BR112015021985A2 - compostos e seus usos para a modulação de hemoglobina - Google Patents

compostos e seus usos para a modulação de hemoglobina

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Publication number
BR112015021985A2
BR112015021985A2 BR112015021985A BR112015021985A BR112015021985A2 BR 112015021985 A2 BR112015021985 A2 BR 112015021985A2 BR 112015021985 A BR112015021985 A BR 112015021985A BR 112015021985 A BR112015021985 A BR 112015021985A BR 112015021985 A2 BR112015021985 A2 BR 112015021985A2
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BR
Brazil
Prior art keywords
alkyl
optionally substituted
ring
independently
group
Prior art date
Application number
BR112015021985A
Other languages
English (en)
Other versions
BR112015021985B1 (pt
Inventor
Xu Qing
L Gwaltney Ii Stephen
Li Zhe
Original Assignee
Global Blood Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US13/815,735 external-priority patent/US8952171B2/en
Application filed by Global Blood Therapeutics Inc filed Critical Global Blood Therapeutics Inc
Publication of BR112015021985A2 publication Critical patent/BR112015021985A2/pt
Publication of BR112015021985B1 publication Critical patent/BR112015021985B1/pt

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
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    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract

relatório descritivo da patente de invenção para "compostos e seus usos para a modulação de hemoglobina" domínio da invenção [0001] esta invenção proporciona compostos e composições farmacêuticas adequados como moduladores alostéricos de hemoglobina, métodos e intermediários para a sua preparação, e métodos para o seu uso no tratamento de distúrbios mediados por hemoglobina e distúrbios que irão beneficiar de oxigenação tecidual e/ou celular. estado da técnica [0002] a doença de células falciformes é um distúrbio dos eritrócitos, que se encontra particularmente entre descendentes africanos e mediterrânicos. a base da doença de células falciformes se encontra em hemoglobina falciforme (hbs), que contém uma mutação pontual relativamente à sequência peptídica prevalecente da hemoglobina (hb). [0003] a hemoglobina (hb) transporta moléculas de oxigênio dos pulmões para vários tecidos e órgãos em todo o corpo. a hemoglobina se liga e libera oxigênio através de alterações conformacionais. a hemoglobina falciforme (hbs) contém uma mutação pontual pela qual ácido glutâmico é substituído por valina, permitindo que a hbs se torne suscetível a polimerização, dotando os eritrócitos contendo hbs de sua forma falciforme característica. as células falciformes também são mais rígidas do que eritrócitos normais, e sua falta de flexibilidade pode conduzir a bloqueio de vasos sanguíneos. us 7,160,910 divulga compostos que são moduladores alostéricos de hemoglobina. no entanto, são necessários agentes terapêuticos adicionais que possam tratar distúrbios que são mediados por hb ou por hb anormal, como hbs. sumário da invenção [0004] esta invenção refere-se genericamente a compostos e composições farmacêuticas adequados como moduladores alostéricos de hemoglobina. em alguns aspectos, esta invenção refere-se a métodos para tratar distúrbios mediados por hemoglobina e distúrbios que irão beneficiar de oxigenação tecidual e/ou celular. [0005] em certos aspectos da invenção, é proporcionado um composto da fórmula (a): (a) ou um respectivo tautômero, ou um sal farmaceuticamente aceitável de cada um daqueles ou um respectivo sal farmaceuticamente aceitável, em que l1 é uma ligação ou é nr70, o, s, ou (cr71r72)d; em que cada r70, r71, e r72 independentemente é hidrogênio ou c1-c6 alquila; d é 1, 2 ou 3; l2 é c=o ou so2; cada y e z é independentemente cr10r11, o, s, so, so2, ou nr10; cada r10 e r11 é independentemente hidrogênio ou c1-c3 alquila opcionalmente substituído com 1-3 halo, oh, ou c1-c6 alcoxi, ou cr10r11 é c=o, desde que, se um de y e z for o, s, so, so2, então o outro não é co, e y e z não são ambos heteroátomos ou respectivas formas oxidadas; em que y está ? ou ? substituído relativamente a –l1l2r3; em que z e –cv1v2h são unidos a átomos adjacentes no anel c; v1 e v2 independentemente são c1-c6 alcoxi; ou v1 e v2, em conjunto com o átomo de carbono ao qual estão ligados, formam um anel da fórmula: em que cada v3 e v4 é independentemente o, s, ou nh, desde que, quando um de v3 e v4 é s, o outro seja nh, e desde que v3 e v4 não sejam ambos nh; q é 1 ou 2; cada v5 é independentemente c1-c6 alquila ou co2r60, em que cada r60, independentemente, é c1-c6 alquila ou hidrogênio; t é 0, 1, 2, ou 4; ou cv1v2 é c=v, em que v é o, nor80, ou nnr81r82; r80 é c1-c6 alquila opcionalmente substituído; r81 e r82, independentemente, são selecionados do grupo consistindo de hidrogênio, c1-c6 alquila opcionalmente substituído, cor83 e co2r84; r83 é hidrogênio ou c1-c6 alquila opcionalmente substituído; e r84 é c1-c6 alquila opcionalmente substituído, e r3, b, e c são definidos do modo seguinte. [0006] em um caso, r3 é c1-c6 alquila, c3-c8 cicloalquila, c1-c6 alcoxi, c3-c8 cicloalcoxi, ou –nr1r2; cada r1 e r2 independentemente é hidrogênio, c1-c6 alquila, c3-c8 cicloalquila, c6-c10 arila, heterociclo de 4-10 membros ou heteroarila de 5-10 membros, cada um contendo até 5 heteroátomos de anel, em que o heteroátomo é selecionado do grupo consistindo de o, n, s, e formas oxidadas de n e s, em que cada alquila, cicloalquila, heterociclo, arila ou heteroarila está opcionalmente substituído, ou r1 e r2, em conjunto com o átomo de nitrogênio ao qual estão ligados, formam um heterociclo de 4-7 membros opcionalmente substituído; o anel b é um c6-c10 arila opcionalmente substituído, heteroarila de 5-10 membros opcionalmente substituído tendo 1-3 átomos de nitrogênio ou formas oxidadas de n, ou heterociclo de 4-10 membros opcionalmente substituído contendo até 5 heteroátomos de anel, em que o heteroátomo é selecionado do grupo consistindo de o, n, s, e formas oxidadas de n e s; e o anel c é um c6-c10 arila opcionalmente substituído ou heteroarila de 5-10 membros opcionalmente substituído contendo 1-3 átomos de nitrogênio, ou uma forma oxidada de n, em que certos substituintes preferenciais incluem oh, halo, c1-c6 alcoxi, c3-c6 cicloalcoxi ou o-r, em que r é uma fração de pró-fármaco, em que o c1-c6 alcoxi está opcionalmente substituído com 1-5 halo. [0007] em outro caso, r3 é c6-c10 arila, ou um heteroarila de 5-10 membros, em que o heteroátomo é selecionado do grupo consistindo de o, n, s, e formas oxidadas de n e s, em que cada um do arila, ou heteroarila está opcionalmente substituído com 1-4 c1-c6 alquila; o anel b é um heterociclo de 4-10 membros opcionalmente substituído contendo até 5 heteroátomos de anel, em que o heteroátomo é selecionado do grupo consistindo de o, n, s, e formas oxidadas de n e s; o anel c é c6-c10 arila ou um heteroarila de 5-10 membros contendo até 5 heteroátomos de anel, em que o heteroátomo é selecionado do grupo consistindo de o, n, s, e formas oxidadas de n e s, cada um dos quais está opcionalmente substituído com 1-4: halo, oxo, -or19, c1-c6 alquila, e/ou c1-c6 alcoxi, em que o c1-c6 alquila está opcionalmente substituído com 1-5 halo, c1-c6 alcoxi e/ou um heterociclo de 4-10 membros contendo até 5 heteroátomos de anel, em que o heteroátomo é selecionado do grupo consistindo de o, n, s, e formas oxidadas de n e s, em que certos substituintes preferenciais incluem oh, halo, c1-c6 alcoxi, c3-c6 cicloalcoxi ou o-r, em que r é uma fração de pró-fármaco, em que o c1-c6 alcoxi está opcionalmente substituído com 1-5 halo; e r19 é hidrogênio ou uma fração de pró-fármaco r. [0008] em certos aspectos da invenção, é proporcionado um composto da fórmula (ii): (ii) ou um respectivo tautômero, ou respectivo sal farmaceuticamente aceitável de cada, em que r3 é c1-c6 alquila, c3-c8 cicloalquila, c1-c6 alcoxi, c3-c8 cicloalcoxi, ou –nr1r2; cada r1 e r2 independentemente é hidrogênio, c1-c6 alquila, c3-c8 cicloalquila, c6-c10 arila, heterociclo de 4-10 membros ou heteroarila de 5-10 membros, cada um contendo até 5 heteroátomos de anel, em que o heteroátomo é selecionado do grupo consistindo de o, n, s, e formas oxidadas de n e s, em que cada alquila, cicloalquila, heterociclo, arila ou heteroarila está opcionalmente substituído, ou r1 e r2, em conjunto com o átomo de nitrogênio ao qual estão ligados, formam um heterociclo de 4-7 membros opcionalmente substituído; l é uma ligação ou é nr70, o, s, ou (cr71r72)d; em que cada r70, r71, e r72, independentemente, é hidrogênio ou c1-c6 alquila; d é 1, 2 ou 3; o anel b é um c6-c10 arila opcionalmente substituído, heteroarila de 5-10 membros opcionalmente substituído tendo 1-3 átomos de nitrogênio ou formas oxidadas de n, ou heterociclo de 4-10 membros opcionalmente substituído contendo até 5 heteroátomos de anel, em que o heteroátomo é selecionado do grupo consistindo de o, n, s, e formas oxidadas de n e s; cada y e z é independentemente cr10r11, o, s, so, so2, ou nr10; cada r10 e r11 é independentemente hidrogênio ou c1-c3 alquila opcionalmente substituído com 1-3 halo, oh, ou c1-c6 alcoxi, ou cr10r11 é c=o, desde que, se um de y e z for o, s, so, so2, então o outro não é co, e y e z não são ambos heteroátomos ou respectivas formas oxidadas; em que y está ? ou ? substituído relativamente a –lcor3; o anel c é um c6-c10 arila opcionalmente substituído ou heteroarila de 5-10 membros opcionalmente substituído contendo 1-3 átomos de nitrogênio, ou uma forma oxidada de n; em que z e –cv1v2h são unidos a átomos adjacentes no anel c; v1 e v2 independentemente são c1-c6 alcoxi; ou v1 e v2, em conjunto com o átomo de carbono ao qual estão ligados, formam um anel da fórmula: em que cada v3 e v4 é independentemente o, s, ou nh, desde que, quando um de v3 e v4 é s, o outro seja nh, e desde que v3 e v4 não sejam ambos nh; q é 1 ou 2; cada v5 é independentemente c1-c6 alquila ou co2r60, em que cada r60, independentemente, é c1-c6 alquila ou hidrogênio; t é 0, 1, 2, ou 4; ou cv1v2 é c=v, em que v é o, nor80, ou nnr81r82; r4 é oh, halo, c1-c6 alcoxi, c3-c6 cicloalcoxi ou o-r, em que r é uma fração de pró-fármaco, em que o c1-c6 alcoxi está opcionalmente substituído com 1-5 halo; r80 é c1-c6 alquila opcionalmente substituído; r81 e r82, independentemente, são selecionados do grupo consistindo de hidrogênio, c1-c6 alquila opcionalmente substituído, cor83 e co2r84; r83 é hidrogênio ou c1-c6 alquila opcionalmente substituído; e r84 é c1-c6 alquila opcionalmente substituído. [0009] em certos aspectos da invenção, é proporcionado um composto da fórmula (iv): (iv) em que r3 é c6-c10 arila, ou um heteroarila de 5-10 membros, em que o heteroátomo é selecionado do grupo consistindo de o, n, s, e formas oxidadas de n e s, em que cada um do arila, ou heteroarila está opcionalmente substituído com 1-4: c1-c6 alquila; l1 é uma ligação ou é nr70, o, s, ou (cr71r72)d; em que cada r70, r71, e r72 independentemente é hidrogênio ou c1-c6 alquila; d é 1, 2 ou 3; l2 é c=o ou so2; o anel b é um heterociclo de 4-10 membros opcionalmente substituído contendo até 5 heteroátomos de anel, em que o heteroátomo é selecionado do grupo consistindo de o, n, s, e formas oxidadas de n e s; cada y e z é independentemente (cr10r11)e, o, s, so, so2, ou nr10; e é 1 até 4, preferencialmente 1; cada r10 e r11 independentemente é hidrogênio ou c1-c3 alquila opcionalmente substituído com 1-3 halo, oh, ou c1-c6 alcoxi, ou cr10r11 é c=o, desde que, se um de y e z for o, s, so, so2, então o outro não é co, e y e z não são ambos heteroátomos ou respectivas formas oxidadas; em que y está ? ou ? substituído relativamente a –l1l2r3; o anel c é c6-c10 arila ou um heteroarila de 5-10 membros contendo até 5 heteroátomos de anel, em que o heteroátomo é selecionado do grupo consistindo de o, n, s, e formas oxidadas de n e s, cada um dos quais está opcionalmente substituído com 1-4: halo, oxo, -or2, c1-c6 alquila, e/ou c1-c6 alcoxi, em que o c1-c6 alquila está opcionalmente substituído com 1-5 halo, c1-c6 alcoxi e/ou um heterociclo de 4-10 membros contendo até 5 heteroátomos de anel, em que o heteroátomo é selecionado do grupo consistindo de o, n, s, e formas oxidadas de n e s; r2 é hidrogênio ou uma fração de pró-fármaco r; e em que z e –cv1v2h são ligados a átomos adjacentes no anel c; v1 e v2 independentemente são c1-c6 alcoxi; ou v1 e v2, em conjunto com o átomo de carbono ao qual estão ligados, formam um anel da fórmula: em que cada v3 e v4 é independentemente o, s, ou nh, desde que, quando um de v3 e v4 é s, o outro seja nh, e desde que v3 e v4 não sejam ambos nh; q é 1 ou 2; cada v5 é independentemente c1-c6 alquila ou co2r60, em que cada r60, independentemente, é c1-c6 alquila ou hidrogênio; t é 0, 1, 2, ou 4; ou cv1v2 é c=v, em que v é o, nor80, ou nnr81r82; r80 é c1-c6 alquila opcionalmente substituído; r81 e r82, independentemente, são selecionados do grupo consistindo de hidrogênio, c1-c6 alquila opcionalmente substituído, cor83 e co2r84; r83 é hidrogênio ou c1-c6 alquila opcionalmente substituído; e r84 é c1-c6 alquila opcionalmente substituído. [0010] em uma modalidade, o anel b é unido a l1 ou l2 via um átomo de nitrogênio. em outra modalidade, r3 é unido a l2 via um átomo de nitrogênio. [0011] em aspectos adicionais da invenção, é proporcionada uma composição compreendendo qualquer um dos compostos descritos aqui, e pelo menos um excipiente farmaceuticamente aceitável. [0012] ainda em outros aspectos da invenção, é proporcionado um método para aumentar a afinidade para oxigênio de hemoglobina s em um sujeito, em que o método compreende administrar a um sujeito necessitado uma quantidade terapeuticamente eficaz de qualquer um dos compostos ou composições descritos aqui. [0013] em aspectos adicionais da invenção, é proporcionado um método para tratar deficiência de oxigênio associada a anemia de células falciformes, em que o método compreende administrar a um sujeito necessitado uma quantidade terapeuticamente eficaz de qualquer um dos compostos ou composições descritos aqui. descrição detalhada da invenção definições [0014] deve ser notado que, como usado aqui e nas reivindicações adjuntas, as formas singulares "um", "uma" e "o", "a" incluem referentes plurais, a menos que o contexto claramente imponha o contrário. assim, por exemplo, referência a “um solvente” inclui uma pluralidade de tais solventes. [0015] como usado aqui, é pretendido que o termo “compreendendo” ou “compreende” signifique que as composições e métodos incluem os elementos apresentados, mas não excluindo outros. “consistindo essencialmente de”, quando usado para definir composições e métodos, significa excluir outros elementos de qualquer importância essencial para a combinação para o propósito apresentado. assim, uma composição ou processo consistindo essencialmente dos elementos como definido aqui não exclui outros materiais ou etapas que não afetem materialmente a(s) característica(s) básica(s) e nova(s) da invenção reivindicada. “consistindo de” significa excluir mais do que elementos traço de outros ingredientes e etapas de métodos substanciais. modalidades definidas por cada um destes termos de transição pertencem ao escopo desta invenção. [0016] a menos que indicado em contrário, todos os números expressando quantidades de ingredientes, condições reacionais, e assim por diante usados na especificação e reivindicações devem ser entendidos como estando modificados em todos os casos pelo termo “cerca de.” em conformidade, a menos que indicado em contrário, os parâmetros numéricos apresentados na seguinte especificação e reivindicações adjuntas são aproximações. cada parâmetro numérico deve ser pelo menos considerado à luz do número de dígitos significativos relatados e aplicando técnicas comuns de arredondamento. o termo “cerca de”, quando usado antes de uma designação numérica, por exemplo, temperatura, tempo, quantidade, e concentração, incluindo intervalo, indica aproximações que podem variar por ( + ) ou ( - ) 10 %, 5 % ou 1 %. [0017] como usado aqui, cm-cn, como c1-c12, c1-c8, ou c1-c6, quando usado antes de um grupo, refere-se a esse grupo contendo m até n átomos de carbono. [0018] o termo “alcoxi” refere-se a –o-alquila. cicloalcoxi refere-se a –o-cicloalquila. [0019] o termo “alquila” refere-se a grupos hidrocarbila alifáticos saturados monovalentes tendo desde 1 até 30 átomos de carbono (isto é, c1-c30 alquila) ou 1 até 22 átomos de carbono (isto é, c1-c22 alquila), 1 até 8 átomos de carbono (isto é, c1-c8 alquila), ou 1 até 4 átomos de carbono. este termo inclui, a título de exemplo, grupos hidrocarbila lineares e ramificados, como metila (ch3-), etila (ch3ch2-), n-propila (ch3ch2ch2-), isopropila ((ch3)2ch-), n-butila (ch3ch2ch2ch2-), isobutila ((ch3)2chch2-), sec-butila ((ch3)(ch3ch2)ch-), t-butila ((ch3)3c-), n-pentila (ch3ch2ch2ch2ch2-), e neopentila ((ch3)3cch2-). [0020] o termo “arila” refere-se a um anel mono- ou bicíclico monovalente aromático tendo 6-10 átomos de carbono de anel. exemplos de arila incluem fenila e naftila. o anel condensado pode ou não ser aromático, desde que o ponto de ligação seja em um átomo de carbono aromático. por exemplo, e sem limitação, o seguinte é um grupo arila: . [0021] o termo “éster -co2h” refere-se a um éster formado entre o grupo –co2h e um álcool, preferencialmente um álcool alifático. um exemplo preferencial inclui –co2re, em que re é um grupo alquila ou arila opcionalmente substituído com um grupo amino. [0022] o termo “fração quiral” refere-se a uma fração que é quiral. tal fração pode possuir um ou mais centros assimétricos. preferencialmente, a fração quiral é enantiomericamente enriquecida, e mais preferencialmente é um único enantiômero. exemplos não limitativos de frações quirais incluem ácidos carboxílicos quirais, aminas quirais, aminoácidos quirais, como os aminoácidos de ocorrência natural, álcoois quirais incluindo esteroides quirais, e similares. [0023] o termo “cicloalquila” refere-se a um anel hidrocarbila mono-, bi-, ou tricíclico monovalente, preferencialmente saturado, tendo 3-12 átomos de carbono de anel. não obstante cicloalquila se referir preferencialmente a anéis hidrocarbila saturados, como usado aqui, também inclui anéis contendo 1-2 ligações duplas carbono-carbono. exemplos não limitativos de cicloalquila incluem ciclopropila, ciclobutila, ciclopentila, ciclohexila, cicloheptila, adamentila, e similares. os anéis condensados podem ou não ser anéis hidrocarbila não aromáticos desde que o ponto de ligação seja em um átomo de carbono de cicloalquila. por exemplo, e sem limitação, o seguinte é um grupo cicloalquila: . [0024] o termo “halo” refere-se a f, cl, br, e/ou i. [0025] o termo “heteroarila” refere-se a um anel aromático monovalente mono-, bi-, ou tricíclico tendo 2-16 átomos de carbono de anel e 1-8 heteroátomos de anel selecionados preferencialmente de n, o, s, e p e formas oxidadas de n, s, e p, desde que o anel contenha pelo menos 5 átomos de anel. exemplos não limitativos de heteroarila incluem furano, imidazol, oxadiazol, oxazol, piridina, quinolina, e similares. os anéis condensados podem ou não ser um anel aromático contendo heteroátomo desde que o ponto de ligação seja um átomo de heteroarila. por exemplo, e sem limitação, o seguinte é um grupo heteroarila: . [0026] o termo “heterociclila” ou heterociclo refere-se a um anel não aromático, mono-, bi-, ou tricíclico contendo 2-12 átomos de carbono de anel e 1-8 heteroátomos de anel selecionados preferencialmente de n, o, s, e p e formas oxidadas de n, s, e p, desde que o anel contenha pelo menos 3 átomos de anel. não obstante heterociclila se referir preferencialmente a sistemas de anéis saturados, também inclui sistemas de anéis contendo 1-3 ligações duplas, desde que o anel não seja aromático. exemplos não limitativos de heterociclila incluem azalactonas, oxazolina, piperidinila, piperazinila, pirrolidinila, tetrahidrofuranila, e tetrahidropiranila. os anéis condensados podem ou não conter um anel não aromático contendo heteroátomo desde que o ponto de ligação seja um grupo heterociclila. por exemplo, e sem limitação, o seguinte é um grupo heterociclila: . [0027] o termo “hidrólise” refere-se à quebra de uma fração rh–o-co-, rh-o-cs-, ou rh–o-so2- em um rh–oh, preferencialmente por adição de água através da ligação quebrada. uma hidrólise é realizada usando vários métodos bem conhecidos do técnico experimentado, cujos exemplos não limitativos incluem hidrólise acídica e básica. [0028] o termo “oxo” refere-se a um grupo c=o, e a uma substituição de 2 átomos de hidrogênio geminais com um grupo c=o. [0029] o termo “opcionalmente substituído” refere-se a um grupo substituído ou não substituído. o grupo pode estar substituído com um ou mais substituintes, como, por exemplo, 1, 2, 3, 4 ou 5 substituintes. preferencialmente, os substituintes são selecionados do grupo consistindo de oxo, halo, -cn, no2, -n2+, -co2r100, -or100, -sr100, -sor100, -so2r100, -nr101r102, -conr101r102, -so2nr101r102, c1-c6 alquila, c1-c6 alcoxi, -cr100=c(r100)2, -ccr100, c3-c10 cicloalquila, c3-c10 heterociclila, c6-c12 arila e c2-c12 heteroarila, em que cada r100 independentemente é hidrogênio ou c1-c8 alquila; c3-c12 cicloalquila; c3-c10 heterociclila; c6-c12 arila; ou c2-c12 heteroarila; em que cada alquila, cicloalquila, heterociclila, arila, ou heteroarila está opcionalmente substituído com 1-3 halo, 1-3 c1-c6 alquila, 1-3 c1-c6 haloalquila ou 1-3 grupos c1-c6 alcoxi. preferencialmente, os substituintes são selecionados do grupo consistindo de cloro, fluoro, -och3, metila, etila, iso-propila, ciclopropila, vinila, etinila, -co2h, -co2ch3, -ocf3, -cf3 e -ochf2. [0030] r101 e r102, independentemente, são hidrogênio; c1-c8 alquila, opcionalmente substituído com -co2h ou um respectivo éster, c1-c6 alcoxi, oxo, -cr103=c(r103)2, -ccr, c3-c10 cicloalquila, c3-c10 heterociclila, c6-c12 arila, ou c2-c12 heteroarila, em que cada r103 independentemente é hidrogênio ou c1-c8 alquila; c3-c12 cicloalquila; c3-c10 heterociclila; c6-c12 arila; ou c2-c12 heteroarila; em que cada cicloalquila, heterociclila, arila, ou heteroarila está opcionalmente substituído com 1-3 grupos alquila ou 1-3 grupos halo, ou r101 e r102, em conjunto com o átomo de nitrogênio ao qual estão ligados, formam um heterociclo de 5-7 membros. [0031] o termo “farmaceuticamente aceitável” refere-se a seguro e não tóxico para administração in vivo, preferencialmente humana. [0032] o termo “sal farmaceuticamente aceitável” refere-se a um sal que é farmaceuticamente aceitável. [0033] o termo “sal” refere-se a um composto iônico formado entre um ácido e uma base. quando o composto proporcionado aqui contém uma funcionalidade acídica, tais sais incluem, sem limitação, sais de metais alcalinos, metais alcalinoterrosos, e amônio. como usado aqui, sais de amônio incluem sais contendo bases nitrogenadas protonadas e bases nitrogenadas alquiladas. cátions exemplares, e não limitativos úteis em sais farmaceuticamente aceitáveis incluem cátions na, k, rb, cs, nh4, ca, ba, imidazólio, e amônio baseados em aminoácidos de ocorrência natural. quando os compostos usados aqui contêm uma funcionalidade básica, tais sais incluem, sem limitação, sais de ácidos orgânicos, como ácidos carboxílicos e ácidos sulfônicos, e ácidos minerais, como haletos de hidrogênio, ácido sulfúrico, ácido fosfórico, e similares. ânions exemplares e não limitativos úteis em sais farmaceuticamente aceitáveis incluem oxalato, maleato, acetato, propionato, succinato, tartarato, cloreto, sulfato, bisalfato, fosfato mono-, di-, e tribásico, mesilato, tosilato, e similares. [0034] os termos “tratar”, “tratando” ou “tratamento”, como usados aqui, incluem aliviar, mitigar ou melhorar uma doença ou estado clínico ou um ou mais sintomas do mesmo, prevenir sintomas adicionais, melhorar ou prevenir as causas metabólicas subjacentes dos sintomas, inibir a doença ou estado clínico, por exemplo, travar ou suprimir o desenvolvimento da doença ou estado clínico, acalmar a doença ou estado clínico, causar regressão da doença ou estado clínico, atenuar um estado clínico causado pela doença ou estado clínico, ou suprimir os sintomas da doença ou estado clínico, e é pretendido que incluam profilaxia. os termos também incluem atenuar a doença ou estados clínicos, por exemplo, causando a regressão de sintomas clínicos. os termos incluem adicionalmente alcançar um benefício terapêutico e/ou um benefício profilático. por benefício terapêutico pretende-se significar erradicação ou melhoria do distúrbio subjacente sendo tratado. além disso, um benefício terapêutico é alcançado com a erradicação ou melhoria de um ou mais dos sintomas fisiológicos associados ao distúrbio subjacente, de modo que uma melhoria é observada no indivíduo, não obstante o indivíduo ainda estar afetado com o distúrbio subjacente. para benefício profilático, as composições são administradas a um indivíduo em risco de desenvolver uma doença particular, ou a um indivíduo relatando um ou mais dos sintomas fisiológicos de uma doença, mesmo que ainda não tenha sido feito um diagnóstico desta doença. [0035] os termos “prevenindo” ou “prevenção” referem-se a uma redução do risco de contrair uma doença ou distúrbio (isto é, fazendo com que pelo menos um dos sintomas clínicos da doença não se desenvolva em um sujeito que pode estar exposto ou predisposto à doença mas que ainda não sente nem exibe sintomas da doença). os termos incluem adicionalmente fazer com que os sintomas clínicos não se desenvolvam, por exemplo, em um sujeito em risco de sofrer de tal doença ou distúrbio, desse modo afastando substancialmente o surgimento da doença ou distúrbio. [0036] o termo “quantidade eficaz” refere-se a uma quantidade que é eficaz para o tratamento de um estado clínico ou distúrbio por uma administração intranasal de um composto ou composição descrito aqui. em algumas modalidades, uma quantidade eficaz de qualquer uma das composições ou formas galênicas descritas aqui é a quantidade usada para tratar um distúrbio mediado por hemoglobina ou um distúrbio que irá beneficiar de oxigenação tecidual e/ou celular de qualquer uma das composições ou formas galênicas descritas aqui em um sujeito necessitado. [0037] o termo “transportador”, como usado aqui, refere-se a compostos químicos ou agentes relativamente não tóxicos que facilitam a incorporação de um composto em células, por exemplo, eritrócitos, ou tecidos. [0038] como usado aqui, um “pró-fármaco” é um composto que, após a administração, é metabolizado ou convertido de outro modo em uma forma ativa ou mais ativa no que se refere a pelo menos uma propriedade. para produzir um pró-fármaco, um composto farmaceuticamente ativo pode ser quimicamente modificado de modo a torná-lo menos ativo ou inativo, mas a modificação química é tal que uma forma ativa do composto é gerada por processos metabólicos ou outros processos biológicos. um pró-fármaco pode ter, relativamente ao fármaco, estabilidade metabólica ou características de transporte alteradas, menos efeitos secundários ou menor toxicidade. por exemplo, ver a referência nogrady, 1985, medicinal chemistry a biochemical approach, oxford university press, nova iorque, páginas 388-392. pró-fármacos também podem ser preparados usando compostos que não são fármacos. compostos [0039] em certos aspectos da invenção, é proporcionado um composto da fórmula (i): (i) ou um respectivo tautômero, ou um sal farmaceuticamente aceitável de cada um daqueles ou um respectivo sal farmaceuticamente aceitável, em que l1 é uma ligação ou é nr70, o, s, ou (cr71r72)d; em que cada r70, r71, e r72 independentemente é hidrogênio ou c1-c6 alquila; d é 1, 2 ou 3; l2 é c=o ou so2; cada y e z é independentemente cr10r11, o, s, so, so2, ou nr10; cada r10 e r11 é independentemente hidrogênio ou c1-c3 alquila opcionalmente substituído com 1-3 halo, oh, ou c1-c6 alcoxi, ou cr10r11 é c=o, desde que, se um de y e z for o, s, so, so2, então o outro não é co, e y e z não são ambos heteroátomos ou respectivas formas oxidadas; em que y está ? ou ? substituído relativamente a –l1l2r3; em que z e –cv1v2h são unidos a átomos adjacentes no anel c; v1 e v2 independentemente são c1-c6 alcoxi; ou v1 e v2, em conjunto com o átomo de carbono ao qual estão ligados, formam um anel da fórmula: em que cada v3 e v4 é independentemente o, s, ou nh, desde que, quando um de v3 e v4 é s, o outro seja nh, e desde que v3 e v4 não sejam ambos nh; q é 1 ou 2; cada v5 é independentemente c1-c6 alquila ou co2r60, em que cada r60, independentemente, é c1-c6 alquila ou hidrogênio; t é 0, 1, 2, ou 4; ou cv1v2 é c=v, em que v é o, nor80, ou nnr81r82; r4 é oh, halo, c1-c6 alcoxi, c3-c6 cicloalcoxi ou o-r, em que r é uma fração de pró-fármaco, em que o c1-c6 alcoxi está opcionalmente substituído com 1-5 halo; r80 é c1-c6 alquila opcionalmente substituído; r81 e r82, independentemente, são selecionados do grupo consistindo de hidrogênio, c1-c6 alquila opcionalmente substituído, cor83 e co2r84; r83 é hidrogênio ou c1-c6 alquila opcionalmente substituído; e r84 é c1-c6 alquila opcionalmente substituído. e r3, b, e c são definidos do modo seguinte. [0040] em um caso, r3 é c1-c6 alquila, c3-c8 cicloalquila, c1-c6 alcoxi, c3-c8 cicloalcoxi, ou –nr1r2; cada r1 e r2 independentemente é hidrogênio, c1-c6 alquila, c3-c8 cicloalquila, c6-c10 arila, heterociclo de 4-10 membros ou heteroarila de 5-10 membros, cada um contendo até 5 heteroátomos de anel, em que o heteroátomo é selecionado do grupo consistindo de o, n, s, e formas oxidadas de n e s, em que cada alquila, cicloalquila, heterociclo, arila ou heteroarila está opcionalmente substituído, ou r1 e r2, em conjunto com o átomo de nitrogênio ao qual estão ligados, formam um heterociclo de 4-7 membros opcionalmente substituído; o anel b é um c6-c10 arila opcionalmente substituído, heteroarila de 5-10 membros opcionalmente substituído tendo 1-3 átomos de nitrogênio ou formas oxidadas de n, ou heterociclo de 4-10 membros opcionalmente substituído contendo até 5 heteroátomos de anel, em que o heteroátomo é selecionado do grupo consistindo de o, n, s, e formas oxidadas de n e s; e o anel c é um c6-c10 arila opcionalmente substituído ou heteroarila de 5-10 membros opcionalmente substituído contendo 1-3 átomos de nitrogênio, ou uma forma oxidada de n; [0041] em outro caso, r3 é c6-c10 arila, ou u
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