US 8,263,755 B2Granted

Synthesis of compounds useful as modulators of amyloid-beta production

AssigneeSatori Pharmaceuticals, Inc.

InventorMark A. Findeis

Life of this patent

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Abstract

As described herein, the present invention provides methods for preparing compounds useful for treating or lessening the severity of a neurodegenerative disorder. The present invention also provides methods of treating or lessening the severity of such disorders wherein said method comprises administering to a patient a compound of the present invention, or composition thereof. Said method is useful for treating or lessening the severity of, for example, Alzheimer's disease.

Claims15

Dependent claims

A method for preparing a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
each of Ring A, Ring B, Ring C, Ring D, and Ring E is independently saturated, partially unsaturated or aromatic;
G is S, CH2, NR, or O;
R1 and R2 are each independently halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, N(R)2, or a suitably protected amino group, or R1 and R2 are taken together to form a 3-7 membered saturated, partially unsaturated, or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen, an optionally substituted C1-6 aliphatic group, or an optionally substituted 3-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein:
two R on the same nitrogen atom are optionally taken together with said nitrogen atom to form a 3-8 membered saturated, partially unsaturated, or aryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
n is 0-2;
R3, R4, R7, and R8 are each independently selected from halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, SO2R, OSO2R, N(R)2, a suitably protected amino group, NR(CO)R, NR(CO)(CO)R, NR(CO)N(R)2, NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R)2, or O(CO)N(R)2;
m is 0-2;
R5 is T-C(R′)3, T-C(R′)2C(R″)3, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, SO2R, OSO2R, N(R)2, a suitably protected amino group, NR(CO)R, NR(CO)(CO)R, NR(CO)N(R)2, NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R)2, or O(CO)N(R)2, or:
each T is independently a valence bond or an optionally substituted straight or branched, saturated or unsaturated, C1-6 alkylidene chain wherein up to two methylene units of T are optionally and independently replaced by —O—, —N(R)—, —S—, —C(O)—, —S(O)—, or —S(O)2—;
each R′ and R″ is independently selected from R, OR, SR, SO2R, OSO2R, N(R)2, NR(CO)R, NR(CO)(CO)R, NR(CO)N(R)2, NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R)2, or O(CO)N(R)2;
R9 and R9′ are each independently selected from halogen, R, OR, SR, or N(R)2, or R9 and R9′ are taken together to form a 3-7 membered saturated, partially unsaturated, or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Q is a valence bond or an optionally substituted straight or branched, saturated or unsaturated, C1-6 alkylidene chain wherein up to two methylene units of Q are optionally and independently replaced by —O—, —N(R)—, —S—, —C(O)—, —S(O)—, or —S(O)2—;
and
R10 is R, a suitably protected hydroxyl group, a suitably protected thiol group, a suitably protected amino group, an optionally substituted 3-8 membered saturated, partially unsaturated, or aryl monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a detectable moiety selected from the group consisting of radioisotopes, mass-tags, fluorescent labels, biotin, and antigen labels, a polymer residue selected from the group consisting of poly(alkylene oxides), a peptide, or a sugar-containing or sugar-like moiety selected from the group consisting of cyclic and acyclic cyclitols, glycosides, arabinopyranoside, xylopyranoside, or erythritol,
comprising the steps of:
(a) providing a compound of formula II:
and
(b) converting the compound of formula II to the compound of formula I, where the conversion is achieved by intramolecular dehydration reaction.

17 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/515,703Filed 20 Nov 2007 · us provisional application
Priority: 20 Nov 2006
Published: US 2010/0197615 A15 Aug 2010
Granted: 11 Sep 2012
Term ends: Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07J 71/00
Steroids in which the cyclopentahydrophenanthrene skeleton is condensed with a heterocyclic ring
A61P 25/16
For treating abnormal movements, e.g. chorea, dyskinesia: anti-Parkinson drugs
A61P 25/28
Drugs for disorders of the nervous system: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents,…
A61P 27/00
Drugs for disorders of the senses

Family

Application60/860,185Us provisional application · filed 20 Nov 2006
US 2010/0197615 A1Pre-grant publication · published 5 Aug 2010
US 8,263,755 B2This patent

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

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Abstract

A method for preparing a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
each of Ring A, Ring B, Ring C, Ring D, and Ring E is independently saturated, partially unsaturated or aromatic;
G is S, CH2, NR, or O;
R1 and R2 are each independently halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, N(R)2, or a suitably protected amino group, or R1 and R2 are taken together to form a 3-7 membered saturated, partially unsaturated, or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen, an optionally substituted C1-6 aliphatic group, or an optionally substituted 3-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein:
two R on the same nitrogen atom are optionally taken together with said nitrogen atom to form a 3-8 membered saturated, partially unsaturated, or aryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
n is 0-2;
R3, R4, R7, and R8 are each independently selected from halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, SO2R, OSO2R, N(R)2, a suitably protected amino group, NR(CO)R, NR(CO)(CO)R, NR(CO)N(R)2, NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R)2, or O(CO)N(R)2;
m is 0-2;
R5 is T-C(R′)3, T-C(R′)2C(R″)3, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, SO2R, OSO2R, N(R)2, a suitably protected amino group, NR(CO)R, NR(CO)(CO)R, NR(CO)N(R)2, NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R)2, or O(CO)N(R)2, or:
each T is independently a valence bond or an optionally substituted straight or branched, saturated or unsaturated, C1-6 alkylidene chain wherein up to two methylene units of T are optionally and independently replaced by —O—, —N(R)—, —S—, —C(O)—, —S(O)—, or —S(O)2—;
each R′ and R″ is independently selected from R, OR, SR, SO2R, OSO2R, N(R)2, NR(CO)R, NR(CO)(CO)R, NR(CO)N(R)2, NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R)2, or O(CO)N(R)2;
R9 and R9′ are each independently selected from halogen, R, OR, SR, or N(R)2, or R9 and R9′ are taken together to form a 3-7 membered saturated, partially unsaturated, or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Q is a valence bond or an optionally substituted straight or branched, saturated or unsaturated, C1-6 alkylidene chain wherein up to two methylene units of Q are optionally and independently replaced by —O—, —N(R)—, —S—, —C(O)—, —S(O)—, or —S(O)2—;
and
R10 is R, a suitably protected hydroxyl group, a suitably protected thiol group, a suitably protected amino group, an optionally substituted 3-8 membered saturated, partially unsaturated, or aryl monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a detectable moiety selected from the group consisting of radioisotopes, mass-tags, fluorescent labels, biotin, and antigen labels, a polymer residue selected from the group consisting of poly(alkylene oxides), a peptide, or a sugar-containing or sugar-like moiety selected from the group consisting of cyclic and acyclic cyclitols, glycosides, arabinopyranoside, xylopyranoside, or erythritol,
comprising the steps of:
(a) providing a compound of formula II:
and
(b) converting the compound of formula II to the compound of formula I, where the conversion is achieved by intramolecular dehydration reaction.

17 more elements

Facts

Application

12/515,703Filed 20 Nov 2007 · us provisional application

Priority

20 Nov 2006

Published

US 2010/0197615 A15 Aug 2010

Granted

11 Sep 2012

Term ends

Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07J 71/00
Steroids in which the cyclopentahydrophenanthrene skeleton is condensed with a heterocyclic ring
A61P 25/16
For treating abnormal movements, e.g. chorea, dyskinesia: anti-Parkinson drugs
A61P 25/28
Drugs for disorders of the nervous system: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents,…
A61P 27/00
Drugs for disorders of the senses