arginine, lysine, or by other methods known in the art. Can be.

"Defoamers" reduce the coagulation of aqueous dispersions, bubbles in the final film, or bubbles in the process that can generally damage the process. Examples of antifoaming agents include silicon emulsions or sorbitan sesquioleates and the like.

Examples of "antioxidants" include butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium metabisulfite and tocopherol. In certain embodiments, antioxidants improve chemical stability when necessary.

In certain embodiments, the compositions provided herein can also include one or more preservatives that inhibit microbial activity. Suitable examples of preservatives include mercury-containing materials such as merpenes and thiomersal; Stabilized chlorine dioxide; And quaternized ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

The combinations described herein can benefit from antioxidants, metal chelating agents, thiol containing compounds and other common stabilizers. Non-limiting examples of such stabilizers include (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80 (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (1) pentosan polysulfate and others Heparinoids, (m) divalent cations such as magnesium and zinc; Or (n) combinations thereof.

"Binders" impart cohesive properties, examples of which include alginic acid and salts thereof; Cellulose derivatives such as carboxymethylcellulose, methylcellulose (e.g. Methocel®), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose (e.g. Klucel®), ethylcellulose (e.g. Ethocel®) and microcrystalline cellulose (eg, Avicel®); Microcrystalline dextrose; Amylose; Magnesium aluminum silicate; Polysaccharide acid; Bentonite; gelatin; Polyvinylpyrrolidone / vinyl acetate copolymers; Crospovidone; Povidone; Starch; Pregelled starch; Tragacanth, dextrins, sugars such as sucrose (eg, Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (eg, Xylitab®) and lactose; Natural or synthetic gums, such as acacia, tragacanth, gati gum, isocarpech viscous, polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone® XL -10), larch arabgalactan, Veegum®, polyethylene glycols, waxes, sodium alginate and the like.

"Bioavailability" refers to the weight ratio of the compound disclosed herein to be delivered to the general circulation of the animal or human being tested. Total exposure (AUC _(O-∞) ) upon intravenous administration of the drug is generally defined as 100% bioavailability (F%). "Oral bioavailability" refers to the extent to which the compounds disclosed herein are absorbed into the large circulation when oral administration of the pharmaceutical composition compared to intravenous injection.

"Plasma concentration" refers to the concentration of a compound provided herein in the plasma component of a subject's blood. It is to be understood that the plasma concentrations of the compounds provided herein may vary widely from individual to individual due to variability in metabolism and / or possible interactions with other therapeutic agents. In one embodiment disclosed herein, the plasma concentrations of the compounds provided herein may vary from subject to subject. Likewise, values such as maximum plasma concentration (C _max ) or time to reach maximum plasma concentration (T _max ) or total area under the plasma concentration time curve (AUC _(O-∞) ) may vary from subject to subject. Because of this variability, the amount required to constitute a "therapeutically effective amount" of a compound provided herein may vary from individual to individual.

A "carrier material" may include any commonly used excipient in pharmacy and should be selected based on the affinity with the compounds disclosed herein and the release profile nature of the desired dosage form. Examples of carrier materials include binders, suspending agents, disintegrating agents, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents and the like. Non-limiting examples of "pharmaceutical affinity carrier materials" include acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, polyvinylpyrrolidone (PVP), cholesterol, Cholesterol esters, sodium caseinate, soy lecithin, taurocholic acid, phosphatidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose and cellulose conjugates, sugar sodium stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelation Starch and so on. See, eg, Remington: The Science and Practice of Pharmacy , Nineteenth Ed (Easton, Pa .: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences , Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Form , Marcel Decker, New York, NY, 1980; Pharmaceutical Dosage Forms and Drug Delivery Systems , Seventh Ed. See Lippincott Williams & Wilkins 1999.

"Dispersants" and / or "viscosity modifiers" include substances that control the diffusion and homogeneity of a drug through a liquid medium or by granulation or mixing. In certain embodiments, these agents also promote the efficacy of the coating or erosion matrix. Examples of diffusion promoters / dispersants include hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commonly known as Plasdone®) and carbohydrate-based dispersants such as hydroxy Propyl cellulose (e.g. HPC, HPC-SL and HPC-L), hydroxypropyl methylcellulose (e.g. HPMC K100, HPMC K4M, HPMC K1 5M and HPMC K100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose , Hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), amorphous cellulose, magnesium silicate, triethanolamine, polyvinyl alcohol (PVA), vinyl pyrrolidone / vinyl acetate Copolymer (S630), 4- (1,1,3,3-tetramethylbutyl) -phenolic polymer (known as tyloxapol) with ethylene oxide and formaldehyde, poloxamer (eg, Pluronics F68® F88® and F108®, block copolymers of ethylene oxide and propylene oxide); And Poloxamine (e.g. Tetronic 908®), also known as Poloxamine 908®, a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (Pashi, NJ, USA). BASF Corporation of Fannie)), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or polyvinylpyrrolidone K30, polyvinylpyrrolidone / vinyl acetate copolymer (S- 630), polyethylene glycol, for example polyethylene glycol having a molecular weight of about 300 to about 6,000 or about 3,350 to about 4,000 or about 7,000 to about 5,400, sodium carboxymethylcellulose, methylcellulose, polysorbate-80, sodium alginate, gum Such as gum tragacanth and gum acacia, guar gum, xanthan gum, xanthan, sugars, celluloses such as sodium carboxymethylcellulose, methylcellulose, nat Carboxymethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, carbomer, polyvinyl alcohol (PVA), alginate, chitosan And combinations thereof. Plasticizers such as cellulose or triethyl cellulose can be used as dispersants. Particularly useful dispersants for liposome dispersions and automatic emulsifying dispersions are dimyristoyl phosphatidylcholine, natural phosphatidylcholine from eggs, natural phosphatidyl glycerol from eggs, cholesterol and isopropyl myristate.

Combinations of one or more erosion promoters and one or more diffusion promoters may be used in the present compositions.

The term "diluent" refers to a chemical compound used to dilute it prior to delivery of that compound. Diluents can also be used to stabilize compounds as they can provide a more stable environment. Salts dissolved in buffers (which may also provide pH control or maintenance) are used in the art as diluents, examples of which include, but are not limited to, phosphate buffered saline. In certain embodiments, the diluent increases the volume of the composition to facilitate compression or to produce sufficient volume in the homogeneous mixture for capsule filling. Examples of such compounds include lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel®; Dibasic calcium phosphate, dicalcium phosphate dihydrate; Tricalcium phosphate, calcium phosphate; Anhydrous lactose, spray dried lactose; Pregelled starch, compressed white sugar such as Di-Pac® Amstar; Mannitol, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose diluent, refined sugar; Monobasic calcium sulfate monohydrate, calcium sulfate dihydrate; Calcium lactate trihydrate, dexrate; Hydrolyzed cereal solids, amylose; Powdered cellulose, calcium carbonate; Glycine, kaolin; Mannitol, sodium chloride; Inositol, bentonite and the like.

The term "disintegrate" includes both dissolution and dispersion of the dosage form upon contact with gastrointestinal fluid. A "disintegrant or disintegrant" promotes the decomposition or disintegration of a substance. Examples of disintegrants include starch, for example natural starch, such as corn starch or potato starch, pregelled starch, such as National 1551 or Amijel® or sodium starch glycolate, such as Promogel® or Explotab®. Trademarks), celluloses such as wood products, methylcrystalline celluloses such as Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel (R), Vivacel (R), Ming Tia (R) and Solka-Floc (R), methylcellulose, croscarmellose or crosslinked cellulose such as crosslinked sodium carboxymethylcellulose (Ac-Di- Sol®), crosslinked carboxymethylcellulose or crosslinked croscarmellose, crosslinked starch such as sodium starch glycolate, crosslinked polymer such as crospovidone, crosslinked polyvinylpy Lidons, alginates, such as alginic acid or salts of alginic acid, such as sodium alginate, clays, such as Veegum® Magnesium Silicate, gums such as agar, guar, low custard, karaya, pectin or tragacanth , Sodium starch glycolate, bentonite, natural sponges, surfactants, resins such as cation exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination starch and the like.

"Drug uptake" or "absorption" typically refers to the process by which a drug moves from a site of administration of a drug across a blocker into a blood vessel or to a site of action, such as a drug from the gastrointestinal tract to the portal or lymphatic system. do.

"Enteric bark" is a substance that is almost intact in the stomach, but in which the drug is dissolved and released in the small intestine or colon. Enteric coatings generally comprise polymeric materials which interfere with release in the low pH environment of the stomach, but which are ionized at higher pH, typically pH 6-7, to sufficiently decompose in the small intestine or colon to release the active agent.

"Erosion promoter" includes substances that control the erosion of certain substances in gastrointestinal fluids. Erosion promoters are generally known to those skilled in the art. Examples of erosion promoters include hydrophilic polymers, electrolytes, proteins, peptides and amino acids.

A "filler" is a compound such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrate, dextran, starch, pregelated starch, sucrose, xylitol , Lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol and the like.

Examples of "flavourers" and / or "sweetening agents" useful in the formulations described herein include acacia syrup, acesulfame K, altime, anise, apple, aspartame, banana, barbarian cream, berry, black currant, butterscotch, Calcium Citrate, Camper, Caramel, Cherry, Cherry Cream, Chocolate, Cinnamon, Bubble Gum, Citrus, Citrus Punch, Citrus Cream, Cotton Candy, Cocoa, Cola, Cool Cherry, Cool Citrus, Cyclamate, Silamate, Dextrose, Eucalyptus , Eugenol, fructose, fruit punch, ginger, glycyrrhetinate, licorice syrup, grapefruit, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycinate (registered) Brand)), maltol, mannitol, maple, mashmallow, menthol, mint cream, mix berry, neohesperidin dc, neo-teme, orange, pear, peach, peppermint, peppermint cream, prosweet ( Rock, Powder, Raspberry, Root Beer, Rum, Saccharin, Saffol, Sorbitol, Spearmint, Spearmint Cream, Strawberry, Strawberry Cream, Stevia, Sucralose, Sucrose, Sodium Saccharin, Saccharin, Aspartame, Acesulfame Potassium, Mannitol, Any combination of Tallinn, Silitol, Sucralose, Sorbitol, Swiss Cream, Tagatose, Tangerine, Taumatin, Tuti Fruity, Vanilla, Walnut, Watermelon, Wild Cherry, Camellia oil, Xylitol or Flavoring Ingredients, for example Anais-menthol , Cherry-anais, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint and mixtures thereof.

"Lubricants" and "lubricants" are compounds that interfere with, reduce or inhibit adhesion or friction of materials. Examples of lubricants include stearic acid, calcium hydroxide, talc, sodium stearyl fumerate, hydrocarbons such as mineral oil or hydrogenated vegetable oils such as hydrogenated soybean oil (Sterotex®), higher fatty acids and their alkali and alkaline earth metal salts such as aluminum , Calcium, magnesium, zinc, stearic acid, sodium stearate, glycerol, talc, wax, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol (e.g. PEG-4000) or methoxy Polyethylene glycols such as Carbowax® sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium or sodium lauryl sulfate, colloidal silica, such as Syloid Cab-O-Sil®, starch Such as corn starch, silicone oils, surfactants and the like.

"Measurable serum concentration" or "measurable plasma concentration" typically refers to blood serum or plasma concentrations measured in units of mg, μg or ng of therapeutic agent per milliliter, liter or liter of serum absorbed into the bloodstream after administration. As used herein, measurable plasma concentrations are typically measured in ng / ml or μg / ml units.

"Pharmacodynamic" refers to a factor that measures the observed biological response to the concentration of a drug at the site of action.

"Pharmacokinetics" refers to factors that measure the attainment and maintenance of appropriate concentrations of a drug at the site of action.

A "plasticizer" is a compound used to soften microencapsulating material or membrane coatings to make them less brittle. Examples of suitable plasticizers include polyethylene glycols such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350 and PEG 800, stearic acid, propylene glycol, oleic acid, triethyl cellulose and triacetin. In certain embodiments, the plasticizer may also act as a dispersing or wetting agent.

"Solubilizers" are compounds such as triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium docuate, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N Hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cyclodextrin, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salt, polyethylene glycol 200-600, glycofurol, Transcutol, propylene glycol and dimethyl isosorbide and the like.

Examples of “stabilizers” are compounds such as any antioxidants, buffers, acids, preservatives, and the like.

As used herein, "steady state" is when the amount of drug administered corresponds to the amount of drug removed within one dosing interval resulting in flat or constant plasma drug exposure.

“Suspension agents” include compounds such as polyvinylpyrrolidone, such as polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or polyvinylpyrrolidone K30, vinyl pyrrolidone / Vinyl acetate copolymer (S630), polyethylene glycol, for example polyethylene glycol having a molecular weight of about 300 to about 6,000 or about 3,350 to about 4,000 or about 7,000 to about 5,400, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose , Hydroxymethylcellulose acetate stearate, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums such as gum tragacanth and gum acacia, guar gum, xanthan gum, xanthans, sugars, celluloses such as Sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethyl cellulose And the like switch, polysorbate -80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone poly to poly.

"Surfactants" include compounds such as sodium lauryl sulfate, sodium docusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxomer , Bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, such as Pluronic® (BASF), and the like. Certain other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils such as polyoxyethylene (60) hydrogenated castor oil; And polyoxyethylene alkyl ethers and alkylphenyl ethers such as octoxynol 10, octoxynol 40 and the like. In certain embodiments, surfactants may be included to improve physical stability or for other purposes.

Examples of "viscosity improvers" include methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetate stearate, hydroxypropylmethyl cellulose phthalate, carbomer, polyvinyl Alcohols, alginates, acacia, chitosan and combinations thereof.

"Wetting agents" include compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, Sodium docusate, sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin, Tween 80, vitamin E TPGS, ammonium salts and the like.

Dosage Form

The compositions disclosed herein are administered to a subject by any conventional method, including but not limited to oral, parenteral (eg, intravenous, subcutaneous or intramuscular), buccal, intranasal, rectal or transdermal routes of administration. It may be formulated to. As used herein, the term “individual” is intended to mean an animal, preferably a mammal, including a human or non-human. The terms patient and individual can be used interchangeably.

In addition, the pharmaceutical compositions described herein, including the compounds provided herein, may be used for oral intake by patients to be treated, such as aqueous oral dispersions, solutions, gels, syrups, elixirs, slurries, suspensions, etc., solid oral dosage forms, aerosols Controlled release formulations, rapid melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations and mixed immediate release and controlled release It may be formulated in any suitable dosage form, including but not limited to the combination.

Pharmaceutical preparations for oral use may be prepared by mixing one or more solid excipients with one or more of the compounds described herein, milling the resulting mixture, optionally adding the appropriate adjuvant and then processing the mixture of granules to tablets or dragees. You get a core. Examples of suitable excipients include fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; Cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; Or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If necessary, the disintegrant can be added, for example, crosslinked croscarmellose sodium, polyvinylpyrrolidone, agar or alginic acid or salts thereof, such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used and may optionally comprise gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. . Dyestuffs or pigments may be added for identification of tablets or dragee coatings or for characterizing the active compound dosages of various combinations.

Pharmaceutical preparations that can be used orally include push-fit capsules made with gelatin, as well as soft sealed capsules made with gelatin and plasticizers such as glycerol or sorbitol. The push-fit capsules may comprise active ingredients in admixture with fillers such as lactose, binders such as starch and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. For soft capsules, the active compounds may be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin or liquid polyethylene glycols. In addition, stabilizers may be added. All combinations for oral administration should be in dosages suitable for such administration.

In certain embodiments, solid dosage forms disclosed herein include tablets (including suspension tablets, rapid melt tablets, bite-disintegration tablets, rapid disintegrating tablets, effervescent tablets or caplets), pills, powders (sterile packaging) Powders, including disposable powders or effervescent powders), capsules (including soft or hard capsules, for example capsules or “water spray capsules” generated from animal or vegetable derived HPMC), solid dispersions, solid solutions, bioerodible dosage forms , Controlled release formulations, pulsatile release formulations, multiparticulate dosage forms, pellets, granules or aerosols. In other embodiments, the pharmaceutical combination is in the form of a powder. In other embodiments, the pharmaceutical combination is in the form of a tablet, including but not limited to rapid melt tablets. In addition, the pharmaceutical combinations of the present invention may be administered as a single capsule or in multiple capsule dosage forms. In certain embodiments, the pharmaceutical combination is administered in two or three or four capsules or tablets.

In certain embodiments, solid dosage forms, such as tablets, effervescent tablets and capsules, are produced by mixing particles of a compound provided herein with one or more pharmaceutical excipients to form a bulk blend composition. When referring to such bulk blend compositions as homogeneous, they are uniformly dispersed in the composition so that the particles of the compounds provided herein can be easily divided into equally effective unit dosage forms such as tablets, pills and capsules. Individual unit dosage forms can also include a membrane coating that disintegrates upon oral ingestion or upon contact with a diluent. These combinations can be prepared by conventional pharmacological techniques.

Examples of conventional pharmacological techniques include one of (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation or (6) fusion or Combinations thereof. See, eg, Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Examples of other methods include spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (eg wurster coating), tangential coating, top spraying, tableting, extrusion and the like.

The pharmaceutical solid dosage forms described herein comprise compounds provided herein and one or more pharmaceutically acceptable additives such as affinity carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrants, dispersants, surfactants, Lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, permeation enhancers, wetting agents, antifoaming agents, antioxidants, preservatives or one or more combinations thereof. In other embodiments, membrane coatings are provided around the combination of compounds provided herein using conventional coating procedures, such as those described in Remington's Pharmaceutical Sciences , 20th Edition (2000). In one embodiment, some or all of the compound particles provided herein are coated. In another embodiment, some or all of the particles of a compound provided herein are microencapsulated. In another embodiment, the particles of the compounds provided herein are not microencapsulated and coated.

Suitable carriers for use in the solid dosage forms described herein include acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, phosphoric acid Tricalcium, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglycerides, pregelled starch, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose , Mannitol, and the like, but is not limited thereto.

Examples of suitable fillers for use in the solid dosage forms described herein include lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrate, dextran, starch, Pregelled starch, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, etc. There is, but is not limited to this.

In order to release the compounds disclosed herein from the solid dosage form substrates as efficiently as possible, disintegrants are often used in the formulations, especially when the dosage form is compressed with a binder. Disintegrants help to rupture the dosage form substrate by swelling or capillary action when moisture is absorbed into the dosage form. Suitable disintegrants for use in the solid dosage formulations described herein include natural starch, such as corn starch or potato starch, pregelled starch, such as National 1551 or Amijel® or sodium starch glycolate, such as Promogel®. Trademark) or Explotab®, celluloses such as wood products, methylcrystalline cellulose such as Avicel®, Avicel® PH101, Avicel® H102, Avicel® PH105, Elcema P100, Emcocel (R), Vivacel (R), Ming Tia (R) and Solka-Floc (R) methylcellulose, croscarmellose or crosslinked cellulose such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose or crosslinked croscarmellose, crosslinked starch such as sodium starch glycolate, crosslinked polymers such as Crospovidone, cross-linked polyvinylpyrrolidone, alginate salts such as alginic acid or salts of alginic acid such as sodium alginate, clays such as Veegum® magnesium aluminum silicate, gums such as agar, guar, locust bean , Karaya, pectin or tragacanth, sodium starch glycolate, bentonite, natural sponges, surfactants, resins such as cation exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination starch, and the like. It is not limited to this.

The binder imparts cohesion to the solid oral dosage formulation formulations, and in the case of powder filled capsule formulations, they assist in the formation of plugs that can be filled into tablet formulations and into soft or hard shell capsules, which are in an intact state of the tablet after compression. It ensures to maintain and helps to ensure blend uniformity prior to the compression or filling step. Examples of materials suitable for use as binders in the solid dosage forms described herein include carboxymethylcellulose, methylcellulose (eg, Methocel®), hydroxypropylmethylcellulose (eg, Hypromellose USP Pharmacoat-603), hydride Hydroxypropylmethylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (eg Klucel®), ethylcellulose (eg Ethocel®) and microcrystalline cellulose ( E.g. Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acid, bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelled starch, Tragacanth, dextrin, sugars such as sucrose (e.g. Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), Lactose, natural or synthetic gums, such as acacia, tragacanth, gati gum, slime of starch shells, starch, polyvinylpyrrolidone (e.g. povidone® CL, Kollidon® CL, Polyplasdone® Trademarks) X1-10 and Povidone® K-12), larch arabgalactan, Veegum® polyethylene glycol, wax, sodium alginate, and the like.

In general, a binder content of 20 to 70% is used in powder filled gelatin capsule formulations. The binder use content in the tablet formulations depends on the use of direct compression, wet granulation, roller compaction or other excipients such as fillers which serve as suitable binders by themselves. One skilled in the art can determine the binder content for the blend, but the binder content in the tablet blend is typically 70% or less.

Examples of lubricants or glidants suitable for use in the solid dosage forms described herein include stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumerate, alkali metal and alkaline earth metal salts such as aluminum, calcium, magnesium, zinc , Stearic acid, sodium stearate, magnesium stearate, zinc stearate, wax, Stearowet® boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol or methoxypolyethylene glycol, such as Carbowax® PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like.

Examples of suitable diluents for use in the solid dosage forms described herein include sugars (including lactose, sucrose and dextrose), polysaccharides (including dexrate and maltodextrin), polyols (including mannitol, xylitol and sorbitol), cyclodextrins Etc., but is not limited thereto.

The term "water-insoluble diluent" is a compound commonly used in the formulation of a medicament, such as calcium phosphate, calcium sulfate, starch, modified starch and microcrystalline cellulose and microcellulose (eg, having a density of about 0.45 g / cm 3, eg Such as Avicel, powdered cellulose) and talc.

Examples of humectants suitable for use in the solid dosage forms described herein include oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxy ethylene sorbitan monooleate, Polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (eg, Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docuate, triacetin, vitamin E TPGS and the like.

Examples of suitable surfactants for use in the solid dosage forms described herein include sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxomers, bile salts, glyceryl mono Stearates, copolymers of ethylene oxide and propylene oxide, such as Pluronic® (BASF) and the like.

Examples of suspending agents suitable for use in the solid dosage forms described herein include polyvinylpyrrolidone, such as polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or polyvinylpyrrole. Ralidone K30, polyethylene glycol, for example polyethylene glycol having a molecular weight of about 300 to about 6,000 or about 3,350 to about 4,000 or about 7,000 to about 5,400, vinyl pyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethylcellulose , Methylcellulose, hydroxy-propylmethylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums such as gum tragacanth and gum acacia, guar gum, xanthan gum, xanthan, sugar, cellulose Such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose , Polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and the like, but is not limited thereto.

Examples of antioxidants suitable for use in the solid dosage forms described herein include butylated hydroxytoluene (BHT), sodium ascorbate and tocopherol.

It is to be understood that significant overlap may exist between the additives used in the solid dosage forms described herein. Thus, it is to be understood that the additives set forth above are merely examples of the types of additives that may be included in the solid dosage forms of the present invention and are not intended to be limiting. The content of such additives can be readily determined by one skilled in the art, depending on the particular desired properties.

In other embodiments, one or more layers of the pharmaceutical combination are plasticized. By way of example, plasticizers generally become high boiling solids or liquids. Suitable plasticizers may be added at about 0.01% to about 50% (w / w) of the coating composition. Examples of plasticizers include diethyl phthalate, citrate esters, polyethylene glycols, glycerol, acetylated glycerides, triacetin, polypropylene glycols, polyethylene glycols, triethyl citrate, dibutyl sebacate, stearic acid, stearates, stearates and Castor oil and the like, but is not limited thereto.

Compressed tablets are solid dosage forms produced by compacting a bulk blend of the foregoing formulations. In various embodiments, the compressed tablets to be dissolved in the mouth include one or more flavoring agents. In other embodiments, the compressed tablets comprise a membrane surrounding the final compressed tablet. In certain embodiments, the membrane coating can provide delayed release of the compounds disclosed herein from the blend. In other embodiments, the membrane coating assists in patient compliance (eg, Opadry® coating or sugar coating). Membrane coatings comprising Opadry® may typically be from about 1% to about 3% of the tablet weight. In other embodiments, the compressed tablets include one or more excipients.

Capsules can be produced, for example, by placing a bulk blend of a combination of the foregoing compounds inside the capsule. In certain embodiments, the combinations (non-aqueous suspensions and solutions) are placed in soft gelatin capsules. In other embodiments, the formulations are placed in standard gelatin capsules or non-gelatin capsules, such as capsules comprising HPMC. In other embodiments, the blend is placed in a watering capsule, where the capsule can swallow the whole or open the capsule and water the contents into the food before eating. In certain embodiments, the therapeutic formulation is divided into a plurality of (eg, 2, 3 or 4) capsules. In certain embodiments, the total dosage of the combination is delivered in a capsule formulation.

In various embodiments, particles of a compound disclosed herein and one or more excipients are dry mixed and less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, orally after oral administration. The formulation is released into the gastrointestinal fluid by compressing it into a mass such as a tablet having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates in less than 55 minutes or less than about 60 minutes.

In another embodiment, the dosage form may comprise a microencapsulated combination. In certain embodiments, one or more other affinity materials are present in the microencapsulation material. Exemplary materials include pH adjusting agents, erosion promoters, antifoams, antioxidants, flavoring and carrier materials such as binders, suspending agents, disintegrating agents, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents and diluents. However, the present invention is not limited thereto.

Examples of materials useful for microencapsulation described herein include materials having affinity with compounds disclosed herein that sufficiently separate the compounds disclosed herein from other non-affinity excipients. A substance having affinity with a compound disclosed herein is to delay the release of the compound disclosed herein in vivo.

Examples of microencapsulating materials useful for delaying the release of a formulation comprising a compound disclosed herein include hydroxypropyl cellulose ethers (HPC), such as Klucel® or Nisso HPC, low-substituted hydroxypropyl cellulose ethers ( L-HPC), hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, Benecel MP824 and Benecel MP843, methylcellulose Polymers such as Methocel®-A, hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG, HF-MS) and Metolose®, ethylcellulose (EC) and mixtures thereof, such as E461, Ethocel®, Aqualon®-EC, Surelease®, polyvinyl alcohol (PVA) such as Opadry AMB, hydroxyethylcellulose, such as Natrosol®, carboxymethylcellulose and carbox Salts of dimethylcellulose (CMC) such as Aqualon®-CMC, polyvinyl alcohol and polyethylene glycol copolymers such as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified Food starch, acrylic polymers, and mixtures of acrylic polymers and cellulose ethers, such as Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 3OD Eudragit® L100-55, Eudragit ( L100, Eudragit (R) S100, Eudragit (R) RD100, Eudragit (R) E100, Eudragit (R) L12.5, Eudragit (R) S12.5, Eudragit (R) NE30D And Eudragit® NE 4OD, cellulose acetate phthalate, Sepifilms such as mixtures of HPMC and stearic acid, cyclodextrins and mixtures of these materials, and the like.

In other embodiments, plasticizers such as polyethylene glycols such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350 and PEG 800, stearic acid, propylene glycol, oleic acid and triacetin are incorporated into the microencapsulated material. . In other embodiments, the microencapsulation material useful for delaying the release of the pharmaceutical composition is from USP or National Formulary (NF). In other embodiments, the microencapsulation material is Klucel. In other embodiments, the microencapsulation material is metocell.

Microencapsulated compounds disclosed herein can be formulated in a manner known by those skilled in the art. Examples of such known methods include spray drying processes, spin disk-solvent processes, hot melt processes, spray cooling methods, fluidized beds, electrostatic deposition, centrifugal extrusion, rotary suspension separation, polymerization at liquid-gas or solid-gas interfaces. , Pressurized extrusion or spray solvent extraction baths. In addition, various chemical techniques can be used, such as complex droplet formation, solvent evaporation, polymer-polymer affinity, interfacial polymerization in liquid media, in situ polymerization, drying in liquid and desolvation in liquid media. Other methods may also be used, such as roller compaction, extrusion / spherization, droplet formation or nanoparticle coating.

In one embodiment, particles of a compound disclosed herein are microencapsulated prior to compounding in one of the above forms. In another embodiment, some or most of the particles are coated prior to further compounding using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences , 20th Edition (2000).

In other embodiments, the solid dosage formulations of the compounds disclosed herein are plasticized (coated) in one or more layers. By way of example, plasticizers are generally high boiling solids or liquids. Suitable plasticizers can be added at from about 0.01% to about 50% by weight (w / w) of the coating composition. Examples of plasticizers include diethyl phthalate, citrate esters, polyethylene glycols, glycerol, acetylated glycerides, triacetin, polypropylene glycols, polyethylene glycols, triethyl citrate, dibutyl sebacate, stearic acid, stearates, stearates and Castor oil and the like, but is not limited thereto.

In other embodiments, powders comprising a combination with a compound disclosed herein may be formulated to include one or more pharmaceutical excipients and flavorings. Such powders can be produced, for example, by blending a blend and any pharmaceutical excipients to form a bulk blend composition. Further embodiments include suspending agents and / or wetting agents. Such bulk blends are evenly divided into unit dosage forms or plural dosage forms.

In other embodiments, the expandable powder is produced by the present disclosure. Effervescent salts are used to disperse drugs in water for oral administration. Effervescent salts are generally granules or coarse powders comprising the pharmaceutical preparation in a dry mixture consisting of sodium bicarbonate, citric acid and / or tartaric acid. When the salts of the present invention are added to water, the acids and bases react to release carbon dioxide gas, thus causing "foaming". Examples of effervescent salts are sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid and / or tartaric acid, and the like. Any acid-base combination that will release carbon dioxide can be used in place of the combination of sodium bicarbonate and citric acid and tartaric acid, as long as the component is suitable for pharmaceutical use, and the pH is at least about 6.0.

In other embodiments, the formulations described herein, including the compounds disclosed herein, are solid dispersions. Methods of making such solid dispersions are known in the art, and non-limiting examples thereof are disclosed in US Pat. Nos. 4,343,789, 5,340,591, 5,456,923, 5,700,485, 5,723,269 and US Application Publication No. 2004/0013734, and the like. In other embodiments, the formulations described herein are solid liquids. The solid liquid incorporates the material with the active agent and other excipients such that the heating of the mixture dissolves the drug and the resulting composition is a solid blend that can be cooled and further compounded or added directly to a capsule or compressed into tablets. To provide. Methods of producing such solid liquids are known in the art, and non-limiting examples thereof include US Pat. Nos. 4,151,273, 5,281,420, 6,083,518, and the like, which are incorporated herein by reference.

Pharmaceutical solid oral dosage forms comprising a formulation described herein comprising a compound disclosed herein may be further formulated to provide controlled release of the compounds disclosed herein. Controlled release refers to the release of a compound disclosed herein from a dosage form that is incorporated according to a predetermined profile over an extended period of time. Examples of controlled release profiles include sustained release, extended release, pulsatile release and delayed release profiles. In contrast to immediate release compositions, controlled release compositions allow for delivery of the agent to an individual over an extended period of time by a predetermined profile. This release rate can provide a therapeutically effective concentration of the formulation for an extended period of time, thereby providing a long-term pharmacological response with minimal side effects compared to conventional rapid release dosage forms. Such longer time reactions provide a number of inherent advantages that are not achieved using such short acting immediate release formulations.

In certain embodiments, the solid dosage form described herein is an enteric skin delayed release oral dosage form, ie, oral administration of a pharmaceutical composition as described herein using enteric skin that affects release in the small intestine of the gastrointestinal tract. It can be formulated as a formulation. Enteric skin dosage forms are compressed or molded or extruded tablets / moulds (coated or comprising granules, powders, pellets, beads, or particles of the active and / or other compositional ingredients, coated or uncoated themselves). Uncoated). In addition, the enteric dermal oral dosage form may be a capsule (coated or uncoated) comprising pellets, beads or granules of a solid carrier or composition, coated or uncoated on its own.

As used herein, the term “delayed release” refers to delivery that allows release to be achieved at certain generally foreseeable positions in the distal gut than is achieved when no delayed release modification is present. In certain embodiments, the method of delaying release is a coating. Any coating must be applied to a thickness sufficient to allow the entire coating to dissolve in gastrointestinal fluids at pH below about 5, but at pH above about 5. It is contemplated that any anionic polymer exhibiting a pH-dependent solubility profile can be used as enteric skin in the practice of the present invention for delivery to the lower gastrointestinal tract. In certain embodiments, the polymer for use in the present invention is an anionic carboxyl polymer. In other embodiments, examples of polymers and affinity mixtures thereof and some of their properties include, but are not limited to:

Shellac: Also referred to as purified lac, a purified product obtained from the dendritic secretion of an insect. This coating is dissolved in a medium of pH> 7;

Acrylic Polymers: The performance of acrylic polymers (primarily solubility in biological fluids) may vary depending on the degree of substitution and the type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. Eudragit series E, L, S, RL, RS and NE (Rom Pharma) are available dissolved in organic solvents, aqueous dispersions or dry powders. Eudragit series RL, NE and RS are insoluble in the gastrointestinal tract, but can be permeable and are mainly used for colonic targets. Eudragit series E dissolve in the stomach. Eudragit series L, L-30D and S are insoluble in the stomach and dissolve in the intestine.

Cellulose Derivatives: Examples of suitable cellulose derivatives include ethyl cellulose; Reaction mixture of a partial acetate ester of cellulose with phthalic anhydride. The performance may vary depending on the degree of substitution and the type of substitution. Cellulose acetate phthalate (CAP) is dissolved at pH> 6. Aquateric (FMC) is water based and spray dried CAP pseudolatex with particles <1 μm. Other components in Aquateric may include Pluronic, Tweens and acetylated monoglycerides. Other suitable cellulose derivatives include cellulose acetate trimellitate (eastman); Methylcellulose (Pharmacote, Methocel); Hydroxypropylmethyl cellulose phthalate (HPMCP); Hydroxypropylmethyl cellulose succinate (HPMCS); And hydroxypropylmethylcellulose acetate succinate (eg, AQOAT (Shin-Etsu)). The performance may vary depending on the degree of substitution and the type of substitution. For example, HPMCPs such as HP-50, HP-55, HP-55S, HP-55F grades are appropriate. The performance may vary depending on the degree of substitution and the type of substitution. Examples of suitable grades of hydroxypropylmethylcellulose acetate succinate are, for example, AS-LG (LF) dissolved at pH 5, AS-MG (MF) dissolved at pH 5.5, AS- dissolved at higher pH. HG (HF) and the like, but is not limited thereto. Such polymers are provided as granules or as fine powders for aqueous dispersions.

Polyvinyl Acetate Phthalate (PVAP): PVAP is soluble at pH> 5 and much less permeable to water vapor and gastric juice.

In certain embodiments, the coating may include, and generally include, plasticizers and possibly other coating excipients known in the art, such as colorants, talc and / or magnesium stearate. Examples of suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, Acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol and dibutyl phthalate. In particular, anionic carboxylic acrylic polymers generally comprise 10-25% by weight of plasticizers, in particular dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin. The coating is applied using conventional coating techniques such as spray or pan coating. The coating thickness should be sufficient to remain intact until the oral dosage form reaches a site of topical delivery in the intestine.

Colorants, tackifiers, surfactants, antifoams, lubricants (eg, carnuba wax or PEG) can be added to the coating in addition to the plasticizer to solubilize or disperse the coating material and to improve coating performance and coated products.

In other embodiments, the formulations described herein comprising a compound disclosed herein are delivered using a pulsatile dosage form. The pulsatile dosage form can provide one or more immediate release beats after a controlled delay time or at a given point in time. Pulsatile dosage formulations comprising the formulations described herein, including the compounds disclosed herein, can be administered using a variety of pulsatile combinations known in the art. For example, such combinations include, but are not limited to, those described in US Pat. Nos. 5,011,692, 5,017,381, 5,229,135, and 5,840,329, which are incorporated herein by reference. Examples of other pulsatile release dosage forms suitable for use with the present formulations include US Pat. Nos. 4,871,549, 5,260,068, 5,260,069, 5,508,040, 5,567,441 and 5,837,284, etc., which are incorporated herein by reference. There is this. In one embodiment, the controlled release dosage form is a pulsatile release solid oral dosage form comprising two or more groups of particles (ie, multiparticulates) each comprising a combination described herein. The first group of particles provide for substantial immediate administration of a compound disclosed herein upon ingestion by a mammal. The first group of particles may be uncoated or include a coating and / or sealant. The second group of particles is from about 2 to about 75 weight percent, preferably from about 2.5 to about 70 weight percent, more preferably from about 2 to about 75 weight percent of the total dosage of the compounds disclosed herein in a blend mixed with at least one binder. Coated particles comprising from 40 to about 70 weight percent. The coating comprises a pharmaceutically acceptable component in an amount sufficient to provide a delay of about 2 hours to about 7 hours after ingestion prior to release of the second administration. Suitable coatings include one or more differentially degradable coatings, such as pH sensitive coatings (entertaining), such as acrylic resins (eg Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D, Eudragit (registered trademark) L100-55, Eudragit (registered trademark) L100, Eudragit (registered trademark) S100, Eudragit (registered trademark) RD100, Eudragit (registered trademark) E100, Eudragit (registered trademark) L12.5, Eudragit (registered trademark) ) S12.5 and Eudragit® NE30D®, Eudragit® NE 40D®) alone or in admixture with cellulose derivatives such as ethylcellulose or combinations comprising the compounds disclosed herein Non-enteric skin with varying thickness to provide differential release of

Many other controlled release system types are known to those skilled in the art and are suitable for use with the formulations described herein. Examples of such delivery systems include polymeric systems such as polylactic and polyglycolic acid, polyanhydrides and polycaprolactones; Porous matrices, nonpolymeric systems that are lipids, including sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono-, di- and triglycerides; Hydrogel release system; Silastic type; Peptide system; Wax coatings, bioerodible dosage forms, compressed tablets using conventional binders and the like. See, eg, Lierman et al., Pharmaceutical Dosage Forms , 2 Ed., Vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology , 2 ^nd Ed., Pp. 751-753 (2002)], US Pat. Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,140, 5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977,175, See 6,465,014 and 6,932,983.

In certain embodiments, pharmaceutical formulations are provided that include a compound disclosed herein and particles of one or more dispersing or suspending agents for oral administration to a subject. The blend may be a powder and / or granules for suspension, which results in a substantially uniform suspension when mixed with water.

Liquid formulation dosage forms for oral administration may be, but are not limited to, aqueous suspensions selected from the group consisting of pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels and syrups. See, eg, Singh et al., Encyclopedia of Pharmaceutical Technology , 2 ^nd Ed., Pp. 754-757 (2002). In addition to the particles of the compounds disclosed herein, liquid dosage forms include additives such as: (a) disintegrants; (b) dispersants; (c) wetting agents; (d) one or more preservatives, (e) viscosity improving agents, (f) one or more sweetening agents, and (g) one or more flavoring agents. In certain embodiments, the aqueous dispersions can further include crystalline inhibitors.

The aqueous suspensions and dispersions described herein can remain homogeneous for at least 4 hours as defined by The USP Pharmacists' Pharmacopeia (2005 edition, chapter 905). Homogeneity should be determined by sampling methods in connection with determining homogeneity of the overall composition. In one embodiment, the aqueous suspension can be resuspended into a homogeneous suspension by physical agitation lasting less than one minute. In another embodiment, the aqueous suspension can be resuspended into a homogeneous suspension by physical agitation lasting less than 45 seconds. In another embodiment, the aqueous suspension can be resuspended into a homogeneous suspension by physical agitation lasting less than 30 seconds. In another embodiment, stirring is not necessary to maintain a homogeneous aqueous dispersion.

Examples of disintegrants for use in aqueous suspensions and dispersions include starch, for example natural starch, such as corn starch or potato starch, pregelled starch, such as National 1551 or Amijel® or sodium starch glycolate, such as Promogel (Registered trademark) or Explotab (registered trademark); Celluloses such as wood products, methylcrystalline cellulose, for example Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel® Trademark), Vivacel (R), Ming Tia (R) and Solka-Floc (R), methylcellulose, croscarmellose or crosslinked cellulose such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol (R) Trademarks)), crosslinked carboxymethylcellulose or crosslinked croscarmellose; Crosslinked starch such as sodium starch glycolate; Crosslinked polymers such as crospovidone; Crosslinked polyvinylpyrrolidone; Alginic acid salts such as alginic acid or salts of alginic acid such as sodium alginate; Clays such as Veegum® HV (magnesium aluminum silicate); Gums such as agar, guar, locust bean, karaya, pectin or tragacanth; Sodium starch glycolate; Bentonite; Natural sponge; Surfactants; Resins such as cation exchange resins; Citrus pulp; Sodium lauryl sulfate; Sodium lauryl sulfate in combination starch; Etc., but is not limited thereto.

In certain embodiments, suitable dispersants for the aqueous suspensions and dispersions described herein are known in the art, and examples thereof include hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone ( PVP; commonly known as Plasdone®) and carbohydrate-based dispersants such as hydroxypropylcellulose and hydroxypropyl cellulose ethers (e.g. HPC, HPC-SL and HPC-L), hydroxypropyl methylcellulose and hydroxide Hydroxypropyl methylcellulose ether (e.g. HPMC K100, HPMC K4M, HPMC K15M and HPMC K100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, hydroxypropylmethyl-cellulose acetate stearate Laterate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone / vinyl ah Cetate copolymer (Plasdone®, for example S-630), 4- (1,1,3,3-tetramethylbutyl) -phenolic polymer (as thyloxapol) with ethylene oxide and formaldehyde Known), poloxamers (eg, Pluronics F68® F88® and F108®, which are block copolymers of ethylene oxide and propylene oxide); And Tetronic, known as poloxamine (e.g., Poloxamine 908®, a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine, BASF Corporation, Parsippany, NJ). 908 (registered trademark)). In other embodiments, the dispersing agent may be selected from hydrophilic polymers; Electrolyte; Tween® 60 or 80; PEG; Polyvinylpyrrolidone (PVP); Hydroxypropylcellulose and hydroxypropyl cellulose ethers (eg, HPC, HPC-SL and HPC-L); Hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers (eg, HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M and Pharmacoat® USP 2910 (Shin-Etsu)); Carboxymethylcellulose sodium; Methylcellulose; Hydroxyethyl cellulose; Hydroxypropylmethyl-cellulose phthalate; Hydroxypropylmethyl-cellulose acetate stearate; Non-crystalline cellulose; Magnesium aluminum silicate; Triethanolamine; Polyvinyl alcohol (PVA); 4- (1,1,3,3-tetramethylbutyl) -phenol polymer with ethylene oxide and formaldehyde; Poloxamers (eg, Pluronics F68®, F88® and F108®, which are block copolymers of ethylene oxide and propylene oxide); Or poloxamine (eg, Tetronic 908®, known as Poloxamine 908®).

Wetting agents suitable for aqueous suspensions and dispersions described herein are known in the art, examples of which are cetyl alcohol, glycerol monostearate, polyoxyethylene sorbitan fatty acid esters (eg, commercially available Tweens®, eg Examples include Tween 20® and Tween 80® (IC Specialty Chemical) and polyethylene glycols (e.g. Carbowaxs 3350® and 1450® and Carbopol 934® (Union Carbide) ), Oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium la Usil Sulfate, Sodium Docusate, Triacetin, Vitamin E TPGS, Sodium Taurocholate, Simethicone, Phosphotidylcholine Etc., but is not limited thereto.

Examples of suitable preservatives for the aqueous suspensions or dispersions described herein include potassium sorbate, parabens (e.g. methylparabens and propylparabens), benzoic acid and salts thereof, other esters of parahydroxybenzoic acid such as butylparabens, alcohols such as Ethyl alcohol or benzyl alcohol, phenolic compounds such as phenol or quaternized compounds such as benzalkonium chloride and the like. As used herein, preservatives are incorporated into the dosage form at a concentration sufficient to inhibit microbial growth.

Examples of suitable viscosity improving agents for the aqueous suspensions or dispersions described herein include methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, Plasdon® S-630, carbomer, Polyvinyl alcohol, alginate, acacia, chitosan and combinations thereof, but is not limited thereto. The concentration of the viscosity improving agent depends on the formulation chosen and the desired viscosity.

Examples of suitable sweeteners for the aqueous suspensions or dispersions described herein include acacia syrup, acesulfame K, altime, anise, apple, aspartame, banana, barbarian cream, berry, blackcurrant, butterscotch, calcium citrate, camphor, caramel , Cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, silamate, dextrose, eucalyptus, eugenol, fructose Fruit punch, ginger, glycyrrhetinate, licorice syrup, grapefruit, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycinate (MagnaSweet®), maltol, Mannitol, Maple, Mash Mallow, Menthol, Mint Cream, Mix Berry, Neohesperidin DC, Neo-Tame, Orange, Pear, Peach, Peppermint, Peppermint Cream, Prosweet (etc. Powder) Raspberry, Root Beer, Rum, Saccharin, Saffol, Sorbitol, Spearmint, Spearmint Cream, Strawberry, Strawberry Cream, Stevia, Sucralose, Sucrose, Sodium Saccharin, Saccharin, Aspartame, Acesulfame Potassium, Mannitol, Tallinn , Sucralose, sorbitol, swiss cream, tagatose, tangerine, taumartin, tutti fruity, vanilla, walnut, watermelon, wild cherry, green tea oil, xylitol or any combination of these flavoring ingredients, for example anise-menthol, cherry- Anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint and mixtures thereof. In one embodiment, the aqueous liquid dispersion may comprise a sweetening or flavoring agent at a concentration in the range of about 0.001% to about 1.0% of the volume of the aqueous dispersion. In another embodiment, the aqueous liquid dispersion may comprise a sweetening or flavoring agent at a concentration within the range of about 0.005% to about 0.5% of the volume of the aqueous dispersion. In another embodiment, the aqueous liquid dispersion may include sweetening or flavoring agents at a concentration within the range of about 0.01% to about 1.0% of the volume of the aqueous dispersion.

In addition to the additives set forth above, liquid formulations may also include inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers. Examples of emulsifiers include ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, sodium lauryl sulfate, sodium docusate, cholesterol, Cholesterol esters, taurocholic acid, phosphatidylcholine, oils such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, fatty acid esters of sorbitan or mixtures of these materials There is this.

In certain embodiments, the pharmaceutical combinations described herein can be automated emulsifying drug delivery systems (SEDDS). Emulsions are generally dispersions of phases which are immiscible with one another in the form of droplets. In general, emulsions are produced by violent mechanical dispersion. In contrast to emulsions or microemulsions, SEDDS spontaneously forms emulsions when added to excess water without any external mechanical dispersion or agitation. The advantage of SEDDS is that only gentle mixing is required to distribute the droplets through the liquid. In addition, the water or aqueous phase can be added immediately before administration to ensure the stability of the unstable or hydrophobic active ingredient. Thus, SEDDS provides an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients. SEDDS can provide improvements in bioavailability of hydrophobic active ingredients. Methods of making automated emulsion dosage forms are known in the art, and examples thereof include, but are not limited to, US Pat. Nos. 5,858,401, 6,667,048 and 6,960,563, each of which is incorporated herein by reference.

It is understood that there may be overlap between the commonly presented additives used in the aqueous dispersions or suspensions described herein, which often means that certain additives are differentially classified by various experts in the art or that any of a variety of different This is because they are commonly used for action. Thus, the additives set forth above are merely illustrative of, but are not limited to, the types of additives that may be included in the formulations described herein. The content of the additive can be easily determined by those skilled in the art according to the specific properties desired.

Intranasal formulations

Intranasal formulations are known in the art and are described, for example, in US Pat. Nos. 4,476,116, 5,116,817 and 6,391,452, each of which is incorporated herein by reference. Formulations comprising a compound provided herein, prepared by these and other techniques known in the art, include benzyl alcohol or other suitable preservatives, fluorocarbons and / or other solubilizers known in the art. Or as a solution in brine using a dispersant. See, eg, Ansel, HC et al., Pharmaceutical Dosage Forms and Drug Delivery Systems , Sixth Ed. (1995). Preferably these compositions and combinations are produced using suitable nontoxic pharmaceutically acceptable ingredients. These ingredients are known to those skilled in the art in the preparation of nasal dosage forms, some of which can be found in the standard literature in the art, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 21st edition, 2005. The choice of a suitable carrier depends largely on the exact nature of the desired nasal dosage form, such as a liquid, suspension, ointment or gel. Nasal dosage forms generally contain large amounts of water in addition to the active ingredient. Small amounts of other components may also be present, such as pH adjusters, emulsifiers or dispersants, preservatives, surfactants, gelling or buffering agents, and other stabilizers and solubilizers. Nasal dosage formulations should preferably be isotonic with nasal secretions.

For administration by inhalation, the compounds disclosed herein may be in the form of aerosols, mists or powders. The pharmaceutical compositions described herein are conveniently delivered in the form of aerosol spray presentation from pressurized packs or nebulizers, and include suitable propellants such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, Use carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered content. Capsules and cartridges of gelatin can be formulated, for example for use in an inhaler or blower, including a powder mix of a compound described herein and a suitable powder base such as lactose or starch.

Buccal formulation

Buccal formulations comprising the compounds disclosed herein can be administered using various combinations known in the art. For example, examples of such combinations include, but are not limited to, US Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739,136, each of which is incorporated herein by reference. In addition, the buccal dosage form described herein may further comprise a bioerodible (hydrolyzable) polymer carrier that serves to attach the dosage form to the buccal mucosa. The buccal dosage form is prepared to be progressively corroded over time, wherein delivery of the compounds disclosed herein is provided almost entirely. As will be appreciated by those skilled in the art, buccal drug delivery can avoid the disadvantages encountered with oral drug administration, such as slow absorption, degradation of the active agent by body fluids present in the gastrointestinal tract and / or inactivation of first pass in the liver. . With regard to bioerodible (hydrolyzable) polymer carriers, substantially any such carrier does not compromise a given drug release profile, and the carrier may be present in the buccal dosage unit and the compounds disclosed herein and any other component It is understood that it can be used as long as it has affinity with. Generally, polymeric carriers include hydrophilic (water soluble and water swellable) polymers that adhere to the moist surface of the buccal mucosa. Examples of polymer carriers useful herein include those known as acrylic acid polymers and copolymers, such as "Carbomer" (an example of such polymers is Carbopol® available from B. Goodrich). Can be mentioned. In addition, other ingredients may be incorporated into the buccal dosage forms described herein, examples of which include, but are not limited to, disintegrants, diluents, binders, lubricants, flavors, colorants, preservatives, and the like. For buccal or sublingual administration, the compositions may take the form of tablets, lozenges or gels formulated in conventional manner.

Transdermal formulation

The transdermal formulations described herein can be administered using various devices described in the art. Examples of such devices are, for example, US Pat. Nos. 3,598,122, 3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636, 3,972,995, each of which is incorporated herein by reference. No. 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084, 4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303,168,168 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and 6,946,144 and the like, but are not limited thereto.

The transdermal dosage forms described herein may incorporate certain pharmaceutically acceptable excipients conventional in the art. In one embodiment, the transdermal formulations described herein comprise three or more components: (1) a combination of a compound disclosed herein; (2) permeation enhancers; And (3) aqueous adjuvants. In addition, transdermal formulations may include, but are not limited to, additional ingredients such as gelling agents, creams, ointment bases, and the like. In certain embodiments, the transdermal formulation may further comprise a woven or nonwoven backing material that improves the absorption of the transdermal formulation from the skin and prevents its removal. In other embodiments, the transdermal formulations described herein can remain saturated or supersaturated to facilitate diffusion into the skin.

Formulations suitable for transdermal administration of the compounds described herein can use transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered aqueous solutions dissolved and / or dispersed in a polymer or adhesive. Such patches may be rescued for continuous, pulsatile or on-demand delivery of the pharmaceutical formulation. Still, transdermal delivery of the compounds described herein can be accomplished by iontophoresis patches and the like. In addition, transdermal patches can provide controlled delivery of the compounds disclosed herein. The rate of absorption can be delayed by using a rate controlling membrane in the polymer matrix or gel or by entrapping the compound. In contrast, absorption enhancers can be used to increase absorption. Absorption enhancers or carriers may include absorbable pharmaceutically acceptable solvents to aid passage through the skin. For example, the transdermal device may be a support member, a reservoir containing the compound, optionally with a carrier, a rate controlling block for delivering the compound to the skin of the host at a predetermined rate controlled for an extended period of time, and the device into the skin. It is in the form of a bandage comprising means for fixing the.

Injectable Formulations

Formulations comprising a compound disclosed herein suitable for intramuscular, subcutaneous or intravenous injection may be used as a physiologically acceptable sterile aqueous or non-aqueous liquid, dispersion, suspension or emulsion and sterile powder for reconstitution into sterile injectable solutions or dispersions. It may include. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene-glycol, glycerol, cremofo, etc.), suitable mixtures thereof, vegetable oils (such as olive oil) and injectables. Organic esters such as ethyl oleate and the like. Proper fluidity can be maintained, for example, by the use of coatings such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Formulations suitable for subcutaneous injection may also include additives such as preservatives, wetting agents, emulsifiers and dispersants. Prevention of microbial growth can be formed by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical formulations can be caused by the use of agents that delay absorption, such as aluminum monostearate and gelatin.

For intravenous injection, the compounds described herein may be formulated in aqueous solutions, preferably physiological affinity buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, the penetrant appropriate for the barrier to be permeated is used in the formulation. Such penetrants are generally known in the art. For other parenteral injections, suitable combinations may include aqueous or non-aqueous solutions, preferably physiological affinity buffers or excipients. Such excipients are generally known in the art.

Parenteral injections may include bolus injections or continuous infusions. Injectable formulations may be presented together with preservatives added in unit dosage form, eg, ampoules or multi-dose containers. The pharmaceutical compositions described herein may be in a form suitable for parenteral injection as sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and may include formulations such as suspensions, stabilizers and / or dispersants. . Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In addition, suspensions of the active compounds can be produced as appropriate oily injection suspensions. Examples of suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters such as ethyl oleate or triglycerides or liposomes. Aqueous injection suspensions may include substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may contain suitable stabilizers or agents that increase the solubility of the compounds to enable the preparation of highly concentrated solutions. Alternatively, the active ingredient may be a powder formulation for constitution with a suitable vehicle, eg, sterile pyrogenic deionized distilled water, before use.

Other formulations

In certain embodiments, delivery systems for pharmaceutical compounds may be used, such as liposomes and emulsions. In certain embodiments, the compositions provided herein also include carboxymethylcellulose, carbomer (acrylic acid polymer), poly (methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate And mucoadhesive polymers selected from dextran.

In certain embodiments, the compounds described herein can be administered topically and can be formulated in a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, dosage sticks, balms, creams, or ointments. . Such pharmaceutical compounds may include solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

In addition, the compounds described herein include rectal compositions such as enema, rectal gels, rectal foams, including conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. , Rectal aerosols, suppositories, jelly suppositories or retention enemas. In a suppository form, a low melting wax, such as a mixture of fatty acid glycerides, optionally mixed with cocoa butter, is first melted.

Dosing method and treatment regimen

The compounds described herein can be used in the manufacture of a medicament for the treatment of diseases or conditions that at least partially benefit from inhibition of fatty acid amide hydrolase or inhibition of fatty acid amide hydrolase. In addition, methods of treating any of the diseases or conditions described herein in an individual in need thereof may include one or more of the compounds disclosed herein or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable N-oxide, a pharmaceutical Administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug, or a pharmaceutically acceptable solvate.

Compositions comprising the compound (s) described herein can be administered for prophylactic and / or therapeutic treatments. In therapeutic applications, a composition is administered to a patient already suffering from the disease or condition in an amount sufficient to treat or at least partially arrest the signs of the disease or condition. The amount effective for this use depends on the severity and course of the disease or condition, prior treatment, the patient's health condition, weight and response to the drug, and the judgment of the attending physician. One skilled in the art regards the therapeutically effective amount as being determined by routine experimentation, including, but not limited to, dose escalation clinical trials.

In prophylactic applications, a composition comprising a compound described herein is administered to a patient susceptible to or at risk of suffering from a particular disease, disorder or condition. This content is defined as "prophylactically effective amount or administration." In this use, the exact content is determined by the patient's state of health, weight, and the like. Determining such a prophylactically effective amount by routine experimentation (eg, dose escalation clinical trials) is considered to be within the skill of the art. When an effective amount for this use is used in a patient, it will depend on the severity and route of the disease, illness or condition, prior treatment, the patient's health condition, the response to the drug and the judgment of the attending physician.

If the patient's condition does not improve, at the discretion of the attending physician, the administration of the compound is administered over a prolonged period of time, i.e. for an extended period of time, such as over the life of the patient in order to ameliorate or control or limit the symptoms of the patient's disease or condition. can do.

If the condition of the patient improves, administration of the compound may be presented continuously at the discretion of the attending physician; Alternatively, the dose of drug administered may be temporarily reduced or temporarily stopped for a predetermined time (ie, a “drug holiday”). The length of the drug holiday is given by way of example only 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, It can be changed within 2 days to 1 year, including 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days or 365 days. Drug discontinuation during the drug holiday is merely an example of 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% , 80%, 85%, 90%, 95%, or 100%, including 100%.

If an improvement in patient condition occurs, a maintenance dose is administered if necessary. Thereafter, the dosage or cycle or both of the administration can be reduced to the extent that an improved disease, disease or condition is maintained as a function of the indication. However, patients may require prolonged intermittent treatment at any recurrence of signs.

The amount of a given agent corresponding to the above content may vary depending on factors such as the specific compound, disease or condition and its severity, and the identity (eg body weight) of the individual or host in need of treatment, but nevertheless It may be determined conventionally by methods known in the art depending on the particular agent being administered, the route of administration, the condition to be treated and the particular circumstances surrounding the case, including the individual or host to be treated. In general, however, the dosages used to treat adult humans typically range from 0.02 to 5,000 mg per day, preferably 1 to 1500 mg per day. Preferred dosages may be conveniently presented in a single dose or in divided doses (or over a short time) administered simultaneously or at appropriate time intervals, eg, 2, 3, 4 or more sub doses per day. Can be.

The pharmaceutical compositions described herein can be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the combination is divided into unit doses containing appropriate amounts of one or more compounds. The unit dosage may be in the form of a package containing distinct amounts of the combination. Non-limiting examples are packaged tablets or capsules and powders in vials or ampoules. The aqueous suspension composition may be packaged in a container that is not reclosable in a single content. Alternatively, multiple doses of reclosable containers can be used, in which case it is customary to include a preservative in the composition. By way of example only, combinations for parenteral injection may be presented in unit dosage form, including but not limited to ampoules, or in multiple dose containers with added preservatives.

Suitable daily dosages for the compounds described herein are about 0.01-2.5 mg / kg body weight. Suggested daily dosages in larger mammals, including but not limited to humans, include, but are not limited to, from about 0.5 mg to about 100 mg, conveniently up to 4 times per day or extended release formulations. ) In divided doses. Suitable unit dosage forms for oral administration comprise from about 1 to 50 mg active ingredient. This range suggests that only a large number of variables are associated with the individual treatment regimen, and that significant deviations from such recommended values are common. Such dosage will vary depending on a number of variables, such as the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of each individual, the severity of the disease or condition to be treated and the judgment of the attending physician. Can be.

Toxicity and therapeutic efficacy of such therapeutic regimens include, but are not limited to, measurements of LD ₅₀ (50% lethal dose of the population) and ED ₅₀ (dose therapeutically effective at 50% of the population). In culture or experimental animals can be measured by standard pharmaceutical procedures. The dose ratio between toxic and therapeutic efficacy is the therapeutic index and can be expressed as the ratio between LD ₅₀ and ED ₅₀ . Compounds with high therapeutic indices are preferred. Data obtained from cell culture assays and animal experiments can be used to formulate a range of dosages for use in humans. Doses of such compounds are preferably included within the range of circulating concentrations comprising ED ₅₀ with minimal toxicity. Dosage may vary within a range depending upon the dosage form employed and the route of administration used.

Concurrent treatment

In addition, the compositions and methods described herein can be used with other known therapeutic agents selected for their particular utility for the condition to be treated. In general, in the embodiments using the compositions described herein and in combination therapy, other agents need not be administered to the same pharmaceutical composition, and due to different physical and chemical properties, they must be administered by various routes. . Where possible, determination of the mode of administration and the adequacy of administration in the same pharmaceutical composition is possible within the knowledge of the clinician. Initial administration can be generated by established protocols known in the art, and then based on the efficacy observed, the dosage, mode of administration, and frequency of administration can be altered by the clinician.

In certain cases, it may be appropriate to administer one or more compounds described herein in combination with another therapeutic agent. By way of example only, if one of the side effects suffered by a patient receiving one of the compounds herein is nausea, it may be appropriate to administer the anti-nausea in combination with the initial therapeutic agent. Or, by way of example only, the therapeutic efficacy of one of the compounds described herein can be improved by administration of an adjuvant (ie, the adjuvant itself has minimal therapeutic efficacy, but in combination with another therapeutic agent Improve the overall therapeutic efficacy). Or, by way of example only, the efficacy experienced by a patient can be increased by administering one of the compounds described herein in combination with another therapeutic agent (also including therapeutic therapy) that also has therapeutic efficacy. In any case, irrespective of the disease, condition or condition to be treated, the overall efficacy experienced by a patient may be an addition of two therapeutic agents or the patient may experience synergistic efficacy.

The particular choice of compound used depends upon the diagnosis of the attending physician, the judgment of the patient's condition and the appropriate treatment protocol. The compounds may be administered simultaneously or in sequence depending on the disease, the nature of the disease or condition, the condition of the patient and the actual choice of the compound used (eg simultaneously, almost simultaneously or within the same therapeutic protocol). Determination of the order of administration and the repeated number of administration of each therapeutic agent in a treatment protocol is included within the knowledge of the attending physician after evaluating the condition to be treated and the condition of the patient.

It is known to those skilled in the art that a therapeutically effective amount can be altered when the drug is used in a therapeutic combination. Methods for experimentally determining therapeutically effective dosages of drugs and other agents for use in a combination therapy regimen are described in the literature. For example, it is widely described in the literature that the use of rules correctly, ie, to provide less dosage more often in order to minimize toxic side effects. The combination treatment further includes periodic treatments that start and stop at various times to assist with clinical management of the patient.

For the combination treatments described herein, the dosage of the co-administered compound is of course determined by the type of co-drug used, the particular drug used, the disease or condition to be treated, and the like. In addition, when co-administered with one or more biologically active agents, the compounds provided herein can be administered simultaneously or sequentially with the biologically active agent (s). If administered sequentially, the attending physician will determine the proper sequence for administering the protein in parallel with the biologically active agent (s).

In any case, a plurality of therapeutic agents, one of which is a compound disclosed herein, may be administered in any order or even simultaneously. When administered simultaneously, the plurality of therapeutic agents may be provided in a single unified formulation or in a plurality of formulations (only as a single pill or as two separate pills, for example). One of the therapeutic agents may be provided in plural administrations or all of them may be provided as plural administrations. If not simultaneous, the time interval between the plurality of doses may be greater than zero weeks or less than four weeks. In addition, the combination of methods, compositions and combinations is not limited to the use of only two agents, and the use of multiple treatment combinations is also possible.

It is understood that the dosage regimen intended to treat, prevent or ameliorate the condition (s) desired to obtain remission may be modified by a variety of factors. These factors include the disease the individual suffers from, the age, weight, sex, diet and medical condition of the individual. Thus, the dosage regimen actually used may vary widely, and thus may vary from the dosage regimens described herein.

The pharmaceutical formulations constituting the combination therapy disclosed herein may be in separate dosage forms for simultaneous administration or in parallel dosage forms. In addition, the pharmaceutical agents that make up the combination therapy may be administered sequentially, and the therapeutic compound is administered by the therapy required for two-step administration. Two-step administration regimens may require sequential administration of the active agent or spaced apart administration of separate active agents. Two-step administration regimens may require sequential administration of the active agent or spaced apart administration of separate active agents. The time between the plurality of administration steps can be from several minutes to several hours depending on the nature of each pharmaceutical agent, such as efficacy, solubility, bioavailability, plasma half-life and the mechanical profile of the pharmaceutical agent. In addition, cyclic variations in target molecule concentration can determine the optimal dosing interval.

In addition, the compounds described herein can be used in combination with procedures that can provide additive or synergistic efficacy to a patient. By way of example only, the patient is expected to seek therapeutic and / or prophylactic efficacy in the methods described herein, wherein the combination of the compounds disclosed herein with the pharmaceutical compositions and / or other therapeutic agents are specific. It is combined with genetic testing to determine whether it is a carrier of a mutant gene known to correlate with a disease or condition.

The compounds and combination therapies described herein may be administered before, during, or after the disease or condition, and the time of administering the composition comprising the compound is variable. Thus, for example, the compound can be used as a prophylactic and can be administered continuously to an individual who tends to develop the condition or disorder in order to prevent the occurrence of the disease or condition. The compounds and compositions may be administered to the subject as soon as possible or during the onset of the indication. Administration of the compound is initiated within the first 48 hours of the onset of the indication, preferably within the first 48 hours of the onset of the indication, more preferably within the first 6 hours of the onset of the indication, most preferably within the first 3 hours of the onset of the indication. Can be. Initial administration can be by any practical route, such as by intravenous injection, bolus injection, infusion, pill, capsule, transdermal patch, buccal delivery, or the like, or a combination thereof over 5 minutes to about 5 hours. The compound is preferably administered as soon as possible after the onset or suspected onset of the disease or condition and for the time required for the treatment of the disease, such as from about 1 month to about 3 months. The length of treatment can be varied for each individual and the length can be determined using known criteria. For example, the compound or combination containing the compound may be administered for at least two weeks, preferably for one month to about five years, more preferably for about one month to about three years.

Kit / Manufactured Goods

Kits and articles of manufacture have been described herein for use in the therapeutic applications described herein. Such kits may comprise a package or container compartmentalized to receive a carrier, one or more containers, such as vials, test tubes, etc., each container (s) comprising one of the separate members intended for use in the methods described herein. do. Examples of suitable containers include bottles, vials, syringes and test tubes. Such containers may be formed of various materials, such as glass or plastic.

The article of manufacture provided herein includes a packaging material. Packaging materials for use in packaging pharmaceutical products are known to those skilled in the art. See, for example, US Pat. Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, test tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, selected combinations of administration and treatment, and any packaging materials appropriate for the intended manner. It is not limited. Various arrangements of combinations of the compounds and compositions provided herein are directed to any disease, condition or condition that is efficacious by inhibition of fatty acid amide hydrolase (FAAH) or where FAAH is a vehicle or donor for signs or causes. There are various treatments for.

For example, the container (s) may optionally include one or more compounds described herein in combination with or in combination with other agents as disclosed herein. The container (s) may optionally have a sterile access port (eg, the container may be an intravenous liquid bag or vial having a stopper punctured by a hypodermic needle). Such kits optionally comprise a compound with instructions or labels or identifications relating to use in the methods described herein.

Kits may typically comprise one or more additional containers, each of which is one or more of a variety of materials (such as formulations, optionally concentrated forms and / or devices) that are desirable from a commercial and user standpoint for use of the compounds described herein. It includes. Non-limiting examples of such materials include buffers, diluents, filters, needles, syringes; Test tube labels and / or instructions for use, including carriers, packages, containers, vials and / or contents, and package inserts with instructions for use. In addition, a set of instructions is typically included.

The label may be located on or in relation to the container. The label may be present on the container surface when the letters, numbers or other symbols forming the label are attached, molded or etched to the container itself; The label may be associated with the container, for example as a package insert, if present in a reservoir or carrier supporting the container. The label can be used to indicate that the contents are intended for use in a particular therapeutic application. The label may also indicate instructions for the use of the contents, for example in the methods described herein.

In certain embodiments, the pharmaceutical composition can be presented as a pack or dispenser device that can include one or more unit dosage forms comprising a compound provided herein. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. In addition, the pack or dispenser is accompanied by a notice relating to the container in the form prescribed by the governmental authority that regulates the manufacture, use or sale of the drug, which is approved by the governmental authority of the drug formulation for human or veterinary administration. Indicates. Such notice may be, for example, a label approved by the US Food and Drug Administration for prescription drugs or approved product inserts. In addition, a composition comprising a compound provided herein formulated in an affinity pharmaceutical carrier can be produced, placed in an appropriate container, and labeled for the treatment of the indicated condition.

Treatment and / or Use of FAAH Inhibitor Compounds

Enzymes FAAH are endogenous amide and ester derivatives of various fatty acids such as N-arachidonoylethanolamine (anandamide), N-palmitoylethanolamine, N-oleoylethanolamine, oleamide and 2-arachidonoylglycerol Catalytic decomposition is not limited thereto. Such derivatives exhibit various pharmacological activities, in particular by interacting with cannabinoids and vanilloid receptors. The compounds provided herein block these degradation pathways and increase the tissue content of these endogenous materials. It may be used in the present embodiment for the prevention and treatment of pathologies involving endogenous cannabinoids and / or any other substrate dashed by the enzyme FAAH.

In certain embodiments, the compounds provided herein can be used in particular for the treatment and / or prophylaxis of morning sickness, dizziness, vomiting and nausea following chemotherapy.

In certain embodiments, the compounds provided herein can be administered to relieve pain in an individual. The therapeutic agent may be prophylactic or therapeutic. The therapeutic agent may be administered to a human subject. The therapeutic agent may or may not be administered in combination therapy with another pain relief or anti-inflammatory agent.

In certain embodiments, the compounds provided herein include pain associated with cough, pain associated with cancer, preoperative pain, joint pain and other forms of chronic pain such as postoperative pain, lumbar pain, muscle-skeletal pain, headache, It can be used for the treatment of all kinds of pain, including migraine, muscle pain, lower back and neck pain, toothache and the like. In certain embodiments, the compounds provided herein are useful for the treatment of neuropathic pain. Neuropathic pain syndrome can occur after neuronal injury, and the resulting pain can persist for months or years even after the original injury has healed. Neuronal damage can occur in peripheral nerves, dorsal root reflexes, spinal cord in the brain, or in certain areas. Neuropathic pain syndrome is typically classified by the disease or case that promotes it. Neuropathic pain syndromes include diabetic neuropathy; Sciatica; Non-specific lower back pain; Multiple sclerosis pain; Fibromyalgia; HIV-associated neuropathy; Neuralgia, such as post shingles neuralgia and trigeminal neuralgia; And pain from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions. Signs of neuropathic pain are heterogeneous and are often described as spontaneous blunt and egg pain or ongoing, burning pain. In addition, pain typically associated with non-painful sensations such as “pins and needles” (sensitisation and sensory disturbances), increased sensitivity to sensations (sensitivity), painful sensations after harmless stimulation (dynamic, static or thermal) Allodynia), increased sensation of noxious stimuli (thermal, cold, mechanical hyperalgesia), pain sensations (pain sensitization) that persist after stimulus removal or absence or deficiency in selective sensory pathways (pain).

In certain embodiments, the compounds provided herein include pain, in particular acute or chronic neurological pain, migraines, forms associated with herpes virus and diabetes, acute or chronic pain associated with inflammatory diseases; It is useful for the prevention and / or treatment of arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, irritable bowel syndrome and neuropathic pain, including acute / sharp or chronic pain in the peripheral.

In certain embodiments, the compounds and compositions provided herein can be used to treat non-inflammatory pain and / or inflammatory pain. Compounds are administered as therapeutics for various types of non-inflammatory pain, including:

Peripheral neuropathic pain, which is pain caused by lesions or dysfunction in the peripheral nervous system, for example, painful neuropathy in which the pain persists for a long time after the tissue damage has been cured;

-Pain caused by lesions or dysfunction of the central nervous system, for example central pain, which is a thalamic lesion accompanied by severe pain in unaffected parts of the body;

Pain caused by loss of sensation imparted to the central nervous system, for example, afferent afferent blockage, which is pain from damage to the site where the dorsal root is removed from the spinal cord;

Chronic invasive pain, for example certain types of cancer pain;

Pain felt in response to harmful stimuli of invasive receptors, such as tissue damage or impending tissue damage;

Annular pain, a pain that is felt in parts of the body that no longer exist;

Pain felt by a psychotic patient, a pain in which no physical reason may exist;

-Moving pain, in which the pain repeatedly changes its position in the body.

The compounds provided herein can be used to treat both non-inflammatory pain and inflammatory pain.

In another embodiment, a composition provided herein has a compound provided herein and is effective in oral dosage forms and preferably is an analgesic substance or anti-inflammatory known in the art and effective in an oral dosage form. Contains substances. Examples of analgesic and anti-inflammatory compounds recognized in the art include aspirin, carbaspirin, choline salicylate, diflunisal, magnesium salicylate, salicylate, salicylic acid, salsarate, sodium thiosalicylate, acetaminophen, pena Cetine, Aminopyrin, Mephenamic Acid, Metotrimeprazine, Oxyfenbunazone, Phenylbutazone, Indomethacin, Ibuprofen, Suldinak, Pyroxycamp, Meclofenamate, Zomepilac, Codeine, Morphine, Meperidine , Petinine, alphaprodine, fentanyl, levorpanol, methadone, phenazosin, butorpanol, etobeptzin, nalbuphine, pentazosin, propoxyphene, phenopropene, naproxen, tolmetone, It is not limited to this. In a preferred embodiment, the compounds provided herein are administered with analgesic and / or anti-inflammatory compounds recognized in the art to produce synergistic anti-inflammatory and / or analgesic efficacy.

In another embodiment, the compounds and compositions provided herein can be used to reduce neuropathic pain.

As used herein, the term "neuropathic pain" means pain from nerve injury. Neuropathic pain is distinguished from invasive pain, which is pain caused by acute tissue damage, including small skin nerves or small nerves in muscle or connective tissue. Pain with invasive mechanisms is generally limited to the duration of tissue repair and is alleviated by commonly available analgesic or opioid agents (Myers, Regional Anesthesia 20: 173-184 (1995), herein incorporated by reference). Quoted).

Neuropathic pain is usually long or chronic and often progresses several days or months after the initial acute tissue injury. Neuropathic pain may involve persistent instantaneous pain, as well as allodynia, a painful response to stimuli that is not normally painful. Neuropathic pain may also be characterized by hyperalgesia, which is generally a painful stimulus such as a pronounced response to the terminal. The compounds provided herein can be used to relieve neuropathic pain regardless of the etiology of pain. In certain embodiments, the compounds and compositions provided herein include neuropathic pain resulting from peripheral neurological diseases, such as neuroma; Nerve compression; Nerve contusion, nerve elongation or incomplete nerve transsection; It can be used to alleviate mononeuropathy or polyneuropathy.

Neuromas can be formed easily after traumatic injury of the nerves, especially if the entire nerve is severely left or transversely cut. In neuromas, neurite proliferations that normally regenerate peripheral nerves are abnormal or misguided due to, for example, physical obstruction, such as wound tissue. Thus, regenerative nerve fibers are entangled in an environment where mechanical and physical factors promote abnormal electrophysiological activity and pain. (Myers, et al., 1995). Cleavage neuroma can, for example, cause annular pain or can cause pain that is initiated by the use of limb implants. As disclosed herein, such neuropathic pain can be alleviated by administration of a FAAH inhibitor, such as a compound provided herein.

Nerve compression also results in neuropathic pain. Nerve compression may occur abruptly, as in the case of traumatic nerve contusion, or is prolonged and appropriate and secondary to tumor growth or wound formation in the vicinity of the major nerve bundle. Compression neuropathy can lead to alterations in the bloodstream to the nerves, leading to severe ischemia and thus nerve damage (Myers, homology, 1995).

In other embodiments, the compounds and compositions provided herein include a disease, such as dorsal root ganglion compression; Inflammation of the spinal cord; Cuts in bruises, tumors or spinal cord; Brain stem, thalamic or cortical tumors; Or neuropathic pain from trauma to the brainstem, thalamus or cortex.

In certain embodiments, administration of a compound provided herein alleviates neuropathic pain from mononeuropathy or polyneuropathy. As used herein, neuropathy is a functional disorder or pathological change in the peripheral nervous system and is clinically characterized by sensory or motor neuron abnormalities. The term mononeuropathy indicates that a single peripheral nerve is affected, and the term polyneuropathy indicates that several peripheral nerves are affected. The pathogenesis of neuropathy may or may not be known (e.g., Myers, Hom., 1995; Galer, Neurology 45 (suppl 9): S17-S25 (1995); Stevens and Lowe, Pathology , Times Mirror International Publishers Limited, London (1995)] Known etiologies include complications of diseases or toxic states, for example diabetes is the most common metabolic disease that causes neuropathy In certain embodiments, compounds provided herein Relieves neuropathic pain of mononeuropathy due to, for example, diabetes, irradiation, ischemia or vasculitis In other embodiments, the compounds provided herein can be used, for example, in polio syndrome, diabetes, alcohol, amyloid, Relieves neuropathic pain of multiple neuropathy from toxins, HIV, hypothyroidism, uremia, vitamin deficiency, chemotherapy, ddC or Fabry disease. Standing, the compounds provided herein alleviates the neuropathic pain of unknown etiology.

In certain embodiments, the compounds provided herein can be used to treat inflammatory diseases, such as auto-immune diseases.

The term "inflammatory disease" refers to pain (pain from the generation of harmful substances and stimulation of nerves), fever (calories from vasodilation), redness (redness due to vasodilation and increased blood flow), swelling (excessive influx of fluid) Or a disease or condition characterized by one or more of the signals of a tumor due to limited outflow) and a loss of function (which can be partial or complete, transient or permanent). Inflammation takes many forms, examples of which are acute, adherent, atrophic, catarrh, chronic, cirrhosis, diffuse, sowing, exudative, fibrinose, fibrosis, topical, granulomatous, hyperplasia, hypertrophy, interstitial, metastatic cancer Necrotic, obstructive, parenchymal, hyperplastic, proliferating, breeding, caustic, pus, hardening, longitudinal plastic, serous, simple, specific, subacute, purulent, toxic, traumatic and / or ulcer inflammation There is, but is not limited to this. Inflammatory diseases include blood vessels (polyarteritis, coronary arteritis); Joints (arthritis: crystalline, bone-, psoriasis, reactive, rheumatic, lighter); Gastrointestinal tract (Crohn's disease, ulcerative colitis); Skin (dermatitis); Or affecting a plurality of organs and tissues (systemic lupus erythematosus), and the like. Harrison's Principles of Internal Medicine , 16th Edition, Kasper DL, et al, Editors; McGraw-Hill, publishers]

Examples of immune diseases, such as autoimmune diseases, which can be treated using a compound provided herein or a composition comprising a compound provided herein include arthritis (rheumatic arthritis, spondyloarthropathy, gouty arthritis, degenerative joint disease (ie osteoarthritis) Systemic lupus erythematosus, Sjogren's syndrome, ankylosing spondylitis, undifferentiated spondylitis, Besett's disease, hemolytic autoimmune anemia, multiple sclerosis, amyotrophic lateral sclerosis, amylose, acute painful shoulder, psoriasis and pediatric arthritis), asthma, Atherosclerosis, osteoporosis, bronchitis, tendinitis, bursitis, cutaneous inflammatory diseases (ie psoriasis, eczema, laceration, dermatitis), enuresis, eosinophil disease, gastrointestinal diseases (inflammatory bowel disease, peptic ulcer, local enteritis, diverticulitis, gastrointestinal bleeding, Diseases that are ameliorated by Crohn's disease, gastritis, diarrhea, irritable bowel syndrome and ulcerative colitis and gastrointestinal stimulants (ie Obstruction, for example postoperative ileus and sepsis in sepsis; gastroesophageal reflux disease (GORD or its synonyms (GERD); eosinophilic esophagitis, gastric palsy, such as diabetic gastric palsy; food intolerance and food allergies and other functional intestines) Diseases such as non-ulcer dyspepsia (NUD) and non-cardiac thoracic pain (NCCP).

In addition, a composition comprising a compound provided herein includes, for example, vascular disease, migraine, tension headache, nodular periarthritis, thyroiditis, aplastic anemia, Hodgkin's disease, scleroderma, rheumatic fever, type I diabetes, severe It may be used to treat inflammation associated with myasthenia gravis, sarcoidosis, nephrotic syndrome, Beset syndrome, multiple myositis, gingivitis, irritability, conjunctivitis, multiple sclerosis and ischemia (eg myocardial ischemia). The compounds may be useful for treating neuroinflammatory diseases associated with brain diseases (eg, Parkinson's disease and Alzheimer's disease) and chronic inflammation associated with cranial radiation damage. The compounds may be useful for treating acute inflammatory conditions (such as those resulting from infection) and chronic inflammatory conditions (such as those resulting from asthma, arthritis and inflammatory bowel disease). In addition, the compounds may be useful for treating inflammation associated with trauma and non-inflammatory myalgia. In addition, the compounds may be administered either preoperatively or prior to ingestion of the anticoagulant. Compounds provided herein include thrombotic or thromboembolic stroke, myocardial ischemia, myocardial infarction, angina pectoris, transient ischemic attack (TIA; transient dark vision), reversible ischemic nerve defects and any vascular image (intestinal, kidney, aortic, peripheral, etc.) Risk of thrombotic cardiovascular events, defined as any breakthrough event of the type known to be caused by platelet aggregation, thrombosis, and subsequent ischemic clinical events, including any similar thrombotic events.

Compounds provided herein include influenza or other viral infections, colds, sprains and modifications, myositis, neuralgia, synovitis, injuries such as motor impairment and, after surgery and dental procedures, coagulation disease, nephropathy (eg, impaired) Renal function), eye diseases (including glaucoma, retinitis, retinopathy, uveitis, wet macular degeneration and acute damage to eye tissue), liver disease (ie, chronic viral hepatitis B, chronic viral hepatitis C, alcoholic liver damage) , Inflammatory liver disease, including primary biliary cirrhosis, autoimmune hepatitis, non-alcoholic fatty liver and liver transplant rejection) and pulmonary inflammatory diseases (including asthma, allergic rhinitis, dyspnea syndrome, chronic bronchitis and pulmonary edema) It can be used for treatment.

The compounds provided herein can be used to inhibit uterine contractions caused by hormone and prostanoid-induced smooth muscle contraction. The compounds provided herein can be useful for treating preterm birth, dysmenorrhea, dysmenorrhea and dysmenorrhea.

In certain embodiments, the compounds provided herein can inhibit cellular neoplastic conversion and metastatic cancer tumor growth. The compound may be associated with reducing the number of adenomatous colon polyps. Thus, the compounds provided herein may be useful for reducing the risk of certain cancers, such as solid tumor cancers such as colon or colorectal cancer. In certain embodiments, the compounds provided herein include cancer, such as bladder cancer, cancer associated with overexpression of HER-2 / neu cervix, skin cancer, esophageal cancer, head and neck cancer, small cell lung cancer, including lung cancer, kidney cancer, pancreatic cancer, prostate Cancer, gallbladder cancer and cholangiocarcinoma and endometrial cancer, gastric cancer, glioma, hepatocellular carcinoma, colon adenoma, breast cancer, ovarian cancer and salivary adenocarcinoma. In addition, the compounds provided herein can be used to treat colorectal cancer and prostate cancer. In addition, the compound can be used in patients with oral precancerous lesions, cervical epithelial tumors, chronic hepatitis, bile duct hyperplasia, lungs, prostate glandular atypical hyperplasia, intraepithelial tumors, bladder dysplasia, actinic keratosis of the skin, colorectal adenoma, stomach It can be used where there is a risk for cancer, including metabolism and Barrett's esophagus.

In certain embodiments, the compounds provided herein can be used in cancer, such as benign tumors of the skin, papilloma and brain tumors, prostate tumors, brain tumors, glioblastomas, stromal epitheliomas, stromal blastomas, neuroblastomas, tumors of embryonic organs, astrocytes Cell tumor, astrocytoma, ventricular cell tumor, rare oligodendrocyte tumor, frozen tumor, neuroepithelioma, epiphyseal tumor, ventricular blastoma, malignant meningioma, sarcoma, malignant melanoma and schwannoma. In certain embodiments, the compounds provided herein may also have use in the treatment and / or prevention of cyclooxygenase-mediated proliferative diseases, such as may occur in diabetic retinopathy and tumor angiogenesis. . In certain embodiments, the compounds provided herein can be used to inhibit angiogenesis, such as may occur in wet macular degeneration.

FAAH inhibitors, such as the compounds provided herein, include cognitive diseases such as dementia, particularly degenerative dementia (including elderly dementia, Alzheimer's disease (and progenitors thereof), Peak disease, Huntington's chorea, Parkinson's disease and Creutzfeldt-Jakob disease) and vascular dementia As well as dementia associated with intracranial space occupying lesions, trauma, infections and related conditions (including HIV infection), metabolism, toxins, anoxia and vitamin deficiency; And aging-related cognitive impairment, in particular aging-related memory impairment.

FAAH inhibitors, such as the compounds provided herein, can inhibit neuronal damage by inhibiting the production of neuronal free radicals (and hence oxygenous stress), thereby preventing stroke; epilepsy; And epileptic seizures (including large seizures, small seizures, myoclonial epilepsy and partial seizures). FAAH inhibitors, such as the compounds provided herein, can be used to modulate or inhibit seizures (including chemically induced).

In certain embodiments, FAAH inhibitor compounds, such as the compounds provided herein, are used for acute and chronic neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, elderly dementia, Huntington's chorea, cerebral ischemia and lesions associated with cranial and medulla trauma. Can be.

In certain embodiments, FAAH inhibitory compounds, such as the compounds provided herein and compositions comprising the same, may be useful for treating depression and depressive disorders or conditions. The compounds and compositions can be useful for treating major depressive disorders (unipolar depression), mood depressive disorders (chronic, mild depression) and bipolar disorders (manic depression), for example. Depression can be clinical or asymptomatic depression.

FAAH inhibitory compounds, such as the compounds provided herein and compositions comprising such compounds, can be used to treat anxiety and anxiety disorders or conditions. Such compounds and compositions include, for example, anxiety, clinical anxiety, panic disorder, agoraphobia, general anxiety disorders, certain phobias, social phobias, obsessive compulsive disorders, acute stress diseases and post-traumatic stress diseases; And adaptive disorders with anxiety findings, anxiety disorders due to general medical conditions, substance-induced anxiety disorders and the rest of the unspecified classes of anxiety disorders. Treatment can be prophylactic or therapeutic. The compounds may be used to treat only anxiety and anxiety disorders or conditions and / or may be useful for simultaneously treating another disease or condition such as pain, obesity, depression or other diseases.

In certain embodiments, compounds that inhibit the activity of FAAH, such as the compounds provided herein and compositions comprising such compounds, are useful for treating epilepsy and convulsive diseases or seizures. The compounds and compositions of the present invention may be administered alone to reduce the severity or frequency of seizures or seizures.

In certain embodiments, inhibition of FAAH causes sleep (US Pat. Nos. 6,096,784, 6,096,784, 6,271,015, WO98 / 24396). In one embodiment, the compounds provided herein can be administered to a mammal and the subsequent time (e.g., onset, duration) spent on sleep (close eyes, stop motion) can be increased.

In certain embodiments, FAAH inhibitor compounds may be useful for treating schizophrenia and dopamine related diseases. In certain embodiments, the compounds and compositions provided herein are useful for treating schizophrenia, obsessions, paranoid thinking, affective blunts or other related diseases or other diseases of dopamine delivery.

In certain embodiments, a compound provided herein and a composition comprising a compound provided herein can be administered to cause or promote sleep in a mammal. Treatment can be prophylactic or therapeutic and can only be administered to healthy human patients to reduce the severity or frequency or extent of insomnia. In other embodiments, the compounds and compositions provided herein can be used to treat sleep diseases, including but not limited to insomnia and sleep apnea.

In certain embodiments, compounds that inhibit the activity of FAAH, such as those provided herein, and compositions comprising the compounds reduce appetite (s), reduce body fat, and obesity or overweight in mammals In order to treat or prevent the disease, it can be used for the prevention or treatment of diseases associated with these healthy conditions. In one embodiment, administration of a FAAH inhibitor, such as a compound provided herein, reduces appetite, body fat and weight, and treats or prevents obesity or overweight, reduces food intake or desire in mammals. It can be used to treat disorders.

In one embodiment, the compounds and compositions provided herein reduce appetite, body fat or weight, and treat or prevent obesity or overweight, including changes in body mass composition, such as changes in fat percentage or in lean muscle weight. Can be used to reduce food intake or to treat craving disorders in human patients.

In a further embodiment, a FAAH inhibitor, such as a compound provided herein, comprises a) an oleoyl that reduces appetite, reduces food consumption, reduces body fat or reduces body weight, and b) is hydrolyzed by FAAH. Administration is in parallel therapy with ethanolamide (OEA) or another fatty acid alkanolamide compound, homologue or analog.

In certain embodiments, an FAAH inhibitor, such as a compound provided herein, is administered to an individual in an amount sufficient to reduce body fat, weight, or to prevent body fat or weight gain or to reduce appetite (s). In another embodiment, a composition provided herein comprises a FAAH inhibitor, such as a compound provided herein and an oleoylethanolamide or fatty acid amide compound, homologue or analog thereof.

In certain embodiments, FAAH inhibitors such as the compounds provided herein treat various metabolic diseases such as insulin resistance, diabetes, fatty liver, hyperlipidemia, fatty liver disease, non-alcoholic fatty liver, atherosclerosis and atherosclerosis It can be used to Methods for determining the efficacy of a compound provided herein for such a disease are disclosed in US Pat. No. 6,946,491, which is incorporated herein by reference.

In one embodiment, a compound provided herein and a pharmaceutical composition comprising a compound provided herein comprise insulin resistance syndrome and diabetes (primary diabetes mellitus, such as diabetes type I or diabetes type II and secondary ratios). And diabetes mellitus). The administration of a compound or composition provided herein may develop symptoms of diabetes, such as atherosclerosis, hypertension, hyperlipidemia, fatty liver disease, nephropathy, neuropathy, retinopathy, foot ulcers and cataracts or signs of diabetes. And each of these signs is associated with diabetes.

In one embodiment, the compounds provided herein and pharmaceutical compositions comprising the compounds provided herein can be used to treat hyperlipidemia. Administration of the compounds or compositions provided herein can reduce serum triglycerides and free fatty acids in hyperlipidemic individuals. In one embodiment, the compounds and pharmaceutical compositions provided herein can be used to treat fatty liver disease. In another embodiment, the compounds and pharmaceutical compositions provided herein can be used to treat atherosclerosis or arteriosclerosis.

In other embodiments, the compounds and compositions provided herein treat and treat food behavior problems / feeding diseases (ie weight loss associated with eating disorders having various properties, in particular anorexia and cachexia, cancer and other wasting states). Or to prevent it.

In certain embodiments, FAAH inhibitors, such as the compounds provided herein, may be administered to treat or prevent glaucoma or to reduce intraocular pressure. In certain embodiments, the compound can be administered systemically. In other embodiments, the FAAH inhibitor is applied directly to the surface of the eye (eg, as eye drops). Eye carrier formulations for ocular applications are described in Remington's Pharmaceutical Sciences , Gennaro AR ed. 20th edition, 2000: Williams & Wilkins Pa., USA.

In certain embodiments, a compound provided herein and a composition comprising the compound may be administered to treat or prevent glaucoma or to reduce intraocular pressure. In certain embodiments, the compound can be administered systemically. In other embodiments, the compound is applied directly to the surface of the eye (eg, as eye drops).

Examples of other diseases, diseases and / or conditions that can be treated and / or prevented using the compounds provided herein include lung diseases (ie, airway disease, bronchial spasm, cough, asthma, chronic bronchitis, chronic obstruction of the airways). , Lung air species); Urinary incontinence, inflammation of the bladder, urinary incontinence, bladder inflammation, migration diseases, psychomotor diseases, hypertension; Cardiovascular diseases, especially hypertension, deep veins, arteriosclerosis, heart attacks, cardiac ischemia, renal ischemia; Neuropathology, tremor, dyskinesia, dystonia, convulsions, obsessive compulsive behavior, Tourette syndrome, mood disorders, psychosis.

Any combination of the diseases, disorders and / or conditions presented herein can be treated using the compounds provided herein.

Those skilled in the art can further recognize various embodiments and advantages of the present disclosure by reviewing the following illustrative and non-limiting examples.

Example 1 Preparation of Inhibitors of FAAH

Synthesis of 3-acetylphenyl cyclohexylcarbamate

A solution of 3-hydroxyacetophenone (1 mmol, 136 mg), triethylamine (1.1 mmol, 0.19 mL) and cyclohexyl isocyanate (1.1 mmol, 0.14 mL) was stirred at room temperature for 3 hours. The precipitated solid was then filtered and dried under vacuum to afford the product as a white solid.

Example 2 Screening Methods for Compounds for FAAH Inhibitory Activity

In general, FAAH inhibitors used in the methods described herein are identified as inhibitors of FAAH in vitro. Preferred in vitro assays are to increase the level of unmodified FAAH substrate (eg, anandamide, OEA) or release of reaction product (eg, fatty acid amide or ethanolamine) by FAAH-mediated hydrolysis of a substrate, such as AEA or OEA. Detects a decrease. Substrates can be labeled to facilitate detection of released reaction products. High power assays for the presence, absence or quantification of certain reaction products are known to those skilled in the art. In addition, high-power screening systems are commonly available (for example, Zymark Corporation, Hopkinton, Mass .; Air Technical Industries, Mentor, Ohio; Beckman Instruments, Fullerton, Calif., Inc .; Precision Systems, Inc., Natick, Mass., USA). Such systems typically automate the entire procedure, including the final reading of the microplates in the detector (s) appropriate for whole sample and formulation pipetting, liquid dispensing, hourly incubation and analysis. Automated systems allow the identification of multiple in vitro FAAH inhibitors without undue effort.

Candidate in vivo FAAH inhibitors can be identified by their ability to increase systemic levels of one or more FAAs. Examples of suitable FAAs include fatty acid ethanolamides, including 14 to 28 carbons and fatty acid moieties having 0 to 6 double bonds, such as OEA, PEA, AEA and stearoylethanolamide (SEA). Other suitable FAAs include primary fatty acid amides, such as oleamides, having fatty acid moieties comprising 14 to 28 carbons and 0 to 6 double bonds. Examples of biological samples capable of analyzing FAA levels include, but are not limited to, plasma, serum, blood, cerebrospinal fluid, saliva or urine.

FAA levels in biological samples are analyzed by, for example, liquid chromatography serial mass spectrometry (LC-MS / MS). Increased assay reproducibility is achieved by immobilizing biological samples using known amounts of isotopically labeled FAAs that serve as internal standards for the FAAs to be analyzed. In addition, the level of FAA can be measured using spectrophotometric techniques (eg, fluorometry). Alternatively, levels of FAA can be measured using biological assays. In certain embodiments, the level of FAA is measured using a combination of the aforementioned techniques. Any of these assays for FAA levels can be partially or fully automated for high power. In addition to the above and other FAA assays, details on how to analyze changes in FAA levels are known in the art. See, eg, Quistad et al., (2002), Toxicology and Applied Pharmacology 179: 57-63; Quistad et al., (2001), Toxicology and Applied Pharmacology 173, 48-55; Boger et al., (2000), Proc. Natl. Acad. Sci. USA . 97, 5044-49; Cravatt et al., Proc. Natl. Acad. Sci USA . 98, 9371-9376 (2001); Ramarao et al., (2005) Anal. Biochem. 343: 143-51. See also US Pat. No. 6,096,784, US Patent Publication No. 2004/0127518, US Patent Application No. 10 / 681,858, International Patent Publications WO98 / 24396 and WO04 / 033422.

The carbamate compounds shown in FIGS. 1-8 were tested for in vitro inhibition of FAAH against reference compound KDS-4103 and found to have specific inhibitory activity.

Example 3. Compound Screening for Inhibition of FAAH Activity—FAAH LC-MS / MS Screening Assay :

으로 결정한다. 조절에 대하여 정규화된 가수분해 비율은 테스트 샘플의 가수분해 비율(%)을 대조용 샘플의 가수분해 비율(%)로 나누에서 결정한다.In one embodiment, inhibition of FAAH activity was measured using LC-MS / MS. Without the use of FAAH inhibitor (1 μg / ml) and 25 μl of human liver microsomes (31.3 μg) (control) or using anandamide (5 μl of 200 μg / ml) in 5 ml glass test tubes, 0.125% 960 μl of 50 mM ammonium phosphate buffer (pH 7.4) with BSA (w / v), 10 μl of DMSO were mixed. Prior to incubation, 100 μl aliquots were delivered to 96-well plates containing 0.25 mL acetonitrile and D ₄ (deuterated) anandamide (0.2 μM). Each 5 ml test tube was capped and placed in a stirred bath maintained at 37 ° C. for 60 minutes. After 60 min incubation, a second 100 μl aliquot was transferred to a 96-well plate as described above. The 96-well plates were then covered, vortex mixed and placed in HPLC for liquid chromatography / serial mass spectrometry (LC / MS / MS) analysis. HPLC was performed on a Waters 2790 Alliance system (Mildford, Mass.). Separation was carried out using an isocratic mobile phase of acetonitrile: water: formic acid (75: 25: 0.1, v / v / v) on a Phenomenex Polar RP column (2 mm × 150 mm, 4 μ; Torrance, CA). At a low rate of 0.3 mL min ⁻¹ , it was carried out at a column temperature of 45 ° C. The HPLC system is connected to Micromass Quattro Ultima Tandem MS (Beverly, Mass.). Samples were analyzed using electrospray probes in a positive ionization mode with a cone voltage difference set at 40 V and capillary at 3.2 kV. Source and desolvation temperature settings were 130 ° C. and 500 ° C., respectively. The voltage of the CID chamber was set at -20 eV. Multiple reaction monitoring was used for the detection of anandamide as [M + H] (m / z 348> 62) and D ₄ anandamide (internal standard) as [M + H] (m / z 352> 66). It was. Area ratio reaction (anandamide area reaction / D ₄ anandamide area reaction) was measured for each sample. The anandamide hydrolysis ratio of each sample is

Decide on The normalized hydrolysis rate for the control is determined by dividing the percent hydrolysis of the test sample by the percent hydrolysis of the control sample.

To determine IC ₅₀ values for candidate FAAH inhibitor compounds, the method used adjusted FAAH inhibitor concentrations. In the IC ₅₀ assay, FAAH inhibitor was added at a concentration range of about 3 μM to 0.03 nM. The final concentration of the IC ₅₀ was converted to "X = log (X)" and the data was then converted to S using GraphPad Prism version 4.00 for Windows (GraphPad Software, San Diego, Calif., Www.graphpad.com). The curve was determined by analyzing the data with a curve dose-response curve (no constraint) in the shape of a child.

Example 4. Compound Screening for Inhibition of FAAH Activity—FAAH Fluorescent Screening Assay :

이다. 대조군에 대하여 정규화된 가수분해 비율(%)은 테스트 샘플의 가수분해 비율(%)을 대조군 샘플(DMSO)의 가수분해 비율(%)로 나누어서 결정한다.180 μl of arachidylyl 7-amino, 4-methylcoumarin amide (AAMCA, 3 μM), 20 μl of FAAH inhibitor (0.05 μg / ml in DMSO) in black 96-well plate (Nunc, cat # 267342) and 50 Μl of human liver microsomes (0.25 mg / ml) were added. Diluent for AAMCA and human liver microsomes is BSA (1.4 mg / ml) without fatty acids in HEPES / EDTA (50 mM / 1 mM) at pH 7.4. Plates were read on a fluorescent plate reader (SpectraMax GeminiXS, Molecular Device) at excitation 355 nm and emission 460 nm at T = O and incubated at 37 ° C. for 30 minutes. After 30 min incubation, the plates were read at the final time and the percent hydrolysis (normalized to the control) was measured. Calculation for% hydrolysis is

to be. Percent normalized hydrolysis relative to the control is determined by dividing the percent hydrolysis of the test sample by the percent hydrolysis of the control sample (DMSO).

Example 5 Screening Compounds in Vivo FAAH Inhibition in Rats for Inhibition of FAAH Activity

Potential FAAH inhibitors were formulated for oral (p.o.), intraperitoneal (i.p.) or intravenous (i.v.) delivery in rats. The combined compounds were administered and the animals were killed by post administration at the scheduled time. When the animal died, blood samples were collected in EDTA plasma tubes and the whole brain snap snapped in liquid nitrogen. EDTA plasma was separated from blood samples after centrifugation. Brain and plasma samples were stored at −80 ° C. prior to analysis. All samples (brain and plasma) were tested by LC-MS / MS for concentrations of test compound (FAAH inhibitor), metabolite of test compound and endogenous fatty acid ethanolamide levels (including anandamide, oleoylethanolamide and palmitoylethanolamide). Was analyzed. The levels of these compounds were compared over time to determine the pharmacokinetic properties of test compounds and partial pharmacological efficacy (including changes in fatty acid ethanolamide levels) that inhibit FAAH activity.

In one embodiment, additional tissue and body fluid samples were collected when killing. In one embodiment, FAAH activity can also be measured in body fluids and tissue samples by methods known in the art or by the disclosed methods. In one embodiment, the metabolite of the test compound can be measured in body fluids and tissue samples.

Example 6: Measurement of Pharmacokinetics

The pharmacokinetic properties of the compounds provided herein were evaluated in rats after oral administration as a solution. To determine the oral bioavailability of the compounds provided herein, the solution of the test compound is prepared as a 10 mg / ml solution in 80% cremephor and 20% ethanol (w / w) or 90% PEG-400 and 10% Tween. Generated for oral administration as 80 (w / w) 10 mg / ml liquid. Liquids of the test compounds were administered to rats by oral feeding at a dose of 10 mg / kg.

Animal model

Any of a variety of animal models can be used to test the compounds disclosed herein for reducing inflammation and treating pain. Useful compounds may be effective in reducing inflammation or pain in one or more animal models.

Animal Models for Assessing Anti-inflammatory Activity

Example 7 Carrageenan-Induced Foot Edema Model

The model is described, for example, in Winter et al., 1962 Proc Soc Exp Biol Med 111: 544. Briefly, rats are fasted for 17 to 19 hours prior to oral treatment with up to three doses of test compound, indomethacin or celecoxib or a control vehicle (1% methylcellulose in deionized water), and water Allowed to eat freely. One hour after the last treatment, 0.05 ml of 2% carrageenan solution was injected into the left hind paw to cause edema. The volume of the left hind paw of each rat was measured using a volumetric flow meter prior to oral treatment, at carrageenan injection and at 1.5 hours, 3 hours, and 4.5 hours after carrageenan injection. The edema volume of each rat at each time point is expressed as a change from oral treatment, and the anti-inflammatory efficacy in the treated group is percent inhibition of vehicle alone group at 1.5 hours, 3 hours, and 4.5 hours after carrageenan injection. Represented as The significance of the differences between the edemas of the different groups was assessed by one-dimensional analysis of variance (ANOVA) followed by the unpaired Dunnett t test. In this model, hyperalgesia and PGE ₂ production rates can also be measured (Zhang et al., 1997 J Pharmacol and Exp Therap 283: 1069).

Example 8. Complete Freund's Adjuvant (CFA) Induced Arthritis Model

In this model, a well-crushed suspension of dead Mycobacterium tuberculosis (0.3 mg in 0.1 ml of light mineral oil; complete Freund's adjuvant, CFA) was injected on day 1 under the plantar area of the right hind paw to gain weight. Arthritis was induced in groups of eight Lewis induced rat males of 160 ± 10 g. The hind paw volume was measured by water substitution at Day 0, Day 1 and Day 5 (right hind paw with CFA) and Day 0, Day 14 and 18 (left hind paw without CFA), and rats were weighed on Day 0 And on day 18. New test compounds dissolved or suspended in 2% Tween 80 were made daily and administered orally twice daily, starting 1 hour prior to CFA injection for 5 consecutive days (day 1 to day 5). For CFA-injected vehicle control rats, the increase in the volume of the paw at Day 5 is generally 0.7-0.9 ml compared to Day 1 (acute phase of inflammation); On day 18 (delayed stage of inflammation) compared to day 14 it is usually 0.2 to 0.4 ml. Thus, the anti-inflammatory activity in this model can be represented by values calculated during the acute phase as well as the delayed phase. Animal weights are also measured at Day 0 and Day 18; CFA-injected vehicle control animals generally gained 40-60 g body weight during this period. A reduction of at least 30% in hind paw volume compared to vehicle treated controls is considered to have significant anti-inflammatory activity. Mean ± SEM for each treatment group was determined and the Dunnett test was applied for comparison between the vehicle and treatment groups. The difference is considered significant at P <0.05. Polyarthritis of the forefoot, tail, nose and ear was visually graded and marked on the first and last days, where the positive value (+) is for the swelling response and the negative value (-) is normal. In addition, X-ray radiation of the hind paw can be performed for further radiation index measurements of arthritis signs. Hyperalgesia can be measured in this model, which measures the analgesic efficacy of the test compound (Bertorelli et al., 1999 Brit J. Pharmacol 128: 1252).

Example 9 Air Pouch Model

This model is described in Masferrer et al., 1994 Proc Natl Acad Sci USA 91 3228. Briefly, Lewis rat males (175-200 g, Harlan Sprague-Dawley) are injected subcutaneously with 20 ml of sterile air into the back shoulder region to create an air cavity. An additional 10 ml of air is injected into the cavity every three days to allow space to open. At 7 days after the initial air injection, 2 ml of a 1% solution of carrageenan dissolved in sterile saline was injected directly into the pouch to create an inflammatory response. In treated and untreated animals, the volume of exudate was measured and the number of leukocytes present in the exudate was measured by Wright-Giemsa staining. PGE ₂ and 6-keto-PGF _1α were also measured in pouch exudates from treated and untreated animals by specific ELISA (Cayman Chemicals, Ann Haber, Mich.).

Animal Models for Assessing Analgesic Activity

Example 10 Carrageenan-Induced Heat Hyperalgesia

This model is described in Hargarreaves et al., 1988 Pain 32:77. In brief, inflammation caused a 2% carrageenan suspension (0.1 ml) by injection under the plantar foot in the right hind paw. After 3 hours, the invasive threshold was evaluated using heat invasive stimulation (foot sole test). The light beam (44% of maximum intensity) is focused under the hind paw and the thermally invasive threshold is assessed by the paw tailing response latency (cut-off-time: 30 seconds). Pain thresholds were measured in the ipsilateral (inflammatory formation) and contralateral (control) hind paws 1 hour after oral treatment with the test compound or control. The results can be expressed as the ratio of the invasive threshold in seconds and the deviation of the invasive threshold (mean ± SEM) in each hind paw for each rat from the mean value of the vehicle group. Comparison of invasive thresholds between the inflamed foot and the control foot in the vehicle treatment group was made using the Student's t test, and the statistical significance difference is considered for P <0.05. Statistical significance between treatment and vehicle groups was measured by Dunnett's test using the remaining variances after one-dimensional analysis of variance (P <0.05) using SigmaStat Software.

Example 11 Phenylbenzoquinone-Induced Struggle Model

This model is described in Siegmund et al., 1957 Proc Soc Exp Bio Med 95: 729. Briefly, mice were injected with the intraperitoneal route with 0.02% phenylbenzoquinone (PBQ) solution (12.5 mL / kg) 1 hour after oral administration of the test compound, morphine or vehicle. The number of stretches and writhing is recorded for 5-10 minutes after PBQ injection and is also counted for 35-40 minutes and 60-65 minutes to provide a kinetic assessment. The results are expressed as the percentage of deviations in the invasive threshold calculated from the number of stretches and struggles (mean ± SEM) and the mean value of the vehicle-treated group. Statistical significance of any differences between treatment and control groups was determined by Dunnett's test using the remaining variances after one-dimensional analysis of variance (P <0.05) using SigmaStat Software.

Example 12 Kaolin-Induced Arthritis Model

This model is described in Hertz et al., 1980 Arzneim Forsch 30: 1549. Briefly, arthritis was caused by injecting a 0.1 ml kaolin suspension into the knee joint of the rat's right hind leg. Test compounds were administered subcutaneously after 5 minutes and again after 2 hours. Reference compounds may be administered orally or subcutaneously. Gait was assessed every hour for 1.5 to 5.5 hours post-treatment and graded as normal walking (0), slight difficulty (1), intermittent lifting of the leg (2) and lifting of the foot (3). The results are expressed as the average walking grade (mean ± SEM) calculated from the individual values at each time point and the percentage of deviation of the average grade calculated from the mean values of the vehicle-treated groups at 4.5 and 5.5 hours post-treatment. Statistical significance between treatment and vehicle-treatment groups was measured by Dunnett's test using the remaining variance after one-dimensional analysis of variance (P <0.05) at each time point.

Example 13. Peripheral Mononeuropathy Model

This model is described in Bennett et al., 1988 Pain 33:87, and can be used to evaluate the anti-hyperalgesic efficacy of test compounds administered orally in a model of peripheral mononeuropathy. The efficacy of the test substance can be compared to an untreated control or reference substance, for example morphine. Peripheral mononeuropathy is induced by loose ligation of the sciatic nerve in anesthetized Sprague Dawley rat males (Pentobarbital; 45 mg / kg, intraperitoneal route). After 14 days, the invasive threshold was assessed using a mechanical invasive stimulus (painometric foot pressure test; Hugo Basil, Italy). Test and reference compounds and vehicles were administered orally (10 ml / kg supported 1% methylcellulose). Increasing pressure was applied to the hind paws of the animals until an invasive response (prick or paw atrophy) was reached. Pain threshold (contact pressure g) was measured in ipsilateral (damaged) and contralateral (undamaged) hindpaws 60 minutes after treatment. The results are the percentage of invasive threshold calculated from the mean invasive threshold (mean ± SEM) (in g) of contact pressure for damaged and intact feet (vehicle-treated group) and the mean value of the vehicle-treated group. Indicates. Comparison of invasive thresholds between intact feet and injured feet of the vehicle-treated group was performed using the Student's t test. The statistical significance of the difference between the treatment and vehicle groups was the remainder after one-dimensional analysis of variance (P <0.05) using SigmaStat Software (SigmaStat® v. 2.0.3 (SPSS Science Software, Erkrat GmbH). Dispersion was used to measure hind paws damaged by the Dunnett test.

Example 14 Chung Rat Model of Peripheral Neuropathy

In one embodiment, the efficacy of the compounds provided herein to relieve neuropathic pain is demonstrated using the well-known Chung rat model of peripheral neuropathy. In the Chung rat model, spinal nerve partial ligation of the left spinal nerves L-5 and L-6 produces prolonged hypersensitivity to mild pressure in the diseased left foot. Hypersensitivity is similar to the pain experienced by a person with a neuropathy condition of burning pain (Kim and Chung, Pain 50: 355-363 (1992), incorporated herein by reference).

Example 15 Diabetic Neuropathy Foot Pressure Test

Complete protocol details can be found in Rakieten et al., 1963 Cancer Chemother Rep 29:91. In brief, diabetes is caused by intraperitoneal injection of streptozotocin in rats. Three weeks later, invasive thresholds were measured using the foot pressure test to assess hyperalgesia. Test compounds or controls were administered intraperitoneally 30 minutes prior to pain measurement.

Example 16 Acetic Acid Wrought Test

Briefly, test compounds were administered orally 1 hour before intraperitoneal injection of acetic acid (0.5%, 10 ml / kg) in rats. Reduction in the number of writhing of more than 50% (≧ 50) per group of animals observed during 5-11 minutes of acetic acid administration to the vehicle treated control indicates possible analgesic activity. This analysis is described in Inoue, K. et al., 1991 Arzneim. Forsch./Drug Res . 41: 235.

Example 17. Formalin Test

Full protocol details can be found in Hunskaar et al., 1985 Neurosci. Meth. 14:69. Briefly, at 30 minutes after intraperitoneal administration of the test compound or control, 20 μl of 5% formalin solution was injected into the right hind paw of the rat by the sub-plantar route. The number of paw licks was recorded during the initial stages and during the later stages following formalin injection.

Example 18 Tailing Test

Complete protocol details are described in D'Amour and Smith 1941 J Pharmacol. Exp Ther. 72:74. Briefly, 30 minutes after intraperitoneal administration of the test compound or control, the light beam was focused on the tail of the rat. The invasive response latency was characterized by tail atrophy. Cut-off time was set to 15 seconds.

Example 19 Tail Dipping Test

In this test, the tail of the rat was immersed in a water bath at 50 ° C to 60 ° C. The invasive response latency was characterized by tail atrophy (Haubrich et al., 1990 J Pharmacol Exp Ther 255: 511 and Lichtman et al., 2004 Pain 109: 319).

Example 20. Hot Plate Test

Complete protocol details can be found in Eddy et al., 1950 J. Pharmacol. Exp. Ther. 98: 121. Briefly, 30 minutes after intraperitoneal administration of test compound or control, mice were placed in metal hot plates maintained at 52 ° C. The invasive response latency was recorded, either by lick reflexes of the forefoot or by fluttering on a hot plate. Cut-off time was set to 30 seconds.

Assay to assess anti-anxiety activity

Compounds provided herein that inhibit FAAH activity and thus regulate fatty acid amide levels may have anti-anxiety activity. Animal models for assessing anti-anxiety activity are as follows:

Example 21. Elevated Plus Maze

Elevated plus maze consists of four maze arms originating from a central platform that effectively form a plus sine shape as described in van Gaalen and Steckler 2000 Behavioural Brain Research 115: 95. The maze can consist of plexiglass and is generally elevated. Two of the maze arms have no walls (opened) and two have walls (closed). Two open arms let light in and two closed arms darken (Crawley 2000 What's Wrong With My Mouse ?: Behavioral Phenotyping of Transgenic and Knockout Mice. Wiley-Liss, New York). The test is based on natural collisions between the propensity of animals to explore new environments and their aversion to bright, open spaces (Pellow et al., 1985 J. Neuroscience Methods . 14: 149).

Complete protocol details can be found in Fedorova et al., 2001 J. Pharm. Exp. Ther. 299: 332. Briefly, 15 minutes after intraperitoneal administration of the test compound or control, the animals are placed on central platforms, respectively, to face one of the open arms facing the observer. Positioning of the open and closed arms and the rating of the time of stay in different compartments of the maze by the animal (central platform, open and closed arms) are described in Gaalen et al., (Homologous). Graded together Animals are described in Simonin et al., 1998 EMBO J. 17: 886, if all four feet move into the arm, it is recorded as a visit to the arm. Behavior is graded using a video camera and / or by an observer over a 5-minute test period. Larger amounts of animal dwell time or stance in open vs. closed arms are indicative of anti-anxiety activity.

Example 22. Elevated Zero Maze

The elevated zero maze is a variation of the elevated plus maze. The raised zero maze consists of a plexiglass device of circular shape (circular passageway with a diameter of 46 cm and passage width of 5.5 cm) consisting of two open sectors of equal size and two walled sectors. It rises below 1 meter above the ground. Such devices are described in Simonin et al., (Homologous) and Crawley (homologous).

Complete protocol details can be found in Kathuria et al., 2003 Nature Medicine 9: 76. Briefly, 30 minutes after intraperitoneal administration of the test compound or control, the animals are placed in one open sector in front of the closed sector. The time in the new sector is recorded on entry with all four feet. Behavior is graded using a video camera and / or by an observer over a 5-minute test period. Larger amounts of animal dwell time or entry in sectors with open sector versus walls are indicative of anti-anxiety activity.

Example 23 Separation-Induced Ultrasonic Release Test

In another animal model's isolated-induced ultrasound emission test, the compounds provided herein were tested for anti-anxiety efficacy. Separation-induced ultrasound emission testing measures the number of stress-induced vocalizations of rat pups removed from habitat (Insel, TR et al., Pharmacol. Biochem. Behav ., 24, 1263-1267 (1986); Miczek, KA et al, Psychopharmacology , 121, 38-56 (1995); Winslow, JT et al, Biol. Psychiatry , 15, 745-757 (1991); US Pat. No. 6,326,156].

Assay to assess anti-invasive water soluble mechanism

The compound can be tested to determine if it affects pathways associated with pain. The results of these analyzes are used to investigate the mechanism by which test compounds mediate their antiinvasive effects.

Example 24 Increase of 3α, 5α-THP

3α-hydroxy-5α-pregan-20-one (3α, 5α-THP or allopregnanolone) is a pregnan steroid that acts as an agonist of inhibitory GABA _A receptor subtypes and has anti-anxiety and analgesic effects in various animal systems It is known to have all, which supports evidence for similar roles in humans. Thus, compounds that increase 3α, 5α-THP may have anti-invasive efficacy. Levels of 3α, 5α-THP in the brains of animals treated with test compounds can be measured as described in VanDoren et al., 1982 J Neuroscience 20: 200. Briefly, steroids are extracted from each cerebral cortical hemispheres dissected in ice-cold saline after euthanasia. The cortex was frozen at -80 ° C until use. Samples were digested in 0.3 N NaOH by ultrasound and extracted three times in 3 ml aliquots of 10% (v / v) ethyl acetate in heptane. The aliquots were combined and diluted with 4 ml of heptane. The extract was added to a solid phase silica column (Burdick and Jackson, Muskgon, Mich.), Washed with pentane, and a steroid with a polarity similar to 3α, 5α-THP was added 25% (v / v) acetone in pentane. To elute from the column. The eluate was then dried under N ₂ and the steroids were dissolved again in 20% (v / v) isopropanol RIA buffer (0.1 M NaH ₂ PO ₄ , 0.9 M NaCl, 0.1% w / v BSA, pH 7.0). Extraction efficiency was measured in 50 μl of redissolved extract by liquid scintillation spectroscopy and the remaining samples were used for the measurement of 3α, 5α-THP by radioimmunoassay. Reconstituted sample extract (75 μl) and 3α, 5α-THP standard (31% v / v isopropyl alcohol in RIA buffer, 5-40,000 pg in 6.25% v / v ethanol) 725 μl of RIA buffer 100 μl of [ ³ H] 3α, 5α-THP (20,000 dpm) and 100 μl of anti-3α, 5α-THP antibody were added and analyzed in duplicate. Total binding was measured in the absence of unlabeled 3α, 5α-THP and nonspecific binding was measured in the absence of antibody. The antibody binding reaction was allowed to equilibrate at room temperature for 120 minutes and terminated by cooling the mixture to 4 ° C. Bound 3α, 5α-THP was incubated for 20 minutes with 300 μl of cold dextran coated charcoal (DCC; 0.4% powdered charcoal in _double distilled H ₂ O, 0.04% dextran) for unbound 3α, 5α- Isolate from THP. DCC was removed by centrifugation at 2,000 × g for 10 minutes. Bound radioactivity in the supernatant was measured by liquid scintillation spectroscopy. Sample values were compared to 3α, 5α-THP standard curves run simultaneously and corrected for extraction efficacy.

Example 25 Evaluation of Antidepressant Efficacy

In one embodiment, the compounds provided herein were evaluated for anti-depressive efficacy in animal models. Mild chronic stress-induced anesthesia model suggests that mild chronic stress results in a gradual decrease in the sensitivity to reward, for example, the consumption of sucrose, which reduction is dose dependent, and can be achieved by chronic treatment with antidepressants. Based on the observation of inversion. This method is already described in Willner, Paul, Psychopharmacology , 1997, 134, 319-329.

Another test for antidepressant activity is a forced swim test ( Nature 266, 730-732, 1977). In this test, the animals were administered the compound 30 or 60 minutes prior to the test, preferably by the intraperitoneal route or by the oral route. The test animals are placed in a crystallized dish filled with water and timed while they are not moving. The immobility time is then compared to that of the control treated with distilled water. Imipramine (25 mg / kg) can be used as a positive control. Antidepressant compounds reduce the immobility time of mice and allow them to sink.

Another test for antidepressant activity is the tail suspension test in mice ( Psychopharmacology , 85, 367-370, 1985). In this test, it is preferred to treat the animals with the compounds provided herein by the intraperitoneal or oral route 30 minutes to 6 hours before the test. The animal was then suspended by its tail and its dead time was automatically recorded on a computer system. The immobility time was then compared to that of the control treated with the vehicle. Imipramine (25 mg / kg) can be used as a positive control. Antidepressant compounds reduce mouse immobility time.

The antidepressant efficacy of the compounds provided herein can be tested by the DRL-72 test. Tests conducted by the protocol of Andrews et al., "Effects of imipramine and mirtazapine on operant performance in rats" Drug Development Research 32, 58-66 (1994) provide an indication of antidepressant-like activity. The efficacy of the compounds provided herein can be investigated in serotonin diseases and bipolar diseases as described, for example, in US Pat. Nos. 6,403,573 and 5,952,315, which are incorporated herein by reference.

Example 26 Evaluation of Anticonvulsant Effects

In another embodiment, the compounds provided herein were examined for anticonvulsant activity in animal models as described in US Pat. Nos. 6,309,406 and 6,326,156.

Example 27. Efficacy of Compounds on Appetite Behavior

In one embodiment, the compounds provided herein were administered to rats to determine their efficacy on appetite behavior. The efficacy of the administered compound is assessed by examining the intake of sucrose solution by the rat. This method is taught in WC Lynch et al., Physiol Behav , 1993, 54, 877-880. Male Sprague-Dawley rats weighing about 190 g to about 210 g were placed under normal light cycle (7 am to 7 pm) and water and feeding were as desired. Between 11 am and 3 pm for 6 days, food and water bottles were taken and rats were asked to drink 5% sucrose. Rats that drank less than 3 g sucrose were excluded. On day 7, the test was performed at 9:00 AM: food removal, 10 AM: administration of the compound or vehicle provided herein to the test animal, 11 AM = T0: TO + 1 bottle containing sucrose solution of known weight It was put in time, T0 + 2 hours, T0 + 3 hours, T0 + 4 hours, and it carried out according to the procedure which measures sucrose consumption by the weight of a bottle. The comparison of the sucrose intake of the experimental group (administered with the compound provided herein) and the control group is performed. The animal can be, for example, a fat or normal guinea pig, rat, mouse or rabbit. Examples of suitable rats include Zucker rats. For example, normal mice, ALS / LtJ, C3.5W-H-2b / SnJ, (NON / LtJ × NZO / H1J) F1, NZO / H1J, ALR / LtJ, NON / LtJ, KK.Cg-AALR / LtJ, NON / LtJ, KK CgAy / J, B6.HRS (BKS) -Cpefat / +, B6.129P2-GcktmlEfr, B6.V-Lepob, BKS.Cg-m + 1 + Leprdb and diet-induced obesity C57BL / 6J having.

In another test, the efficacy of the compounds of the present invention on the consumption of alcoholic liquids can be manifested in mice. For example, C57BL 6 mouse males were isolated on the day of their arrival in animals received with two bottles filled with water in reverse cycle (dark from 10 am to 10 pm). One week later, for six hours on each day of the test, one of the water bottles was replaced with a bottle containing 10% alcohol. Mice were treated with compounds of the present invention 30 minutes prior to daily alcohol bottle injection. The amount of alcohol and water consumed was measured after 6 hours. The test was repeated for 4 days. The results for the experimental and control or vehicle were compared.

Example 28 Reduction in Weight, Body Fat and Fatty Liver

The efficacy of inhibiting FAAH activity on body weight, body fat, triglyceride levels, and cholesterol levels can be measured in APOE * 3-Leiden transgenic (E3L) mice, an animal model of hyperlipidemia. E3L mice express apoE * 3-Leiden, a mutant variant of human apoE with impaired binding of apoE to the LDL receptor. As a result, E3L mice exhibited reduced clearance of apoB-containing lipoproteins and increased serum lipid levels. Van Vlijmen et al., (1994), J. Clin Invest. , 93: 1403-1410. Under high fat and cholesterol feeding, these mice rely on plasma total cholesterol levels and form various stages of atherosclerotic lesions similar to those found in humans. Groot et al., (1996), Arterioscler. Thromb. Vasc. Biol. , 16: 926-933; Verschuren et al., (2005), Arterioscler. Thromb. Vasc Biol. , 25: 161-167; And Lutgens et al., (1999), Circulation ; 99 (2): 276-283]. Thus, E3L mice are a suitable model for investigating the efficacy of anti-atherosclerosis drugs.

E3L mice were fed a high cholesterol (1% w / w) diet (HC diet) for 4 weeks. The animals were then paired and divided into five groups based on the plasma cholesterol levels of the mice, each of which was maintained in the HC diet. For the remaining experiments daily (4 weeks), the "control" group was fed with no additives, the "fenofibrate" group was fed with fenofibrate (0.04% w / w), and the "oral vehicle" group was given an oral vehicle. Oral suspension of OEA at a dose of 500 mg / kg to the "oral OEA" group and a dose of 10 mg / kg to the "oral carbamate" group. gave.

Blood samples were drawn on days 0, 14 and 28 of the treatment period. At the end of the treatment period, animals were killed and various tissues and organs analyzed.

Example 29. Cannabinoid Receptor Binding

Compounds may bind to one or both of the cannabinoid receptors CB ₁ and CB ₂ to exhibit anti-invasive efficacy. CB ₁ is expressed in the brain (Matsuda et al., 1990 Nature 346: 561) and CB ₂ is expressed by macrophages and in the spleen (Munro et al., 1993 Nature 365: 61). All of these receptors are involved in mediating analgesic efficacy through the binding of agonists (eg Clayton et al., 2002 Pain 96: 253). Thus, the test compound can be analyzed to determine whether it binds to one or both of the human cannabinoid receptors. Assays for CB ₁ binding are described in Matsuda et al., (Homologous). This assay uses recombinant cells expressing CB ₁ . Binding to CB ₂ is measured in the same manner by using a recombinant cell expressing a CB _2. Briefly, to determine the ability to bind test compounds to CB ₁ , labeled CB ₁ ligands such as [ ³ H] WIN 55212-2 (2 nM for CB ₁ and 0.8 nM for CB ₂ ) were used. Binding to membranes isolated from HEK-293 cells expressing recombinant CB ₁ is measured in the presence and absence of compounds. Non-specific binding is measured separately in the presence of a 7-fold excess of unlabeled WIN 55212-2 (5 μΜ for CB ₁ and 10 μΜ for CB ₂ ). Specific ligands bound to the receptor are defined as the difference between total binding and non-specific binding measured in the presence of excess unlabeled WIN 55212-2. IC ₅₀ values and Hill coefficients (n _H ) are measured by nonlinear regression of the competition curve using the substitution of the Hill equation curve. The inhibition constant (K _i ) is calculated from the Cheng Prusoff equation (K _i = IC ₅₀ / (1+ (L / K _D )), where L = concentration of the radioligand in the assay, K _D = for the receptor It is the affinity of radioligand.

Example 30: Pharmaceutical Compositions

Example 30a: Parenteral Composition

To produce a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of the compound described herein was dissolved in DMSO and then mixed with 10 ml of 0.9% sterile saline. The mixture was incorporated into dosage unit formulations suitable for administration by injection.

Example 30b: Oral Compositions

To produce a pharmaceutical composition for oral delivery, 100 mg of the compound described herein was mixed with 750 mg of starch. The mixture was incorporated into oral dosage units such as hard gelatin capsules suitable for oral administration.

Example 30c Sublingual (Hard Lozenges) Composition

To produce a pharmaceutical composition for buccal delivery, such as a hard lozenge, 100 mg of the compound described herein is mixed with 420 mg of powder, 1.6 ml of light corn syrup, 2.4 ml of distilled water and 0.42 ml of mint extract. It was. The mixture was gently mixed and poured into molds to form lozenges suitable for buccal administration.

Example 3 Od: Inhalation Composition

To produce a pharmaceutical composition for inhaled delivery, 20 mg of the compound described herein was mixed with 50 mg of citric anhydride and 100 ml of 0.9% sodium chloride solution. The mixture was incorporated into inhalation delivery units such as nebulizers suitable for inhalation administration.

Example 3 Oe Rectal Gel Composition

To produce a pharmaceutical composition for rectal delivery, 100 mg of the compound described herein was mixed with 2.5 g of methylcellulose (1,500 mPa), 100 mg of methylparaben, 5 g of glycerin and 100 ml of purified water. The resulting gel mixture is then incorporated into rectal delivery units such as syringes suitable for rectal administration.

Example 3Of: Topical Gel Compositions

To produce a pharmaceutical topical gel composition, 100 mg of the compound described herein was mixed with 1.75 g of hydroxypropyl cellulose, 10 ml of propylene glycol, 10 ml of isopropyl myristate and 100 ml of purified alcohol USP It was. The resulting gel mixture is then incorporated into a container, such as a test tube suitable for topical administration.

Example 3 Og: Ophthalmic Liquid Composition

To produce a pharmaceutical ophthalmic solution composition, 100 mg of the compound described herein was mixed with 0.9 g of NaCl in 100 ml of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution was incorporated into an ophthalmic delivery unit such as an eye drop container suitable for ophthalmic administration.

The examples and embodiments described herein are for illustrative purposes only and it is suggested to those skilled in the art that various modifications or variations are included within the spirit or full scope of the present application and appended claims. All publications, patents, and patent applications cited herein are, in fact, incorporated herein by reference.

Claims (24)

A compound of formula (I), a pharmaceutically acceptable salt, a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug or a pharmaceutically acceptable solvate: Formula I

In the above formula, D is O or NR ¹¹ ; One of A or B is (CH ₂ ) _m C (O) -alkyl, (CH ₂ ) _m C (O) -N (R ² ) ₂ , the other is H, alkyl or heteroalkyl, m is 0 , 1, 2 or 3; or A and B together form an optionally substituted oxo-substituted heterocycle; or A and B together form an optionally substituted heteroaromatic group comprising at least one N, NR ² , S or O group; or A and B together form an optionally substituted non-aromatic or aromatic carbocyclic group; or A and B are each H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted ketoalkyl and optionally substituted ketoheteroalkyl Independently from; R ¹ is optionally selected from C ₃ -C ₉ cycloalkyl, C ₁ -C ₄ alkyl (C ₃ -C ₉ cycloalkyl), C ₁ -C ₄ alkyl (aryl) and C ₁ -C ₄ alkyl (heteroaryl) Substituted group, wherein any carbon of the R ¹ cycloalkyl ring may be optionally substituted with Y and Z, each Y and each Z is independently selected from halogen, methyl or trifluoromethyl or Y and Z may together form a 3-, 4- or 5-membered carbocyclic group or oxo (═O); Each R ² is independently selected from H or optionally substituted alkyl, R ¹¹ is H or optionally substituted alkyl. 2. The compound of claim 1, wherein A and B together are —C (O) — (CR ^q R ^q ) _n −, —C (O) —NR ² — (CR ^q R ^q ) _n —, —NR ² —C ( O)-(CR ^q R ^q ) _n- , -C (O) -NR ² -NR ^2- (CR ^q R ^q ) _n- , -C (O) -NR ² -N = (CR ^q )-, -0-C (O) -O-, 0-C (O) -NR ^2- , -NR ² -C (O) -NR ^2- , -OC (O) -O- (CR ^q R ^q ) _n -, -OC (O)-(CR ^q R ^q ) _n -O-, -NC (O)-(CR ^q R ^q ) _n -N-, -OC (O)-(CR ^q R ^q ) _n- N-, -NC (O)-(CR ^q R ^q ) _n -0-, -OC (O) -NR ^2- (CR ^q R ^q ) _n- , -NR ² -C (O) -O- ( CR ^q R ^q ) _n- , -NR ² -C (O) -NR ^2- (CR ^q R ^q ) _n -,-(CR ^q R ^q ) _n -C (O) -O- (CR ^q R ^q ) _n -,-(CR ^q R ^q ) _n -C (O) -NR ^2- (CR ^q R ^q ) _n -,-(CR ^q R ^q ) _n -C (O) -NR ² -NR ^2- ,-(CR ^q R ^q ) _n -C (O)-(CR ^q R ^q ) _n- , -C (O) -O- (CR ^q R ^q ) _n -O-, -C (O) -O -(CR ^q R ^q ) _n -NR ^2- , -C (O) -NR ^2- (CR ^q R ^q ) _n -NR ² , -C (O) -NR ^2- (CR ^q R ^q ) _n- O-, -C (O) -NR ² -CR ^q = CR ^q- , C (O) -CR ^q = CR ^q -NR ^2- , -C (O) -CR ^q = CR ^q -O-,- Form an optionally substituted oxo-substituted heterocycle selected from C (O) -CR ^q = CR ^q -S-, each n is independently 1, 2 or 3, and each R ^q is independently H, Alkyl, substituted alkyl, aryl, substituted aryl, ketoalkyl, substituted ketoalkyl, ketoheteroalkyl, substituted ketoheteroalkyl, heteroalkyl, substituted heteroalkyl, heterocycle or substituted heterocycle compound. The compound of claim 1, wherein R ² is H and D is O. 7. The compound of claim 1, wherein one of A or B is C (O) -alkyl and the other is H; Or one of A or B is C (O) —N (R ² ) ₂ and the other is H. The compound of claim 1, wherein A and B together form an optionally substituted non-aromatic ring group comprising a C (O) — (CH ₂ ) _n − moiety, wherein n is 1, 2, 3 or 4 . The compound of claim 5, wherein n is 2; R ² is H; D is O. The compound of claim 1, wherein A and B together form an optionally substituted heteroaromatic group comprising at least one N, NR ² , S or O group. 8. The compound of claim 7, further comprising a-(CH) _n -moiety, wherein n is 1, 2 or 3. 8. The compound of claim 7, wherein the optionally substituted heteroaromatic group comprises a single N in the ring. 8. The compound of claim 7, wherein R ² is H and D is O. 8. The compound of claim 7, wherein the optionally substituted heteroaromatic group comprises two heteroatoms selected from N, S and O. The compound of claim 11, wherein the optionally substituted heteroaromatic group is selected from an optionally substituted benzoxazole group or an optionally substituted benzthiazole group. The compound of claim 1, a pharmaceutically acceptable salt, a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug or a pharmaceutically acceptable solvate and pharmaceutically acceptable Pharmaceutical compositions comprising possible diluents, excipients or binders. A therapeutically effective amount of the compound of claim 1, a pharmaceutically acceptable salt, a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug or a pharmaceutically acceptable solvate A method of treating a disease, disease or condition, or a method of inhibiting a fatty acid amide hydrolase, wherein the benefit is from the inhibition of fatty acid amide hydrolase activity comprising administering to a patient. 15. The disease according to claim 14, wherein the disease, disease or condition is acute or chronic pain, eating disorders, cardiovascular disease, metabolic disease, disease or condition, renal ischemia, cancer, diseases of the immune system, allergic diseases, parasites, viral or bacterial infectious diseases , Inflammatory disease, osteoporosis, ocular condition, lung condition, gastrointestinal disease and incontinence. Packaging material, the compound of claim 1 effective in inhibiting the activity of fatty acid amide hydrolase (FAAH) in the packaging material and the compound or composition or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable N-oxide, An article of manufacture comprising a label indicating that a pharmaceutically active metabolite, pharmaceutically acceptable prodrug or pharmaceutically acceptable solvate is used to inhibit the activity of fatty acid amide hydrolase (FAAH). A compound of formula II, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug or a pharmaceutically acceptable solvate: Formula II

In the above formula, D is O or NR ¹¹ ; Each X is CH or N; R ¹ is

Is selected from the group consisting of; M is a bond, optionally substituted C ₁ -C ₈ alkylene, optionally substituted 4-atom heteroalkylene, optionally substituted C ₂ -C ₈ alkenylene, optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted C ₂ -C ₈ alkynylene; J is CH or N; K is CH or N; Provided that when K is CH, J cannot be CH; Each R ³ is independently C ₁ -C ₆ alkyl- (aryl), C ₁ -C ₆ alkyl- (heteroaryl), C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamine, C ₁ -C ₆ Alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ heteroalkyl, -C (O) -R ¹² , aryl, aryloxy, heteroaryl, heteroaryloxy, heterocycloalkyl , Heterocycloalkoxy, phenyl, pyridyl, pyridazinyl, piperazinyl, piperidinyl, morpholinyl, furanyl, thiophenyl, thiophenyl, dibenzofuranyl, dibenzothienyl, indolyl, flu Orenyl, carbozolyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, naphthyl, qui Nolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnalol, imidazopyrimidinyl, thienopyrimidinyl, Zofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thieno Is selected from the group consisting of any substituent selected from pyridyl, dihydrothienopyridyl, imidazopyridyl, pyrazolopyridyl, oxalopyridyl, isoxazolopyridyl or thiazolopyridyl; Each R 'is independently H, alkyl or substituted alkyl; Each R ⁵ is independently H, C ₁ -C ₃ alkyl or halogen; R ⁶ is C ₁ -C ₃ alkyl or C ₃ -C ₇ cycloalkyl; R ² and R ¹¹ are H or optionally substituted alkyl; R ¹² is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ heteroalkyl, aryloxy, aryl, heteroaryl, heterocycloalkyl, benzyloxy, furanyl , Phenyl, benzyl or pyridyl; or R ¹ and R ² together

To form; n is 1, 2, 3 or 4; m is 1, 2, 3 or 4; A and B together form an optionally substituted non-aromatic ring group comprising a C (O) — (CH ₂ ) _q − moiety, wherein q is 1, 2, 3 or 4; or A and B together form an optionally substituted aromatic or non-aromatic ring group comprising at least one N, NR ² , S or O group; or One of A or B is -LG and the other is selected from H and optionally substituted C ₁ -C ₆ alkyl; or A and B together form an optionally substituted aromatic carbocyclic group; or A and B together form an optionally substituted oxo-substituted heterocycle; or A and B are each H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted ketoalkyl, optionally substituted amide and optionally Independently selected from substituted ketoheteroalkyl; L is a bond or C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₁ -C ₆ ketoalkylene, -C (O) NR ^9- (CH ₂ ) _j- , -NR ⁹ -C (O)-(CH ₂ ) _j- , -OC (O) O- (CH ₂ ) _j- , -NHC (O) O- (CH ₂ ) _j- , -O (O) CNH- (CH ₂ ) _j- , -C (O) O- (CH ₂ ) _j- , -OC (O)-(CH ₂ ) _j- , -NR ⁹ C (O) N (R ⁹ )-(CH ₂ ) _j -, -S (O)-(CH ₂ ) _j- , -S (O) _2- (CH ₂ ) _j- , -C (= NR ¹⁰ ) N (R ⁹ )-(CH ₂ ) _j -and Is an optionally substituted group selected from -NR ⁹ C (= NR ¹⁰ ) N (R ⁹ )-(CH ₂ ) _j- ; G is tetrazolyl, -NHS (= O) ₂ R ⁸ , -S (= O) ₂ NHR ⁸ , -S (= O) ₂ NH-phenyl, -OH, -SH, -OC (O) NHR ⁸ , -NHC (O) OR ⁸ , -C (O) NHC (O) R ⁸ , -C (O) NHS (= O) ₂ R ⁸ , -S (= O) ₂ NHC (O) R ⁸ , -S (= O) ₂ NHC (O) NHR ⁸ , -NHC (O) R ⁸ , -NHC (O) N (R ⁹ ) ₂ , -C (= NR ¹⁰ ) N (R ⁹ ) ₂ , -NR ⁹ C (= NR ¹⁰ ) N (R ⁹ ) ₂ , -NR ⁹ C (= NR ¹⁰ ) NHC (= NR ¹⁰ ) N (R ⁹ ) ₂ , -NR ⁹ C (= CHR ¹⁰ ) N (R ⁹ ) ₂ , -C (O) NR ⁹ C (= NR ¹⁰ ) N (R ⁹ ) ₂ , -C (O) NR ⁹ C (= CHR ¹⁰ ) N (R ⁹ ) ₂ , -CO ₂ H,-(OP (= O) OH) _x OH, -OP (= O) OR ⁸ OH, -OP (= O) R ⁸ OH, -NR ⁹ P (= O) OR ⁸ OH, -NR ⁹ P (= O) R ⁸ OH , -P (= 0) OR ⁸ OH, -P (= 0) R ⁸ OH, -S (O) _y OH, -OS (O) _y OH, -NR ⁹ S (O) _y OH; Each R ⁸ is independently substituted or unsubstituted C ₁ -C ₆ alkyl; Each R ⁹ is independently H, substituted C ₁ -C ₆ alkyl or unsubstituted C ₁ -C ₆ alkyl; Each R ¹⁰ is independently selected from H, —S (═O) ₂ R ⁸ , —S (═O) ₂ NH ₂ , —C (O) R ⁸ , —CN, and —NO ₂ ; j is 0, 1, 2, 3 or 4; x is 1, 2 or 3; y is 0, 1 or 2; Each optional substituent is C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, benzyl, halogen, nitro, cyano or benzyloxy-C (O) R ′, —C (O) — (alkyl or substituted Alkyl),-(alkyl or substituted alkyl) -C (O) R ', -C (O) N (R') ₂ , -C (O) N (R ')-(alkyl or substituted alkyl), -(Alkyl or substituted alkyl) -C (O) N (R ') ₂ , -OC (O) N (R') ₂ , -OC (O) N (R ')-(alkyl or substituted alkyl) ,-(Alkyl or substituted alkyl) -OC (O) N (R ') ₂ , -N (R') C (O) R ', -NR'C (O)-(alkyl or substituted alkyl), -(Alkyl or substituted alkyl) -NR'C (O) R ', -SR', -S- (alkyl or substituted alkyl), -S (O) _k R ', where k is 1 or 2 , -S (O) _k (alkyl or substituted alkyl), -C (S)-(alkyl or substituted alkyl), -CSN (R ') ₂ , -CSN (R')-(alkyl or substituted alkyl ), -N (R ') CO- (alkyl or substituted alkyl), -N (R') C (O) OR ',-(alkyl or substituted alkyl) -ON = C (R') ₂ ,- (alkyl or substituted alkyl) -C (O) NR '- (alkyl or substituted alkyl), - (alkyl or substituted alkyl), -S (O) _k - (alkyl addition Substituted alkyl) -SR ', - -S-SR ( alkyl or substituted _{alkyl)', -S (O) k} N (R ') 2, -N (R') C (O) N (R ') ₂ , -N (R ') C (S) N (R') ₂ , -N (R ') S (O) _k N (R') ₂ , -C (R ') = NR'-C (R ') = NN (R') ₂ and -C (R ') ₂ -N (R')-N (R ') ₂ are independently selected. 18. The compound of claim 17, wherein the compound of formula III, a pharmaceutically acceptable salt, a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug or a pharmaceutically acceptable Compounds that are solvates: Formula III

In the above formula, p is 0, 1 or 2; q is 0, 1 or 2; R ¹³ and R ¹⁴ is H, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl- (C ₃ -C ₆ Cycloalkyl), aryl, substituted aryl, arylalkyl, -C (O) R ^A , hydroxy- (C ₁ -C ₆ alkyl), amino- (C ₁ -C ₆ alkyl), -CH ₂ -NR ^A R ^B , -0- (C ₁ -C ₄ ), aryloxy, halo, C ₁ -C ₆ haloalkyl, cyano, hydroxy, nitro, amino, -C (O) NR ^A R ^B , -ONR ^A Independently from R ^B , —OC (O) NR ^A R ^B , —SO ₂ NR ^A R ^B ; R ^A and R ^B are each independently selected from hydrogen, C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl. The compound of claim 18, which is a compound of Formula IIIa: Formula IIIa

The compound of claim 19, wherein R ² is H. 20. The compound of claim 17, a pharmaceutically acceptable salt, a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug or a pharmaceutically acceptable solvate and pharmaceutically acceptable Pharmaceutical compositions comprising possible diluents, excipients or binders. A therapeutically effective amount of a compound of claim 17, a pharmaceutically acceptable salt, a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug or a pharmaceutically acceptable solvate A method of treating a disease, disease or condition, or a method of inhibiting a fatty acid amide hydrolase, wherein the benefit is from inhibiting fatty acid amide hydrolase activity in a patient, comprising administering to the patient. 31. The disease according to claim 30, wherein the disease, condition or condition is acute or chronic pain, eating disorders, cardiovascular disease, metabolic disease, disease or condition, renal ischemia, cancer, diseases of the immune system, allergic diseases, parasites, viral or bacterial infectious diseases , Inflammatory disease, osteoporosis, ocular condition, lung condition, gastrointestinal disease and incontinence. Packaging material; A compound of claim 17 effective to inhibit the activity of fatty acid amide hydrolase (FAAH) in the packaging material; Fatty acid amide hydrolysis of compounds or compositions or pharmaceutically acceptable salts thereof, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs or pharmaceutically acceptable solvates An article of manufacture comprising a label indicating that the enzyme is used to inhibit the activity of an enzyme (FAAH).

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